We found that myeloablative conditioning, a T-cell depleted allograft, post-transplant systemic GM-CSF, and early use of DLI was well-tolerated in an older (median age of 56 years) cohort of patients with MDS with high risk features. The “overall toxicity” as measured by TRM and 3 year EFS in our cohort were similar to a group of younger patients (median age 38 years) reported by the IBMTR receiving myeloablative alloBMT[2
] and multiple reported series using reduced intensity regimens. [6
] Comparing the results of alloBMT trials for MDS is difficult because of significant patient and disease heterogeneity, the use of different staging systems for MDS subgroups, and the use of different preparative regimens and GVHD prophylaxis among trials. Nevertheless, it is apparent that younger patients tolerate both preparative regimen and GVHD toxicities better than the older patients, and efforts to lessen these alloBMT toxicities have decreased upfront mortality at the expense of increased post-BMT relapse. Several components of our alloBMT approach likely contribute to its relative tolerability, including low rates of graft failure, limited preparative regimen toxicity, and minimal GVHD. The roles of TCD in minimizing aGVHD and close monitoring of busulfan levels in decreasing VOD (only 2 patients with clinically significant VOD) are well recognized. Moreover, it is possible that the CD34+ add back in combination with the prolonged GM-CSF also improved expected engraftment success with our resultant graft failure <10%.
Our low overall cumulative incidence of aGVHD (30%) and low severe aGVHD (10%) likely played a significant role in tolerability of the transplant. Interestingly, most of the younger patients (age < 50) in our study developed some form of aGVHD (71%) but only one experienced advanced stage aGVHD and subsequently died of disseminated aspergillous infection. These outcomes are in contrast to only 31% of patients age 50 and older developing some form of GVHD. However, the rate of advanced aGVHD was not statistically significantly different between the younger and older cohort (14% versus 9%). The reason for the overall difference in aGVHD incidence is unclear as all clinical features such as diagnosis, disease status, and blast percentage at the time of transplant appeared well matched between the two groups. The use of prolonged, systemic GM-CSF might have been expected to substantially increase the risk of aGVHD through its well recognized effects on dendritic cell maturation and antigen-presenting cell recruitment[25
] with the expectation that the older patients would be the most vulnerable to these effects. However, studies evaluating the role of high dose GM-CSF in the context of vaccine trials now suggest a threshold dose of GM-CSF, that once breached, creates an inhibitory immune environment by inducing a population of myeloid suppressor cells (Gr1+/CD11b+) that functionally impair antigen specific CD4+ T cell response.[26
] Thus, it is plausible that the systemic GM-CSF levels achieved in our study surpassed the “theoretical threshold” and may have had a protective effect resulting in the low severe GVHD rates.
As has been reported in other series using T cell depletion [27
], relapse remained relatively high in our trial. The prolonged administration of GM-CSF following alloBMT was utilized to provide anti-tumor effects and prevent re-emergence of MDS; we have shown previously that growth factors alone and in combination with pharmacologic differentiating agents can induce terminal differentiation in both leukemia cell lines and primary leukemia cells.[13
] However, as described above, GM-CSF may have dose dependent activity with low levels stimulating dendritic cells and increasing antigen presentation and higher levels stimulating production of an inhibitory CD11b+ myeloid population which can dampen T cell and other immune effects. To that end, most relapses occurred outside the planned GM-CSF treatment window with a significant proportion (38%) doing so beyond a year in our study. These results are improved compared to other series showing fewer delayed relapses (25%)[2
] and support the potential biologic activity of the growth factor. The 3 early relapses seen in our study may be partially explained by potentially resistant disease with 2 of them representing patients with the longest disease duration (17 and 22 months) and 1 having significant disease burden (70% blasts) at the time of transplant. In balancing the opposing forces of GM-CSF: 1) the potential increased anti-tumor activity and stimulation of aGVHD through increased antigen presentation or through differentiation of the residual malignant clone versus 2) the potential loss of anti-tumor effects and limited aGVHD through the development of myeloid suppressor populations suppressing the immune response, it appeared that the GM-CSF in our trial did not increase aGVHD and may have delayed time to relapse. The excellent toxicity profile of our transplant platform combined with the finding that most relapses occurred outside of the window of GM-CSF administration suggest that extending the duration of planned growth factor may further delay or eliminate relapse in some of our patients. A second intervention that may lead to lower rates of relapse and overall better outcomes made possible in the setting of this well-tolerated transplant platform (and its low incidence of severe aGVHD) is the earlier discontinuation of immunosuppression that might lead to an increased GVL effect.
On the other hand, DLI clearly showed activity as primary salvage therapy for patients who relapsed following transplant. There are limited data regarding the impact of DLI in patients with MDS, but most reports suggest a limited effect on durable disease control.[29
] Of the 18 initial relapses on this trial, ten received DLI (without chemotherapy). The eight patients who did not receive DLI had rapidly progressive disease or refused (2 patients). Of the ten patients getting DLI for relapsed MDS, three (30%) achieved complete remission. All three patients developed grade II GVHD that resolved with therapy. The impact of DLI was most evident in early and low disease burden relapse with 50% of patients treated with ≤5% bone marrow blasts achieving a CR. Close monitoring and early intervention with DLI may improve the historically poor results with DLI in MDS patients.
Traditionally, the role of induction chemotherapy prior to alloBMT for MDS patients has been controversial.[31
] Our data supports the finding that patients entering alloBMT in remission have a lower risk of relapse.[34
] Unfortunately, there are limited randomized data in this setting and a number of trials are heavily weighted towards AML patients making the direct comparison difficult.[8
] Thus, determining a true denominator of subjects eligible for either approach, rather than having chemotherapy serve as a selection tool for the “best risk” patients, has been challenging. Although the denominator in our series doesn't allow for definitive conclusions, our data would support the position that when successful, induction therapy seems to impact the success of alloBMT. Our data further substantiate the importance of low tumor burden noting an improved EFS in patients transplanted in CR compared to those with marrow blasts > 5%. Other groups have also showed improved outcomes in patients transplanted with lower with lower tumor burden[2
] and suggests that this is an important element in determining the optimal timing for allogeneic transplant.
The curative potential of alloBMT in MDS has primarily been attributed to immunologic anti-tumor effects. However, while reduced intensity conditioning regimens minimize the chemotherapy-related side effects of alloBMT for older patients, emerging literature supports the contributions of the conditioning regimen intensity to disease control in MDS, especially in patients with high risk, advanced disease.[6
], The use of T cell depletion and busulfan monitoring not only appeared to reduce the toxicity of alloBMT while maintaining dose intensity, but also allows for consideration of additional post-BMT interventions to further improve disease control. For example, the low incidence of GVHD with T cell depletion allows consideration of preemptive DLI for patients at high risk of relapse. Alternatively, one of the newly FDA-approved agents for MDS (azacitidine, decitabine, or lenalidomide) may also be incorporated into the post-BMT setting as another means to decrease possible relapses.