Nilotinib Improves Prognosis in Elderly Patients with Ph+ ALL

For the difficult-to-treat elderly population (aged ≥55 years) with Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL), combining age-adapted, low-intensity chemotherapy with nilotinib is highly effective, according to interim phase 2 clinical trial results presented at the 2014 ASH Annual Meeting.

“Despite a high complete hematologic remission rate with imatinib-based therapy, the prognosis of elderly patients with Ph+ ALL is poor, primarily due to relapse,” the researchers wrote in their abstract.

“In the pre-kinase inhibitor era, this highest-risk type of ALL was uniformly fatal unless patients underwent stem cell transplant,” said Oliver G. Ottmann, MD, lead study author, at an ASH press conference. It is now standard, Dr. Ottmann continued, for younger patients with Ph+ ALL to receive chemotherapy with a kinase inhibitor and then go on to allogeneic transplantation. “That’s often not an option for patients in the older age range.”

In the current study, investigators tested whether adding nitolinib (a second-generation tyrosine kinase inhibitor) to a backbone chemotherapy regimen developed by the European Working Group for Adult Lymphocytic Leukemia (EWALL-PH-02) would improve outcomes in elderly patients with Ph+ ALL. Nilotinib is a potent tyrosine kinase inhibitor approved for the treatment of chronic and accelerated-phase chronic myeloid leukemia, but the drug has not been tested extensively in Ph+ ALL.

Dr. Ottmann and colleagues’ clinical trial included 56 newly diagnosed ALL patients with a median age of 65 years (range 55-85 years). Patients had Ph+ and/or BCR-ABL1–positive ALL and were previously untreated, except for prior corticosteroids or single-dose vincristine (or up to three doses of cyclophosphamide).

Given the elderly population, investigators relied heavily on the kinase inhibitor (twice-daily nilotinib 400 mg) in the induction phase, minimizing myelosuppressive chemotherapy and treating with corticosteroids and vincristine. In the consolidation phase, moderately more intensive 3-drug combinations were given in alternating cycles of nilotinib, methotrexate, asparaginase, and cytarabine, with dose adjustments for methotrexate, asparaginase, and cytarabine when patient age was >70 years.

Forty-seven patients were evaluable for efficacy – 12 of whom were aged ≥70 years. The complete hematologic response rate was 87 percent (41 of 47 patients), and the median time to complete response was 41 days (range 25–62 days). Three patients discontinued before the response evaluation, and one patient died during the induction phase.

Duration of remission was also promising: two years after complete responses, 33 patients remain relapse-free (p=0.85). “Median follow-up is still short, but the treatment seems to be highly effective in that we have only a few relapses at this time,” Dr. Ottmann commented.

Nine patients went on to receive stem cell transplantation, although no survival benefit with transplant was apparent. Overall survival at 30 months was 67 percent among all patients and 73 percent among patients without stem cell transplantation (p=0.08). “It will be of interest to see if the transplant-free patients will do as well as those who received transplants,” he said.

Molecular responses continued to deepen during the consolidation phase, Dr. Ottmann noted, with a 3-log major molecular response (defined by BCR-ABL/ABL ratios < 0.1% using the International Standard) rate of 46 percent after induction and 79 percent during consolidation. Undetectable levels were achieved in 11 percent after induction and in 26 percent during consolidation.

“Nilotinib in conjunction with chemotherapy with the EWALL-PH-02 protocol is well tolerated and highly effective in elderly patients with newly diagnosed Ph+ ALL,” Dr. Ottmann concluded.


  • Ottmann OG, Pfeifer H, Cayuela J-M, et al. “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).” Abstract #798. Presented at the American Society of Hematology Annual Meeting, December 9, 2014.