Second Allogeneic Stem Cell Transplantation for Hematologic Malignancies Using Chemotherapy Only Cytoreduction with Clofarabine, Melphalan, and Thiotepa
Authors: Spitzer Barbara , Perales Miguel-Angel , Kernan Nancy A. , Prockop Susan E. , Webb Nicholas , Castro-Malaspina Hugo , Papadopoulos Esperanza B , Young James W. , Scaradavou Andromachi , Kobos Rachel , Giralt Sergio , O'Reilly Richard J , Boulad Farid 
Published: October 2019

Abstract
Background:Allogeneic hematopoietic stem cell transplantation (alloHSCT) plays an important role in the treatment of patients with high-risk hematologic malignancies. However, relapse of disease remains the primary cause of mortality post HSCT. Treatment options for these patients remain limited, and outcomes after salvage attempts are often poor, due to both increased toxicity and high rates of relapse. We describe a chemotherapy-only cytoreductive regimen consisting of clofarabine (Clo), melphalan (Mel) and Thiotepa (Thio) for the treatment of patients undergoing a second or third HSCT (HSCT2 or HSCT3).
Methods: Between November 2005 and December 2012, 19 patients with hematologic malignancies who had relapsed after prior alloHSCT received a HSCT2 (N=17) or HSCT3 (N=2) using this regimen. There were 12 males and 7 females aged 4.5-44 years (median 20.2 years). Diagnoses and stages at the time of HSCT2/3 included: ALL in second complete remission (CR2; N=4) or CR3 (N=8); AML in CR2 (N=2) or CR3 (N=4); and CML in 2nd chronic phase (N=1). Seven patients had extramedullary disease, including CNS (N=5), testicle (N=1), and bone (N=1). Time to relapse following prior HSCT was 0-6 months (N=6), 6-12 months (N=7), or >12 months (N=6). Median time between most recent and present HSCT was 15 months (range 8.5 – 225 months). Thirteen patients received allografts from the same donor used for prior alloHSCT, while 6 pts received allografts from different donors. Grafts comprised conventional/unmodified marrow (cBMT) (N=7), peripheral blood (cPBSCT) (N=6), double umbilical cord blood units (N=1), or T-cell depleted (TCD) PBSCT (N=5). Cytoreduction included Clo 20 (N=18) or 30 (N=1) mg/m2/dose x 5, Thio 10 mg/m2 x 1, and Mel 70 mg/m2/dose x 2. GvHD prophylaxis included tacrolimus + methotrexate or mycophenolate for the unmodified grafts, while recipients of TCD grafts received ATG only pre-transplant for rejection prophylaxis. TCD was achieved by CD34+ selection, with the addition of E-rosetting in one case. All patients received filgrastim from day +7 until neutrophil engraftment.
Results: Neutrophil engraftment occurred in all patients at a median of 12 days (range 9-25). Platelet recovery occurred in 17 evaluable patients at a median of 22 days (range 14-98). Transplant related mortality was limited to 2 patients, one who died of veno-occlusive disease 27 days post-transplant and the other of EBV lymphoma 11 weeks post-transplant. Neither of these patients recovered their platelet counts. Regimen related toxicity included: grade 3-4 mucositis (N=5), grade 4 renal toxicity (N=2), grade 3-4 hypoxia (N=3). Fifteen patients developed grade 3-4 transaminitis beginning immediately following clofarabine administration, which completely resolved in 14/15 cases. Five patients, all recipients of unmodified grafts, developed grade 2-4 acute GvHD, two of whom developed chronic GvHD; one patient who received a cPBSCT developed de novo chronic GvHD.
Seven patients relapsed at a median of 14.6 months (range: 3.5-25.3 months) post-HSCT2/3, and all died of their disease. Ten of 19 patients are alive and disease free with median follow-up of 50.1 months (range 22.8-90.4). Overall and disease-free survival probabilities were 51.5% and 52.6% respectively. There were no statistically significant difference in OS or DFS for the following factors: (1) patient age < or ≥ 21 years, (2) grafts from same or different donor, (3) myeloid vs. lymphoid disease, (4) CR2 vs. CR3 at HSCT, (5) TCD vs. unmodified grafts. Outcome was significantly superior for patients whose relapse occurred > 6 months from prior HSCT, with an OS of 75.2% compared with 0% (p<0.0001) in patients whose relapse was ≤ 6 months. Of the 6 patients who received HSCT2/3 for relapse within 6 months of their first HSCT, 4 died from relapse, and 2 died from transplant related mortality.
Conclusions: This cytoreductive regimen has allowed secondary transplants in a cohort of high-risk patients with ALL and AML who relapsed following a prior transplant using various graft and donor options. Overall, the regimen is well tolerated and has yielded promising results, specifically in patients who relapse more than 6 months from their prior transplant. This salvage treatment merits further study and evaluation in collaborative group studies.

Disclosures
Off Label Use: Clofarabine, melphalan, and thiotepa all off label for bone marrow transplant.. Boulad:Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.