Related Donor Bone Marrow Transplantation Research Articles

Excellent Outcomes Using a Non-Myeloablative Conditioning with Thiotepa and Post -Transplant Cyclophosphamide in Adults Undergoing a Matched Related Donor Bone Marrow Transplant for Severe Sickle Cell Disease

Excellent Outcomes Using a Non-Myeloablative Conditioning with Thiotepa and Post -Transplant Cyclophosphamide in Adults Undergoing a Matched Related Donor Bone Marrow Transplant for Severe Sickle Cell Disease

Bone Marrow Quality Index: A Predictor of Acute Graft-versus-Host Disease in Hematopoietic Stem Cell Transplantation for Thalassemia

Bone marrow continues to be the preferred source of stem cells in allogenic transplantations for non-malignant disorders. Granulocyte-colony stimulating factor (G-CSF)-primed bone marrow (BM) is associated with low rates of acute GVHD and allows reduced collection volumes while ensuring speedy engraftment. However, variability in bone marrow harvest quality is a concern. This report analyses the utility of a novel indicator - Bone Marrow Quality Index (BMQI), which is a ratio of marrow cell count to peripheral blood cell counts, to predict acute GVHD. We analysed 184 consecutive first matched related donor bone marrow transplants for thalassemia using G-CSF-primed bone marrow over 6 years from March-2017 to April-2023 across 2 centres in India. Bone Marrow Quality Index (BMQI) was defined as the ratio of WBC count of G-CSF primed bone marrow to Peripheral WBC count within 24 hours of harvest. EBMT criteria were used for grading GVHD. Log-rank test was used to assess the impact of BMQI on GVHD. Chi-squared test was used to compare categorical data and Wilcoxon test was used to compare the numeric data. Cox proportional-hazards model was used to investigate the association of BMQI vis-à-vis other factors on acute GVHD. Of the 184 patients, 19 had a BMQI <0.9 and 18 between 0.9 and 1. The remaining 147 had BMQI >1. The proportion of patients with acute GVHD grade II-IV was 37%, 22% and 12% respectively for patients who received BMQI <0.9, 0.9-1 and >1 (p= 0.018). Patients who received BMQI <0.9 had a 3.1 times higher chance (95% CI being 0.9 to 10.6) of developing aGVHD II-IV and in those with BMQI 0.9-1 this was 2 times (95% CI being 0.5 to 6.6) higher. BMQI was the significant predictor associated with GVHD hazard (p=0.014). BMQI seems to be the most relevant and controllable predictor of acute GVHD. BMQI is a novel, informative, and very simple indicator which could influence GVHD prophylaxis decision-making. Our indicator is accurately measurable, inexpensive, precise, and timely; further it does not involve any sophisticated equipment, thus may be widely applicable. Prior knowledge of poor marrow quality may help intensify prophylaxis and monitoring for acute GVHD besides triggering review of collection procedures.

Treatment of Omenn syndrome using multiple immunosuppressive strategies: a case series

Introduction: Omenn syndrome represents a therapeutic challenge as a state of florid immune dysregulation born out of autoreactive oligoclonal T cells due to hypomorphic variants in genes associated with severe combined immunodeficiency (SCID).Aims: To describe the therapeutic strategies used in the care of three patients with Omenn syndrome from 2013 to 2022. All had negative maternal engraftment studies and received immunosuppression to control autoreactive T cells. All patients ultimately received myeloablative conditioning with anti-thymocyte globulin (ATG), busulfan, and fludarabine for transplant. All patients are currently alive and well.Case 1: 2-month-old female with adenosine deaminase (ADA)-deficient SCID on pegylated ADA replacement developed respiratory distress, rash, and diarrhea in the setting of rising CD3+/CD4+/CD45RO+ cell count. Treated with high-dose systemic steroids. Due to continued CD3+ increase, systemic tacrolimus was added. She clinically improved and underwent matched unrelated donor cord blood transplant at 5 months of age.Case 2: A male with RAG1-SCID developed generalized erythroderma and rapidly rising CD3+/CD4+/CD45RO+ cell and absolute eosinophil counts soon after birth. Systemic steroids were given with clinical improvement. With taper of steroid, ATG 1 mg/kg was given. Initially, the absolute lymphocyte count (ALC) improved; however, within 5 days, his rash worsened and ALC rose. This necessitated re-initiation of high-dose steroids and addition of tacrolimus until matched related donor bone marrow transplant (MRD BMT) at 2 months old.Case 3: 9-day-old male with RAG1-SCID developed diffuse maculopapular rash, lymphadenopathy, and elevated memory T cells and eosinophils. Initiated high-dose systemic steroids and cyclosporine A (CSA) with quick clinical improvement. CSA discontinued due to toxicity and rising ALC and eosinophils. Given ATG 3 mg/kg/dose for 4 doses over 2 weeks with pattern of quick drop then rapid rise in ALC. Treated with steroids and tacrolimus until MRD BMT at 2 months old. ConclusionsWe describe consistent disease control with immunosuppression by systemic steroids and tacrolimus prior to transplant and suggest ATG as a potential adjunctive consideration in poorly-controlled disease. A growing body of knowledge and experience in optimal Omenn syndrome treatment strategies is imperative to improving outcomes.

Cost-Effectiveness of Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Bone Marrow Transplantation: Evidence from BMT CTN 1101

BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced-intensity conditioning followed by double unrelated umbilical cord blood transplantation (UCBT) versus HLA-haploidentical related donor bone marrow transplantation (haplo-BMT) for patients with high-risk hematologic malignancies. Here we report the results of a parallel cost-effectiveness analysis of these 2 hematopoietic stem cell transplantation (HCT) techniques. In this study, 368 patients were randomized to unrelated UCBT (n=186) or haplo-BMT (n=182). We estimated healthcare utilization and costs using propensity score-matched haplo-BMT recipients from the OptumLabs Data Warehouse for trial participants age <65 years and Medicare claims for participants age ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used to estimate quality-adjusted life-years (QALYs). At a 5-year follow-up, survival was 42% for haplo-BMT recipients versus 36% for UCBT recipients (P=.06). Over a 20-year time horizon, haplo-BMT is expected to be more effective (+.63 QALY) and more costly (+$118,953) for persons age <65 years. For those age ≥65 years, haplo-BMT is expected to be more effective and less costly. In one-way uncertainty analyses, for persons age <65, the cost per QALY result was most sensitive to life-years and health state utilities, whereas for those age ≥65, life- years were more influential than costs and health state utilities. Compared to UCBT, haplo-BMT was moderately more cost-effective for patients age <65 years and less costly and more effective for persons age ≥65 years. Haplo-BMT is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BMT is a preferred choice when considering costs and outcomes.

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

NON-TRANSFERENCE OF FOOD ALLERGY AND FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME (FPIES) AFTER BONE MARROW TRANSPLANT

Introduction Transfer of food allergy after bone marrow and solid organ transplant are well described in literature. Here we report a case of non-transference of IgE mediated food allergy (peanut) and Food Protein-Induced Enterocolitis Syndrome (FPIES) (egg) following related donor bone marrow transplant. Case Description The donor is a 3 year-old female who initially presented with typical symptoms of egg related FPIES at 9 months of age. Subsequently was found to be sensitized to peanut (IgE 0.34 kUA/L). She initially passed peanut challenge, but peanut was never introduced. She lost tolerance and developed IgE mediated allergy to peanuts. Peanut allergy was confirmed upon challenge at 2 years of age. She has since avoided peanuts. She continues to have FPIES to egg. Her most recent FPIES reaction following accidental ingestion of egg and requiring fluid resuscitation was at 2 years of age. During this time, she served as a related bone marrow donor for her sibling. Even after withdrawal of the majority of immunosuppression and immune reconstitution with the donor bone marrow the sibling continues to tolerate both egg and peanut. Discussion Though transfer of food allergy has been reported following bone marrow transplant. This is the first case where transfer of FPIES has been a concern. This case is also unique because both FPIES and anaphylactic food allergy co-existed in the donor. Allergy in the donor was documented before and after transplant and likewise tolerance was documented in the recipient pre and post-transplant.

Allogeneic Matched Related Donor Bone Marrow Transplantation for Pediatric Patients With Severe Aplastic Anemia Using "Low-dose" Cyclophosphamide, ATG Plus Fludarabine.

The combination of cyclophosphamide (CY) and antithymocyte globulin (ATG) has been used as a standard conditioning regimen for matched related donor transplantation in patients with severe aplastic anemia. To decrease the regimen-related toxicity while maintaining appropriate engraftment and survival rates, fludarabine (FLU) was added to the regimen. Four pediatric patients received matched related donor bone marrow transplantation with CY (50 mg/kg×2) (instead of the 50 mg/kg×4 standard dosing), equine ATG (30 mg/kg×3), with the addition of FLU (30 mg/m×4). Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor and methotrexate. No grade 4 acute toxicities occurred during the first 30 days after transplant. All patients engrafted with normalization of peripheral blood counts and transfusion independence. One patient developed grade 1 to 2 acute GvHD, followed by chronic GvHD that resolved. With a median follow-up of 41.7 months, all 4 patients are alive and transfusion free, with complete donor chimerism. This combination of a low-dose CY/ATG+FLU regimen was overall very well tolerated and contributed toward a successful outcome including engraftment, chimerism, and survival. This small pilot study shows that this cytoreductive regimen could be considered as the standard of care for transplantation of pediatric patients with aplastic anemia from HLA-matched siblings.

Human leukocyte antigen-haploidentical stem cell transplantation using T-cell-replete bone marrow grafts

Once considered too dangerous for all but the sickest of patients, partially human leukocyte antigen (HLA)-mismatched, or HLA-haploidentical, related donor bone marrow transplantation (haploBMT) has seen a revival, thanks to the reduced intensity conditioning (RIC) regimens and graft-versus-host disease (GVHD) prophylaxis with high-dose posttransplantation cyclophosphamide (PT/Cy). RIC haploBMT with high-dose PT/Cy is associated with a cumulative incidence of acute grades II-IV GVHD of approximately 30% and incidences of chronic GVHD and nonrelapse mortality (NRM) less than 15%. These results have been confirmed in single and multicenter clinical trials. PT/Cy appears to nullify the detrimental effects of HLA mismatching on the outcome of haploBMT, thereby permitting the selection of haplo donors based upon criteria other than HLA matching. Overall and event-free survivals of RIC haploBMT compare favorably to the outcomes of RIC unrelated adult donor or umbilical cord blood stem cell transplantation. With its improved toxicity profile, haploBMT is a feasible alternative for patients who lack an HLA-matched donor and can now be applied to treat patients with nonmalignant disorders.

Overview of the Current Issues and Advances in Haemopoietic Stem Cell Transplantation for β-thalassemia Major

Bone marrow transplantation (BMT) is the only possible curative treatment for β-thalassemia major. The largest experience occurred in Pesaro, Italy, where the BMT was applied after a standard risk assessment. The patients were divided into 3 risk classes based on liver size by physical examination, the presence or absence of fibrosis by liver biopsy, and adherence to regular iron chelation. Outcomes were mainly affected by the risk status. After modifications to the conditioning regimens, the risk of transplantation-related complications in highrisk recipients reduced considerably. As a result, outcomes after transplantation have become more similar across risk categories. For BMT, most centers use bone marrow instead of peripheral blood in thalassemia. Some studies showed that peripheral blood stem cell transplantation (PBSCT) is better than BMT with regard to hematologic recovery, hospitalization period, leukemia-free survival, overall survival (OS), and transplant-related mortality (TRM). No significant differences were seen in grade II to IV acute GVHD (aGVHD); but the incidence of chronic GVHD (cGVHD) was significantly higher in the PBSCT group. BMT from unrelated donors may offer similar results to those obtained using HLA-identical family donors, at least for patients who are not fully compliant with conventional treatment and do not yet show severe complications of iron overload. All studies conclude that MUD BMT might be a good alternative for patients with less risk factors. Another study concluded that, at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens. In another study unrelated cord blood transplantation (CBT) was compared to related donor transplantation for children with β-thalassemia. The results were comparable to the survival rates of related-donor BMT for thalassemia. It has always been a dream for parents to have a new baby who might be a donor for his/her sibling and save his/her life. Today some families tried to learn the HLA group of the fetus using prenatal diagnosis. The last step in this development was preimplantation genetic diagnosis (PGD). PGD has become available as an alternative to prenatal diagnosis in order to avoid the risk for pregnancy termination, because PGD allows selection of unaffected embryos before a pregnancy is established. Gene therapies, the ultimate idea, involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patientderived autologous haematopoietic stem cells, bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. The successful preclinical studies in thalassaemia mousemodels, the accumulating data on lentiviral vector-mediated HSC transduction and the anticipated increased safety of lineage-restricted globin SIN lentiviral vectors strongly support the initiation of Phase I gene therapy clinical trials in β-thalassaemia.

Long-Term Experience with Allogeneic Bone Marrow Transplant (BMT) in Chronic Myeloid Leukemia

Abstract 4582 Introduction:Introduction of imatinib mesylate has changed the approach towards bone marrow transplantation in Chronic Myeloid Leukemia (CML). Historically considered as a curative therapeutic option, with a probability of disease free survival ranging from 40 to 60%. Its indicated use has been restricted to patients with treatment failure to prior tyrosin-kinase inhibitors or blast crisis. Objective:To assess the outcome of patients with CML who undergo BMT Materials and methods:66 patients who underwent allogeneic BMT between the years 1994 and 2011 in two health care facilities were analyzed. 63 (93%) were performed between 1994 and 2005. At the time of transplantation, patient status was: 56 patients in 1st Chronic Phase and 10 in advanced phases. Fourteen patients received Unrelated Donor BMT and 37 had Related Donor BMT. Transplant risk was assessed, based on the European Bone Marrow Transplantation (EBMT) score (sc). The conditioning regimens which were used included: for patients in chronic phase, cyclophosphamide (Cy) and busulfan (Bu) and for patients in accelerated phase etoposide (VP 16) was added to the previous regimen, and for unrelated donors BuCy + ATG or alentuzumab was used. Prophylaxis for Graft vs Host Disease (GVHD) was performed with a two-drug regimen (cyclosporine, methotrexate), with or without methylprednisone. Result:66 patients were recorded (28 female/38 male), with a mean age of 35 years at the time of transplantation (range 8–55). The source of Stem Cell was bone marrow in 60 patients and peripheral blood in 6 patients. 43% of patients developed GVHD: (29 patients) according to clinical criteria established by the European Cooperative Group. Overall Survival (OS) was 50% with a mean follow-up of 48 months. Analyzed according to the EBMT risk score, OS was 64% in the 0–2 score group and 31% in patients with a 3–5 score. Procedure-related mortality was 16%, and the most frequent causes included: hepatic veno-occlusive disease, infections, GVHD, and graft failure. Conclusions:BMT in patients with CML has been substantially reduced since the introduction of tyrosin-kinase inhibitors. In our experience, this shows its healing potential with an extended follow-up and a prolonged survival. Disclosures:No relevant conflicts of interest to declare.

Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts

AbstractThe Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency Who Received Related Donor Bone Marrow Transplants without Pretransplant Chemotherapy or Post-transplant GVHD Prophylaxis

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency Who Received Related Donor Bone Marrow Transplants without Pretransplant Chemotherapy or Post-transplant GVHD Prophylaxis

Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T- and B-cell function and, in some types, also of NK cells and function. Mutations in thirteen different genes have been found to cause this condition, which is uniformly fatal in the first 2years of life unless immune reconstitution can be accomplished. In the 42years since the first bone marrow transplant was given in 1968, the standard treatment for all forms of SCID has been allogeneic bone marrow transplantation. Both HLA-identical unfractionated and T-cell-depleted HLA-haploidentical bone marrow transplants have been very successful in effecting immune reconstitution, especially if performed in the first 3.5months of life and without pre-transplant chemotherapy. This paper summarizes the longterm outcome, according to molecular type, of 166 consecutive SCID infants given non-conditioned related donor bone marrow transplants at this institution over the past 28.3years and reviews published reports of longterm outcomes of transplants in SCID performed at other centers.

Rapid Recovery of CD4 Counts Following Low Dose Alemtuzumab Conditioning During HLA Matched Related Bone Marrow Transplant for Children with Haemoglobinopathies

AbstractAbstract 2335CMV viraemia and disease remains a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We investigated the impact of low dose alemtuzumab conditioning in paediatric matched sibling allogeneic BMT for haemoglobinopathy on immune reconstitution (early and late CD3/4+, CD3/8+, CD3-/CD56+ cell recovery) and subsequent viral infections in 18 consecutive transplants (14 β thalassaemia major and 4 sickle cell anaemia). A secondary aim was to investigate the impact of immune reconstitution on graft versus host disease but due to the extremely low incidence of acute and chronic graft versus host disease with this protocol (acute grade II to IV 11.6% and chronic 4.6%) we were unable to assess this. Transplant protocol: following hypertransfusion to suppress endogenous haemopoiesis, patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6). Graft versus host disease prophylaxis was provided with ciclosporin for six months and methotrexate 10 mg/m2 on days +4 and +7. All transplants used BM as source of stem cells. CMV PCR surveillance was undertaken twice weekly and CMV reactivation was treated with intravenous foscarnet or ganciclovir, followed by secondary prophylaxis with valganciclovir. Routine peripheral blood immunophenotyping of lymphocyte subsets was performed at 60-, 90-, 120-, 150- and 180- days post-BMT. Results:the median age of transplant recipients was 7 years (range 2 – 17 years) and median follow up 254 days (range 203–378). The median CD3/CD4+ cell count rose above 200 cells/μl by day 180 and above 300 cells/μl by day 254 following the withdrawal of immune suppression at six months (fig 1A), the median CD8+ cell count increased earlier, to >200 cells/μl by day 60 and 300 cells/μl by day 180 (fig 1B) and the median CD56+ cell count reached 200 cells/μl by day 60 and plateaued thereafter (fig 1C). Overall, CMV reactivation occurred in 13 patients (72.2%) after a median interval of 35 days following BM infusion (range day-1 to day +72): 10/13 patients (76.9%) in whom both recipient and donor were CMV positive (CMV +/+); 1/3 patients in whom recipient was CMV negative and donor CMV positive (CMV -/+); and in 1/1 who was CMV positive with a CMV negative donor (CMV +/−). Significantly there was no clinical CMV disease in any patient and with the use of oral valganciclovir there were no subsequent CMV reactivations. CMV reactivation occurred in patients with lower CD4+ cell counts at day 60 (67 cells/μl) compared with the CMV-unaffected group (a median CD4+ count 298 cells/μl; p= 0.0262). Four patients experienced other viral infections: HHV6 infection requiring foscarnet on day +85 (n=1), urinary BK virus not requiring treatment (n=2) and parainfluenza pneumonitis requiring ribavarin on day +12 (n=1). Conclusion:Low dose alemtuzumab conditioning is associated with rapid CD4+ cell recovery (CD4+ >200 cells/μl by day +180) in children undergoing allogeneic matched related donor BMT for haemoglobinopathy. Although there is a high frequency of CMV reactivation (72.2%) in patients with low CD4+ counts at day 60 (median CD4+ count 67 cells/μl), no clinical CMV disease was seen and subsequent reactivations of CMV were prevented by the use of valganciclovir secondary prophylaxis whilst awaiting full immune reconstitution. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency Who Received Related Donor Bone Marrow Transplants without Pretransplant Chemotherapy or Post-transplant GVHD Prophylaxis

To determine long-term health benefits of nonablative bone marrow transplantation for severe combined immunodeficiency (SCID), we investigated our cohort of 161 related donor bone marrow-transplanted patients with SCID. Only 16 (10%) had HLA-identical donors. All 124 survivors were sent questionnaires about their current clinical statuses. Details from clinic visits were also compiled. One hundred eleven patients (90%) were reached. We compared outcomes of patients transplanted before and after 3.5 months of life and by molecular defect. The overall survival rate was 77%, but the rate for the 48 infants transplanted in the first 3.5 months of life was 94%, compared with 70% for the 113 transplanted after 3.5 months (P = .002). Twenty-eight (76%) of the 37 deceased patients died of viral infections present at diagnosis. One or more clinical problems were reported to have been present in the past 2 years in 71 (64%) of the survivors, although 95 (86%) were considered healthy by their families. Most patients with SCID transplanted with related donor marrow without pretransplant chemotherapy have done well in the long term, but those transplanted at <3.5 months of age had a superior survival rate, a lower rate of clinical problems, less need for booster transplants, and better nutritional status.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Poor outcome in a pediatric patient with acute myeloid leukemia associated with a variant t(8;21) and trisomy 6

RUNX1T1/RUNX1 (formerly ETO/AML1) is a molecular marker that is usually associated with a favorable outcome in both pediatric and adult patients with acute myeloid leukemia (AML). We describe a 10-year-old girl with AML associated with an RUNX1T1/RUNX1 fusion. The patient’s karyotype at the time of diagnosis was 46,X,-X,t(4;21;8)(q25;q22;q22),+6. She had an early relapse while being treated on a standard protocol and had significant difficulty in attaining a second remission. She subsequently underwent a matched related donor bone marrow transplant, but a second bone marrow relapse with extensive extramedullary disease followed on day +199. Cytogenetic analysis at second relapse showed evidence of clonal evolution in the form of a highly complex karyotype with numeric and structural abnormalities in addition to the t(4;21;8) and trisomy 6 detected in the diagnostic sample. Trisomy 6 is an uncommon cytogenetic abnormality in myeloid diseases. As a sole abnormality, it has been associated mainly with myelodysplastic syndrome and AML. The presence of this novel variant of t(8;21)(q22;q22) associated with trisomy 6 may have abrogated the usual favorable prognosis associated with RUNX1T1/RUNX1 in AML.

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency (SCID) after Non-Ablative Related Donor Bone Marrow Transplantation

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency (SCID) after Non-Ablative Related Donor Bone Marrow Transplantation

Correction of Clinical Manifestations of Canine Mucopolysaccharidosis I with Neonatal Retroviral Vector Gene Therapy

Mucopolysaccharidosis I (MPS I) (Hurler syndrome) is due to deficient alpha-L-iduronidase (IDUA) activity and is the most common of the MPS disorders. Neonatal MPS I dogs were injected intravenously (IV) with a gamma retroviral vector containing a complete long-terminal repeat (LTR) and an internal human alpha(1)-antitrypsin (hAAT) promoter upstream of the canine IDUA complementary DNA (cDNA). This resulted in stable serum IDUA activity of 366 +/- 344 units (U)/ml (28-fold normal) for up to 1.8 years, which likely derived primarily from secretion of IDUA by transduced liver cells. Retroviral vector (RV)-treated dogs had >18% of normal IDUA activity in organs and had decreased severity and/or incidence of hernias, chest deformities, joint disease, facial dysmorphia, corneal clouding, valvular heart disease, and aortic dilatation as compared with untreated MPS I dogs. The marked reduction that was observed in lysosomal storage in the brain of RV-treated dogs may have been due in part to expression from the LTR of the vector in cells in the brain. This possibility will be explored in future studies, because the potential for insertional mutagenesis has raised concerns about using vectors with an intact LTR. If proven safe, this gene therapy technique may be utilized in treating children with Hurler syndrome.

Long term disease-free survival in acute leukemia patients recovering with increased γδ T cells after partially mismatched related donor bone marrow transplantation

Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased gammadelta T cells following ASCT. gammadelta T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n = 77; acute myelogenous leukemia (AML) n = 76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1-59), and 62% of the patients were in relapse at transplant. Patient-donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n = 46) or OKT3 (n = 107). Five years LFS and overall survival (OS) of patients with increased gammadelta compared to those with normal/decreased numbers were 54.4 vs 19.1%; P < 0.0003, and 70.8 vs 19.6% P < 0.0001, respectively, with no difference in GvHD (P = 0.96). In a Cox multivariate analysis, normal/decreased gammadelta (hazard ratio (HR) 4.26, P = 0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, gammadelta T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.