Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

Abstract

Key Points• Frontline FCA increases progression-free survival in CLL and, in a post hoc analysis, also survival in younger patients.• With the low-dose approach, no increase in treatment related mortality is seen.The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m 2 per day and cyclophosphamide 250 mg/m 2 per day: n 5 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n 5 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P 5 .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P 5 .035). FCA also increased the overall response rate (88 vs 78%, P 5 .036), and the bone marrow minimal residual diseasenegative complete remission rate (64% vs 43%, P 5 .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529. (Blood. 2014;123(21):3255-3262)

Advances in first‐line treatment of chronic lymphocytic leukemia: current recommendations on management and first‐line treatment by the German CLL Study Group (GCLLSG)

“…In an international phase‐III trial by the HOVON group, the combination of fludarabine, cyclophosphamide, and subcutaneous alemtuzumab (FCA) led to a higher frequency of opportunistic infections, without an increase in treatment‐related mortality compared to FC alone. FCA increased overall and complete response rate as well as MRD negativity and prolonged PFS but not OS as compared to FC . Another phase‐III trial by the French group comparing first‐line treatment with FCR and FCA was prematurely stopped due to higher toxicity and treatment‐related mortality as well as a slightly lower efficacy with FCA .…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

Experience With Ibrutinib in Patients With Refractory and Recurrent B-Cell Chronic Lymphocytic Leukemia

“…Попытки усилить эффективность FCR добавлением антра-циклина митоксантрона (FCM-R) [19,20] или иммуномо-дулятора леналидомида (FCR-L) [21,22], добавление или замена ритуксимаба на препарат анти-CD52-антитела алемтузумаб (CFAR, (21) или FCA [24,25]) приводили к повышению токсичности и частоте оппортунистических инфекций и не получили распространения.…”