Nilotinib Shows Efficacy in Phase II Analysis of Elderly Patients With Philadelphia-Positive ALL

Oliver G. Ottmann, MD

Treatment with the tyrosine kinase inhibitor (TKI) nilotinib (Tasigna) in combination with chemotherapy elicited complete hematological remissions (CHR) in 87% of elderly patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Oliver G. Ottmann, MD, presented the results of a planned interim analysis of a phase II study at the 56th Annual Meeting of the American Society of Hematology (ASH).

Ottmann noted during a press briefing Sunday that while the combination of chemotherapy and TKIs is the gold standard in the treatment of Ph+ ALL, elderly patients who are not eligible for stem cell transplantation (SCT) experience poor outcomes with or without addition of a TKI. Individuals on the trial were treated with an age-adapted low intensity chemotherapy regimen developed specifically for patients with Ph+ ALL aged 55 and older by the European ALL Working Group (EWALL).

After induction, 45.5% of patients achieved major molecular response (MMR), while 11.4% had undetectable BCR-ABL1 transcripts. During consolidation, 79% of patients had MMR and 26.3% had undetectable BCR-ABL1 transcripts.

“We have a significant further increase with the consolidation cycles plus the kinase inhibitor,” Ottmann said. “Continuing the treatment with this drug increases the depth of response.”

Nilotinib is a second-generation TKI approved in two settings: for the treatment of patients with newly diagnosed Ph+ chronic myeloid leukemia (CML) in chronic phase and for patients with Ph+ CML in chronic phase and accelerated phase who have progressed on imatinib.

Patients on the trial ranged from 55 to 85 years of age with a median age of 65 years. Eligible patients were defined as Ph+ or BCR-ABL1-positive who had not received prior treatment except with corticosteroids, single-dose vincristine, or three doses of cyclophosphamide. As central nervous system (CNS) involvement can be a problem in ALL, Ottmann said, such involvement was not defined as exclusion criteria. However, no patients with CNS involvement were enrolled.

Patients were administered 400 mg of nilotinib twice per day with initial chemotherapy and then continuously during following phases of chemotherapy. Primary endpoints of the trial focused on the rate of survival without an event such as relapse, treatment discontinuation, serious adverse event, or death at 12 months. Secondary endpoints focused on the rate of CHR after induction, death during induction or CHR, overall survival, and the rate of major molecular (BCR-ABL/ABL ratio < 0.1%) or complete molecular (BCR-ABL/ABL ratio < 0.001%) response. Patients were treated for up to two years.

As of August 13, 2014, 47 patients on the trial were evaluable for efficacy. In total, 87% of those patients (n = 41) achieved CHR while 4% (n = 2) had progressive disease and 2% (n = 1) died upon induction. Six percent (n = 3) of patients discontinued treatment early because of lipase elevation, thromboembolism, and an unknown cause.

“The combination of nilotinib with this age-adapted chemotherapy is highly effective,” said Ottmann, a professor at Goethe University in Frankfurt, Germany. “We do have quite a reasonable overall survival estimate at 2 years of just more than 70%.”

According to Ottmann and colleagues, overall survival estimates showed that 67.1% of patients would be alive after 30 months. Ottmann said the rate of overall survival would be slightly higher (72.7%) if patients underwent SCT.

In Europe, Ottmann said, “allogeneic transplant is still considered an option, even in this elderly population.” The completion of this trial and further trials will hopefully provide an answer as to its benefit.

At the time the researchers compiled their conference abstract, they noted that 43 patients were evaluable for safety assessment, and that the tolerability of the combination was acceptable. In total at that time, 34 serious adverse events had been reported: 11 during induction, 16 (among 37 patients) during consolidation, six during maintenance, and one after discontinuation. Infectious events and neutropenic fever were the most commonly observed serious adverse events. Other serious adverse events included cardiovascular, hepatic, metabolic, neurologic, and renal events.

Ottman OG, Pfeifer H, Cayuela JM, 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). Presented at: 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 798.

<<<

View more from the 2014 ASH Annual Meeting