Historically, total body irradiation has been the main modality to provide both tumoricidal and immunosuppressive effects to facilitate engraftment of donor cells.(16
) Since the initial introduction of the busulfan and cyclophosphamide combination (BuCy-4) as a preparative regimen for leukemias in the mid-1980s, there have been increasing reports of its efficacy.(18
) Modification of this regimen with the reduction of cyclophosphamide to 60 mg/kg/day for 2 days (BuCy-2) was found to be equally efficacious with apparent reduction of toxicity.(19
) Although there were no prospective trials comparing BuCy-2 and BuCy-4, many centers adopted BuCy-2 as standard for this combination. In the present study, we compared the outcome of 1593 patients with myeloid disorders, AML, CML, and myelodysplasia who received URD transplantation facilitated by the NMDP. There was no statistical differences noted in OS, DFS, TRM and relapse between patients who received BuCy or the TBI based regimens.
Presently, five prospective randomized trials have compared TBI-based and BuCy regimens in recipients of sibling donor transplantation.(4
) Most included patients with various stages of acute and chronic myeloid leukemia. In the two studies of patients in chronic phase CML, the treatment-related mortality, overall and disease-free survivals of patients who received TBI and BuCy were similar.(6
) The remaining three studies included patients with early and advanced stages of disease.(4
) Two studies showed a significant survival advantage for patients who received TBI regimens; one in AML in CR1 (4
), and one in advanced disease.(5
) In the French multicenter randomized trial comparing BuCy-2 with a TBI-based regimen in matched sibling transplantation for patients with AML in first remission, there was a significantly higher relapse rate in patients who received the BuCy-2 regimen, resulting in poorer overall and disease-free survival.(4
) There was also a higher relapse in patients who received BuCy for AML in first remission in a retrospective review from the IBMTR.(23
) In this study in spite of the higher relapse rate the survival was equivalent. The higher relapse in both these studies which included sibling transplants may not be directly comparable to our study which only focused on unrelated transplants. In support of our study findings, a published meta-analysis suggested equivalent survival between the regimens.(24
) In addition, a combined long-term follow up of 4 of the previously published randomized trials, patients with CML and AML undergoing HLA-identical sibling transplantation had equivalent survival whether they received Cy/TBI or BuCy regimen.(25
The risk of developing grade III-IV aGVHD was higher in patients who received the high-dose TBI based regimens compared to patients who received either the standard-dose TBI or BuCy regimen. This higher risk of severe acute GVHD in patients who received higher doses of TBI may be related to the increased intensity of the preparative regimen. Preparative regimens that cause more tissue damage (higher intensity regimens) may enhance the risk of GVHD.(26
) It is possible that different preparative regimens, e.g. busulfan-based regimens, may attenuate tissue injury, thus lessening the risk of aGVHD. In the univariate analysis, the cumulative incidence of cGVHD was higher for Cy/TBI regimens at 6 months but only showed a trend at 1 year and 2 years with the incidence of 39% - 48%, which was lower than ~ 70% observed in the prospective clinical trial comparing tacrolimus and cyclosporine in URD transplantation.(28
) The difference of cGVHD incidence is most likely due to lower reporting sensitivity of registry data in patient with limited chronic GVHD compared to prospective data captured in real-time.
Neutrophil engraftment at day 28 and 60 was higher in patients who received standard-dose Cy/TBI compared to patients who received either the BuCy or high-dose Cy/TBI regimens. This was statistically significant in both the univariate and multivariate analysis. Previous studies from the NMDP with CML patients indicated that the rate of neutrophil engraftment was improved in patients who received TBI-based regimens.(11
) The reason was thought to be due to greater immunosuppressive property of TBI-based regimens compared to busulfan-containing regimens. However the patients who received the high-dose TBI-based regimens in our study had a lower incidence of neutrophil engraftment compared to patients who received standard-dose TBI. Several differences in the characteristics of patients who received the high-dose Cy/TBI may account for the differences seen in our current study. Patients receiving the high-dose Cy/TBI regimens had a greater likelihood of receiving an HLA-mismatched transplant and had advanced disease at the time of transplantation; both of these characteristics could potentially impede the recovery of neutrophils. Furthermore, other significant covariates that influenced neutrophil recovery in the multivariate analysis were HLA match status, karnofsky score and total nucleated cell dose, the latter was higher in patients receiving BuCy regimen. Attainment of the desired cell dose in marrow harvest from unrelated donor cannot consistently be achieved due to weight discrepancy and technical skill of the operators. Peripheral blood stem cell harvest is probably less operator dependent and weight discrepancy is less of an issue, thus the issue of neutrophil engraftment might be more consistent. This is being addressed by the just completed BMTCTN trial comparing marrow and peripheral blood stem cell transplantation. It is also possible that the use of targeted blood levels of busulfan and intravenous formulation of busulfan might improve tumor cytoreduction in patients with advanced disease and enhance engraftment.(29
In this study, the relative risk of IPN was similar in all three groups. This finding is similar to previously reported studies on the risk of IPN after transplant.(32
) The pathogenetic mechanism of IPN in the allogeneic transplant setting might not be directly related toxicity of any particular components of the conditioning regimens. Immunologic mechanism might have played a larger role in the development of IPN, thus overriding the impact of the preparative regimen on this complication.(33
) The risk of VOD was higher in patients who received BuCy, compared to either Cy/TBI regimen in our study. The association of the preparative regimen and the risks of VOD were inconclusive in 3 randomized studies. One reported significantly higher incidence of VOD in patients who received busulfan-based regimen (5
); the other 2 studies did not find a difference in the risk of VOD between those who received TBI-based regimen and busulfan-based regimen.(6
) The risk of VOD might be minimized by strategies such as the use of ursodiol as a protective agent,(34
) therapeutic monitoring of busulfan and using pharmacokinetic parameters(35
) or using a targeted steady state plasma level of busulfan at 800-900 mg/mL.(30
) More recently, the introduction of the intravenous formulation of busulfan may also decrease the risk of hepatic veno-occlusive disease.(37
Despite our best effort to delineate the interaction and influence of confounding factors in this large cohort of patients, some practical questions remain unanswered. For instance, these findings do not take into account several changes in the practice of unrelated transplantation and therefore caution must be used in generalization of these results. Certainly, current improvement of clinical practice that includes new microbial agents, antibodies to perturb immune response, GVHD prophylactic regimens, selection of donor based on allelic typing and stem cell source has improved the outcome of unrelated transplants. In addition, the number of PBSC transplants has increased dramatically and now represents the major source of stem cells in patients undergoing unrelated transplantation. It is unclear whether the same observation in marrow transplant recipient as in this study would be true in the recipients of a PBSC transplant. This study does not delineate the role of IV busulfan which is increasingly used in current practice. Intravenous preparations of busulfan can potentially decreased the risk of VOD by avoiding the first pass effects on the liver. Intravenous busulfan was approved by the FDA for use in 1999 and therefore not available for vast majority of patients in this study. Finally, transplantation in CML was the most common myeloid neoplasm in this study, but it is an uncommon necessity since the introduction of tyrosine kinase inhibitors as frontline therapy for this disease.
In this large cohort analysis of CIBMTR registry data, we conclude that Cy/TBI and BuCy regimens result in similar clinical outcome in URD transplant recipient with myeloid malignancies. Whether one regimen is superior in some subsets of URD transplant recipients is uncertain and will need further prospective study. Other prognostic variables might have larger influence on survival than the preparative regimens described in this report.