Frontline Combination Therapy Suggested for Chronic Myelogenous Leukemia

NEW YORK, Aug. 17 -- A double-barreled initial approach to chronic myelogenous leukemia with both imatinib (Gleevec) and dasatinib (SPRYCEL) may prevent treatment-resistant genetic mutations.

Conventional use of dasatinib only after imatinib fails allows for compound drug-resistant mutations that synergistically increase tumor growth, found Charles L. Sawyers, M.D., of Memorial Sloan-Kettering Cancer Center here, and colleagues.

Frontline kinase inhibitor combination therapy could "substantially improve both the depth and durability of clinical responses," particularly in advanced phases of disease, they wrote online in the Journal of Clinical Investigation.

Furthermore, "it is likely that other cancers being treated with kinase inhibitor therapy will benefit from a similar treatment strategy," they added.

Mutations conferring kinase inhibitor resistance have become increasingly common not just in chronic myelogenous leukemia but also in gastrointestinal stromal tumor and lung cancer. As clinical experience with dasatinib grows, some patients have begun to experience relapse on second-line dasatinib, the researchers said.

One mechanism anticipated for prior studies is selection for the T315I mutation, a "gatekeeper" mutation that confers resistance to imatinib, dasatinib, and the related investigational compound nilotinib.

So, the researchers assessed it and other mutations in dasatinib failure. They studied 17 consecutive patients treated at a single center who developed dasatinib resistance after imatinib treatment.

Analysis of their blood samples at relapse showed that all patients had new mutations in the BCR-ABL protein. Twelve had the T315I mutation and one had the relatively resistant F317L mutation.

Six patients had the imatinib-sensitive, dasatinib-resistant mutations V299L, T315A, or F317I.

Two had only the V299L mutation and responded to retreatment with imatinib or nilotinib.

One of these patients responded only briefly to an escalated dose of dasatinib and then returned to imatinib, which effectively reduced myeloblasts from 52% to 12% until starting chemotherapy for a planned allogeneic marrow transplant. The other patient temporarily responded to high-dose imatinib but had a sustained complete hematologic response on investigational nilotinib.

"However, this strategy of cycling between kinase inhibitors is potentially limited by the emergence of compound mutations that, when paired in the same molecule, confer resistance to both drugs," the researchers said.

"Compound mutants not only diminish the chance of retaining sensitivity to a hypothetical 'third-generation' inhibitor due to their potential complexity but also carry the risk of creating [new mutations] with enhanced oncogenic potency," they added.

And, that's what they found.

Of the 17 patients, five developed compound mutations -- two or more changes in the same mRNA -- with a new dasatinib-resistant mutation occurring on the background of their original imatinib-resistant substitution.

Two patients had more than one mutation develop during dasatinib treatment, but separately rather than as a compound mutation.

The compound mutations were likely caused by selective pressure from sequential therapy, Dr. Sawyers and colleagues said.

One patient had a triple compound mutation conferring resistance to both compounds. And, the triple mutation from sequential therapy synergistically made tumor cells grow faster in vitro than expected.

This patient, left without other treatment options, turned to combined imatinib and dasatinib therapy and had a hematologic response sustained for at least two months.

"These findings make a case for upfront therapy with a cocktail of kinase inhibitors that collectively cover a broad range of mutations and prevent the emergence of resistance," the researchers wrote.

However, studies would need to address tolerability and "whether the potential benefit of preventing resistance is outweighed by additional toxicities," they added. Larger, longer studies also need to determine whether sequential therapy has the same effect in early-stage CML.

"Targeted therapy of human malignancies is still in its infancy," the researchers concluded. "Optimal patient management in the future will likely require periodic genotyping to determine the likelihood of response to a particular kinase inhibitor."