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The disease burden in chronic myeloid leukemia (CML) is linked to the activity of its chimeric oncoprotein, the BCR-ABL1 tyrosine kinase. A recent analysis of the IRIS study showed that imatinib, the first tyrosine kinase inhibitors (TKI), resulted in impressive survival and freedom from disease progression in chronic phase patients. However, 20–30% of these patients eventually develop resistance; due largely to mutations at the ABL1 kinase domain.

We investigated whether low-level Bcr–Abl kinase domain mutations can be detected in patients who have stable responses to first-line nilotinib–like it is known to happen in patients receiving imatinib. We screened for mutations twelve such patients by cloning and sequencing. Only one case was found to harbor mutations at low levels (including a T315I). However, major molecular response (MMR) was maintained and it even improved to complete molecular response. Our results suggest that a) Bcr–Abl mutations, even at low level, seem to be very rare in patients in MMR on first-line nilotinib; b) low-level mutations do not always predict for subsequent relapse.

1Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy 2Department of Internal Medicine, Unit of Clinica Medica 1, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy 3Gastroenterology 3 Unit, IRCCS Ca Granda Ospedale Maggiore Policlinico Foundation, Milano, Italy 4Section of Hematology, Department of Critical Care, University of Florence and Istituto Toscano Tumori, Florence, Italy

Clonal cytogenetic abnormalities (CAs) in Philadelphia negative (Ph−) metaphases have been widely observed during imatinib treatment in patients with chronic myeloid leukemia (CML) [1,2]. Recently, the appearance of such abnormalities in some CML patients, treated with dasatinib after imatinib failure, has been described [3,4]. To the best of our knowledge, only one patient has been reported to develop a cytogenetic abnormality in Ph− clone during nilotinib treatment, following imatinib [5]. The incidence and consequences of CAs in Ph− cells during treatment with second generation tyrosine kinase inhibitors (TKIs) should be extensively investigated; this issue, deserves a particular attention, since these new drugs put a far higher pressure on the leukemic and the residual normal hematopoiesis than imatinib.

Philadelphia-positive chronic myeloid leukemia (Ph+ CML) patients who are resistant to imatinib are commonly treated with second-generation tyrosine kinase inhibitors (TKIs). Limited data exist on the possible effects of these drugs on subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT).The outcome of 12 imatinib-resistant CML patients treated with dasatinib or nilotinib or both before allo-HSCT, was retrospectively analyzed. Patients were treated with second-generation TKIs for 1-17 months (median, 8). At the time of transplant, 3 patients were in complete cytogenetic response (CCgR), 3 patients in partial cytogenetic response (PCgR) and 6 patients were in less than PCgR. Donors were HLA-matched related in 4 cases and unrelated in 8 cases. Stem cell source was peripheral blood, bone marrow or cord blood in 6, 5 and 1 cases, respectively. All patients engrafted successfully and all but one achieved a full donor chimerism. Three patients experienced acute and chronic graft-versus-host disease. No cases of transplant-related mortality were recorded. Best response to allo-HSCT was complete molecular response (CMR) in 9 patients, major molecular response (MMR) in 1 patient and CCgR in 2 patients. Median follow-up was 16.5 months. At the last evaluation, 9 patients were in continuous CMR and 1 patient was in MMR; 2 patients had died of disease progression. Second-generation TKIs given before allo-HSCT do not negatively affect transplant engraftment and response rate, nor increases transplant-related toxicity.

Allogeneic bone marrow transplantation is the only way to cure patients with Ph1+ chronic myeloid leukemia. It is commonly assumed that, in order to obtain a cure for the patients, the leukemic clone must be completely destroyed by the conditioning treatment and the donor's bone marrow must repopulate the hemopoietic niches leading to a “complete chimera”. However, cytogenetic analyses, supported by molecular ones, indicate that Ph1+ cells, far from being completely destroyed by chemo-radiotherapy may persist for a long time, probably in the majority of the patients. As demonstrated by the outcome of patients receiving T-cell depleted marrow, immune mechanisms must be involved in controlling and progressively reducing the size of the residual leukemic clone. Furthermore, immunomodulating therapeutic strategies, represented by cyclosporin-A discontinuation or alpha interferon treatment, may successfully reduce the Ph1+ cell population even after a full relapse.