Janis C. Kelly

December 17, 2014

SAN FRANCISCO — Maintenance nilotinib (Tasigna, Novartis) plus relatively mild combination chemotherapy produced an 87% complete remission rate and a 70% rate of survival at 2 years in older patients with acute lymphoblastic leukemia (ALL), new research shows.

The data, from an interim analysis of the ongoing phase 2 trial of the European Working Group for Adult ALL (EWALL), were reported here at the American Society of Hematology 56th Annual Meeting.

These early results could point the way toward a usable therapeutic approach for older ALL patients not able to tolerate the intensive chemotherapy plus stem cell transplantation commonly used to treat younger patients, lead researcher Oliver G. Ottmann, MD, from the University Cancer Center, Goethe University, in Frankfurt, Germany, said during a meeting press briefing.

"Things are getting better for patients with acute leukemias, but not uniformly. Patients who are elderly and can't receive intensive therapy regimens do poorly, and we need to improve outcomes for these patients," said David Steensma, MD, from the Dana-Farber Cancer Institute in Boston, who moderated the briefing.

Dr Oliver G. Ottmann

Dr Ottmann explained that "this clinical trial is dealing with an elderly population that has the highest-risk type of acute lymphoblastic leukemia."

Before tyrosine kinase inhibitors (TKIs), this disease was uniformly fatal unless patients underwent stem cell transplantation, he continued. However, outcomes can still be poor in older patients, for whom transplantation is not always an option.

Study Details

Dr Ottmann and colleagues recruited 56 newly diagnosed untreated or lightly treated patients 55 to 85 years of age who had Philadelphia (Ph)-positive ALL.

For the 47 patients included in the interim analysis, median age was 65 years, and 23 were 70 years or older. Thirty patients expressed p185 BCRABL and 23 expressed p210 BCRABL .

All patients received the standard EWALL low-intensity backbone chemotherapy protocol plus nilotinib, an oral ABL kinase inhibitor approved for treatment of chronic and accelerated-phase chronic myelogenous leukemia.

Table. Study Protocol

Therapy Schedule
   Dexamethasone 10 mg/m² days –7 to –3
   IV cyclophosphamide 200 mg/m² days –3 to –1 (optional)
   Oral nilotinib 400 mg twice daily, starting with induction and continuously thereafter
   IV vincristine 1 mg on 2 days, repeated weekly for 4 weeks
   Dexamethasone 40 mg* with vincristine
   Nilotinib 400 mg twice daily
   IV methotrexate 1000 mg/m²* day 1
   IV asparaginase 10,000 UI/m²* day 2; cycles 1, 3, and 5
   IV cytarabine 1000 mg/m²* twice daily on days 1, 3, and 5; cycles 2, 4, and 6
Maintenance (up to 24 months)  
   Nilotinib 400 mg twice daily
   Mercaptopurine with methotrexate
   IV methotrexate 1000 mg/m²* once weekly for 1 month every other month
   IV vincristine 1 mg in 2-month intervals
   Dexamethasone 40 mg* with vincristine

*Dose halved for patients older than 70 years.


At a median follow-up of 8.5 months, 41 of 47 patients achieved complete hematologic remission, the primary end point.

Median time to complete response was 41 days. There were two partial responses or treatment failures (4%) and one death during induction therapy (2%).

Overall survival at 30 months was 72.7% in patients who did not undergo transplantation and 67.1% in patients who did.

"A number of patients actually underwent allotransplant, which was specifically allowed and even encouraged. At present, there is no survival benefit among the nine patients who underwent transplant. It will be interesting to see whether the nontransplant patients will do as well as the others," said Dr Ottmann.

Three patients (6%) discontinued treatment before assessment — one because of lipase elevation, one because of thromboembolism, and one for unknown reasons. At 2 years, 33 patients remained in relapse-free complete remission.

The nilotinib regimen had a notable impact on the evolution of molecular response. After the completion of induction therapy, the median BCR–ABL to ABL transcript ratio was 1.8 × 10–3. During consolidation therapy, the median ratio had dropped to 3.5 × 10–5. Minimal residual disease (MRD) levels continue to decrease over time, Dr Ottmann reported.

On MRD analysis, response was significantly better with the consolidation cycles plus the kinase inhibitor. "Continuing the treatment in this way increases the depth of response. Analysis of the rate of MRD negativity showed that in one-quarter of patients, transcipts were undetectable on PCR during the consolidation cycles, and approximately 80% achieved what we call a major molecular response," he said.

The researchers conclude that nilotinib, when combined with an age-adapted low-intensity chemotherapy regimen, is highly effective for elderly patients with Ph-positive ALL.

"There are still a lot of patients with acute leukemias for whom current therapies fail," Dr Steensma said. "We need to move the bar forward, and we are trying to do that. Acute leukemia is still a devastating, life-changing diagnosis, but progress is being made."

Dr Ottmann reports financial ties with Novartis. Dr Steensma reports financial ties with multiple pharmaceutical companies.

American Society of Hematology (ASH) 56th Annual Meeting. Abstract 798. Presented December 9, 2014.


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