Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02)

Despite a high complete hematologic remission (CHR) rate with imatinib-based therapy, the prognosis of elderly patients (pts.) with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) is poor, primarily due to relapse. Nilotinib (Tasigna®) is a potent ABL kinase inhibitor (TKI) approved for treatment of chronic and accelerated phase CML, but data on its efficacy in Ph+ ALL are limited. To study the activity of ABL-TKI in the front-line setting, the EWALL (European Working Group for Adult ALL) has developed a joint chemotherapeutic protocol for first-line therapy of elderly Ph+ ALL pts. (aged 55 years or more) that serves as a platform for the addition of targeted therapeutic agents. This chemotherapy backbone was used to test the efficacy and safety of the addition of nilotinib in elderly patients with newly diagnosed Ph+ ALL in a European, investigator-initiated trial.

Male or female pts. > 55 years with Ph+ and/or BCR-ABL1 positive ALL were eligible if they had not been previously treated except with corticosteroids, single dose vincristine or three doses of cyclophosphamide, had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres. The trial was registered under NCT01528085. After a pre-phase with dexamethasone (Dex) 10 mg/m² d-7 to d-3 (cyclophosphamide 200mg/m² i.v. d-3 to d-1 optional), nilotinib was administered at 400 mg BID starting with induction therapy and given continuously thereafter. During induction, nilotinib was combined with IV injections of vincristine (VCR) 1 mg and Dex 40 mg on 2 days (20 mg over 70y), repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate 1000 mg/m² IV d1 (500 mg/m² over 70y) and asparaginase 10,000 UI/m² IV d2 (5,000 UI/m² over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m²/12h IV d1, d3, d5 (500 mg/m² over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP QD and methotrexate once weekly over 1 month every other month, and Dex/VCR in 2 month intervals for up to 24 months of treatment. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints include the rate of CHR after induction, death during induction or in CHR, event free (and overall survival, the rate of major (MMR) or complete molecular response (CMR) defined by BCR-ABL/ABL ratios < 0.1% and < 0.001%, respectively.

As of August 2014, 47 pts. (21 male, 26 female) have been enrolled. Median age is 66 years (55-85 years), twelve pts. are older than 70 years of age. To date, 43 pts. are evaluable for safety and 36 pts. are evaluable for efficacy. The CHR rate is 97% (35 of 36 pts. evaluable for response), one patient was refractory (3%). No patient died during induction therapy. With a median follow-up of 211 days, 31 of 35 evaluable pts. are in CCR and four pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 13 of the 36 pts. with documented induction response have discontinued study treatment prematurely, primarily because of transfer to allogeneic SCT (n=7), as explicitly permitted by the protocol. Six pts. discontinued for various other reasons. Eight of 35 CR pts. have completed the consolidation cycles and have entered maintenance phase, five pts. have completed protocol therapy. The rate of complete molecular remission (CMR) after induction (32 pts. evaluable) was 30%, with 2 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 13 of 31 pts. (42%) had a CMR, and BCR-ABL transcripts were undetectable in 9 of 31 pts. (29%). Tolerability has been acceptable, with thirty-four SAEs reported so far, 11 during induction (of 43 pts.), 16 during consolidation (of 37 pts.), 6 during the maintenance phase and one following study discontinuation. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.

In conclusion, nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is well tolerated and highly effective with a 97% CR in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time.