The Use Of Donor Lymphocyte Infusion (DLI) For Relapse After Related T-Cell Replete HLA-Haploidentical Bone Marrow Transplantation (haploBMT) With Posttransplantation Cyclophosphamide (PTCy)
Authors: Zeidan Amer M. , Forde Patrick , Symons Heather J. , Chen Allen R. , Smith B. Douglas , Fuchs Ephraim J. , Luznik Leo , Jones Richard J. , Bolaños-Meade Javier 
Published: October 2019

Background
HaploBMT with PTCy has now been shown by multiple groups to produce results similar to that seen with matched sibling allogeneic BMT. The use of donor lymphocyte infusion (haploDLI) to treat relapse after haploBMT is not well documented due to theoretical concerns of inducing severe graft-versus-host-disease (GvHD). Here we report our experience of using DLI for relapse after haploBMT.

Methods
We identified all haploBMT recipients at Johns Hopkins University who received haploDLI for relapse between 6/2003 and 10/2012. Responses were evaluated by standard disease-specific criteria. GvHD was scored using the Keystone and Seattle criteria for acute (a) and chronic (c) GvHD. Duration of survival and response were calculated from date of first haploDLI administration. Patients (pts) were followed till 12/2012.

Results
Forty pts received 52 haploDLI doses for relapse after haploBMT (16 acute myeloid leukemia [AML], 3 acute lymphoid leukemia [ALL], 5 Hodgkin lymphoma [HL], 7 non-Hodgkin Lymphoma [NHL], 1 myelodysplastic syndrome [MDS], and 9 others). All pts received PTCy, tacrolimus and mycophenolate mofetil for GvHD prophylaxis after haploBMT. Median time from haploBMT to relapse was 183 days; 7 relapses diagnosed within 3 months (M) of haploBMT, 25 relapses within 1 year (yr). Chemotherapy was preadministered to 33 haploDLI doses in 28 pts. 35 pts received haploDLI for florid hematologic relapse, 4 for new minimal residual disease (MRD) relapse detected by cytogenetics or flow cytometry, and 1 for progressive loss of donor chimerism concerning for relapse. Median age at haploDLI administration was 48 yrs (3-70 yrs). No GvHD prophylaxis was administered after haploDLI. The first haploDLI dose received was 1X10^5 CD3+/kg of recipient ideal weight (IBW) in 5 pts, 1-5x10^6 in 31, and 1x10^7 in 4. Thirty-two pts received 1 dose of haploDLI while 8 pts received escalating doses of DLI. Median follow-up was 7M (0.5–98M).
Ten pts (25%) developed aGvHD (6 pts had grade 3-4 and 8 pts had grade 2-4). Of 8 pts with grade 2-4 aGvHD, 5 pts received a dose of 1x10^6 and 2 pts received 1x10^7 CD3+/kg dose. 2 pts with GvHD (both grade 3) died within 6 weeks of DLI from sepsis. 3 pts developed cGvHD (2 extensive, 1 limited). Twelve pts responded to haploDLI (30%), all with complete responses (CR), with a median response of 13 M (1.5-96 M). 5 pts had AML, 1 ALL, 1 MDS, 1 HL, 3 NHL, and 1 prolymphocytic leukemia. 10 responders received haploDLI within 4 M of relapse. 10 responders received only 1 haploDLI. 9 pts responded to haploDLI dose of 1-5x10^6 CD3+/kg. 11 had pre-haploDLI chemotherapy or radiation. 3 of the 4 pts treated for MRD relapse responded (75%), while 9 of the 35 treated for florid hematologic relapse responded (26%). Eight CR occurred following the 30 haploDLI doses of 1x10^6 CD3+/kg (26.7%). The CR rate following haploDLI among AML pts was 31.3%. At end of follow-up, 8 of the 12 responders were still alive and in CR, including 5 pts beyond 1-yr post DLI. Five responders developed clinically significant GvHD post haploDLI (3 grade 2-4 aGvHD, 2 extensive cGvHD).

Conclusions
In our experience in a relatively small number of pts, haploDLI administration for relapse following T-cell replete haploBMT with PTCy is feasible, not associated with unacceptable toxicities, and can result in lasting favorable outcomes. HaploDLI dose of 1x10^6 CD3+/kg of recipient’s IBW appears to be a reasonable starting dose in this setting. Similar to DLI use in the HLA-matched setting, use of haploDLI for MRD relapse seems to result in better outcomes. The CR rate after haploDLI in AML was 31% (5 of 16 pts), similar to what is reported for DLI use in the HLA-matched setting. Small numbers preclude conclusions about disease-specific efficacy of haploDLI in other diseases. Prospective evaluation is required to confirm these findings.

Disclosures:
Off Label Use: entinostat for MDS. Luznik:Otsuka Pharmaceutical: Research Funding.