Follicular Lymphoma

Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3

1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH

Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8

Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.

Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.

Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38

Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.

We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.

Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2

The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).

The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).

Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.

Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.

A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.

Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50

Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.

A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.

In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.

The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.

Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.

Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.

A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).

Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1

Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.

Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.

In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.

Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.

Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1

Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16

Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.

Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.

Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.

For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1

Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7

The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.

Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1

Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.

Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.

Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68

A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).

Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.

A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.

Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.

Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.

Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.

Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.

Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.

Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.

Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.

Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.

Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.

For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.

The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39

Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22

Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.

Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline

References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, 2010. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed December 17, 2010.
 2. Pfreundschuh M, Trümper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:634–641.
 3. Wunderlich A, Kloess M, Reiser M, et al. Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol 2003;14:881–893.
 4. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–239.
 5. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793–798.
 6. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRC TN 64141244. J Clin Oncol 2009;27:5390–5396.
 7. Gobbi PG, Levis A, Chisesi T, et al. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced- stage Hodgkin’s lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 2005;23:9198–9207.
 8. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395.
 9. Michallet AS, Coiffier B. Recent developments in the treatment of aggressive non- Hodgkin lymphoma. Blood Rev 2009;23:11– 23.
 10. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379–391.
 11. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765.
 12. Hallek M, Fingerle-Rowson G, Fink AM, et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood 2009;114:535.  
 13. Mateos MV, Oriol A, Martinez-López J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010;11:934–941.  
 14. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906–917.  
 15. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non- Hodgkin lymphoma: results from a Multicenter Study. Cancer 2010;116:106–114.  
 16. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378–4384.  
 17. Fischer K, Cramer P, Stilgenbauer S, et al. Bendamustine combined with rituximab (BR) in first-line therapy of advanced CLL: a multicenter phase II trial of the German CLL Study Group (GCLLSG). Blood 2009;114:205.  
 18. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623  
 19. Mayordomo JI, López A, Viñolas N, et al. Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain. Curr Med Res Opin 2009;25:2533–2542.  
 20. Pettengell R, Schwenkglenks M, Leonard R, et al. Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer 2008;16:1299–1309.  
 21. Lyman GH, Kleiner JM. Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. J Natl Compr Canc Netw 2007;5:217–228.  
 22. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187–3205.  
 23. Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol 2010;21(suppl 5):v248–v251.  
 24. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of granulocyte- colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42:2433–2453.  
 25. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.  
 26. Gabrilove JL, Jakubowski A, Scher H, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 1988;318:1414–1422.  
 27. Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44:1503–1508.  
 28. Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 2002;13:903–909.  
 29. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with highrisk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20:727–731.  
 30. Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000;18:2522–2528.  
 31. Trillet-Lenoir V, Green J, Manegold C, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993;29A:319–324.  
 32. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double- blind, placebo-controlled phase III study. J Clin Oncol 2005;23:1178–1184.  
 33. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29–35.  
 34. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003;21:514–519.  
 35. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:3158–3167.  
 36. Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 2010;116:5555– 5563.  
 37. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010;28:2914–2924.  
 38. Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev 2004:CD003189.  
 39. Dale DC, McCarter GC, Crawford J, Lyman GH. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J Natl Compr Canc Netw 2003;1:440–454.  
 40. Duff JM, Leather H, Walden EO, LaPlant KD, George TJ Jr. Adequacy of published oncology randomized controlled trials to provide therapeutic details needed for clinical application. J Natl Cancer Inst 2010;102:702– 705.  
 41. Freedman OC, Zimmermann C, Clemons MJ: Interpreting the results of clinical trials of cancer chemotherapy: the importance of reporting concurrent supportive care. Proceedings from 31st Annual San Antonio Breast Cancer Symposium; December 14, 2008; San Antonio, TX. Abstract 6138.  
 42. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.  
 43. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105– 116.  
 44. Delarue R, Tilly H, Salles G, et al. RCHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03- 6B GELA study. Blood 2009;114:406.  
 45. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725–3732.  
 46. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–1423.  
 47. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003–4008.  
 48. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non- Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-3301.  
 49. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.  
 50. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607–1614.  
 51. Salles GA, Seymour JF, Feugier P, et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010;28[15S]:8004.  
 52. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc.; 2010.  
 53. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus ritux imab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 2009;114:405.  
 54. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 2008;13:167–174.  
 55. Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2008;112:330.  
 56. Arzerra [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.  
 57. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749– 1755.  
 58. Straus DJ, Portlock CS, Qin J, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–3489.  
 59. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21:607–614.  
 60. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.  
 61. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.  
 62. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.  
 63. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607–618.  
 64. Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 65. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–2498.  
 66. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final timeto- event results of the APEX trial. Blood 2007;110:3557–3560.  
  67. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–3901.  
 68. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 69. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.  
 70. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.  
 71. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37.  
 72. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436.  
 73. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664–3670.  
 
 

Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3

1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH

Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8

Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.

Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.

Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38

Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.

We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.

Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2

The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).

The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).

Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.

Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.

A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.

Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50

Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.

A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.

In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.

The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.

Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.

Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.

A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).

Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1

Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.

Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.

In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.

Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.

Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1

Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16

Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.

Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.

Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.

For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1

Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7

The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.

Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1

Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.

Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.

Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68

A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).

Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.

A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.

Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.

Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.

Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.

Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.

Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.

Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.

Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.

Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.

Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.

For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.

The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39

Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22

Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.

Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline

References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, 2010. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed December 17, 2010.
 2. Pfreundschuh M, Trümper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:634–641.
 3. Wunderlich A, Kloess M, Reiser M, et al. Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol 2003;14:881–893.
 4. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–239.
 5. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793–798.
 6. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRC TN 64141244. J Clin Oncol 2009;27:5390–5396.
 7. Gobbi PG, Levis A, Chisesi T, et al. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced- stage Hodgkin’s lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 2005;23:9198–9207.
 8. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395.
 9. Michallet AS, Coiffier B. Recent developments in the treatment of aggressive non- Hodgkin lymphoma. Blood Rev 2009;23:11– 23.
 10. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379–391.
 11. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765.
 12. Hallek M, Fingerle-Rowson G, Fink AM, et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood 2009;114:535.  
 13. Mateos MV, Oriol A, Martinez-López J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010;11:934–941.  
 14. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906–917.  
 15. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non- Hodgkin lymphoma: results from a Multicenter Study. Cancer 2010;116:106–114.  
 16. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378–4384.  
 17. Fischer K, Cramer P, Stilgenbauer S, et al. Bendamustine combined with rituximab (BR) in first-line therapy of advanced CLL: a multicenter phase II trial of the German CLL Study Group (GCLLSG). Blood 2009;114:205.  
 18. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623  
 19. Mayordomo JI, López A, Viñolas N, et al. Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain. Curr Med Res Opin 2009;25:2533–2542.  
 20. Pettengell R, Schwenkglenks M, Leonard R, et al. Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer 2008;16:1299–1309.  
 21. Lyman GH, Kleiner JM. Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. J Natl Compr Canc Netw 2007;5:217–228.  
 22. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187–3205.  
 23. Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol 2010;21(suppl 5):v248–v251.  
 24. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of granulocyte- colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42:2433–2453.  
 25. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.  
 26. Gabrilove JL, Jakubowski A, Scher H, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 1988;318:1414–1422.  
 27. Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44:1503–1508.  
 28. Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 2002;13:903–909.  
 29. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with highrisk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20:727–731.  
 30. Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000;18:2522–2528.  
 31. Trillet-Lenoir V, Green J, Manegold C, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993;29A:319–324.  
 32. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double- blind, placebo-controlled phase III study. J Clin Oncol 2005;23:1178–1184.  
 33. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29–35.  
 34. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003;21:514–519.  
 35. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:3158–3167.  
 36. Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 2010;116:5555– 5563.  
 37. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010;28:2914–2924.  
 38. Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev 2004:CD003189.  
 39. Dale DC, McCarter GC, Crawford J, Lyman GH. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J Natl Compr Canc Netw 2003;1:440–454.  
 40. Duff JM, Leather H, Walden EO, LaPlant KD, George TJ Jr. Adequacy of published oncology randomized controlled trials to provide therapeutic details needed for clinical application. J Natl Cancer Inst 2010;102:702– 705.  
 41. Freedman OC, Zimmermann C, Clemons MJ: Interpreting the results of clinical trials of cancer chemotherapy: the importance of reporting concurrent supportive care. Proceedings from 31st Annual San Antonio Breast Cancer Symposium; December 14, 2008; San Antonio, TX. Abstract 6138.  
 42. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.  
 43. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105– 116.  
 44. Delarue R, Tilly H, Salles G, et al. RCHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03- 6B GELA study. Blood 2009;114:406.  
 45. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725–3732.  
 46. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–1423.  
 47. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003–4008.  
 48. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non- Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-3301.  
 49. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.  
 50. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607–1614.  
 51. Salles GA, Seymour JF, Feugier P, et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010;28[15S]:8004.  
 52. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc.; 2010.  
 53. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus ritux imab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 2009;114:405.  
 54. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 2008;13:167–174.  
 55. Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2008;112:330.  
 56. Arzerra [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.  
 57. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749– 1755.  
 58. Straus DJ, Portlock CS, Qin J, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–3489.  
 59. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21:607–614.  
 60. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.  
 61. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.  
 62. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.  
 63. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607–618.  
 64. Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 65. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–2498.  
 66. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final timeto- event results of the APEX trial. Blood 2007;110:3557–3560.  
  67. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–3901.  
 68. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 69. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.  
 70. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.  
 71. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37.  
 72. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436.  
 73. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664–3670.  
 
 

Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3

1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH

Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8

Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.

Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.

Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38

Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.

We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.

Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2

The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).

The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).

Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.

Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.

A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.

Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50

Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.

A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.

In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.

The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.

Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.

Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.

A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).

Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1

Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.

Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.

In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.

Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.

Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1

Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16

Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.

Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.

Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.

For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1

Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7

The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.

Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1

Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.

Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.

Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68

A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).

Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.

A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.

Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.

Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.

Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.

Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.

Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.

Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.

Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.

Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.

Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.

For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.

The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39

Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22

Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.

Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline

References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, 2010. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed December 17, 2010.
 2. Pfreundschuh M, Trümper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:634–641.
 3. Wunderlich A, Kloess M, Reiser M, et al. Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol 2003;14:881–893.
 4. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–239.
 5. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793–798.
 6. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRC TN 64141244. J Clin Oncol 2009;27:5390–5396.
 7. Gobbi PG, Levis A, Chisesi T, et al. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced- stage Hodgkin’s lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 2005;23:9198–9207.
 8. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395.
 9. Michallet AS, Coiffier B. Recent developments in the treatment of aggressive non- Hodgkin lymphoma. Blood Rev 2009;23:11– 23.
 10. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379–391.
 11. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765.
 12. Hallek M, Fingerle-Rowson G, Fink AM, et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood 2009;114:535.  
 13. Mateos MV, Oriol A, Martinez-López J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010;11:934–941.  
 14. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906–917.  
 15. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non- Hodgkin lymphoma: results from a Multicenter Study. Cancer 2010;116:106–114.  
 16. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378–4384.  
 17. Fischer K, Cramer P, Stilgenbauer S, et al. Bendamustine combined with rituximab (BR) in first-line therapy of advanced CLL: a multicenter phase II trial of the German CLL Study Group (GCLLSG). Blood 2009;114:205.  
 18. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623  
 19. Mayordomo JI, López A, Viñolas N, et al. Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain. Curr Med Res Opin 2009;25:2533–2542.  
 20. Pettengell R, Schwenkglenks M, Leonard R, et al. Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer 2008;16:1299–1309.  
 21. Lyman GH, Kleiner JM. Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. J Natl Compr Canc Netw 2007;5:217–228.  
 22. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187–3205.  
 23. Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol 2010;21(suppl 5):v248–v251.  
 24. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of granulocyte- colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42:2433–2453.  
 25. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.  
 26. Gabrilove JL, Jakubowski A, Scher H, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 1988;318:1414–1422.  
 27. Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44:1503–1508.  
 28. Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 2002;13:903–909.  
 29. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with highrisk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20:727–731.  
 30. Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000;18:2522–2528.  
 31. Trillet-Lenoir V, Green J, Manegold C, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993;29A:319–324.  
 32. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double- blind, placebo-controlled phase III study. J Clin Oncol 2005;23:1178–1184.  
 33. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29–35.  
 34. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003;21:514–519.  
 35. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:3158–3167.  
 36. Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 2010;116:5555– 5563.  
 37. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010;28:2914–2924.  
 38. Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev 2004:CD003189.  
 39. Dale DC, McCarter GC, Crawford J, Lyman GH. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J Natl Compr Canc Netw 2003;1:440–454.  
 40. Duff JM, Leather H, Walden EO, LaPlant KD, George TJ Jr. Adequacy of published oncology randomized controlled trials to provide therapeutic details needed for clinical application. J Natl Cancer Inst 2010;102:702– 705.  
 41. Freedman OC, Zimmermann C, Clemons MJ: Interpreting the results of clinical trials of cancer chemotherapy: the importance of reporting concurrent supportive care. Proceedings from 31st Annual San Antonio Breast Cancer Symposium; December 14, 2008; San Antonio, TX. Abstract 6138.  
 42. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.  
 43. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105– 116.  
 44. Delarue R, Tilly H, Salles G, et al. RCHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03- 6B GELA study. Blood 2009;114:406.  
 45. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725–3732.  
 46. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–1423.  
 47. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003–4008.  
 48. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non- Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-3301.  
 49. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.  
 50. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607–1614.  
 51. Salles GA, Seymour JF, Feugier P, et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010;28[15S]:8004.  
 52. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc.; 2010.  
 53. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus ritux imab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 2009;114:405.  
 54. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 2008;13:167–174.  
 55. Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2008;112:330.  
 56. Arzerra [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.  
 57. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749– 1755.  
 58. Straus DJ, Portlock CS, Qin J, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–3489.  
 59. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21:607–614.  
 60. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.  
 61. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.  
 62. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.  
 63. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607–618.  
 64. Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 65. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–2498.  
 66. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final timeto- event results of the APEX trial. Blood 2007;110:3557–3560.  
  67. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–3901.  
 68. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.  
 69. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.  
 70. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.  
 71. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37.  
 72. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436.  
 73. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664–3670.  
 
 

HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.

The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.

Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.

“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”

Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.

Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.

The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.

Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.

“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.

The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.

“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.

NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.

The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.

Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.

“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”

Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.

Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.

The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.

Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.

“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.

The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.

“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.

NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.

The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.

Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.

“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”

Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.

Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.

The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.

Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.

“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.

The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.

“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.