Dose-Adjusted Rituximab Mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) for Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Not Eligible for High Dose Therapy

Background. There is no current standard of care for the management of patients with relapsed or refractory B-cell non-Hodgkin Lymphoma (R/R B-NHL) ineligible for high-dose therapy. While cytarabine and etoposide are commonly used drugs in salvage regiments for patients eligible for high dose therapy (HDT) and auto-stem cell transplant, data are sparse in the context of ineligibility for high-dose therapy. We designed a dose-adjusted combination of rituximab plus mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) regimen (R-mini-CYVE), for R/R B-NHL patient's ineligible for HDT.

Patients and methods. We retrospectively included patients over 60 years old and ineligible for HDT that received R-mini-CYVE regimen for R/R B-cell NHL between January 2009 and November 2015 at Gustave Roussy, Villejuif, France. Patients must be previously treated with anthracycline-containing chemotherapy regimen. Patients could be included regardless of performance status statement and comorbidity. Treatment consisted of combination of intravenously rituximab mini-CYVE given for six to eight cycles every three weeks. All patients received the same doses of rituximab intravenously 375 mg/m² at day 1, and oral dexamethasone 40 mg/d at days 1-4. Patients received intravenously cytarabine bolus at days 1 and 2 and vepeside at days 1 to 3. Patients were allocated in four dose levels of chemotherapy (cytarabine bolus and vepeside), according to physician discretion among age and comorbidity. Dose levels of cytarabine/vepeside in mg/m²/d were 500/75 for level 1, 1000/75 for level 2, 1000/100 for level 3 and 1500/100 for level 4. Patients were assessed for response after two cycles and at the end of treatment, by computerized tomography scan according to the international harmonized project Cheson 1999 criteria. Primary endpoints were overall survival, and overall response rate (ORR) at the end of treatment. Toxicity was registered according to the CTCAEv4.03.

Results. Thirty-seven patients (21 men and 16 woman) received at least one cycle of rituximab mini-CYVE treatment. Among them, the reasons for no eligibility to HDT were a poor performance status over 2 (n=28), renal impairment with glomerular filtration rate below 60 ml/min (n=7), hearing impairment (n=2). Histological types were diffuse large B-cell lymphoma in 31/37 (84 %) patients and indolent B-cell NHL in 6/37 (16 %) patients. At inclusion, median age was 75 [61-88] years old, median number of prior therapies lines was 1 [1-5], Ann-Arbor stage was 3 or 4 in 28/37 (76%) and serum lactate dehydrogenase was increase in 19/37 (51%) patients. Thirteen, 9, 8 and 7 patients received the dose levels 1, 2, 3 and 4, respectively. Median number of cycles was 4 [1-8]. Hematological adverse events grade 3-5 were experienced in 26/37 (70%) patients, and non-hematological grade 3-4 adverse event in 7/37 (19%) patients. One patient died from febrile neutropenia grade 5 during treatment. Non-hematological grade 3-4 adverse events were sepsis in 6/37 (16%) patients and acute cerebellar syndrome related to aracytine at dose level 2 in 1/37 (3%) of patients. Adverse events led to treatment discontinuation in 4/37 (11 %) of pts. ORR was 43% (16/37 pts) including 35% (13/37 pts) of CR or CRu and 8% (3/37) of PR. Median OS and PFS were 13.2 (95% C.I, 9.8-16.6 months), and 6.4 (95% C.I, 1.2 - 11.5) months. With a median follow-up of 12 [range 1 to 60] months, 25/37 patients (67%) had died from progressive disease (n=21), sepsis (n=3) or pulmonary embolism (n=1).

Conclusion. The dose-adjusted rituximab mini-CYVE regimen demonstrated a favorable safety and efficacy profile in R/R B-cell NHL patients not eligible for high-dose chemotherapy. Further studies are warranted to investigate this regimen in this population of patients.