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Novel CAR T cells drive high objective response rate in multiple myeloma
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
AT THE 2017 ASCO ANNUAL MEETING
Key clinical point: All of 19 patients treated with the CAR T-cell construct targeting B-cell maturation antigen had an objective response.
Major finding: Of 35 patients with relapsed/refractory multiple myeloma treated with BCMA, 33 had remissions.
Data source: A prospective single-arm study of 35 patients, with enrollment planned for 100.
Disclosures: The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
Rituximab Stretches Survival in Follicular Lymphoma
Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.
Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies
The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.
The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.
Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma
“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”
Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204
Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.
Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies
The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.
The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.
Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma
“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”
Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204
Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.
Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies
The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.
The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.
Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma
“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”
Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204
In sickle cell disease, osteomyelitis is a tough call
MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.
As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.
Among 30 patients with SCD who were followed at a single center over a decade, 29 patients had elevated ESR, but only 13 patients had leukocytosis, and only 13 had elevated CRP.
“Prior studies on sickle cell disease have shown that it is very difficult to differentiate between osteoarticular infection and bone infarction. Therefore, oftentimes, this diagnosis is very difficult to make,” Dr. Weisman said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Laboratory findings for osteomyelitis in SCD are often nonspecific, including leukocytosis, elevated CRP and ESR, and blood cultures positive for Staphylococcus aureus (the predominant pathogen in children with osteomyelitis), or, in children with hemoglobinopathies, salmonella.
In children with SCD, CRP levels can vary from normal to elevated. ESR is similarly variable, as low hematocrit values can result in higher ESR values. Additionally, sickle erythrocytes can fail to aggregate, which can lead to lower ESR values.
A decade of data
The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.
Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.
The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.
Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.
Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm2), and an equal number had elevated CRP (greater than 10 mg/L).
In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.
When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).
Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.
Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.
All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.
Recommendations
Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.
When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.
The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.
MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.
As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.
Among 30 patients with SCD who were followed at a single center over a decade, 29 patients had elevated ESR, but only 13 patients had leukocytosis, and only 13 had elevated CRP.
“Prior studies on sickle cell disease have shown that it is very difficult to differentiate between osteoarticular infection and bone infarction. Therefore, oftentimes, this diagnosis is very difficult to make,” Dr. Weisman said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Laboratory findings for osteomyelitis in SCD are often nonspecific, including leukocytosis, elevated CRP and ESR, and blood cultures positive for Staphylococcus aureus (the predominant pathogen in children with osteomyelitis), or, in children with hemoglobinopathies, salmonella.
In children with SCD, CRP levels can vary from normal to elevated. ESR is similarly variable, as low hematocrit values can result in higher ESR values. Additionally, sickle erythrocytes can fail to aggregate, which can lead to lower ESR values.
A decade of data
The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.
Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.
The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.
Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.
Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm2), and an equal number had elevated CRP (greater than 10 mg/L).
In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.
When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).
Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.
Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.
All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.
Recommendations
Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.
When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.
The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.
MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.
As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.
Among 30 patients with SCD who were followed at a single center over a decade, 29 patients had elevated ESR, but only 13 patients had leukocytosis, and only 13 had elevated CRP.
“Prior studies on sickle cell disease have shown that it is very difficult to differentiate between osteoarticular infection and bone infarction. Therefore, oftentimes, this diagnosis is very difficult to make,” Dr. Weisman said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Laboratory findings for osteomyelitis in SCD are often nonspecific, including leukocytosis, elevated CRP and ESR, and blood cultures positive for Staphylococcus aureus (the predominant pathogen in children with osteomyelitis), or, in children with hemoglobinopathies, salmonella.
In children with SCD, CRP levels can vary from normal to elevated. ESR is similarly variable, as low hematocrit values can result in higher ESR values. Additionally, sickle erythrocytes can fail to aggregate, which can lead to lower ESR values.
A decade of data
The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.
Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.
The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.
Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.
Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm2), and an equal number had elevated CRP (greater than 10 mg/L).
In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.
When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).
Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.
Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.
All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.
Recommendations
Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.
When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.
The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.
Key clinical point: ESR may be a better lab marker for osteomyelitis in sickle cell disease than either WBC or CRP.
Major finding: An ESR greater than 100 mm/hr was 100% specific for osteomyelitis in this study.
Data source: A retrospective review of data on 59 patients with sickle cell disease and suspected or probable osteomyelitis.
Disclosures: The study was internally funded. Dr. Weisman reported having no conflicts of interest to disclose.
Chronic Lymphocytic Leukemia in the Real World
A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged ≥ 75 years in a real-world setting.
The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.
They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.
Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.
The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”
Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.
A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged ≥ 75 years in a real-world setting.
The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.
They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.
Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.
The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”
Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.
A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged ≥ 75 years in a real-world setting.
The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.
They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.
Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.
The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”
Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.
Prognostic tool may allow tailored therapy for Hodgkin lymphoma
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
Key clinical point: A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score, or CHIPS, may allow more tailored therapy for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Major finding: Patients who had a low CHIPS of 0 or 1 had excellent 4-year event-free survival (93.1% and 88.5%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (77.6% and 69.2%).
Data source: A cohort study to develop (in 562 patients) and validate (in 541 patients) a score for predicting the response to standard treatment in pediatric Hodgkin lymphoma.
Disclosures: This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
VA Establishes Presumption of Service Connection for Camp Lejeune
Veterans who were exposed to contaminated water at Camp Lejeune are now eligible for VA care and benefits if they have been diagnosed with any of 8 diseases: adult leukemia, aplastic anemia and other myelodysplastic syndromes, bladder cancer, kidney cancer, liver cancer, multiple myeloma, non-Hodgkin lymphoma, and Parkinson disease. The presumption of service connection regulations went into effect March 14.
The newly effective rule complements the health care already provided for 15 illnesses or conditions as part of the Honoring America’s Veterans and Caring for Camp Lejeune Families Act of 2012. The Camp Lejeune Act requires the VA to provide health care to veterans who served at Camp Lejeune and to reimburse family members or pay providers for medical expenses for those who lived there for ≥ 30 days between August 1, 1953, and December 31, 1987.
The act and new rule relate to 2 on-base water wells that were contaminated with trichloroethylene, perchloroethylene, benzene, vinyl chloride, and other compounds. The wells were shut down in 1985.
The presumption of service connection applies to active-duty, reserve, and National Guard members. The presumption also includes all of Camp Lejeune, Marine Corps Air Station New River, as well as satellite camps and housing areas.
Veterans who were exposed to contaminated water at Camp Lejeune are now eligible for VA care and benefits if they have been diagnosed with any of 8 diseases: adult leukemia, aplastic anemia and other myelodysplastic syndromes, bladder cancer, kidney cancer, liver cancer, multiple myeloma, non-Hodgkin lymphoma, and Parkinson disease. The presumption of service connection regulations went into effect March 14.
The newly effective rule complements the health care already provided for 15 illnesses or conditions as part of the Honoring America’s Veterans and Caring for Camp Lejeune Families Act of 2012. The Camp Lejeune Act requires the VA to provide health care to veterans who served at Camp Lejeune and to reimburse family members or pay providers for medical expenses for those who lived there for ≥ 30 days between August 1, 1953, and December 31, 1987.
The act and new rule relate to 2 on-base water wells that were contaminated with trichloroethylene, perchloroethylene, benzene, vinyl chloride, and other compounds. The wells were shut down in 1985.
The presumption of service connection applies to active-duty, reserve, and National Guard members. The presumption also includes all of Camp Lejeune, Marine Corps Air Station New River, as well as satellite camps and housing areas.
Veterans who were exposed to contaminated water at Camp Lejeune are now eligible for VA care and benefits if they have been diagnosed with any of 8 diseases: adult leukemia, aplastic anemia and other myelodysplastic syndromes, bladder cancer, kidney cancer, liver cancer, multiple myeloma, non-Hodgkin lymphoma, and Parkinson disease. The presumption of service connection regulations went into effect March 14.
The newly effective rule complements the health care already provided for 15 illnesses or conditions as part of the Honoring America’s Veterans and Caring for Camp Lejeune Families Act of 2012. The Camp Lejeune Act requires the VA to provide health care to veterans who served at Camp Lejeune and to reimburse family members or pay providers for medical expenses for those who lived there for ≥ 30 days between August 1, 1953, and December 31, 1987.
The act and new rule relate to 2 on-base water wells that were contaminated with trichloroethylene, perchloroethylene, benzene, vinyl chloride, and other compounds. The wells were shut down in 1985.
The presumption of service connection applies to active-duty, reserve, and National Guard members. The presumption also includes all of Camp Lejeune, Marine Corps Air Station New River, as well as satellite camps and housing areas.
Pretreatment Imaging May Help Prevent Hodgkin Lymphoma Recurrence
Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.
Related: Study Points to Risk Factors for Lymphoma
In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.
The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.
Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.
Related: Development and Implementation of a Veterans’ Cancer Survivorship Program
Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”
Source:
Figura N, Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.
Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.
Related: Study Points to Risk Factors for Lymphoma
In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.
The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.
Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.
Related: Development and Implementation of a Veterans’ Cancer Survivorship Program
Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”
Source:
Figura N, Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.
Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.
Related: Study Points to Risk Factors for Lymphoma
In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.
The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.
Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.
Related: Development and Implementation of a Veterans’ Cancer Survivorship Program
Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”
Source:
Figura N, Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.
New approach for monitoring minimum residual disease in multiple myeloma
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Key clinical point: Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma.
Major finding: Of patients who at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001).
Data source: A pilot study of 27 patients with multiple myeloma.
Disclosures: Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
The Link Between Low-Density Lipoproteins and Chronic Lymphocytic Leukemia
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.
In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.
Related: New Treatments for Chronic Lymphocytic Leukemia
Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.
To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.
In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.
Use of Fluorodeoxyglucose-Positron Emission Tomography in the Diagnosis of Intravascular Diffuse Large B-Cell Lymphoma
Patient 1
A white man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.
Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic. 
The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased. The patient was intubated but expired 48 hours after mechanical ventilation was initiated.
Patient 2
A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125. 
After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.
Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.
The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.
Patient 3
A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.
Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).
Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.
Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.
Discussion
Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.
In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.6,14,25
In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.
Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.7,10,12,13,17,23,25 These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.7 These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.
Conclusion
Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.1 Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
Patient 1
A white man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.
Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic.
The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased. The patient was intubated but expired 48 hours after mechanical ventilation was initiated.
Patient 2
A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125.
After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.
Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.
The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.
Patient 3
A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.
Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).
Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.
Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.
Discussion
Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.
In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.6,14,25
In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.
Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.7,10,12,13,17,23,25 These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.7 These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.
Conclusion
Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.1 Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
Patient 1
A white man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.
Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic.
The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased. The patient was intubated but expired 48 hours after mechanical ventilation was initiated.
Patient 2
A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125.
After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.
Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.
The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.
Patient 3
A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.
Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).
Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.
Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.
Discussion
Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.
In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.6,14,25
In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.
Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.7,10,12,13,17,23,25 These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.7 These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.
Conclusion
Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.1 Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.