Overview of Study Design:~In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.~Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft and post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin Oncol. 2013; 31(10):1310-6). MLN9708 will be administered once weekly for 3 weeks on a 28 day cycle for one-year post-transplant. Post-transplant immunosuppression will consist of tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second GVHD prophylactic medication).~The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-transplant. Experience from the literature suggests that following a nonmyeloablative haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse is approximately 50% at one year post-transplant. It is hoped that under this protocol, this rate will be at most 25%. Thus the investigators statistically formalize this study by testing the null hypothesis that p, the PFS rate is 0.25 or less versus the alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a proportion.
In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.