Donor Lymphocyte Infusions and Second Transplantation as Salvage Treatment for Relapsed Myelofibrosis After Reduced-Intensity allografting.
Authors: Kröger Nicolaus , Klyuchnikov Evgeny , Wolff Daniel , Bornhäuser Martin , Kobbe Guido , Nagler Arnon , Shimoni Avichai , Koenecke Christian , Wolschke Christine , Bacher Ulrike , Zander Axel R. 
Published: October 2019

Abstract
Abstract 1300

Introduction:
Around 20–30% patients (pts) with primary myelofibrosis (PMF) experience relapses within 3 years after dose-reduced conditioning followed by allogeneic stem cell transplantation (HSCT). The prognosis for those pts is unclear, and standard treatment recommendations have not yet been proposed. Early withdrawal of post-transplant immunosuppression, use of dose escalating donor lymphocyte infusions (DLIs), and/or 2nd HSCT have been suggested as therapeutic options for pts relapsing after HSCT. Although DLIs were found to be effective in certain disease as salvage approach, the role of 2nd HSCT for non-responding patients remains controversial. Here we report on our multicenter experience on the use of a two-stage salvage strategy including DLIs and a 2nd RIC-HSCT in pts with post-transplant relapse of PMF. It was planned to start salvage therapy with DLI and only non-responding patients as well as patients with transformation to blast crisis and complete loss of donor chimerisms were assigned to receive a second allogeneic stem cell transplantation. Responses were evaluated using the International Working Group consensus criteria for treatment response in myelofibrosis. Additionally, the JAK2V617F mutation level (in 1 case, the MPLW515mut level) and donor chimerism were used to assess the molecular remission status.

Patients/Methods:
Thirty pts with morphologic (n=24) or molecular (n=6) relapse of PMF after 1st HSCT were proceeded to a salvage strategy, including DLIs and/or 2nd RIC-HSCT. Median time from transplantation to relapse was 9 months (range, 2–62). 26 pts received a median of 3 (range, 1–5) DLIs. The initial median dose was 1.2×106 (range, 0.3×104 – 8×107) consequently being increased up to 4×107 CD3+ cells/kg (range, 1×107 – 1.3×108). As a second stage, 13 non-responding pts as well as those who received no DLIs (transformation to blast phase, n=1; complete loss of donor chimerism, n=3) underwent a 2nd RIC-HSCT. The median interval between 1st and 2nd HSCTs was 17 months (range, 11–77). The majority of the patients received a reduced busulfan/fludarabine conditioning regimen for the 1st HSCT. Conditioning regimen at the 2nd RIC-HSCT for most pts (12/17, 71%) consisted of a combination of treosulfan (30-36 g/m2) with fludarabine (150-180 mg/m2), and anti-thymocyte globuline (Thymoglobulin®, 2.5–8 mg/kg). The majority of pts (15/17, 82%) received 2nd allografts from alternative unrelated (HLA-matched, n=8; mismatched, n=5), related (matched, n=1), and haploidentical donors (n=1).

Results:
After DLIs, responses were observed in 10/26 pts (39%; complete remission (CR): n=8; CRu (unconfirmed: no bone marrow histology: n=2). All pts maintain the response during a median follow-up of 31 months (range, 13–45). Acute (grade II-IV) and chronic GvHD occurred in 3/26 (12%) and 7/25 (28%) pts, respectively There were no cases of non-relapsed mortality (NRM), while 3/26 pts expired from progression. Seventeen pts received a 2nd RIC-HSCT and engraftment was documented in 16/17 pts (leukocytes: median, d +14; platelets: median, d +18). Responses were observed in 12/15 evaluable pts (80%; CR, n=8; CRu, n=1; partial remission (PR), n=3). Acute (II-IV) and chronic GvHD were observed in 8/17 (47%) and 6/14 pts (43%), respectively. The 1-year cumulative incidence of NRM was 6% (95% CI: 0%-18%). The cumulative incidence of relapse at 1 year was 24% (95% CI: 0%-50%). Overall for whole study population, after a median follow-up of 27 mo (range, 9 – 61), the 2-year probabilities of OS and PFS was 80% (95% CI: 62% - 98%) and 72% (95% CI: 52% - 92%), respectively.

Conclusions:
DLIs and/or 2nd HSCT are effective and well tolerated salvage approaches, which resulted in the majority of patients in long-term freedom from disease.

Disclosures:
No relevant conflicts of interest to declare.