Donor Specific Antibody Desensitization with Daratumumab Prior to Hematopoietic Cell Transplant for Sickle Cell Disease: A Case Report

To the Editor:

Allogeneic hematopoietic cell transplant (alloHCT) is the only widely available cure for sickle cell disease (SCD), with 3-year event-free survival (EFS) of 89% and 3-year overall survival (OS) 96% in children receiving a myeloablative matched sibling donor (MSD) transplant. Donor paucity of MSD and matched unrelated donors (MUD) limits alloHCT with the latter available for <20% non-Caucasian patients. Although alternative donors have a lower EFS compared to MSD, there is no significant difference in EFS among non-sibling donors.¹ Approximately 23% of patients have detectable HLA-antibodies, that when specific to the donor (DSA) increase the risk of primary graft failure (GF) resulting in worse OS.^2–4 Desensitization strategies to reduce DSA levels include antibody adsorption, therapeutic plasmapheresis, intravenous immunoglobulin (IVIg), immunosuppressive chemotherapy (e.g. cyclophosphamide, fludarabine), and antibody depletion (e.g. rituximab or bortezomib).^{2, 3, 5}

We present a single case report for a pre-transplant immune suppression (PTIS) approach, novel to sickle cell disease, with suboptimal response to traditional PTIS and desensitization with subsequent successful haploidentical donor engraftment.

Our patient is a 23-year-old female with severe sickle-beta thalassemia (HbS/B⁰) characterized by multiple disease specific complications and frequent, prolonged, and progressive vaso-occlusive episodes necessitating multiple hospital admissions annually, chronic pain, and poor quality of life. Hydroxyurea, crizanlizumab and voxelotor were unsuccessful. The patient had a history of red cell antibodies (anti-E, anti-K, anti-Fya, anti-N, and anti-s), and additionally, anti-C and anti-Leb were detected serologically (Bio-Rad IH-1000 System) during our evaluation. Human Erythrocyte Antigen genotyping (Immucor PreciseType Human Erythrocyte Antigen 1.2 BeadChip DNA array) revealed C-, E-, K-, Fya-, N-, s-, and Leb- confirming risk of forming all of the alloantibodies previously detected. The patient received phenotypically matched red cells, nevertheless she developed acute hemolysis following first red cell exchange (RCE) prior to apheresis with a significant decrease in her hemoglobin of 3.6 g/dL. No additional antibodies were detected at this time. Safe phenotypically matched RCEs for multiple expected apheresis cycles for gene therapy protocol became challenging. Given this risk, the patient was removed from the protocol and alloHCT options were explored. In the absence of suitable donors, paternal haploidentical transplantation was her only curative option. HLA class I DSA against A33, B78 and Cw2 at baseline were >10000 MFI (16557, 10720 and 11163 MFI respectively, detected using solid phase immunoassays, including Single Antigen Bead assays for antibody identification). PTIS included rituximab, bortezomib, dexamethasone, fludarabine, cyclophosphamide, and IVIg, followed by 11 therapeutic plasma exchange (TPE) sessions with persistent high DSA levels (Figure 1, Supplementary Table 1). Outside of an IRB protocol, the patient then received in a compassionate approach, 8 doses of daratumumab (Darzalex®, Janssen Biotech, Inc.) with no adverse infusion reactions, followed by 6 additional TPE sessions, and a dose of rituximab given B-cell recovery. This regimen, led to undetectable Cw2 antibody, along with substantial reductions of A33 and B78 (2500 and 600 MFI respectively). She received myeloablative conditioning with model based dosing rabbit anti-thymocyte globulin (rATG)⁶, busulfan (cumulative exposure of 90mg*h/L) and fludarabine (160mg/m2) from days −6 to −2 and haploidentical graft with unmodified peripheral blood stem cells (PBSC) (CD34+ count of 7.09 × 10⁶ cells/kg) followed by post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (MMF) for GVHD prophylaxis. Neutrophils recovered on day +19 with 100% donor chimerism (CD33, CD3, CD56 lineages) at day +28. Given persistent severe thrombocytopenia, a bone marrow evaluation was done on day +45 demonstrating normal cellularity, maturing trilineage hematopoiesis, mild megakaryocytic hypoplasia and 100% donor chimerism. DSA levels on day +51 were <1000 MFI (A33 400 MFI, B78 400 MFI, Cw2 not detected). The patient initiated romiplostim on day +48 achieving platelet transfusion independence by day +72. Follow-up at time of this submission is day + 311 post-transplant and the patient is doing clinically well, off immunosuppression, with no evidence of GVHD. Immune reconstitution was achieved with sustained absolute counts >50 cell/uL (CD4+ = 253 cell/uL), and platelet count improved (97000 cell/uL).

Figure 1.

Correlation of DSA MFI level and desensitization regimen over time

The rationale that PTIS, coupled with targeted intensification of the preparative regimen would facilitate sustained engraftment in patients with mismatched donors has driven the emergence of various PTIS strategies. Anurathapan et al. developed a regimen consisting of two pre-transplant courses of fludarabine and dexamethasone combined with a low dose rATG; conditioning with fludarabine and busulfan; and GvHD prophylaxis with PTCy, tacrolimus or sirolimus, and MMF.⁷ The authors reported outcomes in 83 patients with thalassemia whom received haploidentical filgrastim-mobilized PBSC grafts. Among the first 31 patients, there were two primary GF, both in patients with DSAs > 1:3,000. The protocol was amended to include (1) pre-transplant rituximab and bortezomib for recipients with high-titer DSAs, (2) plasmapheresis for patients with DSA levels >1:1,000 after rituximab/bortezomib, and (3) pharmacokinetic-guided busulfan dosing. Subsequently, there were no primary or secondary GF. Estimated 3-year OS and EFS were 96%. Seven patients developed grade III–IV acute GvHD, and 3 experienced extensive chronic GvHD. Pawlowska et al. reported a series of 4 patients with SCD who underwent haploidentical HCT according to this program.⁸ Three patients received marrow grafts, and one received a PBSC graft. One patient required TPE, IVIg and rituximab for persistently elevated DSA. All patients engrafted with full donor chimerism at 5–11 months post-transplant. There was no grade ≥ II GvHD or treatment-related mortality. Given these successful results, a clinical trial evaluating PTIS with myeloablative conditioning and PTCy in patients with hemoglobinopathy is ongoing (NCT NCT05736419).

In our patient MFI remained >5000 despite intensive desensitization resulting in plasma and B-cell aplasia. Daratumumab is an anti-CD38 humanized monoclonal antibody, approved for refractory/relapsed multiple myeloma, and utilized to manage post-transplant antibody-mediated complications including warm autoimmune hemolytic anemia, Evans syndrome, red cell aplasia and hepatitis.^9–12 There are several reports of the use of daratumumab for antibody-mediated rejection in solid organ transplantation^{13, 14} but only three cases reporting on its use in DSA reduction in the alloHCT setting (Table 1).^{4, 15, 16} To date, this is the first report of this indication in SCD.

Table 1:

Reported Use of Daratumumab for DSA Desensitization

Study	Sex, Age, Diagnosis	Desensitization regimens	DSA MFI (range)	Graft Source	Conditioning	Time to neutrophil engraftment (days)	Donor Chimerism
Lipsitt, et al.4	Female, 21 y Severe aplastic anemia	1st course (Day −147 to 107): Bortezomib (6 doses) Rituximab (4 doses) TPE (5 sessions) 2nd course (Day −93 to −10): Daratumumab (6 doses) Rituximab (2 doses), TPE with IVIg (8 sessions)	Baseline: 8000–25000 Pre-Transplant: <1000 −8000 Post-Transplant: <2000	Haploidentical (related)	RIC (ATG, FLU, CY, TBI)	14	Day +28 100%
Li, et al.14	Female, 36 y B cell acute lymphoblastic leukemia	Leukemia therapy included two cycles of daratumumab combined with etoposide and venetoclax Desensitization post daratumumab: Prednisone (Day −7 to day 0) IVIg (0.5 g/kg, on day −2, −1)	Baseline: 14776 – 19606 Post 2 cycles: 6366 – 10649 Day 0: 6141 – 12144 Day +7: All negative	Haploidentical (related)	MAC (TBI, CY, FLU, ARA-C)	17	Day +28 100%
Ibrahim, et al.15	Female, 60 y JAK2 mutated post-essential thrombocythemia myelofibrosis	First course: Rituximab TPE (3 sessions) Second course: Daratumumab (8 doses) Third course: Daratumumab (9 doses) Bortezomib (8 doses) Followed by TPE (7 sessions) with IVIg, and tacrolimus and MMF (Day – 15 to −1)	Baseline: 18600 Post 1st course: 7069 Post 2nd course: 248 12-week rebound: 11786 Post 3rd course: 4921 Day −1: 534	9/10- HLA matched unrelated donor	MAC (TT, BU, FLU)	25	Day +30, CD33 100% Day +60 CD3 100%

DSA: donor specific antibody; MFI: mean fluorescent intensity; TPE: therapeutic plasma exchange; IVIg: intravenous immunoglobulin; MMF: mycophenolate mofetil; RIC: reduced-intensity conditioning; MAC: myeloablative conditioning; ATG: antithymocyte globulin; FLU: fludarabine; CY: cyclophosphamide; ARA-C: cytarabine; BU: busulfan; TT: thiotepa

AlloHCT recipients with complement binding DSA (positive C1q status) are at the highest risk of primary GF,² however the risk of GF in allo-sensitized patients with negative C1q status remains a concern, and it has not been specifically evaluated in patients with hemoglobinopathies. Therefore, C1q status was not assessed prior to PTIS. This patient received multiple interventions for the reduction of DSA levels and despite the chronology of DSA reduction, we are unable to attribute this result to daratumumab itself. Further study of this intervention should be pursued in the context of a clinical trial. As alternative donor platforms improve, novel strategies towards successful transplantation addressing harmful DSAs are a high priority.