Nilotinib Improves
Prognosis in Elderly
Patients with Ph+ ALL
New options for patients not able
to tolerate chemotherapy and
allogeneic stem cell transplant
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
FIGURE Depth of Molecular Response by Timepoint
Oliver G. Ottman, MD
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 (FIGURE).
“Nilotinib in conjunction with chemotherapy with the EWALLPH-02 protocol is well tolerated and highly effective in elderly patients
with newly diagnosed Ph+ ALL,” Dr. Ottmann concluded. ●
Reference
• 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.
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