ASCO 2006: Update of Studies in Chronic Myeloid Leukemia (CML)

ASCO 2006: Update of Studies in Chronic Myeloid Leukemia (CML)

June 2-6, 2006Atlanta, GeorgiaHagop Kantarjian, MD Chairman, Leukemia Department, M.D. Anderson Cancer CenterThe content presented here was prepared by independent authors under the editorial supervision of OncoEd and is not endorsed or sanctioned by the 42nd Annual Meeting of the American Society of Clinical Oncology.

Introduction

Several interesting reports regarding the management of chronic myeloid leukemia (CML) have been updated at ASCO and will be summarized below. These pertain to new tyrosine kinase inhibitors (TKIs) in CML.

Updated Results of Tyrosine Kinase Inhibitors in CML

The 5-year IRIS update was reported by Druker et al comparing 553 patients receiving Gleevec® (imatinib) to 553 patients receiving interferon + ara-C. Among patients receiving first line Gleevec, 382 are still on therapy at a median daily dose of Gleevec 400 mg daily. The cumulative CHR rate was 98%, major cytogenetic response rate 92%, and complete cytogenetic response rate 87%. Estimated survival rate without accelerated or blastic phase at 5 years was 93%, and the estimated 5-year event-free-survival rate was 83%. The annual rate of transformation to accelerated or blastic phase was 1.5% to 2.8% in the first 3 years, but decreased to less than 1% in years 4 and 5. In patients achieving a complete cytogenetic response, the annual transformation rate was 0.3% in year 3 and 0% in year 4. Predictors for worse outcome were lack of a major cytogenetic response at 12 months and lack of a complete cytogenetic response at 18 months. The estimated 5-year overall survival rate was 89%; it was 95% if non-CML related deaths were excluded.[1] These results confirm the long term durability of responses in CML with Gleevec and its long term efficacy and toxicity.

New Tyrosine Kinase Inhibitors Post Gleevec Failure in CML

Several studies reported on the updates of dasatinib (Sprycel), a dual Src-Abl inhibitor, in CML in different phases post Gleevec failure. Hochhaus reported on 387 patients with Ph + CML post Gleevec resistance or intolerance treated with dasatinib 70 mg BID in a multinational multicenter study. Overall, the CHR rate was 90% and the major cytogenetic response rate was 51% (complete cytogenetic response rate 40%). The major cytogenetic response rate was higher post Gleevec intolerance versus resistance (78% versus 42%). CHR and cytogenetic responses were similar regardless of whether patients did or did not have ABL KD mutations. With a median follow up of 8 months, the estimated 10-month progression-free survival rate was 88%.[2]

Shah et al reported on 150 patients with resistance to Gleevec 400 600 mg daily who were randomized (2:1) to dasatinib 70 mg BID versus Gleevec high dose 400 mg BID. The estimated 3-month complete cytogenetic response rate was 21% with dasatinib and 8% with high dose Gleevec. The time to treatment failure was significantly better with dasatinib. Grade 3-4 neutropenia and thrombocytopenia was higher with dasatinib (56% and 51%) compared with high dose Gleevec (39% and 14%). Nausea, vomiting, weight gain and muscle cramps were more frequent with high-dose Gleevec. Pleural effusions were noted in 11% with dasatinib and 0% with high-dose Gleevec. This study suggests that dasatinib may be a reasonable alternative to high-dose Gleevec in patients who fail standard dose Gleevec.[3]

In accelerated phase CML post Gleevec failure, dasatinib given at 70 mg orally BID to 174 patients resulted in a hematologic response rate of 59%, a CHR rate of 34%, a major cytogenetic response rate of 34%, and a complete cytogenetic response rate of 25%. Progression-free survival estimated at 1 year was 80%. In CML blastic phase and Ph+ CML the hematologic response rates were 33% to 49%, and the complete cytogenetic response rates were 25% to 44%.[4],[5],[6]

Nilotinib (AMN107) is a selective potent Bcr-Abl kinase inhibitor, 30 times more potent than Gleevec. Following the phase I studies, phase II pivotal trials have been initiated. In the phase II study of nilotinib in chronic phase CML post Gleevec failure, 81 patients received nilotinib 400 mg orally BID. Fifty-four had active disease; 53 had resistant disease. Median duration of CML was 5 years. The overall CHR rate was 69% and the cytogenetic response rate was 68%complete in 32% and major in 46%.[7] Side-effects with nilotinib were mostly mild. Grade 3-4 neutropenia was noted in 16% and thrombocytopenia in 19%. Other side effects included rashes in 4%, arthralgias in 5%, and fatigue in 3%.

The preliminary phase II studies of nilotinib in accelerated and blastic phase CML post Gleevec failure were also encouraging. In accelerated phase CML, the hematologic response rate was 40% and the major cytogenetic response rate was 28%. In CML blastic phase/Ph+ ALL, hematologic responses were observed in 35% of patients.[8],[9] Finally, nilotinib has also been given at 400 mg BID to 13 patients with newly diagnosed CML. The 3-month complete cytogenetic response rate was 93%, higher than with standard or high dose Gleevec (36% and 61%).[10]

In summary, the prognosis of CML appears now extremely positive. Long-term results of Gleevec show sustained and durable responses with excellent estimated 5-year survival rates and minimal side effects. For patients with Gleevec intolerance or progression, the new tyrosine kinase inhibitors are providing excellent and durable responses.

References

[1] Druker BJ, Guilhot F, OBrien S, et al. Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6506.

[2] Hochhaus A, Kantarjian H, Baccarani HM, et al. Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 START-C Study. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6508.

[3] Shah NP, Rousselot P, Pasquini R, et al. Dasatinib (D) versus high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6507.

[4] Talpaz M, Apperley JF, Kim DW, et al. Dasatinib (D) in patients with accelerated phase chronic myeloid leukemia (AP-CML) who are resistant or intolerant to imatinib: Results of the CA180005 START-A study. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6526.

[5] Cortes JE, Kim DW, Rosti G, et al. Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): Results of the CA180006 START-B study. *Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I.*Vol. 24, No. 18S (June 20 Supplement), 2006: 6529.

[6] S. Coutre, G. Martinelli, H. Dombret, et al. Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 START-L study. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6528.

[7] Kantarjian HM, Gattermann N, OBrien SG, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib resistant and intolerant patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP). *Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I.*Vol. 24, No. 18S (June 20 Supplement), 2006: 6534.

[8] Le Coutre PD, Ottmann O, Gatterman N, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with chronic myelogenous leukemia (CML) in accelerated phase (AP). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6531.

[9] Giles FG, Larson R, Le Coutre P, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with Ph+ chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). Journal

of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6536.

[10] Jabbour E, Giles F, Cortes J, et al. Preliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No. 18S (June 20 Supplement), 2006: 6591.

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