UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia

Abstract

• Imatinib improves outcomes for adults with Ph1 ALL at least in part by facilitating allogeneic stem cell transplant.• Allogeneic hematopoietic stem cell transplant is not dispensible in Ph1 ALL in the imatinib era.The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (preimatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N 5 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N 5 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P 5 .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P 5 .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS 5 0.64, 95% confidence interval 0.44-0.93, P 5 .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514. (Blood. 2014;123(6):843-850)

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

“…In terms of CHR, these results compare favorably with those reported by other studies in which imatinib was administered concomitantly to chemotherapy or in various schedules during induction or consolidation, with CHR rates ranging from 72% to 96%. 5,6,10,12,13,15,[18][19][20][21]34,35 Furthermore, our schedule has the advantage that there are fewer deaths during induction treatment, in contrast to the majority of the combination studies in which, with few exceptions, 5 toxic deaths were recorded in 2%-7% of cases. 6,8,[12][13][14][18][19][20] Indeed, toxicity was recorded in the initial combination protocol (imatinib+chemotherapy) that led to the final amendment to a sequential strategy.…”

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Prior to the introduction of TKI, prognosis was very poor, with virtually no adult patients (<5%) cured with standard chemotherapy; median survival was 8-10 months unless an allogeneic hematopoietic stem cell transplant (allo-SCT), the only potentially curative strategy, could be performed. [22][23][24][25] Today, treatment with TKI, with [5][6][7][8][9][10][12][13][14][15][18][19][20][21] or without 11,16,17 systemic chemotherapy, represents the most appropriate first-line management of patients with Ph + ALL in terms of rates of complete hematologic remission (CHR) and disease-free survival (DFS). Imatinib has been incorporated into different schedules either in induction [5][6][7]10,[12][13][14][18]…”

“…[22][23][24][25] Today, treatment with TKI, with [5][6][7][8][9][10][12][13][14][15][18][19][20][21] or without 11,16,17 systemic chemotherapy, represents the most appropriate first-line management of patients with Ph + ALL in terms of rates of complete hematologic remission (CHR) and disease-free survival (DFS). Imatinib has been incorporated into different schedules either in induction [5][6][7]10,[12][13][14][18][19][20][21] or following induction 8,10 in cohorts including also elderly patients, 8 with CHR rates varying from 72% to 96%. Moreover, the use of imatinib can also act as a "bridge" to an allo-SCT for those patients eligible.…”

Presence of CD34+CD38−CD58− leukemia-propagating cells at diagnosis identifies patients at high risk of relapse with Ph chromosome-positive ALL after allo-hematopoietic SCT

“…Relapse remains one of the major obstacles to Ph + ALL treatment after allo-HSCT, with an estimated 4-year relapse of 38% in a UKALL12/E2993 study. 4 In a Japanese adult leukemia study, an estimated 3-year CIR of 21% was observed in an imatinib cohort, which was significantly lower than that in the non-imatinib cohort (34%). 5 Our previous study demonstrated that patients treated with imatinib maintenance therapy guided by BCR-ABL monitoring by RQ-PCR after allo-HSCT have a lower estimated 5-year relapse rate (10.2%) compared with patients not treated with imatinib (33.1%).…”

“…Nevertheless, relapse is still the main cause of treatment failure even after allo-HSCT. 1,[3][4][5] Once patients experience a relapse, the outcomes are extremely unfavorable. Therefore, it is imperative to identify novel prognostic factors to predict relapse in Ph + ALL after allo-HSCT.…”