The graft-versus-leukemia effect of nonmyeloablative stem cell allografts may not be sufficient to cure chronic myelogenous leukemia

A total of 50 consecutive patients (median age, 57.5 years) with AML (n ¼ 30) or myelodysplasia (MDS, n ¼ 20) underwent HLA matched related donor (MRD, n ¼ 27) or unrelated donor (MUD, n ¼ 23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n ¼ 19) ± mycophenolate mofetil (n ¼ 31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P ¼ 0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Section: Discussionmentioning

confidence: 84%

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia

Nelson

Schwartz

et al. 2010

“…15,16 Nonmyeloablative regimens are now widely used in allogeneic HSCT with a significantly lower risk of acute organ toxicity, but some patients still develop complications, and myeloablative conditioning may be preferable in certain hematological malignancies. [17][18][19] Genetic polymorphisms in enzyme systems that normally constrain oxidant damage may partly explain the variation in the incidence and/or outcome of regimen-related complications. …”

mentioning

confidence: 99%

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Kallianpur

2004

Summary:The occurrence of toxic complications following hematopoietic stem cell transplantation (HSCT) is highly variable and dependent on a multitude of host, donor, and treatment factors. The increasingly broad indications for HSCT and the need to provide this treatment option to older and/or more debilitated patients emphasizes the importance of refining our methods of predicting and ameliorating these toxicities. Late complications (occurring after day 100) also pose a threat to quality of life after HSCT. Genetic polymorphisms in key molecular pathways in the host are likely to contribute significantly to the observed variability in the development HSCT-associated complications. Hepatic veno-occlusive disease and acute lung injury, two of the most serious organ toxicities that occur, represent useful paradigms for the identification of genetic polymorphisms in enzyme systems that modulate local and systemic responses to oxidant stress during transplant conditioning therapy. Ongoing studies in this area are providing clues to the prevention of adverse clinical outcomes based on the genetic milieu. This review of studies in HSCT that explore genetic risk factors for transplant complications indicates that significant progress is being made in this rapidly evolving area. However, further large-scale clinical and translational studies are needed before genomic screening can be widely used to individualize treatment. Bone Marrow Transplantation (2005) Clinicians are continually challenged by the need to predict the responses of individual patients to potentially toxic treatments. The increasing promise of cure for patients who undergo hematopoietic stem cell transplantation (HSCT) for life-threatening disorders is overshadowed by the very real threat of short-term, often fatal, complications resulting from the transplant regimen and graft-versushost disease (GVHD). However, significant variation is observed between similarly treated individuals in the development of complications. It is an appealing concept, therefore, and one to which many clinicians now subscribe, that a significant portion of this variability has a genetic basis. Identifying important genetic variables will allow for better prediction of HSCT-related outcomes, and in the process of identifying these susceptibilities, it may also be possible to gain sufficient knowledge of the underlying pathophysiology of these toxicities to develop targeted interventions.This review will focus on genomic screening of the host for the prediction of specific complications, touching briefly on selected donor factors. Other rapidly evolving areas that are not covered include molecular genetic testing to predict graft failure and disease relapse after HSCT. The role of clinical and biochemical risk factors in the pre-transplant evaluation of HSCT candidates has also been reviewed recently in this journal. 1 Importance of context-dependent genetic effectsThe study of uncommon disease-associated mutations has been invaluable to our understanding of basic pathophy...

“…Barrett and co-workers stated that NST may not be able to control CML sufficiently. 18 In the presented analysis, the conditioning intensity was reduced stepwise. The dose of TBI was reduced to 8 Gy and fludarabine was incorporated.…”

Section: Discussionmentioning

confidence: 99%

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

Weisser¹,

Schleuning

Ledderose³

et al. 2004

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...