Preliminary Results of a Prospective Randomized Study Comparing First Line Conventional Therapy Versus High Dose Therapy with Autologous CD34+ Purified Progenitor Cell Support in B CLL Patients with B and C Binet Stages: The GOELAMS LLC98 Study.

The role of high dose chemotherapy with autologous stem cell support in first line therapy in patients with B-CLL remains to be defined. The aim of the prospective randomized GOELAMS LLC 98 (Groupe Ouest Est d’etude des Leucemies et Autres Maladies du Sang) trial was to compare two therapeutic strategies in previously untreated B-CLL patients younger than 60 years with B and C Binet stages. Conventional chemotherapy (Arm A) consisted of six monthly courses of CHOP, (i.e. vincristin IV 1 mg/m2 on day 1, doxorubicin IV 25 mg/m2 on day 1, cyclophosphamide (Cy) 300 mg/m2 and prednisone 40 mg/m2 both given orally from day 1 to day 5, followed by 6 CHOP courses every other 3 month in case of response. Fludarabine (25 mg/m2 /d IV for 5 consecutive days) was used in case of progression after 3 CHOP or non response after 6 CHOP. Conventional therapy was compared to high dose therapy with autologous CD34+ purified stem cell support (Arm B), using as consolidation of Complete Remission (CR) (NCI criteria) or Very Good Partial Response (VGPR, defined by >50 % tumoral response and < 30 % bone marrow lymphocyte count) obtained after 3 monthly courses of CHOP. In case of absence of CR or VGPR, 3 to 6 monthly-courses of fludarabine were realized before mobilization with Cy 4 g/m2 + G-CSF administration. Conditioning regimen included TBI 12 Gy and Cy 60 mg /kg /d for 2 days. Study end points included Event Free Survival (EFS), toxicity, feasibility. Between March 1999 and December 2004, 86 patients were randomized of which 79 were evaluable. A number of 38 patients were randomized to CHOP regimen and 41 to high dose therapy. The groups were well-balanced; 29% females, mean age 53 years (35 to 61), 67 % B and 25 % C Binet stages, 2 patients with A stage were included, 1 stage was not mentioned. In Arm B, 13 out of 41 patients were not transplanted because of disease progression (n=7), sepsis shock and death during the first CHOP course (n=1), patient’s refusal (n=1), graft contamination (n=1), mobilization failure (n=2) and violation criteria (n=1). CD34+ cells purification was performed in 69% of the grafts. Post transplant grade 3–4 non-hematological toxicity was mainly infectious (2 CMV and 1 aspergillus infections). Second cancers occurred in 3 patients in Arm A; skin cancer (n=1), breast cancer (n=1), Acute Myeloid Leukemia (AML) + skin cancer (n=1). One pretransplant case of skin cancer was reported in Arm B. Six patients died in Arm A from disease progression (n=5), AML (n=1) and 3 in Arm B from toxic death during the first course of CHOP (n=1), disease progression (n=2). As an intent-to-treat analysis and with a median follow-up time of 30 months (range 1–74), median EFS was 23.6 months in Arm A and 63.1 months in Arm B (p<0,001). In conclusion, front-line high dose therapy with autologous CD34+ purified stem cell support in B and C Binet stages B-CLL patients is feasible and has promising efficacy. Transplant-related toxicity appears to be acceptable. Longer follow-up as well as on-going VH mutational analysis will be necessary to precise the impact of autologous transplantation on overall survival in high-risk B-CLL.