Clofarabine-Based Reduced Intensity Conditioning Regimen with Post-Transplant Cyclophosphamide and Peripheral Stem Cell Graft in Adults with Myeloid Malignancies: Results of the Clo-Baltimore Regimen

Backgound: The Baltimore reduced-intensity conditioning (RIC) regimen using high-dose post-transplant cyclophosphamide (PTCY) is considered as a standard of care for haplo-transplant. However, it is associated with relatively low survivals (OS 46% and EFS 34% at 1 year) and high incidence of relapse (51% at 1 year), especially when considering myeloid malignancies (Luznik, 2008). Here, we have replaced fludarabine by clofarabine, a second-generation purine analogue with high anti-myeloid leukemic activity, as part of the Baltimore regimen (Clo-Baltimore regimen) and we report the results of such an approach in 36 patients with myeloid malignancies.

Methods: This retrospective study included 36 adults with a median age of 60.5 (range: 31-70) years who received an allotransplant between March 2014 and March 2017. They were 18 males. Seventeen cases had acute myeloid leukemia (AML), 13 myelodysplastic syndrome (MDS), 3 myelofibrosis (MF), 1 chronic myeloid leukemia (CML), 1 mixed MDS/myeloproliferative syndrome (MPS), and 1 plasmacytoid dendritic cell neoplasm. The status at transplant was as follows: first complete remission (CR) n=16, second CR n=4, third CR n=1, active disease n=15 (MDS n=10, MF n=3; CML n=1, MDS/MPS n=1). Seven patients had already received a first allograft. Twenty-seven patients received a graft from an haploidentical donor (son n=10; daughter n=2; sister n=7; brother n=4; father n=2; nephew n=2) while 8 cases (AML n=1; MDS n=4, myelofibrosis n=2; mixed syndrome n=1) had a matched donor (sibling n=2, mud n=6) and 1 a 9/10 mis-matched unrelated donor. The Clo-Baltimore regimen consisted of Clofarabine 30 mg/m²/day days -6 to -2, cyclophosphamide 14.5 mg/kg day -6, low dose total body irradiation 2 Grays day-1, and PTCY 50 mg/kg/day days +3 and +4. All patients received PBSC as stem cell source at day 0. All patients provided informed consent for data collection before the graft.

Results: Except one patient who died during aplasia of multiple organ failure (MOF), all patients engrafted. The median time of neutrophils (>1x10⁹/L) and platelets (>50 x10⁹/L) recoveries were 18 (range: 8-27) and 28.5 (range: 11-111) days, respectively. With a median follow-up of 12.3 months for alive patients (range: 3-39.5), 1-year and 18-month OS were both 74% (0.55-0.86), while 1-year and 18-month DFS were 74% (0.55-0.86) and 62% (0.38-0.78), respectively. At 100 days and 1 year, NRM was 5.5% and 8.3%, respectively. Seven patients have relapsed so far with a median time between graft and relapse of 90 days (range: 66-125). The 1-year relapse incidence was 19.4%. Incidences of grade 2-4 and 3-4 acute GVHD were 48% and 11.4%, respectively, while the incidence of chronic GVHD was 20% (limited 6%, extensive 14%). 1-year and 18-month GRFS were 55% (36-71) and 46% (27-64), respectively. At last follow-up, only 9 patients have died, the causes of death being relapse in 5, dermatomyositis in 1, MOF in 1, sepsis in 1 and grade 4 acute GVHD in 1.

In univariate analysis, there were no differences regarding 18-month survivals between patients allografted: 1) in CR vs active disease (OS 65% vs 86%, p=0.13; DFS 56% vs 69%, p=0.18), 2)for AML vs MDS (OS 70% vs 85%, p=0.72; DFS 58% vs 85%, p=0.49), or 3) between haplo-identical vs matched+9/10 mis-matched donors (OS: 69% vs 88%, p=0.29; DFS 59% vs 61%, p=0.57).

Conclusion: The Clo-Baltimore regimen has shown very encouraging results in this series for patients with myeloid malignancies, improving OS and DFS at 1 year compared to the Baltimore regimen. A low rate of relapse was observed even although using a RIC regimen, which is suitable for older patients and cases with co-morbidities. An update of the follow up will be provided at the meeting. These data have to be validated prospectively.