Imatinib and Interferon-Alpha Maintenance Therapy for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Ineligible for Allogeneic Stem Cell Transplantation (SCT).
Authors: Pfeifer Heike , Wassmann Barbara , Käbisch Andreas , Lübbert Michael , Leimer Lothar , Giagounidis Aristoteles , Hoelzer Dieter , Ottmann Oliver G. 
Published: October 2019

Abstract 2042

Poster Board II-19

Introduction:

The tyrosine kinase inhibitor imatinib (IM), alone or in combination with chemotherapy, has become the mainstay of front-line treatment for Ph+ ALL. We recently demonstrated that IM in combination with intensive consolidation chemotherapy of approximately one year duration is feasible in elderly patients with de novo Ph+ ALL, but is associated with a high relapse rate. Allogeneic SCT (alloSCT) is potentially curative but may not be feasible in most elderly or comorbid patients. Maintenance therapy (MT) in such patients is conceptually attractive, but data on whether any type of MT facilitates long-term leukemia-free survival of patients with Ph+ALL in first CR is lacking. Based on data suggesting that interferon-alpha (IFN-a) possesses anti-leukemic activity in patients with Ph+ALL, we conducted a phase II study to determine the feasibility and efficacy of MT consisting of imatinib in combination with low-dose (LD) IFN-a in elderly patients with Ph+ALL who were not eligible for SCT. In addition, we examined whether bcr-abl transcript levels and mutation status were predictive of relapse and remission duration.

Methods:

Nineteen elderly patients (median age 66 yrs; [60-75 yrs.]) who had received IM-based remission induction and consolidation therapy as reported previously (Ottmann et al., Cancer 109:2068-76, 2007) were enrolled in a clinical trial of IM 400 mg daily in combination with LD-IFNa with a target dose of 3 Mio IU/week. At the time of enrollment, the majority of patients (n=12) had received five (n=3) or six (n=9) consolidation cycles, the remaining patients had discontinued intensive front-line therapy after four (n=2), three (n=1), two (n=1), and one (n=1) consolidation cycles, 2 patients were switched to MT after induction. The median number of cycles of consolidation chemotherapy given concurrently with IM was six. Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing.

Results:

The median overall duration of MT is 26 mos. (range 3-92 mos.). Seven of 19 pts. (37 %) are in ongoing CR, with a median remission duration from start of maintenance of 76.7 mos. (54-91 mos.). Median overall survival of all pts. is 61 mos. (range: 20-99 mos.). Eleven of 18 evaluable pts. experienced side effects which lead to a dose reduction of IFN. 9 pts. suffered from moderate depressions or fatigue. Hematologic toxicity was mild: only 2 pts. developed grade 3 cytopenia during MT. Remission duration was independent of the number of previous cycles of intensive chemotherapy, of the MRD response during the first 6 mos. of intensive front-line therapy (16 mos. vs. 26 mos.) and of achievement of PCR negativity at any time during intial therapy. Surprisingly, the bcr-abl transcript level at the start of MT likewise had no impact on time to disease recurrence.

Conclusions:

In elderly Ph+ALL pts. ineligible for allogeneic SCT, maintenance with imatinib in combination with low-dose IFN-a results in long-term sustained remissions in a substantial proportion of patients, with acceptable side effects. Surprisingly, the MRD response and mutation status prior to MT were not significantly predictive of remission duration. Likewise, greater intensity of prior chemotherapy as determined by the number of administered consolidation cycles had no significant benefit with respect to remission duration during MT. More extensive evaluation of tyrosine kinase inhibitors in combination with LD IFNa as MT for Ph+ALL is warrented.

Disclosures:

Ottmann: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.