Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease: A Multidimentional Review.

While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.

Optimal regimen of levetiracetam for prevention of busulfan-induced seizure in patients undergoing hematopoietic stem cell transplantation: A review of available evidence.

OBJECTIVE: This review aimed to summarize the available data and offer a practical recommendation regarding the optimal regimen of levetiracetam (LEV) for the prevention of busulfan-induced seizure (BIS) in patients undergoing hematopoietic stem cell transplantation (HSCT). DATA SOURCES: Published articles by searching databases (PubMed, Google Scholar, Cochrane Library, ScienceDirect) were reviewed. All types of original studies performed in pediatric and adult populations have been investigated and required data was extracted. DATA SUMMARY: Eleven articles were eligible to be included in this review. A loading dose was not used in any of the studies. LEV had been started from 6 to 48 h before busulfan (Bu) initiation and continued up to 24 to 48 h after its termination. The dose range of LEV was 10 to 20 mg/kg/day divided every 12 h in pediatrics and 500 to 1000 mg twice daily in adults. Both oral and intravenous (IV) routes of administration were used. Except for three studies, no seizure had occurred in patients who had received LEV. CONCLUSIONS: Considering the available evidence, LEV with the dose range from 500 to 1000 mg twice daily in adults and 10 mg/kg twice daily (20 mg/kg/day in 2 divided doses) in children orally or IV started from 6 to 24 h before Bu initiation up to 24 to 48 h after the last dose of Bu seems to prevent BIS appropriately. More prospective clinical trials with a larger population are needed to validate the optimal dosing of LEV for BIS prophylaxis in patients undergoing HSCT.

Incidence of hemorrhagic cystitis following unmanipulated peripheral blood stem cell transplantation in acute Leukemia: A retrospective single-center risk factor analysis.

BACKGROUND: Hemorrhagic cystitis (HC) is an important adverse event experienced after hematopoietic stem cell transplantation (HSCT). Severe HC could lead to significant morbidity, prolonged hospitalization with increased health-care costs, and may cause considerable mortality. OBJECTIVES: In order to investigate the influence of different contributing factors other than BK viruria on HC occurrence in a homogenous population, we retrospectively analyzed the potential risk factors. STUDY DESIGN: We conducted a retrospective study among 200 patients (median age 12.4 years, IQR: 7.9-16.1) with acute leukemia who received peripheral blood allogenic HSCT after radiation-free myeloablative conditioning regimen, in pediatric cell therapy department of Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Tehran, Iran, between December 2014 and December 2021. Associations between risk factors and outcomes were examined by univariable and multivariable logistic regression models. RESULTS: A total of 46 patients (23%) had developed HC during the study period. The median onset of HC was 29 (IQR: 24-37) days post-transplant, and it persisted for a median of 33 (7-270) days. The incidence of HC in our patients was estimated to be 3 in 1000 cases (95% CI: 2-4). The results of multivariable logistic model shows that the chance of HC in T-cell acute lymphoblastic leukemia (ALL) compared to B-cell All is nearly five times more (OR = 4.88; 95%CI: (1.51-15.78), P = 0.008). The incidence of HC in patients who underwent HSCT from haploidentical donors was significantly higher than full matched donors (P < 0.001). Undergoing transplant from a matched unrelated and haploidentical donor both augment the chance of HC in about six times more than matched related donors (OR = 6.36; 95%CI: (1.58-25.49), P = 0.009 and OR = 5.7; 95%CI: (1.83-17.75), P = 0.003, respectively). In patients who developed HC compared to non-HC group, overall survival was much worse (P < 0.001). DISCUSSION: Most studies have failed to demonstrate any relationship between late-onset HC and the dose of cyclophosphamide. In our study, although the dose of cyclophosphamide was similar in HSCT from MRD and MUD, the hazard of HC incidence was significantly higher in the latter group. This could be accredited to ATG, as in patients in the MRD group who had not received any ATG, the incidence of HC was much lower than the patients who had underwent HSCT from MUD or haploidentical donor group. CONCLUSIONS: Patients with T-cell ALL and those who under haploidentical HSCT had the highest incidence of HC.

Influential Factors on Survival in Gastric Cancer: A Single-center Study.

Background: Gastric cancer (GC) is one of the conspicuous causes of cancer-related death worldwide. Considering the mounting incidence of this cancer in developing countries such as Iran, determining the influential factors on the survival of involved patients is noteworthy. Hence, we aimed to ascertain the survival rates and the prognostic factors in our GC patients. Materials and Methods: In this retrospective cohort study, data of 314 patients with GC in a referral cancer center in Hamadan province of Iran were studied. The outcome of our study was survival time and the influential factors were gender, age at diagnosis, tumor history, tumor grade, surgery history, radiotherapy history, stage of disease, metastasis history, and lymph node involvement. Kaplan - Meier method and log-rank test were used for the calculation and comparing the survival curves and Cox-proportional hazard model was used for the multivariable analysis of prognostic factors. Results: In a total of 314 GC patients, the median age at the diagnosis was 63 years (range: 21-92) with most patients (74.84%) being males. The median follow-up time was 2.42 years, and the median survival time was 2 years. The multivariable cox analysis of overall survival (OS) indicated that having distant metastasis increased the hazard of death by about 2.5 times (P < 0.0001, heart rates [HR]: 2.53, 95% confidence interval [CI]: [1.71, 3.75]), and receiving surgery as treatment, decreased the hazard of death up to 36% (P = 0.02, HR: 0.64, 95%CI: [0.46-0.89]). The other variables did not have any significant effects on the OS. Conclusion: The results of this study showed that lower survival (greater hazard of death) strongly and significantly associated with having distant metastasis in patients with GC and receiving surgery could significantly decrease the hazard of death in these patients instead.

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis.

Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. A total of 122 patients (median age: 8 years, range: 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day, days -9 to -6), cyclophosphamide (15 mg/kg/day, days -5 to -2), and in vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease prophylaxis with cyclosporine combined with methotrexate. We used the Kaplan-Meier method, log-rank test, and Cox proportional hazards models to analyze patient survival. Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched siblings in 48 (39.3%), matched other relatives in 56 (45.9%), and matched unrelated persons in 18 (14.8%) patients. With a median follow-up time of 24.25 months, graft rejection occurred in only one patient. The 1- and 5-year overall survival rates were 84.14% (95% confidence interval: 76.02-89.70) and 82.16% (95% confidence interval: 73.01-88.45), respectively. Of the patient characteristics documented before transplant, the presence of cardiopulmonary, genitourinary tract, central nervous system, and limb malformations significantly affected survival rates. Our results indicate excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable to aim at optimizing the outcome of HSCT in FA patients in future studies.

The effect of bone marrow-derived mesenchymal stem cell co-transplantation with hematopoietic stem cells on liver fibrosis alleviation and survival in patients with class III ß-thalassemia major.

BACKGROUND: Hepatic fibrosis is a common complication in transfusion-dependent thalassemia patients. Data on the co-transplantation of mesenchymal stem cells (MSCs) with hematopoietic stem cells (HSCs) in beta-thalassemia major patients are scarce. Therefore, we aimed to evaluate the effect of co-transplantation of bone marrow-derived MSC with HSCs on the liver fibrosis alleviation and transplant outcomes in class III beta-thalassemia major. METHODS: Between April 1998 and January 2017, a total of 224 consecutive patients with class III beta-thalassemia major underwent allogeneic HSCT in the Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran. To assess liver fibrotic changes after transplantation, 47 patients participated in the MSC plus HSC group and 30 patients in the HSC only group at the end of the follow-up period. All patients underwent laboratory tests, especially serum ferritin and liver function testing, hepatic T2* MRI, liver biopsy, and FibroScan before and 2 years after transplantation. Kaplan-Meier curves were derived to determine survival and were compared using the log-rank test. Repeated-measure, mixed-effect linear regression models were used to examine the changes in liver fibrosis over time. RESULTS: The 10-year OS rate was 71.84% in the mesenchymal group and 61.89% in the non-mesenchymal group (P value = 0.294), while the 10-year TFS rate was 63.64% in the mesenchymal group and 52.78% in the non-mesenchymal group (P value = 0.285). No significant difference was observed in the 10-year NRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD between the two groups. In addition, the results of repeated-measure, mixed-effect linear regression models showed that none of the variables determining hepatic fibrosis had a significant difference between patients receiving MSCs and patients who did not receive MSCs. CONCLUSIONS: Based on the results of this study, a single infusion of MSCs at the time of HSCT to patients with class III beta-thalassemia major could not significantly improve the liver fibrosis alleviation and transplantation outcomes, including OS, TFS, TRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD.

COVID-19 and cancer: A comparative case series.

BACKGROUND: Cancer patients, with an incidence of more than 18 million new cases per year, may constitute a significant portion of the COVID-19 infected population. In the pandemic situation, these patients are considered highly vulnerable to infectious complications due to their immunocompromised state. MATERIAL & METHODS: In this retrospective case series, the documents of solid cancer patients infected by SARS-CoV-2, hospitalized in Shariati hospital between 20 February and 20 April 2020, were evaluated. The diagnosis of COVID-19 was based on laboratory-confirmed COVID-19 and/or features of chest CT scan highly suggestive for SARS-CoV-2. RESULTS: A total of 33 COVID-19-infected cancer patients were included. Mean age was 63.9 years, and 54.5% of the patients were male. LDH level was significantly higher (1487.5 ± 1392.8 vs. 932.3 ± 324.7 U/L, P-value=0.016) and also serum albumin was significantly lower in non-survivors (3.6 ± 0.5 vs. 2.9 ± 0.6 g/dL, p-value=0.03). Among 16 patients with stage IV cancer, thirteen patients died, which was significantly higher compared to stage I-III cancer patients (81.3% vs. 18.8% P-value= <0.001). In terms of developing complications, sepsis, invasive ventilation and mortality was significantly higher in patients who received cytotoxic chemotherapy within the last 14 days. CONCLUSION: In this study, we showed that the mortality rate among cancer patients affected by COVID-19 was higher than general population and this rate has a significant correlation with factors including the stage of the disease, the type of cancer, the activity of cancer and finally receiving cytotoxic chemotherapy within 14 days before diagnosis of COVID-19.

Co-transplantation of bone marrow-derived mesenchymal stem cells with hematopoietic stem cells does not improve transplantation outcome in class III beta-thalassemia major: A prospective cohort study with long-term follow-up.

Bone marrow transplantation is the only curative treatment for beta-thalassemia major. Data on the co-transplantation of MSCs with HSCs in beta-thalassemia major patients are scarce. We aimed to investigate the outcomes of thalassemia major patients who underwent bone marrow-derived MSC co-transplantation with HSCs compared with those who only received HSCs. This prospective randomized study included patients with class III thalassemia major undergoing HSCT divided randomly into two groups: Thirty-three patients underwent co-transplantation of bone marrow-derived MSCs with HSCs, and 26 patients only received HSCs. Five-year OS, TFS, TRM, graft rejection rate, and GVHD were estimated. The 5-year OS was 66.54% (95% CI, 47.8% to 79.9%) in patients who underwent co-transplantation of MSCs with HSCs vs 76.92% (95% CI, 55.7% to 88.9%) in patients who only received HSCs (P = .54). No significant difference was observed in the 5-year TFS between the two groups (59.1% vs 69.2%; P = .49). The 5-year cumulative incidence of TRM was not statistically significant among patients who underwent co-transplantation of MSCs with HSCs (27.27%) vs those who only received HSCs (19.23%; P = .61). There was no statistically significant difference in graft rejection, acute GvHD, and chronic GvHD between the two groups. Based on our findings, the co-transplantation of MSCs and HSCs to class III thalassemia major patients does not alter their transplantation outcomes including OS, TFS, rejection rate, transplant-related mortality, and GvHD.

An Experience of Donor Lymphocyte Infusion after Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Allogeneic hematopoietic stem-cell transplantation is a well-known curative treatment for patients with chronic granulomatous disease. We present our experiment regarding ten patients with chronic granulomatous disease who underwent a reduced intensity conditioning regimen consisting of melfalan, fludarabine, and antithymocyte globulin. Donor lymphocyte infusion was used in three representative patients who developed mixed donor chimerism. After at least 2 years of median follow-up, 8 of the 10 patients are alive and well.

Hematologic predictors of mortality in hospitalized patients with COVID-19: a comparative study.

Background: The first cases of proved COVID-19 in Iran were reported in February 2020 and has since rapidly spread worldwide. We aimed to clarify the clinical significance of hematologic parameters alteration in COVID-19. Methods: Different hematologic parameters were measured in 225 hospitalized COVID-19 patients in a tertiary care university hospital, during the peak of COVID-19 outbreak and their association with duration of hospitalization, ICU admission and especially mortality was analyzed. Results: Among a total of 225 patients, 24.4% did not survive after admission. Lymphopenia and neutrophilia were observed in 52.7% and 21.4% of the patients, respectively. The mean count of neutrophils was significantly higher in non-survived patients (P = .032). Elevated neutrophil-to-lymphocyte ratio (NLR) was significantly associated with mortality (P < .001). Low hemoglobin (Hb) concentration significantly correlated with mortality (P = .004) and ICU admission (P = .04). Platelet (Plt) count was significantly lower in the non-survived patients (P = .023). Non-survivors had significantly lower nadir Hb and Plt counts than survivors (P < .001 in both parameters). Platelet-to-lymphocyte ratio (PLR) also correlated with mortality and was significantly higher in non-survivors (P = .034). Conclusions: Hematologic laboratory parameters have always been a crucial component of diagnostic and therapeutic strategies in infectious disease. Hematologic predictors of a fatal outcome in COVID19 hospitalized patients in our series include elevated NLR and PLR, lower than normal Hb and Plt, elevated d-dimer and prolonged prothrombin time (PT), together with elevated inflammatory indicators in the blood.

Indicators of male fertility potential in adult patients with beta-thalassemia major: a comparative study between patients undergone allogeneic stem cell transplantation and transfusion-dependent patients.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for thalassemia major (TM). Infertility and its indicators have been assessed in transfusion dependent TM men, but in this study, we sought to compare the fertility indicators of TM patients after HSCT with those in patients treated conventionally. The possible influential factors on reproductive capacity in TM patients undergone allogeneic HSCT were also evaluated. PATIENTS AND METHODS: In this cross-sectional study, we compared the gonadal hormones level, testicular volume, Tanner stage and sperm analysis in transfusion-dependent thalassemia major (TDTM) patients who survived matched sibling HSCT (n = 43) with patients conventionally treated by transfusion and iron chelation (n = 52). RESULTS: The patients' age range was between 16 to 41 years. Tanner stage 4-5 was seen in 39 patients (41%). The prevalence of hypogonadism in our patients was 32.63% but its frequency was not significantly different between the two groups (p = 0.35). Azospermia, oligospermia, astenospermia, teratospermia and even having dry and low volume ejaculate were all significantly more frequent in the post-transplant patients compared to TDTM group. In the post-HSCT group, neither patients' age at transplantation nor the conditioning regimen used in their transplant process did significantly affect their hormonal status and sperm parameters. Chronic graft versus host disease (GVHD) occurred in 14 (40%) patients. No significant difference was observed between the grade of chronic GVHD and hypogonadism (P = 0.853). CONCLUSIONS: Thalassemia patients undergone allogeneic HSCT have lower fertility potential, mainly in sperm parameters compared with patients treated with blood transfusion and chelation. This information is important for thalassemic patients considering HSCT.

Comparable Outcomes of Allogeneic Peripheral Blood versus Bone Marrow Hematopoietic Stem Cell Transplantation in Major Thalassemia: A Multivariate Long-Term Cohort Analysis.

Allogeneic hematopoietic stem cell transplantation (HSCT) currently is the only available curative option for transfusion-dependent thalassemia. Peripheral blood is a more convenient source for HSCT in comparison with bone marrow. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. The aim of this study was to evaluate the pros and cons of using peripheral blood instead of bone marrow as the graft source in thalassemia transplantation. We analyzed the transplant results of 567 transfusion-dependent thalassemia patients who received a transplant between 1998 and 2015 considering their stem cell source as a comparative variable. In multivariate Cox analysis the survival advantage for bone marrow compared with peripheral blood was not significant after adjusting for sex, age, and hepatic fibrosis presence. Rejection incidence was significantly lower in patients who used peripheral blood as their graft source. Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants, but the difference was not statistically significant. This study shows that peripheral blood could be an alternative stem cell source in patients undergoing allogeneic HSCT for thalassemia.

A comparison between gastroesophagheal ultrasonography vs. barium swallow in determining the pattern of gastroesophageal reflux in a pediatric population.

BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal pathology in infants and young children. Ultrasonography (US) has been considered to be a reliable diagnostic tool for GERD but the severity of GERD and the clinical implications based on imaging findings has not been evaluated. AIMS: To compare the diagnostic value of lower esophageal US with that of barium swallow in demonstrating the severity of GERD. MATERIALS AND METHODS: Fifty one pediatric patients, age between 1 month to 12 years, 34 male and 17 female with clinical suspicion of GERD were included. The patients were initially submitted to barium swallow (BS) and subsequently to transabdominal US. During BS, the number of gastroesophageal reflux episodes was documented in a 5-minute period. Transabdominal US documented the number and duration of reflux episodes during a 5-minute period, the angle of His, mucosal thickness, and intraabdominal esophageal length (IAEL). RESULTS: Duration and number of reflux episodes in US were significantly higher in patients that had severe gastroesophageal refluxes at BS. At US the cutoff point of 9.5 seconds (sensitivity 80%, specificity 60%) for reflux duration and more than 2 episodes in 5 minute ultrasound study (sensitivity 75%, specificity 58%) were defined to correlate with severe gastroesophageal reflux at BS.The angle of His, the esophageal wall mucosal thickness, and the IAEL did not correlate with the severity of GERD detected in BS. CONCLUSION: US can predict the severity of GERD. Therefore, except in the case of specific patients in whom mechanical causes are suspected to be responsible for GERD, BS can be replaced by US.

Brain Metastasis in Wilms' Tumor: a Case Report.

Wilms' tumor is the most common abdominal tumor of childhood, and its cerebral metastasis is apparently very rare. The authors report an 18-month-old girl with Wilms' tumor and brain metastasis.