Jignesh Dalal

Role of mesenchymal stem cell therapy in Crohn's disease

Many trials of mesenchymal stem cells (MSCs) have been published in the past 5–6 y. MSCs inhibit T-cell alloreactivity in vitro by soluble factors and direct cell-to-cell contact. They are safe to infuse in humans with no acute toxicity and no ectopic tissue formation. Promising results of MSC infusion for graft-vs.-host disease and fistulizing Crohn’s disease (CD) have been published. Treatment of CD requires a comprehensive treatment approach to maintain symptomatic control, improve health-related quality-of-life measures, and minimize complications from the disease. In this review, we will discuss the results of clinical trials using a novel treatment in the form of MSCs for treatment of CD and related complications. Success of these phase I, II, and III trials have set the stage for usage of this novel treatment for children with CD.

Successful Matched Sibling Donor Marrow Transplantation Following Reduced Intensity Conditioning in Children with Hemoglobinopathies

Fifty‐two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion‐dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan–Meier probabilities of overall and event‐free survival at a median of 3.42 (range, 0.75–11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment‐related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17–18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901). Am. J. Hematol. 90:1093–1098, 2015.

Refractory Pure Red Cell Aplasia Manifesting as Deficiency of Adenosine Deaminase 2

Primary progress has been made in the last 2 years, particularly in finding novel disease-causing genes for a number of autoinflammatory diseases and primary immunodeficiencies. Whole-exome sequencing has dramatically increased the pace at which causative genes are being discovered. CECR1 (Cat eye syndrome chromosome region, candidate 1) gene encodes adenosine deaminase 2 (ADA2) protein. Patients who carry CECR1 mutation(s) suffer from deficiency of ADA2 (DADA2). Here, we describe a patient with pure red cell aplasia discovered to have DADA2. We also review the literature on DADA2. This report will help raise awareness of physicians for this complex disease.

Outcomes after Hematopoietic Stem Cell Transplantation for Children with I-Cell Disease

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.

Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation

To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations.

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality.

Emerging uses for pediatric hematopoietic stem cells

Many new therapies are emerging that use hematopoietic stem and progenitor cells. In this review, we focus on five promising emerging trends that are altering stem cell usage in pediatrics: (i) The use of hematopoietic stem cell (HSC) transplantation, autologous or allogeneic, in the treatment of autoimmune disorders is one. (ii) The use of cord blood transplantation in patients with inherited metabolic disorders such as Hurler syndrome shows great benefit, even more so than replacement enzyme therapy. (iii) Experience with the delivery of gene therapy through stem cells is increasing, redefining the potential and limitations of this therapy. (iv) It has recently been shown that human immunodeficiency virus (HIV) infection can be cured by the use of selected stem cells. (v) Finally, it has long been postulated that HSC-transplantation can be used to induce tolerance in solid-organ transplant recipients. A new approach to tolerance induction using myeloid progenitor cells will be described.

Hematopoietic Stem Cell Transplantation for CD3δ deficiency

BACKGROUND CD3δ deficiency is a fatal form of severe combined immunodeficiency that can be cured by hematopoietic stem cell transplantation (HSCT). The presence of a thymus loaded with T-cell progenitors in patients with CD3δ deficiency may require special considerations in choosing the regimen of conditioning and the type of HSCT. OBJECTIVES To study the outcome of CD3δ deficiency by using various modalities of stem cell transplantation. METHODS We analyzed data on 13 patients with CD3δ deficiency who underwent HSCT in 7 centers. HSCT was performed by using different sources of donor stem cells as well as various conditioning regimens. RESULTS One patient received stem cells from a matched related donor and survived after a second transplant, needing substantial conditioning in order to engraft. Only 2 of 7 other patients who received a mismatched related donor transplant survived; 2 of them had no conditioning, whereas the others received various combinations of conditioning regimens. Engraftment of T cells in the survivors appears incomplete. Three other patients who received stem cells from a matched unrelated donor survived and enjoyed full immune reconstitution. Two patients received unrelated cord blood without conditioning. One of them has had a partial but stable engraftment, whereas the other engrafted well but is only 12 months after HSCT. We also report here for the first time that patients with CD3δ deficiency can present with typical features of Omenn syndrome. CONCLUSIONS HSCT is a successful treatment for patients with CD3δ deficiency. The small number of patients in this report prevents definitive statements on the importance of survival factors, but several are suggested: (1) HLA-matched donor transplants are associated with superior reconstitution and survival than are mismatched donor transplants; (2) substantial conditioning appears necessary; and (3) early diagnosis and absence of opportunistic infections may affect outcome.

SUCCESSFUL MOBILIZATION WITH AMD3100 AND FILGRASTIM WITH ENGRAFTMENT OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN A HEAVILY PRETREATED PEDIATRIC PATIENT WITH RECURRENT BURKITT LYMPHOMA

The authors report a case of a 13-year-old female with recurrent Burkitt lymphoma who was heavily pretreated with chemotherapy. During chemotherapy for relapse, she developed serious aspergillus infection of the palate and sinuses. Despite 10 μg/kg of filgrastim for 5 days, peripheral blood CD34+ cells remained ≤1/μL. Hematopoietic progenitor cells were subsequently successfully mobilized with a combination of AMD3100 and filgrastim without tumor or fungus contamination. After transplantation, the patient achieved complete engraftment without exacerbation of fungal infection. This is the first case report of a pediatric patient with relapsed Burkitt lymphoma with mobilization of hematopoietic progenitor cells by AMD3100 without any adverse reactions.

Successful Treatment of Fanconi Anemia and T-Cell Acute Lymphoblastic Leukemia

Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia.