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There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores ≥ 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies., (Copyright © 2018. Published by Elsevier Inc.)

While matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for transfusion-dependent beta-thalassemia (TDT), the use of alternative sources has increased, resulting in the exploration of novel transplant-conditioning regimens to reduce the contribution of graft-versus-host disease (GVHD) and graft failure (GF) to transplant-related morbidity and mortality. Alemtuzumab is a CD52 monoclonal antibody that has been successfully incorporated into myeloablative conditioning regimens for other hematologic conditions, yet there have been limited studies regarding the use of alemtuzumab in HSCT for TDT. The purpose of this study was to evaluate engraftment, incidence of GVHD, and transplant related morbidity and mortality in patients with TDT who received alemtuzumab in addition to standard busulfan-based conditioning. The primary endpoint was severe GVHD-free, event-free survival (GEFS). Our cohort included 24 patients with a median age of 6.8 years (range 1.5-14.9). Eleven patients received a 10/10 MRD HSCT, eleven 10/10 unrelated donor (UD), and two mismatched UD. All patients achieved primary engraftment. For all patients, 5-year GEFS was 77.4% and 5-year overall survival (OS) was 91%. The 5-year cumulative incidence of GF (attributed to poor graft function) without loss of donor chimerism was 13.8% (95% CI: 4.5, 35.3). We report low rates of significant acute GVHD grade II–IV (12.5%) and chronic GVHD (4.4%). Younger age and MRD were associated with significantly improved GEFS, OS and EFS. Our results show that the use of alemtuzumab promotes stable engraftment, may reduce rates of severe GVHD, and results in acceptable GEFS, OS, and EFS. [ABSTRACT FROM AUTHOR]

Abstract: Relapsed ALK‐positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow‐up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced‐toxicity conditioning regimen containing fludarabine, alemtuzumab, and low‐dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant‐related complications were experienced. One patient developed chronic renal disease secondary to transplant‐associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients’ post‐CRZ monotherapy, and further studies may be warranted. [ABSTRACT FROM AUTHOR]

High risk or relapsed pediatric acute myeloid leukemia (AML) is potentially curable with allogeneic hematopoietic stem cell transplantation (HSCT). Significant improvements have been made with supportive care practices, but there are limited HSCT outcome data for pediatric AML patients in the contemporary era. We report retrospective data in 87 pediatric patients with high risk or relapsed AML, who underwent HSCT at a single institution between 2008 and 2018. The median age at time of HSCT was 8 years (range: 0.6-20 years). Forty three patients (49%) were transplanted in CR1, 18 (21%) in CR2, and 26 (30%) with active disease (defined as any evidence of disease at the time of HSCT). Patients were transplanted using matched related (MRD, n=21), matched unrelated (MUD, n=25), mismatched unrelated (MMUD, n=15), haplo-identical (haplo, n=12) or umbilical cord blood (UCB, n=14) grafts. The majority of patients (78/87, 90%) received myeloablative conditioning. MRD and UCB graft recipients did not receive serotherapy. All other graft recipients (n=52) received serotherapy, the majority using an alemtuzumab-based conditioning regimen, 42/52 (81%). Haplo-identical transplants were performed using CD34+ selected grafts. Three-year overall survival (OS) and disease free survival (DFS) for the entire cohort were 52% (95% CI: 41-62%) and 49% (95% CI: 38-59%) respectively. OS differed significantly according to disease status at time of transplant (p=0.018), with 3 year OS: 60%, (95% CI: 43-74%) for those in CR1, 56%, (95% CI: 31-75%) for those in CR2 and 34% (95% CI: 17-52%) for those with active disease. OS differed by donor type (p=0.058). OS was comparable for patients with MRD (71%, 95% CI: 46-86%) and 10/10 MUD (59%, 95% CI: 37-75%) (p=0.67). Patients with alternate donor sources had worse outcomes (MMUD 33%, 95% CI: 10-59%; UCB 43%, 95% CI: 18-66%; Haplo 33%, 95% CI: 10-59%) as compared to MRD (MMUD vs MRD, p=0.042, UCB vs MRD, p=0.046, haplo vs MRD p=0.017). There was a low incidence of Grade III-IV acute GVHD (8%, n=7) and extensive chronic GVHD (9%, n=7) likely secondary to the use of alemtuzumab-based conditioning regimens. The 3-year non-relapse mortality was low at 11% (95% CI: 5-19%). The primary cause of death was relapse, with a 3-year cumulative incidence of relapse of 40%, (95% CI: 30-50%). Patients with active disease at HSCT had significantly higher cumulative incidence of relapse (sHR: 2.42, 95% CI: 1.18-4.95, p=0.016) compared to patients in remission. In the contemporary era, outcomes after allogeneic HSCT are comparable for MRD and 10/10 MUD for pediatric AML. Myeloablative and alemtuzumab based conditioning regimens were well tolerated with low rates of NRM and GVHD. Relapse remains the major cause of treatment failure. Future trials evaluating use of cellular therapies and targeted agents post-HSCT will be needed. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for transfusion-dependent b-thalassemia (TDT). Application of alternative donor HSCT for TDT is more accepted as rates of graft failure (GF) and GVHD decline. Alemtuzumab is a CD52 monoclonal antibody with potent lymphocytic activity that can reduce GVHD risk, though infectious associations have limited its use. We hypothesize that the addition of alemtuzumab to standard myeloablative conditioning in HSCT for TDT will reduce rates of GVHD without affecting engraftment or transplant-related mortality (TRM). We retrospectively reviewed engraftment, GVHD, and survival for TDT patients (pts) who underwent HSCT at Texas Children's Hospital between 2004-2018. All pts received myeloablative conditioning with IV targeted busulfan (AUC of 800-1200 μM per minute), cyclophosphamide 50 mg/kg daily for 4 days, and IV alemtuzumab (5-15kg= 3mg; 15-30kg=5mg; >30kg=10mg) from d -5 through d -2. Pts receiving MUD/MMUD HSCT additionally received fludarabine 30 mg/m2 for 4 days. GVHD prophylaxis included methotrexate (d +1,3,6,11) and a calcineurin inhibitor. Twenty-one consecutive pts underwent MRD (10), MUD (9), or MMUD (2) HSCT with a median age at HSCT of 6.5 yrs (range: 1.5-14.9). Stem cell source consisted of bone marrow (17), peripheral blood (3), MRD umbilical cord and marrow (1). Neutrophil engraftment (ANC>500/ml x 3 d) was achieved in all patients at a median of 19 d (range: 13-29). Median platelet engraftment (platelet > 20,000 × 7 d without transfusion) was 35.5 d (range: 15-123). Median RBC engraftment (Hb >8 g/dL x 7 d without transfusion) was 24 d (range: 10-115). No GF was observed. Poor graft function (PGF) was seen in 2 pts (9.5%) requiring stem cell boost or 2nd HSCT. Overall incidence of acute (grade II-IV) and chronic GVHD (all limited) of 9.5% and 14.2%, respectively. Five-year overall survival was 89.9% with a median follow-up of 3.6 yrs (range: 0-14.4). Two deaths occurred secondary to infections complications in the setting of PGF and GVHD, respectively. Myeloablative conditioning with alemtuzumab minimized the incidence of severe GVHD with good overall survival. GF, GVHD, and TRM rates were improved from previous reports in TDT. PGF in our UD cohort was comparable to previous reports of engraftment complications. The addition of Alemtuzumab is a reasonable strategy to reduce GVHD risk in MRD and UD HSCT for TDT, though durability of engraftment after UD HSCT requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD). Alemtuzumab is a 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 with alemtuzumab in MRD HCT for SCD to concurrently prevent GVHD and promote durable engraftment. Methods We retrospectively reviewed outcomes for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan intravenously every 6 hours for 4 days (target AUC: 800-1200 μM per minute) and cyclophosphamide 50 mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15 kg=3 mg, 15-30 kg=5 mg, >30 kg= 10 mg daily), methotrexate and a calcineurin inhibitor. Donor chimerism was evaluated periodically via short tandem repeats or fluorescent-in-situ hybridization of nucleated cells from the peripheral blood. 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: 2.9-18.4 yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 60.5% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 23 patients (13.0%) 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 were not observed in any patient. No additional cell products were given to manage mixed chimerism. Overall incidence of significant acute GVHD (grade II-IV) was 5.3%. 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 on day +318. Conclusions Myeloablative conditioning was well tolerated, and the addition of alemtuzumab minimized occurrence of significant GVHD. Chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred. This regimen may be a promising approach for patients with SCD that can tolerate myeloablative chemotherapy. [ABSTRACT FROM AUTHOR]