Allogeneic stem cell transplantation (allo-SCT) has been for many years the treatment of choice of Philadelphia positive chronic myeloid leukemia (CML), with a long-term overall survival ranging between 10 and 80% depending on the risk.1 Although allo-SCT is curative, relapse is still a significant cause of failure. Once relapse occurs, several therapeutic procedures are available, including Interferon alpha (IFNα), which is now rarely used, and a second allo-SCT, which is burdened by a high morbidity and mortality. In 1990, donor lymphocyte infusions (DLI) were introduced in the attempt to explore the immunological reaction of the original donor lymphocytes against leukemia.2 At present, DLI is the standard front-line approach for CML recurrence after allografting, since it has proved to restore full donor chimerism and to produce long-term molecular remissions.3, 4 However, it requires the availability of the donor and may be associated with the development of severe graft-versus-host-disease (GvHD) and/or marrow aplasia. Moreover, DLI may be unsafe when severe GvHD is present. More recently, imatinib (IM) has been successfully used in the treatment of CML relapse after allo-SCT.5, 6, 7 We reviewed the cases of all the patients who relapsed after allo-SCT between July 2001 and June 2004. Six of these patients were treated only with DLI and/or IFNα. Sixteen patients received IM as first- or second-line therapy.
These patients were submitted to allo-SCT in chronic phase in four different centers between March 1988 and January 2003. Median age at transplant was 38 years (range 27–57 years). Stem cell donors were HLA-identical siblings in 11 cases and HLA matched unrelated donors in five cases. The standard conditioning regimen was total body irradiation-cyclophosphamide based in eight patients and busulphan-cyclophosphamide in eight. No T-cell depletion was performed. Median interval from allo-SCT to relapse was 34 months (range 7–162). The data are reported in Table 1.
Relapse was hematologic in five cases, cytogenetic in nine cases and molecular in two cases. IM was administered as first line treatment of relapse in 12 cases (patients no. 1–12). Patients 13–16 received IM as the second- or third-line of therapy, after DLI and/or IFNα failed to reinduce a complete cytogenetic response (CCgR) or molecular negativity. Interval from first relapse to start of IM therapy was 27, 13, 60 and 24 months, respectively.
IM was administered at the dose of 400 mg daily in 12 cases and 600 mg in five cases. All patients were in CCgR after 3–12 months (median: 3 months). All patients but one (case no. 4) achieved a molecular negativity after 3–27 months (median: 9 months) and all patients but four are reverse transcription-polymerase chain reaction (RT-PCR) negative after 12–45 months (median: 30 months). Molecular response was measured and expressed as described elsewhere as reduction of the BCR-ABL transcript to β2 microglobulin ratio by quantitative RT-PCR8 or negativity of qualitative nested PCR in bone marrow samples.9 A BCR-ABL/β2 microglobulin ratio below the sensitivity of the reaction (i.e. below 0.00001) was defined as RT-PCR negativity. Molecular response was evaluated in bone marrow and/or peripheral blood samples every 3 months after allo-SCT, at start of IM therapy and every 3 months during treatment.
All patients are still on treatment with IM except for patient no. 12, who discontinued the therapy 8 months ago and remains RT-PCR negative. Apart from IM, no other treatment was administered, with the exception of patients no. 1 and no. 12, whose molecular response to IM was reinforced with DLI, performed seven and three times, respectively. Interval from last DLI to IM therapy was 6 and 5 months, respectively. In the other patients, DLI has not been performed either upon decision of the treating physicians or because they were not available.
Chimerism analysis has been performed by variable number tandem repeats (VNTR) analysis in five cases and by FISH in three sex mismatched cases. Before IM therapy, full-donor chimerism was lost in seven cases and was fully recovered in all seven patients after the achievement of RT-PCR negativity.
Neutropenia grade III was observed in four patients and thrombocytopenia grade III was noted in one patient with previously normal granulocyte and platelet counts. Two patients experienced muscoloskeletal pain and periorbital edema grade II. These effects were resolved with dose adjustments and/or temporary drug discontinuations.
At the start of IM therapy, two patients had limited chronic skin GvHD, which did not worsen during treatment. No GvHD reaction was seen after IM therapy.
In these patients, the response rate to IM is as expected from treatment with DLI alone. All patients but one achieved cytogenetic and molecular responses, which were associated with reconstitution of full-donor chimerism without increasing GvHD, and all patients but four are currently RT-PCR negative.
Even patients treated with IM while in hematologic relapse obtained durable molecular responses (specifically, the patients achieved RT-PCR negativity after 3, 3, 6 and 18 months of IM therapy). It is also noteworthy that the patient who relapsed in blast crisis received a combined therapy with IM and DLI and is in ongoing RT-PCR negativity after a follow-up of 45 months, possibly thanks to residual graft-versus-leukemia effect.
In conclusion, we showed that IM is effective and feasible, with a high overall response and a manageable side-effects profile. Therefore, IM should be considered the best first-line therapy if DLI is not available or if it carries contraindications. Achieving molecular negativity is relatively rare in patients who are treated with IM.10 When IM is given for relapse after allo-SCT, RT-PCR negativity is achieved more frequently, but the acquisition of molecular negativity is not necessarily a proof of cure. We think that IM may not provide a cure even in this setting and that association with DLI may be required.7 Prospective studies will explore the efficacy of IM and lower doses of DLI, in order to reduce the risk of GvHD induction and to maintain the control of the disease after IM withdrawal.
Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998; 352: 1087–1092.
Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.
Dazzi F, Szydlo RM, Cross NC, Craddock C, Kaeda J, Kanfer E et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716.
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Olavarria E, Ottmann OG, Deininger M, Clark RE, Bandini G, Byrne J, et al., Chronic Leukaemia Working Party of the European Group of Bone and Marrow Transplantation (EBMT). Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 2003; 17: 1707–1712.
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