Ryan C. Lynch

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

OBJECTIVES While 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. MATERIALS AND METHODS We 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. RESULTS Of 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). CONCLUSION These 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.

Chemotherapy options for previously untreated acute myeloid leukemia.

Introduction: Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents. Areas covered: We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients. Expert opinion: While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.

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). We 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. Weight 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). Average 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. Logistic 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. We 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). Table I Demographic 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). In 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). Table II Multivariate Odds Ratios1 for Treatment-Related Mortality. Consistent 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). The 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. The 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. Overall, 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.

Surveillance imaging for lymphoma: pros and cons

There is no international consensus on the optimal frequency or duration of computed tomography or positron emission tomography scanning for surveillance in patients who achieve complete remission after initial therapy for lymphoma. Although some clinical practice guidelines suggest periodic imaging is reasonable, others suggest little or no benefit to this practice. From a theoretical perspective, the frequency and duration of surveillance imaging is largely dependent upon the lymphoma subtype. Aggressive lymphomas with a fast growth rate will require surveillance more frequently and for a shorter duration compared to the indolent lymphomas. Historically, relapse has been detected in a majority of patients based upon clinically evident signs and symptoms. Currently, no study has demonstrated an overall survival difference for patients with relapse detected by imaging as opposed to clinical evaluation, although one study did demonstrate a lower second-line International Prognostic Index in patients with relapse detected by surveillance imaging. Enthusiasm for this finding has been tempered by recent studies highlighting the potential long-term risk of secondary malignancies because of ionizing radiation exposure from diagnostic imaging. These factors along with the significant costs associated with diagnostic imaging have contributed to an ongoing debate regarding the relative costs, risks, and benefits of radiographic surveillance. Herein we present perspectives for and against routine surveillance imaging in an effort to facilitate a better understanding of the issues relevant to what is ultimately a clinical decision made by an oncologist and his or her patient.

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

BACKGROUND Body 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. METHODS A 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. RESULTS Three 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% CI = 15.7% 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% CI = 14.8% 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% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74). CONCLUSIONS DLBCL 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.

Clinical Impact of the 2016 Update to the WHO Lymphoma Classification

Opinion statementThe 2016 revision of the WHO classification of lymphoid neoplasms includes new entities along with a clearer definition of provisional and definitive subtypes based on better understanding of the molecular drivers of lymphomas. These changes impact current treatment paradigms and provide a framework for future clinical trials. Additionally, this update recognizes several premalignant or predominantly indolent entities and underscores the importance of avoiding unnecessarily aggressive treatment in the latter subsets.

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.

Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT.

Although patients with advanced-stage classic Hodgkin lymphoma have excellent outcomes with contemporary therapy, the outcomes of patients with refractory disease is suboptimal. Identification of these high-risk patients at diagnosis is challenging as the differences in outcomes using clinical criteria are less marked using current modern therapy. Data suggest that an interim PET-CT may be a powerful tool in risk-stratifying patients. Retrospective studies show that a negative interim PET-CT after two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is predictive of favorable outcome independent of IPS score. Currently, there are several ongoing trials that aim to determine whether early-response assessment can be used to select patients who might benefit from modifications of subsequent therapy, either by intensifying or abbreviating regimens and/or omitting radiotherapy with promising early results. Longer follow-up is required to assess whether this strategy impacts overall survival (OS). Herein, we review the results of recent trials using interim PET-CT-based adaptive design in the treatment of advanced HL.

Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88 L265P Mutation

The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.