PHILADELPHIA-Updated data from the largest randomized, controlled (and only phase III) trial of imatinib mesylate (Gleevec) confirm the drug’s superiority to interferon-alfa and cytara-bine as first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML) but raise interesting questions about what happens within the marrow after CML-causing Philadelphia-chromosome-positive (Ph+) cells are beaten down to undetectable levels.
PHILADELPHIAUpdated data from the largest randomized, controlled (and only phase III) trial of imatinib mesylate (Gleevec) confirm the drug’s superiority to interferon-alfa and cytara-bine as first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML) but raise interesting questions about what happens within the marrow after CML-causing Philadelphia-chromosome-positive (Ph+) cells are beaten down to undetectable levels.
Richard Larson, MD, reported 18-month follow-up data on behalf of the IRIS (International Randomized IFN vs STI571) Study Group in a plenary presentation at the 44th Annual Meeting of the American Society of Hematology (ASH abstract 2).
Dr. Larson said that imatinib (which has the additional appeal of being an oral drug) improved complete cytogenetic responses to 76% vs 14% with interferon-alfa plus cytarabine (IFN + Ara-C) and increased 18-month progression-free survival to 92% vs 73% with IFN + Ara-C (see Table ).
Stephen Mackinnon, MD, head of the bone marrow transplant program, University College, London, UK, in his introduction to the presentation, said, "Imatinib [also known as STI571] is clearly the drug of choice for newly diagnosed CML, and a lot of hematologists think STI means ‘stop transplant immediately’."
Dr. Mackinnon pointed out that although the only cure for CML is allogeneic bone marrow transplantation, most patients with CML are unlikely to have allogeneic transplantation either because they are too old or because they lack compatible marrow donors. "Imatinib is probably not a cure, since most patients in cytogenetic complete remission remain PCR [polymerase chain reaction]-positive, but it might be possible to produce a ‘functional cure’ if these remissions have sufficient durability. The durability is yet unknown," he said.
The IRIS study included 1,106 newly diagnosed CML patients randomized either to imatinib 400 mg/d orally or IFN (target dose 5 MU/m2/d subcutaneously) plus Ara-C (20 mg/m2/d subcutaneously) for 10 days every month.
Patients were allowed to cross over to the alternate arm if stringent criteria for treatment failure or intolerance were met, a feature that greatly complicated interpretation of the data on progression-free and overall survival. By the time of this analysis, 86% of patients randomized to imatinib remained on that treatment, but only 11% of those randomized to IFN + Ara-C were still taking that combination, while 58% had crossed over to imatinib.
Data were analyzed on an intention-to-treat basis, and Dr. Larson commented that the crossover effect probably inflated survival results in patients initially randomized to IFN + AraC and might be why there was no significant difference in overall survival (97% vs 95%).
Furthermore, 32% of patients randomized to IFN + AraC withdrew consent and discontinued their first-line therapy "with a notable increase at the time of the Food and Drug Administration’s approval of imatinib," Dr. Larson said. The crossover problem is one reason many European clinical trials use time-to-progression rather than overall survival as a primary endpoint.
The question of what happens after imatinib produces a complete cytogenetic response (CCR), meaning no detectable Ph+ cells, was raised in a second report (abstract 613). The hope has been that CCR would permit re-establishment of normal polyclonal hematopoiesis. Michael Deininger, MD, said that in-depth analysis of a subgroup of patients in CCR suggests that although normal hematopoiesis is restored in most patients with CCR, clonal cytogenetic abnormalities develop in a significant proportion of patients, particularly (but not exclusively) after prior exposure to cytotoxic agents such as cytarabine or idarubicin.
Dr. Deininger re-evaluated cytogenetics in all female patients in cytogenetic remission as well as in 20 male patients with a major cytogenetic response (MCR) or CCR (total = 48). HUMARA (human androgen receptor gene)-PCR of flow-sorted myeloid cells and T cells was informative in 14 patients in CCR, 7 with MCR, 6 who did not have cytogenetic remission, and 10 normal controls.
"It falls to me to break some of the more sobering news regarding patients on imatinib. We found clonal chromosomal abnormalities in Ph-negative cells in 8 (17%) of the 48 patients we studied, and over time there was an increase in abnormal cells, indicating that they are at a proliferative advantage, compared to cells without abnormalities," Dr. Deininger said. Two of these 8 patients progressed to myelodysplastic syndromes and required bone marrow transplantation. "Abnormalities were not found in newly diagnosed patients on imatinib, but this was not statistically significant, and more follow-up is required," he said.
The clinical take-home message, he said, is that meticulous cytogenetic monitoring should be continued every 6 months for patients in CCR with imatinib and should be done more frequently for patients with any evidence of hematologic abnormality such as a decrease in platelets, hemoglobin, or white cells.