Hematopoietic Bone Marrow Transplantation (BMT) for Patients with High-Risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using HLA-Haploidentical Related Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined with Immunosuppression Before and After BMT
Authors: Mawad Raya , O'Donnell Paul , Gooley Ted A. , Rajendran Joseph G , Fisher Darrell R. , Gopal Ajay K. , Deeg H. Joachim , Shields Andrew , Green Damian J. , Maloney David G. , Sandmaier Brenda M. , Storb Rainer , Appelbaum Frederick R. , Press Oliver W. , Pagel John M. 
Published: October 2019

Abstract
Abstract 4164
Patients with advanced leukemia or high-risk MDS undergoing conventional hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality. We previously conducted a series of studies in patients with high-risk AML, ALL or MDS using radiolabeled anti-CD45 antibody as part of an allogeneic HCT preparative regimen employing HLA-matched donors. This approach has made it possible to deliver high doses of radiation relatively specifically to sites of disease while sparing normal organs. This advance may also allow us to maximize the anti-tumor effect and minimize toxicity of a preparative regimen. We have now extended this therapeutic strategy to patients without HLA-matched donors, often patients of mixed ethnicity or belonging to ethnic minority groups. We and others have utilized a combination of immunosuppressive agents, including cyclophosphamide (CY) administered before and after HCT with non-T-cell depleted bone marrow (BM) from HLA-haploidentical donors, to facilitate engraftment and delete highly alloreactive T-cell clones presumably involved in graft-versus-host disease (GvHD). We report a Phase I/II study using 131I-BC8 antibody at escalating doses in combination with a less toxic reduced-intensity conditioning regimen in the setting of haploidentical BMT.
This dose escalation study was designed to determine the maximum tolerated dose of 131I-anti-CD45 (BC8) antibody that can be combined with fludarabine (FLU) and 2Gy total body irradiation (TBI) in addition to pre-and post-BMT CY. Ten patients over 18 years of age with advanced AML, ALL or high-risk MDS (>5% blasts) have been treated with a median of 508 mCi (range: 300–818) of 131I delivering a median of 7.9 Gy (range: 1.8–42) to the BM, a median of 74.6 Gy (range: 45.6–178.8) to the spleen, and a median of 15.8 Gy (range: 12.2–22.1) to the liver (does-limiting organ). Patients then received FLU (30 mg/m2 daily for 5 days), 2 Gy TBI, CY (14.5 mg/kg daily for 2 days), and HLA-haploidentical BM grafts, with GvHD prophylaxis consisting of post-transplant CY, tacrolimus and mycophenolate mofetil. The median age of patients was 47.2 years (range: 31–64). Six patients had AML: one patient was in second complete remission, 2 patients had MDS that progressed to AML, 2 had primary refractory disease, and 1 patient had relapsed after previous HCT. One patient had high-risk MDS, one patient had ALL in second remission with minimal residual disease (MRD) and two patients had CML presenting in blast crisis (one in myeloid blast phase and one in lymphoid blast phase). All AML patients had intermediate or high-risk disease by cytogenetic and molecular criteria. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in all 10 patients, and 8 had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The remaining 2 patients were not tested on day 28, however they achieved 100% donor CD3+ and CD33+ by day 56 chimerism evaluation. The absolute neutrophil count surpassed 500/μL at a median of 14 days (range: 12–16) after BMT, and platelets became self-sustained at ≥ 20,000/μL at a median of 22 days (range: 12–35) after BMT. Four patients are surviving relapse-free for a median of 2.8 years (range: 1.6–4.2) after BMT. Five patients experienced disease relapse at 1.8 to 10.7 months after transplant. The overall day-100 non-relapse mortality was 10%, with one death attributed to sepsis in the setting of steroid-refractory GvHD. This study demonstrates that, in addition to a reduced intensity transplant regimen, 131I labeled anti-CD45 antibody can deliver an average of 14.2 Gy of targeted radiotherapy to BM, and an average of 89.2 Gy to the spleen, without a marked increase in 100-day mortality. The maximum tolerated dose of absorbed radiation has not been estimated, and we continue to escalate the radiation dose, with the most recently enrolled patient receiving 24Gy to the liver. This study shows that anti-CD45 radioimmunotherapy yields encouraging results with haploidentical BMT for patients who lack an HLA-matched donor.

Disclosures:
No relevant conflicts of interest to declare.