Dasatinib Highly Effective for Imatinib Intolerant/Resistant CML

Abstract & Commentary

By Andrew S. Artz, MD, MS, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: The prognosis for CML blast crises remains poor even with imatinib therapy. Dasatinib is an oral multi-targeted tyrosine kinase inhibitor of BCR/ABL and Src with clinical activity against imatinib-resistant CML. Cortes and colleagues report preliminary phase II data pooled from two studies of dasatinib for imatinib resistant or intolerant CML in either myeloid blast crises (MBC) or lymphoid blast crises (LBC). Among the 116 patients, 64% had MBC and 36% had LBC. Dasatinib induced major hematologic responses in 34% and 31% of MBC and LBC, respectively. Major cytogenetic responses were achieved by 31% and 50% of MBC and LBC, respectively. At 8 months of follow-up, 88% of MBC and 46% of LBC maintained their responses. Cytopenias and GI toxicities were common. Six percent had serious pleural effusion. Dasatinib is active for imatinib resistant or intolerant blast crises CML. Longer term follow-up data is needed to determine the response duration.

Source: Jorge Cortes, et al. Blood. 2007; 109:3207-3213.

Chronic myeloid leukemia (CML) has become the prototypical disease for targeted therapy. The BCR/ABL fusion protein derived from a translocation between chromosomes 9 and 22 has been successfully targeted using Imatinib (Gleevec™).1 The large randomized IRIS study, confirmed significantly enhanced activity and reduced toxicity compared to interferon,2 moving imatinib to front-line therapy for CML.

Nevertheless, imatinib resistance can emerge, often due to point mutations in the BCR/ABL3 and less often through the Src kinase pathway. Resistance is particularly problematic in advanced stages of CML and the prognosis remains dismal. Although Imatinib achieves hematologic responses in over 50% of imatinib naïve CML blast crises patients, cytogenetic responses are uncommon and relapse is the rule.1

New more potent inhibitors of BCR/ABL hold promise to be effective against BCR/ABL mutations conferring imatinib resistance. The two drugs most advanced in clinical development are dasatinib (Sprycel, formerly BMS-354825) and nilotinib.4,5 Point mutations at T315I remain resistant.

Cortes and colleagues report the preliminary results of dasatinib for imatinib intolerant or resistant blast phase CML. These data were pooled from two phase II open label international trials of dasatinib for myeloid blast crises (MBC) and lymphoid blast crises (LBC).

Imatinib resistance required progression to blast crises from chronic phase on at least 400 mg daily or from accelerated phase on at least 600 mg daily. Alternatively, patients may have been intolerant to these doses.

Standard response definitions were employed. Specifically, cytogenetic responses were defined by the percent of Philadelphia positive metaphases from the bone marrow. Cytogenetic responses were evaluated by once-monthly bone marrow aspirates/biopsies for the first 3 months and every 3 months thereafter. Complete cytogenetic response (CyR) mandated 0% Philadelphia Chromosomes, whereas 1-35% defined partial CyR. Major CyR encompassed those having a complete CyR or partial CyR.

The initial Dasatinib dose of 70 mg orally twice daily could be escalated to 100 mg twice daily for poor response or could be reduced for toxicity. Treatment continued until disease progression or toxicity. No other disease treatment was permitted except for supportive care which included anagrelide or temporary hydroxyurea.

Among the 116 patients, 74 had MBC and 42 LBC. Data were presented for 6 month and 8 month follow-up. Most were enrolled for resistance (91%), rather than intolerance. The median age was 47 years and 33% had a prior stem cell transplant.

In the MBC cohort, major hematologic responses at 8 months occurred in 34%. Major CyR were induced in 31%, with the majority being complete CyR (27% of all MBC patients). Among the LBC patients, 31% achieved a major hematologic response. Dasatinib induced a major CyR in 20/42 (50%) of LBC patients, most of which were complete CyR (18/42, 43% of total LBC cohort).

Mutation analysis found imatinib point mutations in 30/70 evaluable MBC patients and 24/40 evaluable LBC patients. Combing both MBC and LBC groups, no responses occurred in the six patients harboring E255K mutations or the eight found to have T315I mutations.

At the 8-month follow-up, 11% of MBC-CML patients discontinued therapy related to toxicity although dose interruptions occurred in 64%. Among LBC-CML patients, one patient discontinued therapy because of toxicity and dose interruptions occurred in 33%. Gastrointestinal disorders (including diarrhea, nausea, vomiting) were the most frequent events in both cohorts. Pleural effusions occurred in 31/116 (27%) of which 6% were at least grade 3. Cytopenias were common but drug related attribution was difficult as many patients had baseline cytopenias.

Commentary

Even in the era of imatinib, blast crises developing on imatinib or de novo has a dismal prognosis. Allogeneic transplant and/or chemotherapy also lead to disappointing results. Imatinib resistance is the major cause of failure often mediated through BCR/ABL point mutations. Thus, more potent inhibitors of BCR/ABL hold promise for imatinib resistant (and intolerant) CML.

In this preliminary report of 116 patients having either myeloid (MBC) or lymphoid blast crises (LBC) CML, dasatinib induced hematologic remissions in approximately 1/3rd of patients with complete cytogenetic remissions in over 1/4th. Remissions occurred within 1-2 months of treatment and many were maintained (especially in MBC) at 8 months follow-up. These patients were heavily pre-treated, including a considerable number of prior stem cell transplants.

The results of BCR/ABL mutation analysis were informative. Activity occurred despite BCR/ABL point mutations. Mutations at T315I and E255K, however, were exceptions where no responses occurred. Nevertheless, in a considerable fraction, BCR/ABL mutations were not detected. This may relate to resistance mediated by another kinase pathway, such as Srk, which dasatinib also inhibits.

Dasatinib was generally well-tolerated. Serious toxicity leading to drug discontinuation only occurred in 1 patient. Toxicity did not appear greater in the imatinib intolerant cohort, suggesting these agents may have non-overlapping toxicity. Importantly, pleural effusions were relatively frequent and 6% were considered at least grade 3. The toxicity profile including pleural effusions was similar to prior reports.5

This study presents a compelling rationale for dasatinib in imatinib intolerance or resistant blast crises CML. A major limitation is the short study duration which precludes data on long-term response durability. Thus, it remains prudent to consider an allogeneic transplant in appropriate candidates if one can achieve a hematologic if not cytogenetic response. However, most patients will not be candidates for transplant or lack donors. The best strategy for imatinib naïve blast crises CML also remains unclear. While the standard approach has been imatinib at 600 mg daily, the lack of durable responses employing imatinib raises the question whether dasatinib might be better initial therapy. An important unanswered question is how dasatinib compares to nilotinib, another highly potent oral BCR/ABL inhibitor in late clinical development. Cytopenias are common with both drugs but otherwise the toxicities profiles differ. Unfortunately, neither agent shows activity against the T315I. Nilotinib may lead to elevated bilirubin and rashes.4

The activity of dasatinib also raises interest in up-front treatment for chronic or accelerated phase CML. Both nilotinib and dasatinib are being actively investigated for earlier stage CML as initial therapy and/or imatinib resistant/intolerant disease. Dasatinib may have serious toxicities, including pleural effusions, and we lack long-term follow-up data. In the IRIS study of chronic phase CML, most patients randomized to imatinib remained on imatinib at 5 years. Further, many cases of imatinib resistance can be salvaged with Dasatinib. Therefore, imatinib remains the initial therapy for most CML patients, especially those with chronic phase. The rapid emergence of cytogenetic and molecular monitoring of imatinib as well as progress in understanding the molecular pathogenesis of drug resistance should enable earlier transition to active agents rather than waiting for morphologic disease progression.

In summary, dasatinib is effective and well-tolerated for imatinib resistant/intolerance blast crises CML but long-term responses remain unknown.

References

1. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037.

2. O'Brien SG, et al. N Engl J Med. 2003;348:994-1004.

3. Lahaye T, et al. Cancer. 2005;103:1659-1669.

4. Kantarjian H, et al: N Engl J Med. 2006;354:2542-2551.

5. Talpaz M, et al. N Engl J Med. 2006;354:2531-2541.