Transplant for non-malignant disorders: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the role of alternative donors, stem cell sources and graft engineering.

Hematopoietic stem cell transplantation (HSCT) is curative for many non-malignant disorders. As HSCT and supportive care technologies improve, this life-saving treatment may be offered to more and more patients. With the development of new preparative regimens, expanded alternative donor availability, and graft manipulation techniques, there are many options when choosing the best regimen for patients. Herein the authors review transplant considerations, transplant goals, conditioning regimens, donor choice, and graft manipulation strategies for patients with non-malignant disorders undergoing HSCT.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

PURPOSE: Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS). METHODS: We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years). RESULTS: With a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%. CONCLUSION: This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04232085.

Primary Immune Deficiency: Patients' Preferences for Replacement Immunoglobulin Therapy.

Purpose: Immunoglobulin (Ig) replacement therapy is an important life-saving treatment modality for patients with primary antibody immune deficiency disorders (PAD). IVIG and SCIg are suitable alternatives to treat patients with PAD but vary in key ways. Existing evidence on patient preferences for Ig treatments given the complexities associated with IVIG and SCIg treatment is limited and fails to account for variations in preferences across patients. For this reason, we sought to evaluate PAD patient preferences for features of IVIG and SCIg across different patient characteristics. Materials and Methods: 119 PAD patients completed a discrete-choice experiment (DCE) survey. The DCE asked respondents to make choices between carefully constructed treatment alternatives described in terms of generic treatment features. Choices from the DCE were analyzed to determine the relative influence of attribute changes on treatment preferences. We used subgroup analysis to evaluate systematic variations in preferences by patients' age, gender, time since diagnosis, and treatment experience. Results: Patients were primarily concerned about the duration of treatment side effects, but preferences were heterogeneous. This was particularly true around administration features. Time since diagnosis was associated with an increase in patients' concerns with the number of needles required per infusion. Also, patients appear to prefer the kind of therapy they are currently using which could be the result of properly aligned patient preferences or evidence of patient adaptive behavior. Conclusions: Heterogeneity in preferences for Ig replacement treatments suggests that a formal shared decision making process could have an important role in improving patient care.

Prevalence of prolonged and chronic poliovirus excretion among persons with primary immune deficiency disorders in the Philippines

OBJECTIVES: As part of the global initiative to eradicate poliovirus infections this study aims to: (1) estimate the prevalence of vaccine-derived poliovirus excretion among persons diagnosed with primary immune (B-cell or combined B/T-cell) deficiency disorders (PIDD) in the Philippines; (2) describe clinical features of these PIDD patients excreting poliovirus; (3) genetically characterize vaccine-derived polioviruses isolated from persons with PIDDs; and (4) determine the duration of poliovirus excretion among subjects who tested positive for vaccine-derived poliovirus excretion. METHODS: Seventy-one (71) Filipino patients (ages 0-35 years of age) with PIDD were recruited retrospectively and prospectively over a period of 16 months. The study participants, after informed consent and administration of a questionnaire for baseline data, underwent further testing of quantitative immunoglobulin levels (IgG, IgA, and IgM) and stool poliovirus isolation using two stool samples. Stool specimens which tested positive for the poliovirus were sent to the Regional Reference Laboratory in Australia for further characterization by Intratypic Differentiation (ITD) and Vaccine-derived polioviruses (VDPV) real-time PCR. These participants were then monitored on a monthly basis until laboratory tests identified two sequential months of negative poliovirus stool specimens. RESULTS: Seventy-one (71) patients underwent interview and quantitative serum immunoglobulin testing. However, one patient expired prior to stool isolate collection. This study, then, documented that none of the remaining 70 Filipino individuals (0-35 years old) with confirmed or suspected PIDDs chronically excreted immunodeficiency-associated vaccine-derived poliovirus (IVDPV). One patient who was a recent OPV-recipient excreted poliovirus Sabin-like 1 transiently (less than 1 month) and two patients excreted non polio-enteroviruses. CONCLUSIONS: Chronic and prolonged poliovirus excretion appears to be uncommon among Filipino patients with diagnosed Primary Immunodeficiency Disease Disorders. However, as part of the continuing global initiative for poliovirus eradication, vigilance is still necessary in patients with primary immunodeficiency diseases. Adequate identification of these patients followed by monitoring their capacity for viral excretion and environmental contamination may be necessary to achieve this goal.