Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease

Abstract

Summary:Allogeneic bone marrow or stem cell transplantation is a curative therapeutic option for chronic myelogenous leukemia. In order to decrease the toxicity of the procedure, the dosage of total body irradiation was reduced from 12 to 8 Gy and subsequently the dose of cyclophosphamide from 120 to 80 mg/kg. The purine analogue fludarabine, ATG, cyclosporine A and a short course of methotrexate were given for immune suppression. So far, 35 elderly CML patients with sibling and unrelated donors have been transplanted. Transplantrelated mortality at day þ 100 was 11%. After engraftment, all patients achieved a complete cytogenetic remission. Relapse occurred in 14% of the patients. The risk of relapse was significantly higher in those patients transplanted in second chronic or accelerated phase (P ¼ 0.048). After a median follow-up of 30 months (range 12-62), 63% of the patients are alive. Those patients transplanted within the first year from diagnosis had an overall survival of 79% (P ¼ 0.049), emphasizing the benefit of early transplantation. Stepwise reduction of conditioning intensity resulted in stable engraftment, low relapse rates and encouraging overall survival in this highrisk patient group. Allogeneic bone marrow transplantation (BMT) has been used successfully for the treatment of chronic myelogenous leukemia (CML). The classical conditioning regimen has been 12 Gy total body irradiation (TBI) or high-dose busulfan plus cyclophosphamide (CY) and optionally ATG. 1,2 Long-term remissions can be achieved in 75-80% of the patients depending on their individual pretransplant risk score. 3,4 Due to a considerable rate of transplant-related mortality (TRM), the procedure has been limited to young patients in good medical condition. The main reasons for this high TRM are therapy related toxicity and graft-versus-host disease (GvHD), occurring more frequently with increasing age and poor medical status. 5 As the median age of the CML patients is beyond the fifth decade, 6 only a minority of the patients were able to benefit from this curative therapy option. In order to decrease toxicity, reducedintensity conditioning (RIC) was introduced. This idea was driven by the finding that the curative potential of allogeneic BMT is not solely based on the intensity of conditioning but also on the immunologic graft-versusleukemia (GvL) effect. The existence of the GvL effect first became evident as CML patients who had suffered a relapse after allogeneic BMT could be successfully transferred into molecular remission via donor lymphocyte infusion (DLI). 7,8 In addition, RIC seems to be associated with less severe GvHD. 9,10 Recently, a variety of RIC protocols have been published. The regimens and substances applied are often as heterogeneous as the underlying hematological malignancies. So far, there are limited data on patients in the early-stage CML transplanted with RIC. Initial studies reported a considerable amount of graft rejection and relapse. 9,[11][12][13][14][15] In order to decrease toxicity without compro...

How I treat chronic myeloid leukemia in the imatinib era

“…Such "nonmyeloablative" or "reduced intensity conditioning" transplantations should be particularly valuable for patients older than 50 years or younger patients with comorbid conditions. Although a number of small singlecenter series and an analysis of outcome for 186 patients treated in 38 centers reporting to the EBMT have been published, [18][19][20][21][22] it is not yet possible to conclude that a reduced intensity conditioning allo-SCT offers a major advantage for the younger patient who would otherwise be a candidate for an allograft with conventional conditioning. It is undoubtedly an option for the older patient who could not normally be considered for a transplantation with myeloablative conditioning.…”

Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet

“…44 Reduced intensity conditioning (RIC) is currently being evaluated for CML. [45][46][47][48] The EBMT has reported on registry data of 187 patients (median age, 50 years) who were submitted to RICalloHSCT between 1994 and 2002, mainly from matched-related donors. 49 Three-year OS was 70% for the patients with an EBMT score of 0 to 2, 50% for the patients with a score of 3 to 4, and about 30% for those with a score of 5 or higher.…”

The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: results of the Latin American Cooperative Oncohematology Group (LACOHG) prospective, multicenter study

“…Our data and that from others indicate that RIST is effective for allografting individuals with CML; [6][7][20][21][22][23][24][25] despite the fact that most studies with reduced-intensity conditioning have a relatively short follow-up, there is information indicating that the procedure has a lower prevalence and severity of GVHD, 26 and similar efficacy to conventional allografting; the low prevalence of chronic GVHD in this study supports this observation, which may be related to the diminished organ damage induced by the conditioning schedule. Since this method is more feasible and affordable for patients and physicians in developing countries, the number of allografts in these places has increased substantially, as well as the publications related to bone marrow transplantation stemming from places where this therapeutic maneuver was considered as unaffordable previous to the development of this technology.…”

“…6 Later, Or et al, 7 they found a 5-year overall survival (OS) of 85%. 7 More recently, Weisser et al, 20 in Germany reported their experience in 35 elderly CML given RIST in different phases of the disease, emphasizing the benefit of early transplantation, within the first year of diagnosis. Other authors have included CML patients in their reports of RIST.…”

“…Allogeneic RIST has been shown to be useful in individuals with CML. 6,7,[20][21][22] We published in 2002 the first series of patients in Me´xico with CML given an RIST; in that group, we included individuals with CP, accelerated and blastic phases. 6 Later, Or et al, 7 they found a 5-year overall survival (OS) of 85%.…”