Hematopoietic stem cell transplantation from non‐sibling matched family donors for patients with thalassemia major in Jordan

There are limited data on the outcome of patients with thalassemia receiving HSCT from non‐sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non‐sibling matched family donors identified. We report on seven patients with a median age of eight yr (4–21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4–47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13–20) and 16 days (11–20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow‐up of 69 months (7–110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non‐sibling matched family donor can result in excellent outcome.     

Autoimmune thyroiditis following HLA‐matched sibling hematopoietic stem cell transplantation for Wiskott‐Aldrich syndrome

WAS is a fatal X‐linked combined immunodeficiency syndrome, the only cures for which are HSCT or gene therapy. AID occur in up to 72% of patients with WAS who do not receive HSCT, likely arising secondary to impaired multilineage immune autoregulatory function; AITD is not typically seen. In this article, we describe the case of a male patient who underwent HLA‐matched HSCT for WAS at the age of 5 months, with his sister (a WAS carrier) acting as his donor and subsequently developed AITD 12 months post‐transplant, with marked elevation of antithyroid peroxidase antibody titer. His donor sister was subsequently found to have elevated antithyroid peroxidase antibody titer with increasing trend and normal thyroid function. Although several mechanisms exist by which our patient may have developed AITD, we suggest the transfer of autoreactive donor immune cells as the most plausible explanation.     

Hematopoietic stem cell transplantation with a reduced‐intensity conditioning regimen in pediatric patients with Griscelli syndrome type 2

Partial albinism with variable immunodeficiency are the two major characteristics of Griscelli syndrome type 2 (GS‐2). This syndrome is usually associated with a high mortality rate and commonly results in early childhood death. Patients suffer from different infections and experience crisis of HLH. HSCT remains the sole curative treatment for GS‐2. We prospectively analyzed the outcomes of transplantation with RIC regimen in five patients. The median age at transplantation was 21.6 months (range: 12–30). All of the patients underwent HSCT from HLA‐matched related donors. Currently, four patients are cured, and symptoms of recurrent infections and HLH crisis are not seen in them. The only patient who died had undergone HSCT in the accelerated phase of HLH. One patient who developed acute GvHD had a favorable response to therapy. No chronic GvHD occurred in patients. It seems that the use of RIC regimen as a method of transplant preparation is effective and tolerable in this group of patients with various comorbidities. It is recommended to carry out HSCT in these patients at lower ages, before presentations of different infections and HLH crisis.     

Non‐total body irradiation myeloablative conditioning with intravenous busulfan and cyclophosphamide in hematopoietic stem cell transplantation for malignant infantile osteopetrosis

HSCT is the only curative treatment for MIOP. We prospectively investigated the outcome of HSCT using intravenous busulfan‐based conditioning regimen from 2008 to 2013. Nineteen patients (median age = 17 months) underwent transplantation from HLA‐matched related donors (n = 14), HLA‐haploidentical related donors (n = 2), partially matched cord blood donors (n = 2), and HLA‐matched unrelated donor (n = 1). Bone marrow (n = 9), peripheral blood (n = 8), and cord blood (n = 2) were used as stem cell sources. All but one patient demonstrated primary engraftment. Two patients experienced secondary graft failure. During the follow‐up period, three patients showed mixed chimerism (45%, 45%, and 70% of donor cells were engrafted in each one of these patients) but are disease free. Two‐yr OS and DFS were 84.2% and 73.7%, respectively. Improvement of visual acuity and partial reversal of mild conductive hearing loss occurred in two and four patients, respectively. The causes of death among three patients were infection, GvHD, and disease progression. In conclusion, due to major side effects of MIOP such as visual and hearing loss, early treatment using myeloablative conditioning without irradiation HSCT is suggested. The use of an HLA‐matched related donor seems to be highly successful in this regard. Also, according to results of our study, mixed chimerism may be sufficient to resolve symptoms of disease.     

Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita

DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen.     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

Transplant‐related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant‐related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high‐risk group (P = .006). High‐risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.     

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

Pillai A, Hartford C, Wang C, Pei D, Yang J, Srinivasan A, Triplett B, Dallas M, Leung W. Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.
Pediatr Transplantation 2011: 15: 628–634. © 2011 John Wiley & Sons A/S. Abstract: To assess whether a tolerance‐induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA‐matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT (n = 5). Immunoprophylaxis was CSA and short‐course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow‐up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I–II: 1 (11%), Grade III–IV: 0%; MUD, Grade I–II: 1 (20%), Grade III–IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive‐compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.     

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome

Background

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT).

Procedure

In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center.

Results

A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant.

Conclusions

Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.     

Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation

Liu H, Wang X, Geng L, Tang B, Tong J, Yao W, Wang Z, Sun Z. Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.
Pediatr Transplantation 2010: 14:465–470. © 2009 John Wiley & Sons A/S. Abstract: GF is a common and life‐threatening complication of UCBT. Here, we report that successful second transplantation of five patients using G‐CSF‐mobilized maternal stem cells with non‐myeloablative conditioning after GF following double UCBT. The median interval between the two transplants were 38 days. The first transplantation was administered after myeloablative conditioning for hematologic malignancies (n = 3), and rabbit ATG in combination with cyclophosphamide for SAA (n = 2). The second conditioning consisted of Flu and ATG‐based non‐myeloablative regimen. All five patients acquired quick and sustained engraftment after the second transplant. Treatment‐related toxicity was minimal. Three patients developed acute GVHD (>grade II = 1). Three patients developed chronic GVHD (limited = 1, extensive = 2). Severe infectious episodes were significant but manageable. With a median follow‐up of 713 days (592–1127), all patients have currently had an event‐free survival. These results indicate that a second transplant with non‐myeloablative conditioning using mother as the donor for young patient after GF is feasible.     

Outcomes of pediatric identical living‐donor liver and hematopoietic stem cell transplantation

Chronic IS is associated with significant morbidity in transplant recipients. Moreover, IS does not prevent chronic graft failure frequently. Allograft immune tolerance in LT can be induced by complete donor chimerism through allogenic HSCT combined with identical LDLT. This approach may exempt patients from chronic lifelong IS. However, it is unclear whether its benefits justify its risks. Here, we present three cases from our institution and analyze seven additional reports of children treated with HSCT/LDLT, all receiving HSCT due to hemato‐oncological indications. In eight of 10 cases, donor macrochimerism resulted in allograft tolerance. Nine patients survived. One patient died due to fulminant ADV infection. Further complications were GvHD (n = 3) and bone marrow failure (n = 2). In conclusion, donor‐specific allograft tolerance can be achieved by identical‐donor HSCT/LDLT. However, at present, this approach should generally be limited to selected indications due to a potentially unfavorable risk–benefit ratio. Novel toxicity‐reduced conditioning protocols for HSCT/LDLT in the absence of malignant or non‐hepatic disease may prove to be a sufficiently safe approach for inducing graft tolerance in children receiving a LDLT in the future. This concept may reduce the burden of lifelong IS.     

Allogeneic hematopoietic stem cell transplantation for Chediak–Higashi syndrome

The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC‐HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease.     

Purtscher‐like retinopathy: A rare presentation of hematopoietic stem cell transplant‐associated thrombotic microangiopathy

Hematopoietic stem cell transplant (HSCT)‐associated (TA) thrombotic microangiopathy (TMA) is an acquired disorder and a potentially life‐threatening complication after allogeneic HSCT. TA‐TMA causes endothelial damage and results in micro‐thrombi in capillaries and arterioles. Early detection and treatment of complications associated with TA‐TMA might improve outcomes. Purtscher‐like retinopathy (PLR) is associated with micro‐thrombi that occlude the retinal arteries and cause retinal injury. PLR has been associated with multiple entities, including HUS and TTP, but has not previously been described in the setting of TA‐TMA. Here, we describe an 18‐year‐old male who underwent a mismatched unrelated donor HSCT for relapsed acute lymphoblastic leukemia. The patient was diagnosed with TA‐TMA based on standard defined criteria. He presented with acute onset of blurred vision with findings of multiple white retinal patches, retinal hemorrhages, and macular edema, thought initially to be hypertensive retinopathy. However, on further evaluation using fluorescein angiography and optical coherence tomography, the diagnosis was determined to be PLR. The patient was treated with intravitreal steroid injections (triamcinolone acetonide) with dramatic improvement of vision. The aim of this report is to make clinicians aware of PLR as a potential ocular complication associated with TA‐TMA and that prompt intervention might reverse visual impairment.     

Changing outcomes for children requiring intensive care following hematopoietic stem cell transplantation

Past literature has shown that respiratory failure following hematopoietic stem cell transplant is associated with a universally poor outcome with mortality rates approaching 100%. More recent studies have suggested that patient survival is improving. We report our experience with the patients from our institution, a large children's hospital, who were admitted to the intensive care unit (ICU). Medical records of 183 patients, who received a bone marrow transplant between 1992 and early 2004, who were <20 yr of age, were retrospectively reviewed. Various factors that might influence mortality were examined. Over the course of the study, the ICU survival increased from 18% during the period 1992-1999 to 59% between 2000 and early 2004. In the latter period, 54% of the patients discharged from the ICU were alive at 100 days post-transplant. Factors that were significant predictors of poor outcome were malignancy as the reason for transplant, dialysis during the ICU stay, or extreme respiratory failure with a ratio of arterial oxygen tension (PaO2)/inspired oxygen concentration (FiO2) <300. Analysis of patients who required a high positive end-expiratory pressure or were ventilated with permissive hypercapnia showed that they also had a higher mortality. The impact on survival of factors such as age at time of transplant, graft-vs.-host disease, pneumonia, bacteremia, sepsis, post-transplant days, Pediatric Risk of Mortality III score, engraftment status, or veno-occlusive disease did not reach statistical significance in this cohort. Survival has improved for children who require intensive care following a bone marrow transplant, even for those who require mechanical ventilation. Patients with extreme respiratory failure and those requiring dialysis continue to have poor outcome. Because of an overall improvement in survival, children whose condition following transplant requires intensive care should be treated aggressively.     

Successful use of reduced‐intensity conditioning and matched‐unrelated hematopoietic stem cell transplant in a child with Diamond‐Blackfan anemia and cirrhosis

For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14‐yr‐old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%.