Improved Post-Transplant Outcomes in Hematologic Malignancy Patients Undergoing Non-Myeloablative Hematopoietic Stem Cell Transplant (NMHSCT) Using a 400 cGy Total Body Irradiation (TBI) Dose with Fludarabine.
Authors: Sobecks Ronald M. , Theil Karl S. , Rybicki Lisa , Macklis Roger , Pohlman Brad , Andresen Steve , Brown Stacey , Kuczkowski Elizabeth , Cherni Kelly , Baker Janet , Bernhard Laura , Kalaycio Matt , Bolwell Brian 
Published: April 2020

Fludarabine and TBI (200 cGy) is a common NMHSCT preparative regimen. However, this regimen resulted in a 14% graft rejection rate and 42% incidence of disease relapse at our institution. We hypothesized that escalation of the TBI dose to 400 cGy may improve post-transplant outcomes. From 12/10/03 to 4/19/05, 17 patients (pts) with hematologic malignancies underwent NMHSCT using a preparative regimen of fludarabine 30 mg/m2/d IV on days −5, −4 and −3 and TBI 200 cGy on days −1 and 0 (total dose 400 cGy). Immunosuppressant therapy consisted of cyclosporine and mycophenolate for matched sibling donor pts (n = 10) or Tacrolimus and mycophenolate for matched unrelated donor pts (MUD) (n = 7), which was started day −1 and discontinued day +56 in the absence of GVHD. Diagnoses included 4 NHL, 3 AML, 2 MDS, 2 myelofibrosis (MFB), 1 Hodgkin lymphoma (HL), 1 ALL, 1 multiple myeloma (MM), 1 CLL, 1 chronic myeloproliferative disorder (CMD) and 1 bilineal acute leukemia (BAL). Only 2 (12%) pts were in complete remission at the time of transplant (both AML). The median time from diagnosis to transplant was 11 months (range, 3–246 months). All transplants were performed as an outpatient, but 16 (94%) pts required hospitalization and the most common reason was for fever (9 pts– 56%). The median CD34+ and CD3+ cell doses infused were 4.92 x 106/kg and 4.44 x 108/kg, respectively. The median time to absolute neutrophil count recovery of ≥500/μL was 10 days (range, 8–13 days) while time to platelet recovery ≥20K/μL was 12 days (range, 11–16 days). T-cell (CD3+) chimerism was monitored by short tandem repeat analysis and complete donor chimerism (CDC) was defined as ≥ 95% donor DNA in CD3+ T-cells. CDC was achieved in 14 (82%) pts at a median of 28 days (range, 21–130 days), whereas, in our prior analysis with pts receiving 200 cGy TBI, 75% of pts achieved durable CDC at a median of 77 days (range, 14–310 days). Ten (59%) pts developed acute GVHD at a median of 61 days (range, 13–85 days) with 4 grade I, 4 grade II, 1 grade III, and 1 grade IV. Chronic GVHD developed in 5 (29%) pts at a median of 10 months (range, 3–13 months) and only 1 (6%) developed extensive chronic GVHD. Responses included 4 CR (1 NHL, 1 AML, 1 CLL, 1 MFB), 4 PR (2 NHL, 1 HL, 1 MM), 2 stable disease (1 CMD, 1 NHL), and 3 not evaluable (2 MDS, 1 MFB). Graft rejection occurred in only 1 AML patient with a MUD and HLA-B and -Cw disparities. Three (18%) pts (1 ALL, 1 AML, 1 BAL) had disease relapse at a median of 6 months post-transplant (range, 2–12 months). The Kaplan-Meier method reported a median relapse-free survival of 11.6 months. Seven pts died, 3 within 100 days of NMHSCT; estimated median survival was 12.7 months. Causes of death included 2 acute GVHD, 1 chronic GVHD, 1 relapse, 1 sepsis, 1 ARDS, 1 cardiac arrest. We conclude that escalation of the TBI dose to 400 cGy in combination with fludarabine for NMHSCT is an effective approach which when compared to the 200 cGy regimen has resutled in less graft rejection (6% vs. 14%, respectively) and a lower relapse rate (18% vs. 42%, respectively). The more rapid achievement of T-cell CDC may be responsible for these differences. Further investigation and follow-up with this regimen is warranted.