B Cell Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

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EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]