Myeloablative Conditioning with Alemtuzumab in Matched Related Donor Hematopoietic Cell Transplant for Sickle Cell Disease Prevents Graft-Versus-Host Disease without Compromising Engraftment
Authors: John Tami D , Yassine Khaled , Naik Swati , Sasa Ghadir , Omer Bilal , Martinez Caridad A. , Tewari Priti , Krance Robert A. , Leung Kathryn S 
Published: October 2019

Introduction:

Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD) despite risk of graft-versus-host disease and graft rejection. Alemtuzumab is a potent lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy in conjunction with alemtuzumab in MRD HCT for SCD as a method to concurrently prevent GVHD and promote durable engraftment.

Methods:

We retrospectively reviewed engraftment, GVHD and survival for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan dose adjusted to achieve target area under the curve of 800-1200μM per minute with doses administered intravenously every 6 hours for 4 days and cyclophosphamide 50mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15kg=3mg, 15-30kg=5mg, >30kg= 10mg daily), methotrexate and a calcineurin inhibitor.

Donor chimerism was evaluated via short tandem repeats (STR) or fluorescent-in-situ hybridization (FISH) of nucleated cells from the peripheral blood. If MDC was detected, follow-up chimerism studies were obtained every 1-4 weeks until stabilization on 2 or more consecutive evaluations. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up.

Results:

Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor to augment cell dose. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 62.8% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 22 patients (13.6%) with persistent MDC had <50% donor cells. The single patient with severe MDC <25% stabilized at 24% at 2 yrs post-HCT with concurrent Hgb S <50% on electrophoresis reflective of sickle cell trait in the donor. Graft rejection and recurrence of SCD related symptoms (vaso-occlusive crises, acute chest syndrome, stroke) were not observed in any patient at last follow-up. No additional cell products were given to manage mixed chimerism in any patient. Overall incidence of acute GVHD and severe acute GVHD (grade II-IV) were 26.3% and 5.3%, respectively. One patient developed limited chronic GVHD. Overall survival was 94.7% with a median time to last follow-up of 2.9 yrs (range: 90-4627 days). Two deaths occurred secondary to transplant-related complications including 1 death <100 days from HCT due to disseminated Mycobacterium tuberculosis and 1 secondary to hemophagocytic syndrome of uncertain etiology on day +318 from HCT.

Conclusions:

Myeloablative conditioning was well tolerated in this patient population, and the addition of alemtuzumab minimized occurrence of severe GVHD. While MDC was observed, chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred with a median follow-up of 2.9 yrs. The use of this regimen may be a promising approach to achieve low rates of GVHD while maintaining low rates of transplant related complications for patients with SCD that can tolerate myeloablative chemotherapy.

Disclosures

No relevant conflicts of interest to declare.