Overall Project Summary The development post-transplant cyclophosphamide (PTCy) to modulate GVHD is a prime example of our group’s successful translational research. Not only does PTCy allow safe haploidentical (haplo) blood or marrow (BMT) in patients up to at least age 75, but the outcomes of haplo BMT with PTCy, confirmed by now many international as well as registry studies, appear similar to those seen with matched donors. Our group has also shown that PTCy also allows the application of safe and effective mismatched unrelated donor BMT. The reduction in GVHD complications associated with PTCy has lowered the non-relapse mortality (NRM) to less than 10% even in the mismatched setting, removing one of the major hurdles to successful allogeneic (allo) BMT, donor availability. PTCy has helped open up alloBMT to virtually anyone in need. With the reduction in NRM, relapse has become by far the major complication of alloBMT. Emerging data suggest that a new non- tolerant and non-exhausted transplanted immune system has the ability to augment the activity of most anticancer agents, small molecule as well as immunologic. Thus, the major objective of this proposal is to study maintenance therapy after alloBMT as a means to reduce relapse. In fact, our data, as well as from other groups, already appear promising with such an approach, perhaps best exemplified by the impressive results seen in FLT3/ITD AML with alloBMT and post-transplant FLT3 tyrosine kinase inhibitors despite many of these agents showing limited activity in the non-transplant setting. There are also emerging data suggesting that other agents generally lacking curative activity as single agents, such as rituximab in lymphomas, TKIs in Ph+ leukemias, and azaciditine for acute myeloid leukemia/myelodysplastic syndrom may demonstrate curative activity in the post-alloBMT setting. The minimal residual disease state post-alloBMT should also optimize novel antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. This new proposal will build on our work demonstrating that the post alloBMT setting provides a unique environment for decreasing relapse after alloBMT. In addition, the now near universal availability of the procedure, enabled by the favorable safety and cost profile associated with PTCy, opens up examining BMT for unique applications. The overall goals/specific aims of this proposal are to: 1) investigate the ability of post- transplant maintenance therapy to decrease relapse after BMT, 2) study alloBMT as a platform for enhancing novel therapies for solid tumors, and 3) study whether alloBMT with PTCy can eliminate HIV.