Combined treatment with a tyrosine kinase inhibitor (TKI) and ALL-type induction and consolidation chemotherapy followed by allogeneic SCT is standard front-line therapy for younger patients with Ph+ALL, but the value of adding intensive chemotherapy to a TKI in elderly patients is controversial. More than 90% of elderly patients achieve a complete remission, irrespective of the type of TKI-based induction, but relapse is the major cause of treatment failure. In a previously reported randomized trial examining imatinib combined with intensive induction and consolidation chemotherapy for Ph+ALL in elderly patients (n=55), the probability of overall survival (OS) after 24 months was 42% ± 8% (Ottmann OG et al., Cancer. 2007; 109:2068-76). To date, very little published data on long-term outcome of elderly patients with Ph+ALL are available.
We conducted the present analysis to determine whether subsets of patients derive long-term benefit from combined imatinib plus intensive chemoptherapy, examine the characteristics of long-term survivors, determine whether such patients can be identified by assessment of MRD, and obtain preliminary results on the feasibility and efficacy of SCT in this population of elderly patient.
Our current analysis includes a total of 121 patients (119 ALL, 2 CML in lymphoid blast crisis), with a median age of 66 years (range 54–80). Fifty-five patients were enrolled in a previously reported randomized clinical trial comparing single-agent imatinib and chemotherapy as induction therapy, followed by up to 6 cycles of consolidation chemotherapy; a further 67 patients were subsequently treated according to this protocol as per recommendation by the GMALL Study Group.
The overall CR rate was 88%, median time to progression was 14.5 months (range 0.5–102) and OS was 18.6 months (range 0.5–102), respectively. Probabilities of remission duration, survival and TTP at 5 years were 19%, 22% and 19%, respectively. The type of initial induction therapy had no significant impact on OS and DFS. Of 113 pts, who were evaluable for comorbities, pulmonary disease was the only comorbidity associated with inferior outcome (median OS 13 months vs. 20 months, univariate analysis p=0.02). Allogeneic SCT was performed in CR1 in 12 patients and as salvage therapy in another 7 patients. Median age of these 19 patients was 62y (range 54–69). The time from diagnosis to SCT in CR1 was 4.6 months (2.9 mo – 16.8 mo) and from relapse to SCT in >CR1 3 months (2.1 mo – 6.1 mo).
The 5yr OS in patients transplanted in CR1 vs. non-transplanted patients was superior (48% vs 22%). Remarkably, OS of the 7 patients transplanted beyond CR1 as part of salvage therapy was 43% after 4.5 years. With a median follow-up of 21.6 months (range 3.3– 54) after SCT, 8 patients are in ongoing CR with a median OS of 51.8 months from initial diagnosis (range 35 – 66), 5 pts. died in CR, 6 pts. relapsed.
The combination of imatinib with intensive chemotherapy is feasible in elderly patients, but long-term survival is poor primarily due to high relapse rate. Allogeneic SCT in CR1 is superior to conventional therapy and should be considered as front-line therapy in this elderly patient population. The encouraging results of allogeneic SCT performed beyond CR1 suggest that SCT should be considered as definite postremission therapy in a larger proportion of elderly patients than is current practice.
Ottmann:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.
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