Blood Journal: BMT Review 2011

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Offline Andy Battaglia

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Blood Journal: BMT Review 2011
« on: March 05, 2011, 01:06:06 AM »
This is the latest review of the current state of bone marrow transplants. The entire report is attached as a pdf file. The discussion is reprinted below.


In this report, we have attempted to capture most of the most recent transplantation experience outside Italy that included children with  -thalassemia major who were treated with HLA-matched sibling BMT. Thus, this represents the largest contemporary series yet reported and generates new information about assigning transplantation risk, which should assist in optimizing outcomes and selecting suitable candidates for transplantation. These results must be interpreted while also considering recent advances in supportive therapy, particularly in iron chelation therapy, which have reduced the risks of morbidity and mortality in those who do not proceed to transplantation.2,16,19-21 Our results confirm that HLA-matched sibling BMT for  -thalassemia major is a suitable therapeutic option to consider, as we also observed DFS rates that exceeded 90% in children with good-risk features (Figure 1).4,9 However, as noted in the initial Pesaro experience, children with high-risk features fared much worse, with an event-free survival rate that approached 50%.4,22,23 These observations underscore the importance of carefully selecting good-risk patients for transplantation, but also if treating high-risk patients, the importance of using modifications to the transplantation regimen that might improve the safety of the procedure.6,7,11,24 We were able to identify 2 readily accessible prognostic indicators in a cohort of high-risk thalassemia recipients, namely, liver size and patient age, which other groups also have identified.  19,20 The observed effects of age and liver size were independent of each other, although liver size is highly correlated with Pesaro risk group. By classifying this high-risk cohort by these criteria (ie, age and liver size), it was possible to refine and broaden the class II and III Pesaro risk groupings into distinct patterns of survival and event-free survival, which are represented in Figures 1 and 2. The 5-year survival probabilities, which ranged from 53% to 96%, are broader than the initial Pesaro experience.4,9,20 Although these criteria do not supplant the utility of a liver biopsy, which provides important information about liver histology and can also direct post-transplantation interventions to reduce iron overload, there may be situations where a liver biopsy and the ability to assess liver histology and iron concentration are not readily available. Using the risk features identified in the current analysis, it may be possible to assign a conditioning therapy that is better suited to those who are most in need of such modifications and in clinical settings where assigning a Pesaro risk classification is not possible.7,12,22 We speculate that, for the diverse cohort in the current analysis, it may be appropriate to dispense with the Pesaro classification in high-risk patients and rely on this facile and novel risk assignment.
It appears that much of the toxicity of transplantation observed in this series might have been related to impaired hepatic function and a propensity for developing interstitial pneumonitis and VOD, particularly in the older, high-risk patients. Previously, a high rate of regimen-related toxicity and graft rejection was noted in class II and III patients after standard busulfan and cyclophosphamide preparation, particularly in young adult patients with thalassemia, for whom the transplantation-related mortality was 35%.25An early study of busulfan pharmacokinetics as a predictor of clinical outcome in thalassemia major failed to identify a relationship between the busulfan level and toxicity, although this analysis included transplantation regimens that differed in their cyclophosphamide dosing and in postgrafting immunosuppression.26 Other studies in children with hematologic malignancies have demonstrated the utility of busulfan pharmacokinetics in predicting the risk of toxicity and have generally endorsed the adoption of targeted busulfan dosing to avoid this toxicity.27-29 Moreover, a more recent clinical study defined the important contribution by cyclophosphamide and its metabolites to the toxicity of the busulfan and cyclophosphamide regimen, suggesting that the administration of busulfan before cyclophosphamide alters cyclophosphamide pharmacokinetics and thus might also exacerbate the risk of VOD in patients with underlying hepatic injury.30,31 To mitigate these risks, investigative teams in Italy have reduced the dosing of cyclophosphamide in high-risk patients.7 Alternatively, the replacement of cyclophosphamide with fludarabine might also mitigate the risk of significant transplantation-related toxicity.32 Intravenous busulfan in lieu of oral busulfan also appears to improve the safety profile of busulfan as does the practice of therapeutic drug monitoring.11,33-35 The observations made in this series thus highlight the importance of modifying the standard busulfan and cyclophosphamide regimen in very high-risk patients to avoid unacceptably high transplantation-related mortality.  In other patient series, graft rejection after HLA-matched sibling BMT is generally accompanied by thalassemia recurrence and recovery of autologous hematopoietic function.5,36,37 However, in this series graft failure, which occurred in nearly 10% of cases, was fatal in 11 cases and required rescue by second transplantation to restore normal hematopoiesis. The reasons for this are unclear.  The use of ATG did not appear to be useful in reducing the risk of graft failure. In the future, it is possible that the development of alternative regimens that provide more intensive immune suppression before transplantation without myeloablation might reduce the elevated risk of graft failure we observed in high-risk patients with thalassemia.24,38 When defining the role of transplantation for  -thalassemia major, which is a chronic, nonmalignant condition, one must also consider the natural history of the disorder and the impact of improved supportive care measures on patient outcomes. In selected regions of the world, the outcomes are outstanding when there is ready access to expanded supportive care services, with very few persons dying of thalassemia or of complications related to its treatment through the third and fourth decades of life.12,20,21 In other areas of the world, however, supportive care measures are often difficult to access, which as predicted, has had a negative impact on survival.39,40 We speculate that many of the transplant recipients included in this series lacked ready access to vital supportive care measures, such as regular iron chelation therapy, and there may have been delays in proceeding to transplantation in cases where resources were limited. For these reasons, the results shown here reflect a variety of healthcare issues that have the potential to affect outcomes in children with  -thalassemia who reside outside North America and Europe. Considering the impact of these mitigating factors, we think that the transplantation outcomes reported should motivate families and their physicians to strongly consider the possibility of HLA-matched sibling BMT earlier in the course of their disease, particularly when there are limited resources for chronic thalassemia-centered medical care.

All we are saying is give thals a chance.


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