Successful Hematopoietic Stem Cell Transplantation Research Articles

EVALUATION OF PREDICTABILITY OF BONE MARROW CELL CELLULARITY FROM RELATED AND UNRELATED DONORS

Introduction: For successful hematopoietic stem cell transplantation, a minimum number of total nucleated cells should be obtained (TNC) during the bone marrow (BM) harvest procedure. Objectives: Evaluate the predictability of the BM TNC collected from an interim sample collected during the procedure and the factors related to high-cellular harvest. Methodology: This is a retrospective observational study including BM donors and recipient from 2017 to 2019. The final TNC was based on an interim quantification of TNC and was compared with the actual final TNC obtained. Results: 81 donors were included and interim TNC of 53 donors were available. Based on linear regression, a significant correlation was found between the volume of BM collected and the interim and final TNC (n=53; R2=0.83; P<0.001). The relationship between donor and recipient weight significantly influenced the collection yield. There was also a positive correlation between the volume of BM collected and the interim and final count of TNC (n=53; r=0.88; p<0.001). The difference in donor and recipient weight also had a positive correlation (p<0.02). Conclusion: Our results showed that interim TNC quantification can help to achieve a better performance during the procedure, allowing real-time re-estimation of the volume needed to be harvested.

Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia.

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.

Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD).

Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.

Cardiovascular Complications in Hematopoietic Stem Cell Transplanted Patients

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many patients suffering from hematologic malignancies, solid tumors, inborn errors of metabolism or genetic disorders. Despite decades of successful HSCT, clinical outcomes are still far from satisfactory due to treatment-related complications, including graft-versus-host disease (GvHD) and cardiovascular complications (CVC). CVC may affect patients in the acute period post-HSCT; however, the occurrence is far higher among long-term survivors. Induction treatment using cardiotoxic treatments, e.g., anthracyclines and radiotherapy, conditioning regimens containing cyclophosphamide, and post-HSCT comorbidities, including GvHD, are factors contributing to CVC. Cardiac function evaluation prior to and post-transplantation is an important strategy for choosing the proper conditioning regimen, HSCT protocol and post-HSCT supportive care. Cardiac systolic function evaluation by echocardiography, in addition to serum cardiac biomarkers, such as troponins and brain natriuretic peptides, is recommended as a routine follow-up for HSCT patients. Angiotensin-converting enzyme inhibitors, angiotensin-II-receptor blockers, and beta-blockers, which are mostly used for the treatment of chemotherapy-induced cardiotoxicity, might be used as treatments for HSCT-related CVC. In summary, the present review reveals the urgent need for further investigations concerning HSCT-related CVC both at the preclinical and clinical levels due to the lack of knowledge about CVC and its underlying mechanisms.

Successful allogeneic hematopoietic stem cell transplantation in a patient with acute myeloid leukemia and preexisting pulmonary nocardiosis.

Successful allogeneic hematopoietic stem cell transplantation in a patient with acute myeloid leukemia and preexisting pulmonary nocardiosis.

Evaluation of CD34+ Cell Count at Different Time Points Following Plerixafor Administration in Autologous Hematopoietic Stem Cell Transplantation

Background: In apheresis, collecting an adequate number of CD34+ cells is required for successful autologous hematopoietic stem cell transplantation (auto-HSCT) procedure. It is difficult to harvest a sufficient number of stem cells in certain patients due to their old age and history of intensive chemotherapy. Plerixafor could mobilize stem cells and facilitate peripheral blood hematopoietic stem cell collection. However, not enough information is available on the appropriate time intervals from plerixafor administration to apheresis. Objectives: In this study, we aimed at evaluating the level of peripheral blood CD34+ cells at plerixafor administration time and every three hours to identify the peak time of circulating CD34+ cells. Methods: Circulating CD34+ cells were enumerated by flow cytometry on day 4 post mobilization. Plerixafor was administered to patients with poor mobilization based on the count of peripheral blood hematopoietic stem cells. The number of circulating CD34+ cells was evaluated before and 3, 6, 9, and 12 hours after plerixafor administration to assess the time it takes for stem cells to reach their peak level. Results: The highest level of stem cell concentration was found in 9 hours after plerixafor administration with an increasing trend. A statistically significant relationship was also observed between factors including platelet count on the first day of GCSF injection and the day of stem cell infusion, leukocyte count on admission, and basal levels of CD34+ cells in peripheral blood and the amount of harvested stem cells. Conclusions: We demonstrated that plerixafor causes an incremental trend in CD34+ cells mobilization, reaching its peak after 9 hours. Further research should be performed to provide insights into graft cells’ population and hematologic and immunological recovery.

P-027: SICKLE CELL DISEASE AND AUTOIMMUNE LIVER DISORDERS: SHOULD HEMATOPOIETIC STEM CELL TRANSPLANTATION BE DISCUSSED EARLY?

Purpose: Patients with sickle cell disease (SCD) are prone to dys- or autoimmune disorders, such as autoimmune hepatitis (AIH), sclerosing cholangitis, or ulcerative colitis. Sclerosing cholangitis can develop in young children with an unusually severe course due to associated vaso-occlusion and ischemia. Liver transplantation may be indicated early but is a challenging procedure in SCD, with uncertain outcomes (Hurtova Liver Transpl 2011, Duvoux [abstract] JFHOD 2021). Hematopoietic stem cell transplantation (HSCT) can cure SCD, although conditioning may induce hepatic complications. Herein we report a series of 6 children with SCD and autoimmune disorders, 3 for whom liver or digestive symptoms resolved after successful HSCT, and 3 for whom cirrhosis precluded HSCT conditioning. Materials and methods: Of the 6 children (5 girls), 5 were HbSS and 1 was HbSC. Dysimmune symptoms appeared at a median age of 4.5 (3-12) years and were colitis (n=2), cerebral vasculitis (n=1), and AIH (n=3). In 4/6 patients, liver disease was an overlap AIH-sclerosing cholangitis, while 2/6 patients had either isolated AIH or sclerosing cholangitis. Liver biopsy showed cirrhosis in 3 patients. Median age at last follow-up (FU) was 13.5 (8-17) years. Results: The 3 patients without cirrhosis, including 2 with sclerosing cholangitis and dilated bile ducts, underwent HSCT with a geno-identical donor, at 6, 11.5 and 16 years old. Autoimmune disease was controlled with steroids, azathioprine, infliximab or cyclophosphamide with plasma exchanges and rituximab. Conditioning included hepatotoxic drugs busulfan (n=2) and treosulfan (n=1), with antilymphocyte globulins, fludarabine (n=3) and thiotepa (n=1). Transient hepatitis developed in 1 patient and moderate graft-vs-host disease (GVHD) in 2, which resolved after adapting immunosuppression treatment. HSCT was uneventful in the third patient. With a FU of 1 to 2.5 years, all 3 patients had no digestive or liver symptoms, normal or mildly elevated liver enzymes and unchanged liver imaging. The 3 patients with cirrhosis upon first visit, at ages 7, 8.5, 13 years old, were on regular exchange transfusions at last FU. One patient developed recurrent infectious cholangitis and received a liver transplant at age 10, with many complications; at 7 years of FU, sclerosing cholangitis relapsed and re-transplantation was discussed. Another had moderate portal hypertension, bilirubin levels of 100-200 µM, and prothrombin time 60%, on steroids. The third patient was on tacrolimus, had presented 2 episodes of reversible liver failure, bilirubin levels of 100 µM and prothrombin time 45% at last FU and had developed myasthenia. Conclusion: Autoimmune liver disease in children with SCD may rapidly lead to end-stage liver disease. Upon diagnosis, these disorders should be considered as severe complications of SCD and prompt early discussion of HSCT. HSCT should be performed before conditioning with hepatotoxic drugs is not feasible. If a geno-identical donor is not available, alternative donors could be considered (haplo-identical, unrelated). If the liver disease is not stabilized after HSCT, liver transplantation could be performed with a standard risk, in a patient rid of SCD. If liver transplantation must be performed before HSCT, HSCT could be discussed rapidly afterwards to avoid possible relapse of SCD-related liver disease and dysimmune liver disease. The authors do not declare any conflict of interest

Novel NHEJ1 pathogenic variant linked to severe combined immunodeficiency, microcephaly, and abnormal T and B cell receptor repertoires.

BackgroundDuring the process of generating diverse T and B cell receptor (TCR and BCR, respectively) repertoires, double-strand DNA breaks are produced. Subsequently, these breaks are corrected by a complex system led by the non-homologous end-joining (NHEJ). Pathogenic variants in genes involved in this process, such as the NHEJ1 gene, cause severe combined immunodeficiency syndrome (SCID) along with neurodevelopmental disease and sensitivity to ionizing radiation.ObjectiveTo provide new clinical and immunological insights on NHEJ1 deficiency arising from a newly diagnosed patient with severe immunodeficiency.Materials and methodsA male infant, born to consanguineous parents, suspected of having primary immunodeficiency underwent immunological and genetic workup. This included a thorough assessment of T cell phenotyping and lymphocyte activation by mitogen stimulation tests, whole-exome sequencing (WES), TCR repertoire Vβ repertoire via flow cytometry analysis, and TCR and BCR repertoire analysis via next-generation sequencing (NGS).ResultsClinical findings included microcephaly, recurrent pneumonia, and failure to thrive. An immune workup revealed lymphopenia, reduced T cell function, and hypogammaglobulinemia. Skewed TCR Vβ repertoire, TCR gamma (TRG) repertoire, and BCR repertoire were determined in the patient. Genetic analysis identified a novel homozygous missense pathogenic variant in XLF/Cernunnos: c.A580Ins.T; p.M194fs. The patient underwent a successful hematopoietic stem cell transplantation (HSCT).ConclusionA novel NHEJ1 pathogenic variant is reported in a patient who presented with SCID phenotype that displayed clonally expanded T and B cells. An adjusted HSCT was safe to ensure full T cell immune reconstitution.

Experience of successful autologous hematopoietic stem cell transplantation in patients with an unfavorable prognosis of systemic scleroderma

One of the methods of treating severe forms of systemic scleroderma is hematopoietic stem-cell autotransplantation (auto-HSCT). The article describes two clinical cases of auto-HSCT followed by rituximab (RTM) therapy in patients with diffuse systemic scleroderma with progressive interstitial lung disease (ILD), high immunological activity, high skin score, and an unfavorable prognosis. The assessment of the course of these diseases was carried out in the course of dynamic observation of patients for 10–11 years. In all cases, auto-HSCT followed by RTM made it possible to achieve remission / low activity, as well as to stabilize the progressive of ILD.

Successful Kidney and Hematopoietic Stem Cell Transplantation for Malignant Lymphoma from Different Donors: A Case Report and Literature Review

There are particularly few reports on kidney transplantation after hematopoietic stem cell transplantation (HSCT) for malignant lymphoma, and none of the cases reported a favorable outcome in patients who received kidney transplantation from a different donor to HSCT. In this report, we describe the first case of kidney transplantation from a different donor to HSCT with a successful outcome. Furthermore, we reviewed the previously reported cases. A 59-year-old female patient received an HSCT from her younger brother after chemotherapy for malignant lymphoma. After HSCT, she did not have graft-versus-host disease (GVHD) requiring maintenance treatment. The patient developed chronic kidney disease requiring kidney replacement therapy, probably due to drug toxicity or cardio-renal syndrome. At age 65, she underwent an ABO-compatible, HLA-A, -B, -DR 5/6 mismatched kidney transplantation from her husband. Immunosuppressive therapy with tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab was administered. The patient had urinary tract infections at 7 days, 9 weeks, and 4 months after kidney transplantation, and cytomegalovirus antigenemia at 9 weeks after kidney transplantation, which improved with antibiotic and valganciclovir, respectively. When each infection occurred, we weakened immunosuppressive therapy. Four years after kidney transplantation, the patient is in good clinical condition with a serum creatinine of 1.2 mg/dL, without critical infection or malignancy. In this case, we believe that it was important to optimize the immunosuppressive therapy. In addition, from a review of previous cases, it seemed important that there was no GVHD requiring maintenance therapy in order to prevent excessive immunosuppression.

Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes?

Human and mouse CD4+FoxP3+ T cells (Tregs) comprise non-redundant regulatory compartments which maintain self-tolerance and have been found to be of potential therapeutic usefulness in autoimmune disorders and transplants including allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is substantial literature interrogating the application of donor derived Tregs for the prevention of graft versus host disease (GVHD). This Mini-Review will focus on the recipient’s Tregs which persist post-transplant. Although treatment in patients with low dose IL-2 months post-HSCT are encouraging, manipulating Tregs in recipients early post-transplant is challenging, in part likely an indirect consequence of damage to the microenvironment required to support Treg expansion of which little is understood. This review will discuss the potential for manipulating recipient Tregs in vivo prior to and after HSCT (fusion proteins, mAbs). Strategies that would circumvent donor/recipient peripheral blood harvest, cell culture and ex-vivo Treg expansion will be considered for the translational application of Tregs to improve HSCT outcomes.

Current status and prospects of hematopoietic stem cell transplantation in China.

Hematopoietic stem cell transplantation (HSCT) is a highly effective and unique medical procedure for the treatment of most hematological malignancies. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then, the field has evolved and expanded worldwide. The first successful allogenic HSCT (allo-HSCT) in China was conducted in 1981. Although the development of allo-HSCT in China lagged, China has since made considerable contributions to the process of HSCT worldwide, with more than 10,000 HSCTs performed annually. In particular, haploid HSCT (haplo-HSCT) technology represented in the Beijing Protocol has demonstrated similar efficacy to human leukocyte antigen-matched HSCT and has gradually become the pre-dominant choice for allo-HSCT in China. Currently, the number of haplo-HSCT procedures exceeds 5000 per year, and the Beijing Protocol has been greatly improved by implementing updated individualized strategies for controlling complications, relapse, and infection management. In addition, innovative haplo-HSCT technologies developed by different medical transplantation centers, such as Soochow, Zhejiang, Fujian, Chongqing, and Anhui, have emerged, providing inspiration for the refinement of global practice. This review will focus on the current activity in this field and highlight important trends that are vital in China's allo-HSCT process, examining the current viewpoint and future directions.

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

The first successful European hematopoietic stem cell transplantation (HSCT) was performed in 1968 as treatment in a newborn with IL2RG deficiency using an HLA-identical sibling donor. Because of declining naive T and natural killer (NK) cells, and persistent human papilloma virus (HPV)-induced warts, the patient received a peripheral stem cell boost at the age of 37 years. NK and T cells were assessed before and up to 14 years after the boost by flow cytometry. The boost induced renewed reconstitution of functional NK cells that were 14 years later enriched for CD56dimCD27+ NK cells. T-cell phenotype and T-cell receptor (TCR) repertoire were simultaneously analyzed by including TCR Vβ antibodies in the cytometry panel. Naive T-cell numbers with a diverse TCR Vβ repertoire were increased by the boost. Before and after the boost, clonal expansions with a homogeneous TIGIT and PD-1 phenotype were identified in the CD27− and/or CD28− memory population in the patient, but not in the donor. TRB sequencing was applied on sorted T-cell subsets from blood and on T cells from skin biopsies. Abundant circulating CD8 memory clonotypes with a chronic virus-associated CD57+KLRG1+CX3CR1+ phenotype were also present in warts, but not in healthy skin of the patient, suggesting a link with HPV. In conclusion, we demonstrate in this IL2RG-deficient patient functional NK cells, a diverse and lasting naive T-cell compartment, supported by a stem cell boost, and an oligoclonal memory compartment half a century after HSCT.

Predictors of growth patterns in children with mucopolysaccharidosis I after haematopoietic stem cell transplantation.

Mucopolysaccharidosis type I (MPS I) is an autosomal‐recessive metabolic disorder caused by an enzyme deficiency of lysosomal alpha‐l‐iduronidase (IDUA). Haematopoietic stem cell transplantation (HSCT) is the therapeutic option of choice in MPS I patients younger than 2.5 years, which has a positive impact on neurocognitive development. However, impaired growth remains a problem. In this monocentric study, 14 patients with MPS I (mean age 1.72 years, range 0.81–3.08) were monitored according to a standardised follow‐up program after successful allogeneic HSCT. A detailed anthropometric program was carried out to identify growth patterns and to determine predictors of growth in these children. All patients are alive and in outpatient care (mean follow‐up 8.1 years, range 0.1–16.0). Progressively lower standard deviation scores (SDS) were observed for body length (mean SDS −1.61; −4.58 – 3.29), weight (−0.56; −3.19 – 2.95), sitting height (−3.28; −7.37 – 0.26), leg length (−1.64; −3.88 – 1.49) and head circumference (0.91; −2.52 – 6.09). Already at the age of 24 months, significant disproportions were detected being associated with increasing deterioration in growth for age. Younger age at HSCT, lower counts for haemoglobin and platelets, lower potassium, higher donor‐derived chimerism, higher counts for leukocytes and recruitment of a matched unrelated donor (MUD) positively correlated with body length (p ≤ 0.05). In conclusion, this study characterised predictors and aspects of growth patterns in children with MPS I after HSCT, underlining that early HSCT of MUD is essential for slowing body disproportion.

Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD (IRENE-G study) \u2013 design and rational of a randomized controlled trial

BackgroundGraft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present “Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD” – Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients.MethodsIRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion.DiscussionTo our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment.Trial registrationClinicalTrials.gov: NCT05111834. Registered 8 November 2021 – Retrospectively registered.

Metabolic syndrome in long-term survivors after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and non-malignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. Hematopoietic stem cell transplantation can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was the evaluation of the prevalence of metabolic syndrome (MS) among survivors of allogeneic HSCT. We analyzed 74 patients with a median age at transplant of 35 years, who had been followed for a median of 5 years (2-23 years) after allogeneic HSCT. MS was defined according to the National Cholesterol Education Programs Adult Treatment Panel III (NCEP ATP III) criteria and by the International Diabetes Federation (IDF) definition. The prevalence of MS among HSCT recipients was 40.5% applying the NCEP ATP III definition and 39.2% the IDF, a 2.02-fold increase compared to the general Slovak population. MS was more common in men. The most common MS features were abdominal obesity, hypertriglyceridemia and hypertension. The lowest prevalence of MS was in the age group of 20-29 years; and the highest prevalence in the age group of 60-69 years. The 10-year cumulative incidence of MS was 32.5%. The most significant risk factor for MS was total body irradiation, positive family history and age &gt; 40 years at HSCT. Seven patients (9.45%) developed cardiovascular complications. The median 10-year general cardiovascular risk scores for males and females were found to be 13.3% and 6.68%, respectively. Detected increased prevalence of metabolic syndrome after allogeneic HSCT in patients surviving more than 2 years after this procedure may provide next stimulus to promote longer follow-up studies and to design of interventions to prevent late effects among survivors of serious hematologic diseases.

Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis.

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1,321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007–2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60–64; 65–69; 70+). With median follow-up of nearly 3 years, patients aged 60–64 had modestly, though significantly better OS, DFS and lower TRM than those either 65–69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p=0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥ 3. Conditioning intensity was not a significant predictor of OS in the 60–69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p=0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.

Differences in longitudinal growth patterns of children and adolescents with transfusion-dependent hemoglobin E/β-thalassemia and those achieving successful hematopoietic stem-cell transplantation.

Short stature is a very common endocrinopathy among children with transfusion-dependent (TD) thalassemia. Hematopoietic stem-cell transplantation (HSCT) is the only effective curative treatment for TD thalassemia. This study aimed to identify and compare the longitudinal growth patterns of children with TD hemoglobin E (Hb E)/β-thalassemia against those of children successfully undergoing HSCT. We reviewed the medical records of 39 patients with TD Hb E/β-thalassemia receiving regular blood transfusions, and 39 post-HSCT patients. Longitudinal weight and height Z-scores at each year of age were recorded for TD patients, and longitudinal weight and height Z-scores at each year before and after HSCT were obtained for post-HSCT patients. The mean weight and height Z-scores of TD patients decreased gradually and were lowest at age 13. However, post-HSCT subjects saw significant improvement in their mean weight and height Z-scores 6 and 3years after HSCT, respectively, relative to pre-HSCT baseline values. Longitudinal growth patterns differed between patients successfully undergoing HSCT and children and adolescents with TD Hb E/β-thalassemia. HSCT significantly improved height outcomes of children and adolescents with TD Hb E/β-thalassemia.

Clinical, immunological and genomic characteristics of children with X-linked agammaglobulinemia from Kerala, South India

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis. Using next-generation and Sanger sequencing we have identified 10 unique pathogenic and likely pathogenic variants in 17 patients. This encompasses three nonsynonymous, two stop-gain, two frameshifts, two structural, and one splicing variant, out of which two of them are novel. Based on the type of variant, patients had variable clinical features and treatment responses. We have also evaluated Btk protein expression for six patients in comparison to the healthy individuals and determined mosaic Btk expression patterns in four mothers. We have also performed family screening in 6 families using Sanger sequencing and identified 19 carriers for the variant. The diagnosis for the patients led to the proper treatment i.e. 15 patients were on intravenous immunoglobulin (IVIG) and the other two had successful hematopoietic stem cell transplantation (HSCT). Unfortunately, two of our patients died due to sepsis, while on IVIG. We envision the present study could help in better understanding of patients with XLA and help in family screening and prenatal diagnosis. To the best of our knowledge, this is the largest case series of patients affected with XLA from South India.

Identification of the minimum requirements for successful haematopoietic stem cell transplantation.

SummaryHistorically, defining haematopoietic subsets, including self‐renewal, differentiation and lineage restriction, has been elucidated by transplanting a small number of candidate cells with many supporting bone marrow (BM) cells. While this approach has been invaluable in characterising numerous distinct subsets in haematopoiesis, this approach is arguably flawed. The haematopoietic stem cell (HSC) has been proposed as the critical haematopoietic subset necessary for transplantation. However, due to the presence of supporting cells, the HSC has never demonstrated sufficiency. Utilising the homeobox B5 (Hoxb5)‐reporter system, we found that neither long‐term (LT) HSCs nor short‐term (ST) HSCs alone were sufficient for long‐term haematopoietic reconstitution. Critically, reconstitution can be rescued by transplanting combined LT‐ and ST‐HSCs, without supporting cells; a fraction we term the ‘Minimum Subset for Transplantation’ (MST). The MST accounts for only 0·005% of nucleated cells within mouse BM, and this MST can be cultured, expanded and genetically modified while preserving its rapid haematopoietic engraftment potential. These results support the consideration of an MST approach for clinical translation, especially for gene therapy approaches that require HSC compartment modification.