J.J. Bleesing

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman–Diamond syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman–Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III–IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.

Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT.

Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.

Outcomes following hematopoietic cell transplantation for Wiskott–Aldrich syndrome

HLA-identical sibling donor transplantation remains the treatment of choice for Wiskott–Aldrich Syndrome (WAS). Since 1990, utilization of alternative donor sources has increased significantly. We report the hematopoietic cell transplantation (HCT) outcomes of 47 patients with WAS treated at a single center since 1990. Improved outcomes were observed after 2000 despite the increased number of alternative donors. Five-year OS improved from 62.5% (95% CI: 34.9% to 81.1%) to 90.8% (95% CI: 67.7% to 97.6%) for patients transplanted during 1990–2000 and 2001–2009, respectively. In multivariate analysis, transplant era significantly impacted OS (P=0.04), whereas age was only marginally significant (P=0.06, Cox proportional hazard analysis). No TRM occurred within the first 100 days among patients transplanted during 2001–2009 compared with 3/16 during 1990–2000, (P=0.03, Fishers exact test). The extent of HLA mismatch did not significantly affect the incidence of acute GVHD, chronic GVHD or survival. Post-HCT autoimmune cytopenias were frequently diagnosed after 2001: 17/31 (55%) patients. Their occurrence was not associated with transplant donor type (P=0.53), acute GVHD (P=0.74), chronic GVHD (P=0.12), or post-transplant mixed chimerism (P=0.50).

Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen

Allogeneic hematopoietic cell transplantation (HCT) in patients with Hurlers syndrome can improve survival and ameliorate many aspects of Hurlers syndrome including neurologic decline and cardiac compromise. Unfortunately, the toxicity of traditional preparative regimens to organs affected by the syndrome may have deleterious effects. Additionally, despite the intensity of these regimens, achieving stable donor chimerism can be difficult. We report transplant outcomes following a reduced intensity, highly immunosuppressive preparative regimen consisting of alemtuzumab, fludarabine and melphalan prior to HCT in seven patients with Hurlers syndrome treated at two centers. Six patients received grafts from unrelated donors and one received a sibling donor graft. The preparative regimen was well tolerated. All patients had initial donor engraftment at 100 days; one patient had delayed loss of donor chimerism. There was no severe acute GVHD (no GI GVHD of grade II or more, no grade IV skin GVHD). Six of the seven children are surviving at a median of 1014 (726–2222) days post transplant. This reduced intensity preparative regimen has the potential to support engraftment and improve survival and outcome in patients with Hurlers syndrome undergoing HCT.

Pulmonary hypertension associated with bronchiolitis obliterans after hematopoietic stem cell transplantation.

Pulmonary hypertension (PH) is a rare and potentially fatal complication of hematopoietic stem cell transplantation (HSCT). PH arises from increased pulmonary vascular resistance leading to increased right ventricular pressure (RVP), right heart failure and death.1 PH is often difficult to diagnose as symptoms can be nonspecific, including shortness of breath, fatigue, weakness and hypoxemia, and may also result in death if left untreated.2

The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.

A Prospective Study of Alemtuzumab as a Second-Line Agent for Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric and Young Adult Allogeneic Hematopoietic Stem Cell Transplantation

We describe a single-center prospective study of alemtuzumab as a second-line agent for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) in pediatric and young adult allogeneic hematopoietic stem cell transplant recipients. Alemtuzumab was administered for grades II to IV aGVHD if patients did not improve within 5 days or worsened within 48 hours after corticosteroids. Interim analyses of alemtuzumab levels and response were performed after every 5 patients enrolled, resulting in 3 dosing cohorts, as follows: (1) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 31 mg over 5 days) and .2 mg/kg/dose (not exceeding 10 mg/dose) on days 15, 22, and 29; (2) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 43 mg over 5 days) and .2 mg/kg/dose on day 7, 10, 15, 22, and 29; and (3) .2 mg/kg subcutaneously on days 1 to 5 and .2 mg/kg/dose on day 7, 10, 15, and 22. Alemtuzumab levels were assessed before starting alemtuzumab and at days 1, 3, 6, 10, and 14 and weekly until day 99, where day 1 was the day of first alemtuzumab dose. Fifteen patients (median age, 10 years; range, 1.4 to 27) received alemtuzumab for grades II (6%), III (74%), and IV (20%) SR-aGVHD. The overall response rate was 67%, with complete response (CR) in 40%, partial response (PR) in 27%, and no response in 33%. The median day 6 alemtuzumab level was 2.79 µg/mL (interquartile range, 1.34 to 4.89) in patients with CR compared with .62 µg/mL (interquartile range, .25 to 1.45) in patients with PR + no response (P < .05). Ninety percent (n = 9) of patients with a CR or PR reduced corticosteroid doses within 8 weeks from first alemtuzumab dose. Side effects included fever (26%) and transient thrombocytopenia (53%). Asymptomatic viremias occurred in all patients but invasive viral disease occurred in 2 patients. One patient developed Epstein-Barr virus-post-transplantation lymphoproliferative disorder. Eighty percent (n = 12) of patients were alive at 6 months, of whom 53% (n = 8) were free of GVHD whereas 13% (n = 2) developed chronic GVHD. Alemtuzumab is an effective second-line agent for children and young adults with SR-aGVHD. Higher alemtuzumab levels are associated with CR. A real-time dose adjusted alemtuzumab study is needed to further optimize the dose of alemtuzumab in aGVHD.

A Single-Center Experience Comparing Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning with Myeloablative Busulfan, Cyclophosphamide, and Antithymocyte Globulin for Chronic Granulomatous Disease

Myeloablative conditioning (MAC) regimens are commonly used in transplantation for chronic granulomatous disease (CGD) but are associated with toxicity. Reduced-intensity conditioning (RIC) regimens have lower toxicity but may fail to achieve stable donor chimerism. We report a comparison between 4 patients who received a RIC regimen consisting of alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) and 14 patients who received a MAC regimen consisting of busulfan (area under the curve, 1800 to 2000 µMol/min twice daily × 4 days), cyclophosphamide (50 mg/kg/day × 4), and antithymocyte globulin (15 mg/kg twice daily on days -2 and -1, then daily on days +1 and +2). Seventy-five percent (n = 3) of RIC patients developed mixed chimerism and needed either withdrawal of immune suppression (n = 1) or additional stem cell products (n = 2) to achieve stable donor chimerism. Ninety-two percent (n = 13) of patients in the MAC group maintained >95% donor chimerism. Complications included acute graft-versus-host disease (MAC 64%, RIC 0%), chronic graft-versus-host disease (MAC 28%, RIC 0%), sinusoidal obstructive syndrome (MAC 7%, RIC 0%), bacteremia (MAC 42%, RIC 0%), fungemia (MAC 14%, RIC 0%), viral disease (MAC 7%, RIC 25%), and death (MAC 21%, RIC 0%). A RIC regimen has lower toxicity but frequently requires interventions to maintain donor chimerism compared with a MAC regimen in CGD.

Impaired immune function in children and adults with Fanconi anemia

Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA.