Clofarabine Cytoreduction Followed by a Second Transplant Using Haploidentical Donors for Relapsed Acute Leukemia After First Allogeneic Hematopoietic Stem Cell Transplantation: Early Outcome, Infection and Toxicity.
Authors: Tischer Johanna , Fritsch Susanne , Prevalsek Dusan , Hubmann Max , Bücklein Veit , Zöllner Anna K , Schulz Christoph , Reibke Roland , Engel Nicole , Rieger Christina T , Schmid Christoph , Ledderose Georg , Hiddemann Wolfgang , Hausmann Andreas 
Published: October 2019

Abstract
Abstract 3071

Background:
Prognosis of relapse after first allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor, and no standard treatment is available. Second HSCT (HSCT2) is a valuable treatment option for selected patients. Change of donor for HSCT2 is a frequently used strategy to enhance the graft-versus leukemia-activity, although its role for improving the outcome is still unclear. However, identification and activation of a new donor for HSCT2 is time consuming and might delay or even prevent a second transplant. In contrast, haploidentical family donors are rapidly available in the vast majority of patients and might therefore be an alternative for HSCT2, once change to a new donor is planned.
Based upon these considerations, HSCT2 from haploidentical family donors was used as preferred treatment for acute leukemia relapse after allo-HSCT in our transplant center since August 2009. According to the concept of sequential therapy (as introduced by the FLAMSA-RIC regimen), patients initially received cytoreductive chemotherapy, followed, after three days of rest, by reduced intensity conditioning (RIC). Based on the Baltimore protocol for haploidentical HSCT using RIC and post-transplant cyclophosphamide for depletion of allo-reactive T-cells, individual and disease-specific modification of this regimen were used for preparation before HSCT2.

Patients and Methods:
Fourteen adult patients (7 male, median age: 37 years) suffering from AML (n=11) or ALL (n=3) with an ECOG score of <=1 and with a partially HLA-matched (haploidentical) family donor available, were eligible. They had relapsed after first (n=12) or second (n=2) HLA matched related (n= 5), matched unrelated (n=8) and partially matched related (n=1) allo-HSCT. Median duration of remission prior to haploidentical HSCT2 was 400 days (range 45–1701). Median interval between relapse and HSCT2 was 78 days (range 27–205). Initially all patients received cytoreductive chemotherapy with clofarabine (30mg/kg IV on day -15 to -11), and conditioning treatment consisted of fludarabine (30 mg/m2 IV on day -7 to -3) and cyclophosphamide (14,5 mg/kg, IV on day -7 to -6) plus either melphalan (110 mg/m2 IV on day -2, n=9) or treosulfan (3×10 g/m2 IV on day -4 to -2, n=3) or TBI (200 or 400 cGy on day -1, n=2) followed by a non T-cell depleted bone marrow infusion on day 0. Post-grafting immuno-suppression consisted of cyclophosphamide (50mg/kg IV on day +3 and +4) plus tacrolimus (days 5–180) and mycophenolate mofetil (days 5–35).

Results:
Neutrophil and platelet engraftment was achieved in 12 (85,7%) and 10 (71,4%) patients, respectively. Median time to neutrophil engraftment was 32 days (range 24–90). No primary graft rejection was observed. Complete remission could be induced by day +30 in 11 patients (78,6%), whereas 1 patient died early and 2 patients had refractory disease. Full donor chimerism by day +30 was achieved in 10 patients (71,4%).
After a median follow-up of 6 months (range 4 days–33 months) cumulative incidence of non-relapse mortality at day + 30, + 100 and +360 was 7%, 24% and 24 %, respectively. Rate of grade II-IV acute GvHD was 24,7%. Mild or moderate chronic GvHD was seen in 2 patients (14,3%). 8 patients died from relapse (n=4), infection (n=3) or infection and toxicity (n=1). Estimated overall survival and progression-free survival at one year from HSCT2 was 53 % (+/− 14 %) and 36 % (+/− 17 %), respectively.
Infection was frequent detected in 13 (92,9%) patients with at least one episode of neutropenic fever in 8 patients, probably or proven invasive aspergillosis in 5 patients and a moderate rate of virus-reactivation/-infection (CMV 21,4%, HSV 14,2%, EBV 28,6%, HHV-6 28,6%, Polyomavirus 28,6%, Adenovirus 21,4%,). No patient developed a post-transplant lympho-proliferative disorder.
Regimen related grade III-IV toxicity was observed in 9 (64,3%) patients with transient elevation of liver enzymes in 7 (50%), mucositis in 5 (35,7%), headache in 5 (35,7%), hand-foot syndrome in 3 (21,4%), hyper-bilirubinemia in 3 (21,4%) and severe deterioration of kidney function in 2 (14,3%) patients, respectively, as the most common observed toxicities.

Conclusion:
Haploidentical HSCT2 following initial cytoreduction with clofarabine, RIC and high-dose cyclophosphamide post-transplant is feasible in patients with acute leukemia relapsing after first allo-HSCT. Early results are promising, but long-term results are still pending.

Disclosures:
Off Label Use: Clofarabine is a novel purine nucleoside with immunosuppressive and anti-leukemic activity in hematologic malignancies, off-label use in adults.