First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone (R-GCVP) for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial
Authors: Fields Paul , Webb Andrew , Pocock Christopher FE , Townsend William , Smith Paul , Kirkwood Amy , El-Mehidi Nadjet , Johnson Peter W , Radford John , Linch David C , Cunningham David 
Published: October 2019

Abstract
Abstract 1634FN2

Introduction:
The treatment of patients with DLBCL who are unsuitable for anthracycline containing chemotherapy remains a clinical challenge. Gemcitabine is a nucleoside analogue which has proven efficacy in the relapse setting in both non Hodgkin's and Hodgkin's lymphoma. We therefore developed a protocol incorporating Gemcitabine in a first line approach combined with CVP-R chemo-immunotherapy in DLBCL patients considered unfit for anthracycline containing chemotherapy.

Methods:
We performed a prospective, multicentre phase II trial in patients with DLCBL who were considered unfit for anthracycline containing chemo-immunotherapy. Eligibility criteria included ejection fraction < 50%, or ejection fraction ≥ 50% but with the presence of attendant significant co-morbidities (including: ischaemic heart disease, hypertension, diabetes mellitus), and ECOG PS 0–3. Patients received 6 cycles of Rituximab (375 mg/m2 IV D1), Cyclophosphamide (750mg/m2 IV D1), Vincristine (1.4 mg /m2 IV D1), Prednisolone (100mg, orally D1–5) and Gemcitabine IV D1 and D8. The Gemcitabine dose, if tolerated was sequentially escalated from 750mg/m2 in cycle 1 to 875mg/m2 in cycle 2 to 1000mg/m2 in cycle 3 with the dose maintained at 1000mg/m2 for cycles 4–6. Cycles were repeated every 21 days with growth factor support administered on day 9 of each cycle (pegfilgrastrim 6mg s/c).The primary endpoint was to achieve an overall response rate of > 40% assessed by CT scan at the end of treatment according to the Cheson criteria. Secondary endpoints were progression free survival and overall survival.

Results:
62 patients were recruited from 32 UK sites over a 28 month period from April 2008 to July 2010. 66% were male. Median age was 76 years (range 52–90), 48 (77%) were > 70 years. 43 (69%) had stage III/IV disease and 46 (72%) had high – intermediate or high IPI (3–5) disease. ECOG performance status was ≥ 2 in 50% patients. Left ventricular ejection fraction (LVEF) was < 50% in 28 patients (45%). The 34 patients with LVEF ≥ 50% had significant co-morbidities, 22 (65%) had multiple co-morbidities. 44 (70%) received ≥ 3 cycles of treatment, reasons for early termination of treatment in the remaining 18 patients were progression (n=2), toxicity (n=5), death (n=6) patient choice (n=1) and other (n=4). 29 patients (47%) received the full 6 cycles. A total of 250 treatment cycles were delivered. Of the 44 patients who received ≥ 3 cycles of treatment, the dose of Gemcitabine was escalated to the full dose (1000mg/m2) in 67%. Day 8 Gemcitabine was delivered in 215/250 (86%) cycles of treatment. The overall response rate (CR/CRu/PR) at end of treatment for all 62 patients was 60%. For patients who received ≥ 3 cycles of treatment (n =44) the ORR was 79.5% at the end of treatment. There was no significant difference in ORR between those with LVEF <50% and those with LVEF ≥ 50% (71% vs 53%, p=0.155). At a median follow up of 18.2 months the 1 year progression free survival rate for all patients was 52.9% (95% CI 39.4–64.8). The 1 year overall survival (OS) rate is 62.4% (95% CI 48.5–73.6). For the group with LVEF <50% OS was 70.8% (95% CI: 48.4, 84.9) and LVEF group ≥ 50% OS was 55.9% (95% CI 37.1–71).Grade 3/4 haematological toxicity was observed in 54.1% patients. Grade 3/4 infection was observed in 24.6% of patients. The death rate observed related to infection for the whole cohort was 11%.

Conclusion:
This multicentre trial demonstrates that the R-GCVP regimen delivers excellent overall response rates with durable remissions in a group of patients where anthracycline use was precluded. The efficacy attained in this difficult group of patients provides a platform for testing the regimen in subsequent randomised phase II and phase III studies to confirm its efficacy.

Disclosures:
No relevant conflicts of interest to declare.