Curative potential of chemoimmunotherapy in diffuse large B cell lymphoma with hepatic and/or renal dysfunction

The results of most clinical trials in previously untreated diffuse large B cell lymphoma (DLBCL) are based on patients with normal organ function. Recently, the American Society of Clinical Oncology and Friends of Cancer Research produced a statement emphasizing the need to broaden clinical trial eligibility criteria to make results more representative and generalizable (Kim et al, 2017). In DLBCL, hepatic and/ or renal dysfunction may occur due to tissue infiltration with lymphoma or obstruction due to lymphadenopathy. There is a paucity of data to guide therapy in DLBCL presenting with organ dysfunction. We retrospectively collected baseline characteristics for all newly diagnosed adult (≥18 years) DLBCL patients who presented to Levine Cancer Institute with hepatic and/or renal dysfunction between November 2013 and July 2016. Hepatic dysfunction defined as serum aspartate transaminase or alanine transaminase ≥3 9 upper limit of normal (ULN) or bilirubin >1 5 9 ULN and renal dysfunction defined as serum creatinine >2 or creatinine clearance <40 ml/min within 5 days of initiating upfront chemoimunotherapy. Organ dysfunction was graded by Common Terminology Criteria for Adverse Events v5.0 (https://ctep.cancer.gov/pro tocolDevelopment/electronic_applications/docs/CTCAE_v5_ Quick_Reference_8.5x11.pdf). Dose adjustments were made at the discretion of the treating physician and the pharmacist. For patients on haemodialysis, cyclophosphamide was administered without dose reduction after dialysis. Response to therapy was assessed according to the Lugano criteria for lymphoma (Cheson et al, 2014). Kaplan Meier techniques were utilized to estimate survival distributions. Out of 146 previously untreated DLBCL, we identified 20 patients that had hepatic and/or renal dysfunction that met the above eligibility criteria. Patient characteristics are summarized in Table I. Median follow up was 27 5 months (range 0 2–53 8 months). Seventeen patients (85%) were high risk according to the International Prognostic Index. Sixteen patients (80%) had advanced stage disease. Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP or R mini CHOP (if ≥80 years)] was used in 80% of patients and 20% patients received dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Seven (35%) patients presented with hepatic dysfunction, 9 (45%) had renal dysfunction and 4 (20%) had both hepatic and renal dysfunction. Grade 2 and 3 hepatic dysfunction was noted in 4 and 7 patients, respectively. Grade 1, 2, 3 and 4 renal dysfunction was noted in 1, 7, 2 and 3 patients, respectively. Nineteen patients (95%) had organ dysfunction due to lymphoma. One patient had pre-existing renal dysfunction secondary to chronic kidney disease. Organ dysfunction was due to intraorgan dissemination in 15 (79%) patients and extrinsic compression in 4 (21%) patients. Two out of 4 patients that were started on steroids prior to initiating chemoimmunotherapy had improvement in organ function. Median time from haematology consultation to starting treatment was 3 days. During cycle 1, dose reductions due to organ dysfunction were made in 5 (25%) patients (Table SI). Doxorubicin was dose-reduced in 1 patient and held in 1 patient for ≥grade 3 hepatic dysfunction. Vincristine was dose-reduced in 2 patients and held in 2 patients with ≥grade 3 hepatic dysfunction. Etoposide was dose-reduced in 3 out of 5 patients that received R-EPOCH for either ≥grade 3 hepatic dysfunction or creatinine clearance <40 ml/min. Cyclophosphamide or rituximab were not dose-reduced. Median time to reversal of impaired organ function was 12 days. Full dose chemotherapy was resumed in 18 patients (90%) by cycle 2 and in 1 patient by cycle 3 due to improvement in organ function. Cycle 1 was administered in the inpatient setting for 18 (90%) patients. Eight of the 20 patients (40%) had subsequent unplanned hospitalizations. Two of 4 (50%) patients in the R-EPOCH group and 6 of 16 (38%) patients in the RCHOP group were hospitalized. Four patients were admitted for neutropenic fever, and one each for septic shock, syncope and dehydration, port-associated deep venous thrombosis (DVT) and seizures. Peripheral neuropathy led to withholding vincristine in 3 patients. One patient developed cardiomyopathy with significantly decreased ejection fraction after 3 cycles of EPOCH. Complete response (CR) was obtained in 17 patients (85%). The estimated 3-year progression-free survival and overall survival was 80% (95% confidence interval: 62 5– 97 5%; Fig 1). Of the 4 patients who expired, one patient died after the first cycle of treatment due to septic shock, one achieved CR but was lost to follow-up and expired from an unknown cause, and two patients had primary refractory disease and expired shortly after completing 6 cycles of chemoimmunotherapy. One patient experienced disease relapse 3 1 years after diagnosis. Despite having high risk disease and not meeting criteria for enrolment in prospective