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SAN DIEGO -- A reduced-intensity "half-matched" bone marrow transplant (BMT) protocol demonstrated durable donor engraftment, with encouraging survival rates, in adults with severe sickle cell disease (SCD) for whom stem cell transplantation is ordinarily not feasible, according to a study presented here.

The estimated 2-year event-free survival (EFS) rate among evaluable patients with the modified transplant regimen was 88% (95% CI 73.5-94.8), while the 2-year overall survival (OS) rate post-transplant was 95% (95% CI 81.5-98.7), reported Adetola Kassim, MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

"These results support haploidentical bone marrow transplant with post-transplant cyclophosphamide as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials," Kassim said during a late-breaking abstract session at the American Society of Hematology annual meeting.

Adults with SCD have a shortened lifespan, with a median survival for hemoglobin SS disease -- the most common type of SCD -- of 48 years. Those who have SCD with multiple organ impairments have particularly poor survival odds.

While children with SCD undergoing allogeneic hematopoietic stem cell transplantation from a matched sibling donor have had excellent outcomes, less than 15% of people with SCD have a matched sibling donor. Moreover, myeloablative conditioning can be prohibitively toxic in adults with SCD, and those with severe disease who have organ dysfunction are usually excluded from undergoing transplant.

"So we need less toxicity and more alternative donors," Kassim explained.

With the recent approval of two gene therapies for SCD -- exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) -- Kassim took the opportunity to compare certain aspects of the trials leading to the approvals to his study.

He noted, specifically, that patients in his study received non-myeloablative conditioning, while those patients in the gene therapy studies received myeloablative conditioning, and that haploidentical BMT appeared to be as effective as the gene therapies in improving donor engraftment and hemoglobin levels.

Considering the expense of gene therapy compared with haploidentical BMT, and the fact that only about 5% of patients with SCD live in high-income countries, Kassim suggested it will be easier to scale up the less expensive therapy in order to reach the other 95%.

In this , patients were eligible if they had two or more episodes of acute chest syndrome in the prior 2 years, three or more episodes of vaso-occlusive crises in the prior 2 years, eight or more transfusions per year for ≥1 year to prevent SCD-related complications, and elevated tricuspid regurgitant velocity.

The study enrolled 54 participants (59.3% men, 92.6% Black, and 3.7% Hispanic) from 19 sites. Median age at enrollment was 22.8 years; 47 enrolled participants had hemoglobin SS disease, 40 had a Lansky/Karnofsky score of 90-100 at baseline, and 41 had a human leukocyte antigen match score of 4/8.

The most common indications for transplant included recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%).

Participants were preconditioned with hydroxyurea 30 mg/kg/day, which was followed by a conditioning regimen that included thymoglobulin, thiotepa, fludarabine, cyclophosphamide, and total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, sirolimus, and mycophenolate mofetil (CellCept).

Of the study enrollees, 42 eventually proceeded to transplant. Ten participants started preconditioning with hydroxyurea but did not proceed to transplant, and two did not start hydroxyurea or proceed to transplant. Reasons included donor issues, withdrawal of consent, insurance coverage, and, in one case, death.

Kassim observed that the EFS and OS rates of 88% and 95% are similar to those reported after matched sibling donor myeloablative BMT in children. EFS was defined as survival without primary or secondary graft failure, second infusion of hematopoietic cells, or death.

The cumulative incidence of neutrophil recovery at 42 days after transplant was 92.9%, while the cumulative incidence of platelet recovery to 50,000 was 88.1% at 60 days and 92.9% at 100 days. On day 28, 88.1% of patients achieved full donor chimerism, and 4.8% had low chimerism. The median time to neutrophil engraftment and platelet engraftment was 25.5 and 34.5 days, respectively. Mean hemoglobin level post-transplant was 13.5 gm/dL.

The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2%, and 4.8% for grades III-IV acute GVHD.

There were two deaths in the first year post-transplant (one due to organ failure and the other to acute respiratory distress syndrome) and none in the second year. Most (78.6%) participants reported at least one readmission post-transplant, mainly due to either bacterial infection or viral reactivation.

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