1. Fuerst, Mark L.

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ORLANDO, Florida-A combination of pegylated-interferon alpha (Peg-IFNa) 2a and the tyrosine kinase inhibitor (TKI) dasatinib as first-line therapy of chronic-phase chronic myeloid leukemia (CML) induces a high rate of deep molecular response during the first year of therapy, according to an oral study reported here at the American Society of Hematology Annual Meeting (Abstract 134).

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The combination of Peg-IFNa and imatinib is known to significantly induce higher rates of molecular responses, including undetectable BCR-ABL transcript, over imatinib alone, as frontline therapy for CML patients, and second-generation TKIs such as dasatinib and nilotinib have been shown to induce faster and deeper molecular response than imatinib.


"Dasatinib, as a dual SRC/ABL kinase, may have distinct effects in combination with Peg-IFNa," said the study's lead author, Lydia Roy, MD, of Centre d'Investigation Clinique de Poitiers in France.


The study included 79 patients with a median age of 48 with newly diagnosed Philadelphia-positive CML who started dasatinib therapy at 100 mg per day. At three months, the patients also received Peg-IFN associated with dasatinib when their platelets were more than 100 x109/L, their neutrophils were higher than 1.5 x109/L, and their lymphocytes were less than 4 x109/L.


The maximum duration of the combination dasatinib and Peg-IFNa was 21 months. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5) at 12 months.


Eighteen patients (23%) were not eligible to receive the interferon because their neutrophil, platelet, and lymphocyte counts did not reach the pre-specified levels, or they did not achieve a complete hematologic response or they were noncompliant with therapy. Two-thirds of these patients had large spleens and three-quarters had moderate to high Sokal scores.


The other 61 patients (77%) started Peg-IFNa at the dose of 30 [mu]g per week in association with dasatinib. After the first three months of therapy, the complete cytogenetic response rate for all 79 patients was 44 percent and the molecular response rate was 48 percent.


Among the 61 patients who took the combination therapy, the complete cytogenetic response rate was 48 percent and the molecular response rate was 52 percent. The rate of major molecular response was 16 percent after three months, 51 percent after 6 months, and 70 percent after nine and 12 months. Data from five patients were still pending at the time of the ASH report.


The cumulative incidence of MR4.5, the primary endpoint, was 36 percent by 12 months for those who took the combination, Roy said.


The rate of major molecular response for the patients who did not receive Peg-IFNa was 27 percent at six months and 50 percent at nine months, with missing data from two patients. Data were pending for six patients at 12 months.


Adverse Effects

The non-hematologic adverse events were expected with the combination, and the majority of them were not higher than grade 2, Roy reported. Hematologic adverse events occurring after three months included neutropenia, thrombocytopenia, and anemia. "Despite grade 3 neutropenia, the rate of infections was not too high-nine percent, and five patients had immune disorders," she said.


There were eight serious adverse events after initiating Peg-IFNa, including two cases of grade 4 neutropenia and one case each of dysthyroitidis, dyspnea, pleural effusion, lymphoid hyperplasia, hemorrhoids, and rectal fistula.


'Confirms the Feasibility of the Combination'

In conclusion, Roy said the study confirms the feasibility of the dasatinib and Peg-IFNa combination. "Overall, the toxicity profile of the combination was manageable, and among eligible patients, 79 percent are still on dasatinib plus Peg-IFNa at 12 months.


"The combination led to a high proportion of deep molecular response. A randomized trial is necessary to confirm the study's findings, but these are promising results that could further increase the rate of treatment-free remission."

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In response to a question about the 10 percent rate of serious adverse events, she acknowledged that, but noted there were no cases of significant lymphoma.


Roy was also asked about the low frequency of pleural effusion. She speculated that may have been due to the selection of younger CML patients as well as a dosage adjustment made by the researchers based on the results of a separate Intergroup trial that has yet to be reported.


'Balance Risk of Stopping Therapy Against Known Benefits'

Asked for his opinion for this article, the moderator of the session at which the results were reported, Neil Shah, MD, PhD, Professor in Hematology-Oncology and Leader of Hematopoietic Malignancies at the University of California, San Francisco, said: "This trial shows that the combination of dasatinib and PegIFNa is safe and should move ahead in a randomized trial.


"Ultimately, we will see whether it enables a higher rate of treatment discontinuation. The goal is to have a higher number of patients who start the combination to stop all CML therapy. On the whole, clinicians need to balance the risk of stopping therapy against the known benefits of TKIs."