Non‐myeloablative human leukocyte antigen‐matched related donor transplantation in sickle cell disease: outcomes from three independent centres

Abstract

Summary Non‐myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim‐mobilized peripheral blood HPC and sirolimus. The median follow‐up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle‐free survival at one and five years were 93% and 85% respectively. Age, sex, pre‐HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft‐versus‐host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle‐related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well‐tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.

Alemtuzumab clearance, lymphocyte count, and T‐cell chimerism after hematopoietic stem cell transplant in sickle cell disease

“…Many nonmyeloablative and reduced-intensity conditioning (RIC) HSCT regimens for SCD utilize alemtuzumab, a monoclonal antibody that targets the cell surface antigen CD52 found on lymphocytes. [11][12][13][14][15] The pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab have been examined, but primarily in patients with malignant conditions. [16][17][18] In a population PK/PD model created based on the data from patients with chronic lymphocytic leukemia (CLL), alemtuzumab appears to have a non-linear, time-dependent clearance that is affected by the white blood cell count (WBC).…”

“…19 In contrast, our HSCT regimens for SCD used gradually increasing doses of alemtuzumab from 0.03 to 0.3 mg/kg/day, totaling 1.03 mg/kg over a 5-day period starting 7 days prior to the hematopoietic stem cell infusion. 11,12 Other HSCT regimens for nonmalignant disorders administered alemtuzumab more distal from the hematopoietic stem cell infusion date, from 22 days pre-HSCT to 19 days pre-HSCT, totaling 33 mg or 48 mg. 20 Because of these varying HSCT regimens, alemtuzumab clearance or the resulting systemic exposure were hypothesized to be a contributing factor to HSCT outcomes. In HSCT, the important elements that determine the overall success of the transplant conditioning regimen are the rates of graft rejection and toxicities from the regimen, such as graft-versus-host disease (GVHD).…”

Long-Term Health Effects of Curative Therapies on Heart, Lungs, and Kidneys for Individuals with Sickle Cell Disease Compared to Those with Hematologic Malignancies

“…While no studies to date report the effects of myeloablative conditioning on FEV1% for adults with SCD, Saraf et al reported that FEV1% significantly improved 1 year post-HSCT compared to baseline in 12 patients with SCD who underwent non-myeloablative conditioning ( Table 3 ) [ 23 ]. In a more recent study of 122 patients, primarily adults, who received non-myeloablative conditioning with a median follow-up of 4 years [ 24 ], FEV1% predicted remained stable throughout follow-up. Further, the proportion of patients with moderate, moderately severe, and severe defects decreased.…”

“…Since then, myeloablative HLA-matched sibling HSCT has emerged as the standard transplant option for eligible children [ 21 ]. HLA-matched sibling HSCT is also highly efficacious in adults using a non-myeloablative approach [ 22 , 23 , 24 ]. As most patients do not have an HLA-matched sibling donor, alternative curative therapy options, including haploidentical HSCT with post-transplant cyclophosphamide, gene therapy, and gene editing, are increasingly available with impressive results [ 25 , 26 , 27 , 28 , 29 , 30 ].…”

Clonal Hematopoiesis and the Risk of Hematologic Malignancies after Curative Therapies for Sickle Cell Disease

“…Indeed, 20% donor myeloid chimerism has been reported to be sufficient to reverse the acute complications of SCD [ 34 , 35 ]. Recently, investigators reported 122 patients, primarily adults, who underwent non-myeloablative HLA-matched sibling HCT at one of three centers [ 36 ]. At a median follow-up of five years, overall survival was 95% and event-free survival 85%.…”