Peter Riedell

Comparative effectiveness of anthracycline-containing chemotherapy in United States veterans age 80 and older with diffuse large B-cell lymphoma

OBJECTIVESnWhile anthracycline-based treatment can cure diffuse large B-cell lymphoma, most patients over age 80 do not receive doxorubicin due to toxicity concerns. This study evaluated this practice, as patients age 80 and older are largely excluded from clinical trials. The primary outcome of interest was overall survival. Secondary outcomes included treatment-related mortality and anthracycline dose intensity.nnnMATERIALS AND METHODSnWe assembled a cohort of 530 newly diagnosed diffuse large B-cell lymphoma patients age 80 or older diagnosed within United States Veterans Health Administration. Treatment and survival information were obtained to determine associations between anthracycline use, dose intensity, treatment-related mortality and overall survival.nnnRESULTSnOf the 530 patients, 285 received systemic treatment and 193 received an anthracycline. After controlling for potential confounders, rituximab decreased mortality (hazard ratio, 0.62; 95% confidence interval [CI]: 0.44-0.88), while doxorubicin was not significantly associated with mortality (hazard ratio, 0.87; 95% CI: 0.64-1.17). Completion of treatment with anthracycline dose intensity ≥85% of expected was only 14%. Patients treated with anthracycline dose intensity <85% had better one year survival compared to those treated at ≥85% (70% vs. 59%, p=0.029).nnnCONCLUSIONnThese results suggest that full dose anthracycline therapy may be less important in the treatment of diffuse large B-cell lymphoma patients over age 80. The low frequency of completion of full dose intensity treatment suggests that standard doses are an unrealistic standard of care for patients this age. Alternate treatment strategies and risk stratification should be considered for these patients.

Impact of body mass index on incidence of febrile neutropenia and treatment-related mortality in United States veterans with diffuse large B-cell lymphoma receiving rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.

In 2012, guidelines from the American Society of Clinical Oncology (ASCO) summarized the literature on chemotherapy dosing based upon actual body weight versus ideal or adjusted body weight. Their conclusion, largely drawn from studies of solid tumor patients, was that chemotherapy administration based upon actual body weight did not increase short-term toxicities. This resulted in the recommendation against the use of empiric dose-reduction solely due to obesity status (Griggs et al, 2012). To better understand if this recommendation could be applied to patients with diffuse large B-cell lymphoma (DLBCL), we examined the associations between body mass index (BMI) and relative dose-intensity with the outcomes of febrile neutropenia and treatment-related mortality in a large cohort of DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). n nWe identified a retrospective cohort of patients with DLBCL within the United States Veterans Health Administration (VHA) using previously published methods and inclusion and exclusion criteria (Carson et al, 2012). Details of chemotherapy, radiotherapy, supportive care medications, and hospitalizations were determined through chart abstraction. n nWeight and height measurements within one month of treatment initiation were used to calculate BMI and body surface area (BSA). Patients were categorized as underweight, normal-weight, overweight, or obese in accordance with the WHO classification. The Romano comorbidity index was calculated using ICD-9 codes (Romano et al, 1993). n nAverage relative dose-intensity was calculated utilizing methods previously published (Lyman et al, 2004). The expected number of chemotherapy cycles was 3 in stage I/II patients receiving radiotherapy and 6 in all other patients. Chemotherapy doses <85% of expected in the first cycle were considered “dose-reduced”. Febrile neutropenia was determined by chart abstraction, and was considered present based upon review of electronic medical records. Treatment-related mortality was defined as death within 30 days of last chemotherapy administration. n nLogistic regression evaluated variables associated with treatment-related mortality in the overall cohort and then among those without first cycle dose-reductions. Missing data on LDH, stage, and B-symptoms were handled through use of multiple imputation (Sterne et al, 2009). All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). All p-values reported are 2-tailed and p-values <0.05 were considered significant. n nWe identified a total cohort of 1,241 DLBCL patients who received R-CHOP within the VHA system. Univariate comparisons stratified by BMI are presented in Table I. There were no significant differences in the average relative dose-intensities or levels of G-CSF support among the BMI groups. Obese patients were not significantly more likely to undergo first cycle dose-reduction. The incidence of febrile neutropenia and treatment-related mortality among the three groups differed significantly, with obese patients experiencing less of both. Across all treatment cycles, obese patients were significantly less likely to experience febrile neutropenia (obese: 17.8%, overweight: 23.0%, normal-weight: 28.9%, age-adjusted p<0.001). Obese patients were also significantly less likely to experience treatment-related mortality (obese: 5.5%, overweight: 8.1%, normal-weight: 11.3%, age-adjusted p=0.017). n n n nTable I n nDemographic Characteristics, Dose Characteristics, and Toxicity Outcomes of United States Veterans with DLBCL Treated with R-CHOP within VHA System by BMI Group (n=1,241). n n n nIn multivariate logistic regression controlling for age, stage, LDH at diagnosis, B-symptoms, comorbidity score, and G-CSF use, obesity was associated with decreased treatment-related mortality compared to normal-weight patients (OR 0.50; 95% CI 0.28–0.90). Overweight patients demonstrated a non-significant trend towards reduced treatment-related mortality (OR 0.73; 95% CI 0.46–1.14). Among patients without first cycle dose-reductions, obesity was still associated with decreased treatment-related mortality (OR 0.46; 95% CI 0.24–0.90), and overweight patients demonstrated a non-significant trend towards reduced treatment-related mortality (OR 0.69; 95% CI 0.42–1.14) (Table II). n n n nTable II n nMultivariate Odds Ratios1 for Treatment-Related Mortality. n n n nConsistent with the ASCO guidelines, we found no evidence that treatment of overweight and obese DLBCL patients with actual body weight chemotherapy doses increased the incidence of febrile neutropenia or treatment-related mortality. In fact, we observed a significantly decreased incidence of febrile neutropenia among obese patients despite similar average relative dose-intensities and G-CSF support. Furthermore, obesity was associated with decreased treatment-related mortality after controlling for age, G-CSF use, and other prognostic factors. This relationship held among patients who received >85% of expected doses in the first treatment cycle, suggesting that fears of excess febrile neutropenia and treatment-related mortality among obese patients are unfounded in this population. This is of particular importance in DLBCL as studies have suggested that achieving average relative dose-intensity >90% is associated with improved long-term outcomes (Bosly et al, 2008). n nThe ASCO guidelines also raised the question of whether dose-reductions might compromise efficacy in obese patients. Evidence suggests improved overall survival among patients experiencing neutropenia or leukopenia during chemotherapy (Shitara et al, 2011). Due to the confounding by indication that is inherent in observational studies, we were unable to fully answer this question (Jepsen et al, 2004). While a trial randomizing obese patients to R-CHOP doses based upon actual vs. ideal body weight would provide a clear answer, it is unlikely that such a study will ever be performed. n nThe strengths and limitations of this study should be highlighted. Since, the VHA is the largest integrated health system in the United States, we were able to assemble a large patient cohort with detailed patient information. However, consistent with the historic military demographics, this cohort was almost entirely men, which may limit the applicability of our findings. An additional limitation of our study is that we could not quantify differences in long-term toxicities among BMI groups. Doxorubicin is known to cause a significant, dose-dependent incidence of heart failure (Gharib & Burnett, 2002). The effect doxorubicin dosing based upon actual body weight on the incidence of doxorubicin-induced cardiomyopathy remains unknown. n nOverall, this study supports the application of the ASCO obesity guidelines in overweight and obese DLBCL patients. Specifically, we found no evidence that treatment with full weight-based therapy in overweight or obese patients increases the risk of febrile neutropenia or treatment-related mortality. Until data emerges suggesting otherwise, in the absence of other contraindications, oncologists treating overweight and obese DLBCL patients with R-CHOP should use actual body weight in dosing calculations.

Incidence of venous thromboembolism in patients with non-Hodgkin lymphoma

INTRODUCTIONnPatients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE). Current risk-prediction models classify NHL as a single entity. We aimed to quantify the difference in VTE risk in follicular lymphoma (FL) versus diffuse large B cell lymphoma (DLBCL).nnnMETHODSnUsing a prospective cohort study, we identified 2730 patients (2037 DLBCL; 693 FL) within the Veterans Administration Central Cancer Registry. A competing risk model assessed the association between VTE risk and histology in the first year after NHL diagnosis. We assessed the effect of additional risk factors for VTE in NHL.nnnRESULTSnIn univariate analysis, DLBCL was associated with increased risk of VTE compared to FL in the first year after diagnosis; this association was no longer significant in adjusted analysis (adjusted hazard ratio (aHR) 1.52; 95% CI 0.97-2.40). Major risk factors for VTE included history of VTE before NHL diagnosis (aHR 4.73, p≤0.0001) and time period during chemotherapy administration (aHR 7.60, p≤0.0001). Additional risk factors included: stage III/IV disease (p=0.02), BMI≥30 (p=0.02), B-symptoms (p=0.02), and doxorubicin (p=0.04). The cumulative incidence of VTE was highest in the period following diagnosis and decreased over time for both histologies.nnnCONCLUSIONnDLBCL is associated with increased risk of VTE compared to FL. This risk is markedly attenuated when adjusting for additional risk factors. The strongest predictors for development of VTE included: time period during chemotherapy administration (especially doxorubicin) and history of VTE. This knowledge can assist clinicians in identifying NHL patients at high risk for VTE.

Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans

BACKGROUNDnBody composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity.nnnMETHODSnA retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided.nnnRESULTSnThree hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CIu2009=u200915.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CIu2009=u200914.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CIu2009=u20098.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CIu2009=u20091.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CIu2009=u20091.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CIu2009=u20092.42 to 8.74).nnnCONCLUSIONSnDLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.

A drug safety evaluation of rituximab and risk of hepatitis B

Introduction: Rituximab is a widely prescribed anti-CD20 mAb for the treatment of CD20+ B-cell non-Hodgkin Lymphoma and many other immune mediated conditions. There is a well-described association between rituximab containing chemo-immunotherapy treatment and reactivation of the hepatitis B virus (HBV). This review summarizes the current literature surrounding rituximab-associated HBV reactivation. Areas covered: Herein, we review the literature detailing the risk of HBV reactivation in inactive carriers and those with resolved hepatitis. The clinical presentation and management of HBV reactivation are also discussed along with a summary of clinical trials evaluating antiviral prophylaxis. Finally, clinical recommendations are detailed. Data from clinical trials, observational studies, reviews, and meta-analyses available in the Medline database were included in this narrative review. Expert opinion: Screening should be performed in all patients prior to the administration of any type of anti-CD20 mAb therapy. Among those with positive screening serology, testing for hepatitis B e antigen or viral load by polymerase chain reaction is appropriate. In those patients with detectable HBV DNA, the decision regarding the use of antiviral prophylaxis or observation should be individualized.

Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B-cell lymphoma treated with CHOP-based chemotherapy

While sarcopenia has been associated with decreased overall survival in diffuse large B‐cell (DLBCL) patients, the impact of sarcopenia on treatment tolerance has not been well‐studied. We evaluated the association of sarcopenia with febrile neutropenia hospitalization, treatment‐related mortality, and ability to complete standard number of cycles in a retrospective cohort of United States veterans diagnosed with DLBCL between 1998 and 2008 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab. Baseline body composition parameters were evaluated using computed tomography analysis. In total, 522 patients were included in the study, of whom 245 (47%) had baseline sarcopenia. After controlling for other variables, baseline sarcopenia was independently associated with increased risk of febrile neutropenia hospitalization (adjusted Odds Ratio (aOR) 1.64, 95% confidence interval (CI) 1.01–2.65) and inability to complete standard number of treatment cycles (aOR 1.49, 95% CI 1.02–2.16) compared with no baseline sarcopenia. There was a non‐statistically significant trend toward higher treatment‐related mortality in sarcopenic patients than non‐sarcopenic patients (aOR 1.77, 95% CI 0.92–3.41). Sarcopenia is associated with increased risk of treatment intolerance and may be useful in guiding treatment planning and supportive care measures. Am. J. Hematol. 91:1002–1007, 2016.

Short- and Long-term weight changes among United States veterans with diffuse large B-cell lymphoma treated with CHOP chemotherapy

Identifying weight changes associated with treatment of diffuse large B-cell lymphoma (DLBCL) has the potential to improve the long-term health of survivors. A retrospective cohort of United States veterans with a new diagnosis of DLBCL between October 1, 1998 and September 30, 2008, with follow-up until April 23, 2013, was assembled. Weight changes were evaluated before, during, and after treatment in 1935 DLBCL patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab (CHOP+/− R). One year prior to treatment, 79% of patients were obese or overweight. During the 12 months leading up to treatment, 57% of the cohort lost weight. Among patients surviving 24 months after treatment initiation, weight increased an average of 2.9 kg above weight at treatment completion. The weight change trends observed in these DLBCL patients suggest that weight management strategies may be an important part of long-term survivorship planning after conclusion of treatment.

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data.