Allogeneic and Matched Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Using a Modified Reduced Intensity Conditioning Regimen.
Authors: Raflores Marion , Rossetti James , Lister John , Shadduck Richard , Lech John , Kaplan Robert , Kennedy Margaret , Schunn Gisa 
Published: April 2020

INTRODUCTION:Use of a reduced intensity conditioning regimen (RICR) in hematopoietic stem cell transplant may result in lower treatment related mortality (TRM), less acute graft versus host disease (aGVHD) and better survivability, utilizing the graft versus tumor effect from HSCT.

METHODS: Our institution’s original RICR protocol conditioning regimen (Trial A) consists of fludarabine 30 mg/m2 (Day-5 to D-2), melphalan 140–180 mg/m2 (Day -3) and ethyol 910 mg/m2 (Day-3) in addition to mycophenolate mofetil 1 g q12H and tacrolimus(serum level 5–15 ng/ml) beginning Day -3 as immunosuppressive therapy. Transplantation was done using peripheral blood stem cells from the best HLA-antigen match sibling (allo) or matched unrelated donor (MUD). We retrospectively compared transplant data from this original protocol to a modified RICR protocol (Trial B) using a lower dose of melphalan 100mg/m2 and addition of thymoglobulin 2mg/kg/d (D-2 to D0).

RESULTS: 46 patients were transplanted in Trial A with median age of 46 years. 25 patients had allogeneic and 21 had MUD transplant. 30 patients were transplanted in Trial B with median age of 44 years. 22 patients had an allogeneic and 8 had a MUD transplant. All patients were heavily pretreated with 13 patients in Trial A and 9 patients in Trial B have undergone at least one previous stem cell transplant. At D30, all patients in Trial B were alive while 11% of patients in Trial A died of treatment related cause. At D100, 51% of patients in Trial A and 70% of patients in Trial B were alive. D100 TRM was 40% in Trial A and 20% in Trial B.

Table 1. Treatment Outcome OS(%) TRM (%) RM (%) Trial A Trial B Trial A Trial B Trial A Trial B OS:overall survival TRM:treatment related mortality RM: relapse mortality 30 Days MUD 81 100 19 0 0 0 Allo 96 100 4 0 0 0 Total 89 100 11 0 0 0 100 days MUD 40 63 60 38 0 0 Allo 60 73 24 14 16 14 Total 51 70 40 20 9 10

1 year overall survival was 30% in trial A and 20% in Trial B. 1 year disease free survival (DFS) was 18% in trial A and 13% in Trial B.

Table 2. 1 year treatment outcome* Overall Survival(%) Disease Free Survival (DFS) % Trial A Trial B Trial A Trial B *for Trial B, 5 living patients have not yet reached 1 year follow-up MUD 21 13 14 0 Allo 37 23 21 18 Total 30 20 18 13

Incidence of aGVHD≥2 in patients not receiving DLI and alive for more than 30 days post transplant was 56% in Trial A (MUD 67%, Allo50%) and 25% in Trial B (MUD63%, Allo 6%). At D100, aGVHD was the most common cause of death in Trial A while overwhelming sepsis was leading cause of death in Trial B. WBC engraftment with ANC&gt;500 was achieved in 98% of patients in Trial A and 93% of patients in Trial B. Average day of engraftment was 13 days in Trial A and 15 days in Trial B. Platelet engraftment with platelet count at least 20,000 was achieved in 80% of patients in both protocols with average day of engraftment at 18 days in Trial A and 21 days in Trial B. 95% of patients in Trial A had achieved at least 80% donor marrow cells at D100 while only 81% achieved this level of chimerism in Trial B.

CONCLUSION: The modified RICR protocol for HSCT is a tolerable regimen which results in a lower incidence of D100 TRM and aGVHD but overall and disease free survival are not improved. Marrow engraftment is achieved although slightly delayed compared to the original protocol.