Introduction

Imatinib (Gleevec®) is the standard initial treatment of newly diagnosed chronic myeloid leukemia (CML). Imatinib produces high rates of complete cytogenetic responses (70% to 85%) and of major molecular responses (20% to 40%) and has improved progression-free and overall survival.¹,² At the 2006 meeting of the American Society of Hematology several abstracts summarized the long-term effects of imatinib for the treatment of various phases of CML.³,⁴ However, imatinib does not eradicate the BCR-ABL clones as detected by polymerase chain reaction (PCR) monitoring.  Furthermore, a small but significant fraction of patients will develop imatinib-resistance or are intolerant to the drug. Patients who fail or are intolerant to imatinib now have treatment alternatives other than allogeneic stem cell transplantation.

Dasatinib (Sprycel®) and nilotinib (Tasigna®) are two new agents that have been developed for the treatment of patients with BCR-ABL-positive CML and acute lymphoblastic leukemia (ALL) that appear to have great promise for the treatment of patients who fail imatinib. Dasatinib has been approved by the US Food and Drug Administration and nilotinib will probably be approved in the near future. Two new second generation kinase inhibitors were introduced at the 2007American Society of Clinical Oncology (ASCO) meeting, bosutinib and INNO-406, both of which show promise as active agents in patients resistant to imatinib and other tyrosine kinase inhibitors. Both nilotinib and dasatinib have also been evaluated in newly diagnosed CML, and the evaluation of combinations of tyrosine kinase inhibitors is likely in the near future.

There is also interest in combining chemotherapy agents with imatinib in order to decrease the development of drug resistance. Two abstracts presented at ASCO 2007 evaluated the addition of cytarabine or interferon alfa to imatinib for the initial treatment of CML in chronic phase; both of these studies were small and inconclusive.⁵,⁶

Treatment of Imatinib Failures and Advanced CML with Dasatinib

An international study compared four dose schedules of dasatinib in 662 patients with CML in chronic phase with resistance or intolerance to imatinib.⁷ The dose schedules evaluated included: 100 mg QD, 50 mg BID, 140 mg QD and 70 mg BID. Major cytogenetic responses (Ph suppression to ≤ 35%) occurred in 42%, 42%, 45% and 45%, respectively. Side effects, including myelosuppression and pleural effusions, were significantly lower with dasatinib 100 mg QD.  Progression-free survival was also better with dasatinib 100 mg QD, presumably because of less interruptions of therapy and more continuous treatment exposure. The authors concluded that the dasatinib 100 mg QD schedule offered the best benefit-risk ratio of the 4 tested schedules.

An international study compared dasatinib 140 mg once per day to 70 mg BID for the treatment of patients with advanced-phase CML or Ph-positive ALL resistant to imatinib.⁸ In this study, 611 patients were randomly allocated to one of the two dose schedules. Complete cytogenetic responses were observed in 27% of patients with accelerated phase CML, 16% and 20% of patients with myeloid blastic phase, 42% and 43% of patients with lymphoid blastic phase and 50% and 37% of patients with Ph-positive ALL. The authors suggested equivalence of both dose schedules and possibly better tolerance for the once a day schedule.

Dasatinib for Treatment of Newly Diagnosed Patients

Researchers from the MD Anderson Cancer Center have reported that dasatinib produced rapid and complete remissions in a high percentage of newly diagnosed patients with chronic myelogenous leukemia.⁹ The current study involved 35 patients with newly diagnosed CML in chronic phase. Patients had a median age of 41 years. The dose of dasatinib administered was 100 mg per day with dose escalation to 140 or 180 mg per day. After 6 months of therapy, 92% of patients had achieved a complete cytogenetic response; by one year 95% of patients had achieved a complete cytogenetic remission. Approximately one quarter of evaluable patients had achieved a major molecular response by 9 months. The authors suggested that patients receiving dasatinib as initial therapy may have a more rapid response than patients receiving imatinib. Almost half the patients had transient reductions of dasatinib doses due mainly to myelosuppression, pleural effusions, rash or fever.

These results are similar to the early results reported at the 2006 meeting of the American Society of Hematology.¹⁰ Future randomized trials will probably be needed to determine if dasatinib is superior to imatinib for initial therapy.

Nilotinib for Treatment of CML Post Imatinib Failure

An international study presented data on 95 patients with CML in chronic phase who were intolerant to imatinib and treated with nilotinib.¹¹ Imatinib intolerance was defined as absence of major cyotogenetic response and discontinuation of imatinib due to Grade 3 or 4 toxicities or persistent or recurrent Grade 2 toxicities. The researchers reported that only 2/80 patients who had non-hematologic toxicities on imatinib had similar toxicities on nilotinib. However, hematologic toxicities appeared to be similar for the two drugs. After 6 months of therapy, 55% of patients had achieved a major cytogenetic response. These data suggest that nilotinib is well tolerated in patients with imatinib intolerance.

In another international study presented at ASCO, 316 imatinib-resistant or intolerant patients with CML in chronic phase were treated with nilotinib.¹² All patients were evaluable for toxicity and 279 for efficacy. Seventy percent of patients were imatinib resistant and 30% were intolerant. Nearly half the patients had CML for 5 years or more, and the median time on imatinib therapy was 33 months. The median treatment time with nilotinib was 247 days. Seventy percent of patients remain on nilotinib therapy. A major cytogenetic response was observed in 52% of patients, of which 34% were complete. The median time to a major cytogenetic response was 2.8 months. Approximately one third of patients had Grade 3 and 4 thrombocytopenia and leukopenia. There were no serious episodes of fluid retention; and in particular, no pleural or pericardial effusions were reported.

In another-international study of 64 patients with accelerated phase of CML, investigators evaluated nilotinib after imatinib failure or intolerance.¹³ Overall, 59% experienced a hematologic response, which was complete in 23%. A major cytogenetic response was observed in 36%; 22% were complete cytogenetic responses. The 12-month survival was 69%, and the median time to progression among responders had not been reached. Toxicities were similar to those observed in the chronic phase study.

The results of an international study that treated 120 patients with CML in blastic phase (BP) with nilotinib were also reported at ASCO.¹⁴ There were 87 patients with myeloid BP and 27 with lymphoid BP. A complete hematologic response was observed in 21% of patients with myeloid BP and in 26% of those with lymphoid BP. The conversion rate to a second chronic phase of CML was 9% and 7%, respectively.

Researchers also evaluated the effects of specific types of BCR-ABL mutations on response to nilotinib.¹⁵ They concluded that nilotinib was efficacious across all mutations (except for mutation T3151) and in patients with BCR-ABL-independent resistance. The authors reported that time to response may depend on the individual type of mutation and the concentration of nilotinib, and suggested that frontline therapy with nilotinib may prevent emergence of resistant clones.

A separate study reported on the outcomes of 41 patients with CML in chronic, accelerated or blastic phases who were imatinib-resistant or intolerant and had failed treatment with dasatinib.¹⁶ All received nilotinib 400 mg BID . The median treatment time was 81 days, and 31% remain on treatment with nilotinib. Six patients discontinued therapy due to toxicity and 16 for disease progression. Forty percent of patients achieved a complete hematologic remission if they had active CML prior to treatment. The authors concluded that nilotinib had significant activity in patients failing dasatinib.

New Tyrosine Kinase Inhibitors

Bosutinib (SKI-606): Bosutinib, a 7-alkoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile, is a potent inhibitor of Src kinase activity. In an ASCO 2007 presentation, 69 patients with chronic phase of CML or ALL who had relapse or resistance to imatinib, were treated with bosutinib.¹⁷ The first part of the study established that the appropriate dose was 500 mg/day. The Phase II part of the study included 51 patients. The major cytogenetic response rate in chronic phase was 52%. In 9 patients with advanced leukemia, 4 had a complete hematological response and 2 had a major cytogenetic response. Bosutinib was also effective in patients with defined imatinib-resistant mutations. The authors concluded that bosutinib was active across a range of mutations. Side effects included diarrhea, nausea, vomiting and abdominal pain. Grade 3 and 4 toxicities (rash, thrombocytopenia) occurred in 5% of patients. Dose reductions were needed in 17 of the 69 patients.

INNO-406: INNO-406 is a dual inhibitor of Abl and Lyn kinases. At ASCO 2007, a Phase I study involving 14 patients with CML or ALL with imatinib intolerance or resistance was presented.¹⁸ Preclinical studies have shown that INNO-406 is a more active Bcr-Abl tyrosine kinase inhibitor than imatinib and also augments apoptosis.¹⁹ Eight of the 14 patients had CML in chronic phase; the remainder had more advanced CML or ALL. Eleven of these patients had failed therapy with nilotinib or dasatinib. Ten patients progressed on therapy and three  remain on therapy with INNO-406. Three patients had evidence of response to therapy with prolonged benefit. The number of patients treated in this study were small and future studies will include patients in earlier stages. However, INNO-406 appeared to have significant activity with little toxicity.

Summary

At the 2007 ASCO meeting it was apparent that there is steady progress in the development and testing of second generation kinase inhibitors, which could ultimately have a major impact on the treatment of CML.

References:

¹ Kantarjian HM, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate versus interferon alfa based regimens in newly diagnosed chronic phase chronic myelogenous leukemia. Blood. 2006;108:1835-1840.

² Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials..  Blood. 2006;108:1478-1484.

³ Baccarani M, Guilhot F, Larson RA, et al. Outcomes by cytogenetic and molecular response at 12 and 18 months of imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) in the IRIS Trial. Blood 2006;108:606a, abstract 2138.

⁴Kantarjian HM, Larson RA, Guilhot F, et al. Declining rates of adverse events (AEs), rare occurrence of serious AEs (SAEs), and no unexpected long-term side effects at 5 years in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) initially treated with imatinib (IM) in the International Randomized Study of Interferon vs STI571 (IRIS). Blood 2006;108:605a, abstract 2136.

⁵ Hurtado-Monroy R, Vargas P, Martinez A, et al. Imatinib (I) + cytarabine (Ara-C) for the frontline treatment of chronic phase (CP) chronic myeloid leukemia (CML). Journal of Clinical Oncology 2007;25:abstract 7048.

⁶ Liberati A, Schippa M, Luzi D, et al. Molecular remission to imatinib-INF-alfa combination or imatinib monotherapy in chronic myeloid leukemia (CML) patients. Journal of Clinical Oncology 2007;25:abstract 17512.

⁷ Shah NP, Kim DW, Kantarjian HM, et al. Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One –year results of CA 180034. Journal of Clinical Oncology 2007;25:abstract 7004.

⁸ Pasquini R, Ottmann OG, Goh YT, et al. Dasatinib mg QD compared to 70 mg BID in advanced-phase CML or Ph)+) ALL resistant or intolerant to imatinib: One year results of CA 180-035. Journal of Clinical Oncology 2007;25:abstract 7025.

⁹ Atallah EL, Kantarjian H, O’Brien S, et al. Use of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML). Journal of Clinical Oncology 2007;25:abstract 7005.

¹⁰ Cortes J, O’Brien S, Jones D, et al. Dasatinib (Sprycel) in patients (Pts) with previously untreated chronic myelogenous leukemia (CML) in chronic phase (CML-CP). Blood 2006;108:613a, abstract 2161.

¹¹ Jabbour E, Le Coutre M, Baccarani M, et al. Nilotinib is associated with minimal cross intolerance to imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP). Journal of Clinical Oncology 2007;25:abstract 7039

¹² Rosti G, Le Coutre P, Bhalla K, et al. A phase II study of nilotinib administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Journal of Clinical Oncology 2007;25:abstract 7007.

¹³ Le Coutre P, Gatterman N, Hochhaus A, et al. A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Journal of Clinical Oncology 2007;25:abstract 7006.

¹⁴ Larson R, Ottman O, Kantarjian H, et al. A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory PH+ acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology 2007;25:abstract 7040

¹⁵ Mueller MC, Branford S, Radich J, et al. Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure. Journal of Clinical Oncology 2007;25:abstract 7024. . Journal of Clinical Oncology 2007;25:abstract 7024.

¹⁶ Giles FJ, Le Coutre P, Bhalla K, et al. A phase II study of nilotinib administered to patients with imatinib resistance or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who also failed dasatinib.Journal of Clinical Oncology 2007;25:abstract 7038

¹⁷ Gambacorti-Passerini C, Blummedorf T, Kantarjian H, et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or AML who failed imatinib. Journal of Clinical Oncology 2007;25:abstract 7006.

¹⁸ Craig AR, Kantarjian HM, Cortes JE, et al. A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (PH+) chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) relapsed, refractory, or intolerant of imatinib. Journal of Clinical Oncology 2007;25:abstract 7046.

¹⁹ Kuroda J, Kimura S, Strasser A, et al. Apoptosis-based dual molecular targeting by INNO-406, a second generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007 May 18; [Epub ahead of print]