Welcome to March/April, 2010 edition of OncoFacts. We are continuing our coverage of the important and potentially practice changing data from the 2009 Annual Meeting of the American Society of Hematology (ASH). This month, we will look at presentations concerning chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and lymphoma.

Chronic Myelocytic Leukemia

Late-Breaking Abstract-1
Giuseppe Saglio presented the initial results of the ENESTnd trial in a late-breaking abstract at ASH. This was a randomized phase III trial involving 846 newly diagnosed, previously untreated patients with Philadelphia-positive chronic phase (Ph1+CP)–CML. Patients were randomized to nilotinib 300 mg twice daily (BID) versus nilotinib 400 mg BID versus imatinib 400 mg daily. The primary endpoint was major molecular response (MMR). All patients had a minimum of 12 months treatment and the median follow-up was 14 months. The results as reported by Dr Saglio demonstrated that both MMR rates and complete cytogenic response (CCyR) rates were significantly higher for both nilotinib doses compared to imatinib after 6 months and 12 months of treatment.

MMR, major molecular response; CCyR, complete cytogenic response; PD, disease progression; AP, accelerated phase; BC, blast crisis

Myelosuppression was greater in the imatinib arm than in the nilotinib arms. The authors concluded that “The superior efficacy and favorable tolerability of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML.” A similar large phase III study of imatinib versus dasatinib is expected to be presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting.

Abstract 1126
In a poster presentation, Michael Deininger updated the results of the IRIS trial at 8 years. During the eighth year of follow-up, there was 1 progression to accelerated phase/blast crisis (AP/BC) and 2 non-CML–related deaths. Major molecular response rates increased over the course of imatinib therapy from 24% at 6 months to 39% at 12 months to 86% of those still on treatment at 8 years. No patient with a documented MMR at 12 months progressed to AP/BC after 8 years of follow-up.

Abstract 505
Dr Dushyant Verma from the M. D. Anderson Cancer Center presented an analysis of patients with CML treated with imatinib from July 2000 to August 2009. Two hundred eighty-one patients were analyzed. Twenty-six percent received an initial dose of imatinib 400 mg daily and 74% received an initial imatinib dose of 800 mg daily. Two hundred forty-eight achieved a complete cytogenetic response (CCyR), 80 achieved major molecular response without complete molecular response (CMR), and 123 achieved CMR on at least one measurement. Major molecular response was sustained over 6 months or more in 34%, and CMR was sustained in 30%. Among the patients who did achieve a CCyR, those who had a sustained CMR by 24 months had an event-free survival (EFS) at 5 years of 100%, compared to 96% for those with MMR without CMR, and 86% for those who failed to achieve MMR.

The rate of survival free-from-transformation to AP/BC at 5 years was 100% for sustained CMR, 96% for MMR, and 91% for CCyR without MMR. By univariate analysis, factors predicting for sustained CMR included platelet count >450,000/mL, CCyR at 3 months, and CCyR at 6 months. The authors concluded that achieving a sustained CMR is an important endpoint for patients with CML treated with imatinib and that novel treatment strategies that improve CMR rate are worth pursuing.

Abstract 337
As noted in the Verma abstract, nearly three-quarters of newly diagnosed patients with CP-CML at the M. D. Anderson Cancer Center treated with imatinib received 800 mg daily rather than the standard 400 mg dose. In abstract 337, Dr Baccarani reported the results of the multicenter TOPS study in which previously untreated patients with CP-CML were randomized to imatinib 800 mg (high dose [HD]) versus 400 mg (standard dose [SD]) in a 2:1 ratio. At 24 months, 82% of the patients treated with SD of 400 mg and 77% of the patients who received HD remained on therapy. TOPS did demonstrate higher MMR rates at 3 and 6 months for the HD imatinib arm, but by 12 months, the differences were no longer significant. It is also interesting to note that there were no differences in the cumulative rates of CCyR at 24 months, and no significant differences in the MMR rates at 12, 18, and 24 months. Also there were no significant differences in EFS, progression-free survival (PFS), or overall survival (OS) at 24 months.

Abstracts 338 & 341
Jorge Cortes from the M. D. Anderson Cancer Center updated the results of 2 phase II studies in newly diagnosed patients with CP-CML using second generation tyrosine kinase inhibitors (TKIs) in front-line therapy. Both of these trials involved approximately 60 patients with CML and were compared with previous patient groups that were treated with imatinib 400 mg or 800 mg. Complete cytogenic response was achieved more rapidly with nilotinib and dasatinib compared to similar imatinib treated patients from previous trials.

Major molecular response rates at 12 months were 74% for dasatinib, 71% for nilotinib, 34% for imatinib 400 mg, and 58% for imatinib 800 mg. The conclusions were that nilotinib and dasatinib induced more rapid CCyRs than imatinib in most patients with acceptable toxicity profiles. In addition, cytogenetic and molecular responses at 12 months were also higher with dasatinib and nilotinib.

Abstract 340
Finally for CML, abstract 340 addressed the question of the role of interferon in front-line therapy for CML. Francois Guilhot reported an update on the Spirit phase III trial comparing imatinib 400 mg with imatinib 600 mg versus imatinib 400 mg plus Ara-C versus imatinib 400 mg plus peg-interferon. Major molecular response, optimal molecular response (OMR [bcr-abl <0.01%]), and undetectable molecular residual disease (UMRD) were assessed at 12 and 24 months. Imatinib + peg-IFN2a produced the best MMR, OMR, and UMRD results at 12 and 24 months, all of which were statistically superior to imatinib 400 mg alone. This was despite the fact that 45% of patients discontinued peg-IFN2a during the first 12 months of therapy. Event-free survival at 48 months was not significantly different for the 4 arms of the study. In the peg-IFN-imatinib arm, MMR, OMR, and UMRD all progressively increased the longer patients were able to continue interferon.

So the question of interferon’s role in front-line therapy of CP-CML remains increasingly interesting but undefined at this time.

References
Saglio G, K DW, Issaragrisil S, et al. Nilotinib demonstrates superior efficacy compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: Results from the international randomized phase III ENESTnd trial. Blood. 2009;114(22). Abstract 1 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114(22). Abstract 1126 and poster presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Verma D, Kantarjian HM, Shan J, et al. Sustained complete molecular response to imatinib in chronic myeloid leukemia (CML): A target worth aiming and achieving? Blood. 2009;114(22). Abstract 505 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Baccarani M, Druker BJ, Cortez-Franco J, et al. 24 months update of the TOPS study: A phase III, randomized, open-lable study of 400mg/d (SD-IM) versus 800mg/d (HD-IM) of imatinib mesylate (IM) in patients (Pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2009;114(22). Abstract 337 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Cortes J, Borthakur G, O’Brien S, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood. 2009;114(22). Abstract 338 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Cortes J, O’Brien S, Jones D, et al. Efficacy of nilotinib in patients (Pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood. 2009;114(22). Abstract 341 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Guilhot F, Preudhomme C, Guilhot J, et al. Significant higher rates of undetectable molecular residual disease and molecular responses with pegylated form of interferon a2a in combination with imatinib (IM) for the treatment of newly diagnosed chronic phase (CP) chronic myeloid leukaemia (CML) patients (pts): Confirmatory results at 18 months of part 1 of the Spirit phase III randomized trial of the French CML Group (FI LMC). Blood. 2009;114(22). Abstract 340 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

OncoFacts™ Editor:

James Epstein, MD

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