Treatment Outcome with Imatinib-Based Maintenance Therapy in Elderly Patients with Philadelphia-Positive Acute Lymphoblastic Leukaemia (Ph+ALL) Ineligible for Allogeneic Stem Cell Transplantation (SCT).
Authors: Pfeifer Heike , Wassmann Barbara , Wystub Sylvia , Wunderle Lydia , Chromik Joerg , Brueck Patrick , Hochhaus Andreas , Binckebanck Anja , Hoelzer Dieter , Ottmann Oliver 
Published: October 2019

Background: The tyrosine kinase inhibitor imatinib (IM), alone or in combination with induction and post-remission chemotherapy, has become the mainstay of front-line treatment for Ph+ ALL, followed by allogeneic SCT as a potentially curative treatment option. However, alloSCT is not feasible in many elderly or comorbid patients. In a prospective, randomized clinical trial of elderly patients with de novo Ph+ ALL, we recently demonstrated that IM induction followed by IM in combination with intensive consolidation chemotherapy of approximately one year duration was feasible in the majority of pts. but associated with a high relapse rate. To assess the impact of IM-based maintenance, we here provide an analysis of maintenance therapy with IM either alone, in combination with low dose interferon-α (LD-IFNα), or with zoledronic acid. In addition, we examined whether determination of minimal residual disease (MRD) and/or BCR-ABL mutation status prior to and during pre-maintenance therapy were predictive of freedom from relapse and remission duration.

Patients and Methods: Remission induction and consolidation therapy have been reported previously (Ottmann et al.,Cancer109:2068–76, 2007). As the present analysis focuses entirely on the maintenance phase, patients who failed to achieve a CR, relapsed or died during the consolidation cycles are not included. Following a median of 6 cycles of remission induction and consolidation chemotherapy given concurrently with IM, 33 CR pts. (n=33; median age 69.5 yrs; [58–75 yrs.]) were enrolled either in a clinical trial of IM in combination with low-dose IFN (n=19), or with zoledronic acid (n=4), or received Glivec as a single agent (n=8). Minimal residual disease was serially assessed by quantitative RT-PCR and mutational analyses was performed by D-HPLC and direct sequencing.

Results: With a median duration of maintenance of 17 months (range 6–72 mos.), 14 of 33 patients (42%) are in ongoing CR, with a median maintenance duration of 46 mos. (20–72 mos.). Median overall survival of all patients is 28 mos. (range: 9–81 mos.). Detection of a BCR-ABL mutation at or within 4 weeks of initial diagnosis was associated with inferior remission duration, 18 mos. versus 27 mos. (p=0.06). Remission was independent of the MRD response during induction and consolidation: 24 mos. and 26 mos. in pts. who did or did not achieve MRD negativity at any time; similarly, detection of MRD at the start of maintenance had no impact on time to progression.

Conclusions: Among elderly Ph+ALL pts. who did not undergo SCT, treatment outcome with IM-based maintenance therapy is encouraging, but remissions are not sustained in the majority of patients. Surprisingly, persistent MRD positivity during consolidation or at the start of maintenance were not associated with an inferior outcome; conversely, relapses occurred even in patients who had achieved prolonged MRD negativity.