Trends in Volumes and Survival After Hematopoietic Cell Transplantation in Racial/Ethnic Minorities.

There has been an increase in volume as well as improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have impacted racial/ethnic minorities equally. In this observational study from Center for International Blood and Marrow Transplant Research of 79,904 autologous (auto) and 65,662 allogeneic (allo) HCTs, we examined the volume and rates of change of auto HCT and allo HCT over time and trends in OS in 4 racial/ethnic groups: Non-Hispanic Whites (NHWs), Non-Hispanic African Americans (NHAAs), Hispanics across five 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs. NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (HR 1.13; 95% CI 1.04-1.22; p=0.004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; p<0.001 had a higher risk of mortality after alloHCT compared to NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT.Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics compared to NHWs. Survival after autoHCT and alloHCT improved over time, however NHAAs have worse OS after alloHCT which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis.

Racial/ethnic minorities have demonstrated worse survival after allogeneic hematopoietic cell transplantation (HCT) compared to whites. Whether the racial disparity in HCT outcomes persists in long-term survivors and possibly may be even exacerbated in this population, which frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study, we compared long-term outcomes among 1-year allogeneic HCT survivors by race/ethnicity and socioeconomic status (SES). The Center for International Blood and Marrow Transplant Research database was used to identify 5473 patients with acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or myelodysplastic syndromes who underwent their first allogeneic HCT between 2007 and 2017 and were alive and in remission for at least 1 year after transplantation. The study was restricted to patients who underwent HCT in the United States. SES was defined using patient neighborhood poverty level estimated from the recipient's ZIP code of residence; a ZIP code with ≥20% of persons below the federal poverty level was considered a high poverty area. The primary outcome was to evaluate the associations of race/ethnicity and neighborhood poverty level with overall survival (OS), relapse, and nonrelapse mortality (NRM). Cox regression models were used to determine associations of ethnicity/race and SES with OS, relapse, and NRM. Standardized mortality ratios were calculated to compare mortality rates of the study patients and their general population peers matched on race/ethnicity, age, and sex. The study cohort was predominately non-Hispanic white (n = 4385) and also included non-Hispanic black (n = 338), Hispanic (n = 516), and Asian (n = 234) patients. Overall, 729 patients (13%) resided in high-poverty areas. Significantly larger proportions of non-Hispanic black (37%) and Hispanic (26%) patients lived in high-poverty areas compared to non-Hispanic whites (10%) and Asians (10%) (P < .01). Multivariable analysis revealed no significant associations between OS, PFS, relapse, or NRM and race/ethnicity or poverty level when adjusted for patient-, disease- and transplantation-related covariates. Our retrospective cohort registry study shows that among adult allogeneic HCT recipients who survived at least 1 year in remission, there were no associations between race/ethnicity, neighborhood poverty level, and long-term outcomes.

Comparing the effectiveness of biosimilar filgrastim (Nivestim®) versus original filgrastim (Neupogen®) for stem cell mobilization in adult and pediatric healthy donors.

INTRODUCTION: Filgrastim is used for the mobilization of stem cells in healthy donors. Though several biosimilar filgrastim products have been approved, there is limited literature evaluating biosimilar products for stem cell mobilization. Therefore, we conducted this study to compare the effectiveness of the original filgrastim, Neupogen®, to the biosimilar product, Nivestim®, for stem cell mobilization(SCM) in healthy donors. METHODS: This was a retrospective study that included all healthy donors: adults and pediatrics, who received Neupogen® or Nivestim® for stem cell mobilization between 2014 and 2016 at a comprehensive cancer center. Donors received filgrastim at a dose of 5 mcg/kg every 12 h for 4 days to achieve the target CD34 + cell count of 5-10 × 106 CD34 + /kg of recipient body weight. Additional doses of filgrastim were administered and/or the dose increased if target CD34 + was not achieved. The primary endpoint was the number of doses required to achieve the target CD34 + cell count. RESULTS: Over the study period, 89 donors received Neupogen® and 68 received Nivestim®. The median age of donors was 19.5 years (3-64) in the Nivestim® group and 15 years (2-16) in the Neupogen® group. The median number of doses required for SCM was eight doses (6-10) in the Nivestim group and eight (6-16) in the Neupogen® group. CONCLUSION: Biosimilar Nivestim® was as effective as the original, Neupogen®, for stem cell mobilization for healthy adult and pediatric donors. Larger randomized studies are necessary to evaluate the safety and transplant outcomes of the use of Nivestim®.

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Effect of Autograft CD34+ Dose on Outcome in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplant for Central Nervous System Tumors.

Consolidation with autologous hematopoietic stem cell transplantation (HSCT) has improved survival for patients with central nervous system tumors (CNSTs). The impact of the autologous graft CD34+ dose on patient outcomes is unknown. We wanted to analyze the relationship between CD34+ dose, total nucleated cell (TNC) dose, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality (NRM), endothelial-injury complications (EIC), and time to neutrophil engraftment in children undergoing autologous HSCT for CNSTs. A retrospective analysis of the CIBMTR database was performed. Children aged <10 years who underwent autologous HSCT between 2008 to 2018 for an indication of CNST were included. An optimal cut point was identified for patient age, CD34+ cell dose, and TNC, using the maximum likelihood method and PFS as an endpoint. Univariable analysis for PFS, OS, and relapse was described using the Kaplan-Meier estimator. Cox models were fitted for PFS and OS outcomes. Cause-specific hazards models were fitted for relapse and NRM. One hundred fifteen patients met the inclusion criteria. A statistically significant association was identified between autograft CD34+ content and clinical outcomes. Children receiving >3.6×106/kg CD34+ cells experienced superior PFS (p = .04) and OS (p = .04) compared to children receiving ≤3.6 × 106/kg. Relapse rates were lower in patients receiving >3.6 × 106/kg CD34+ cells (p = .05). Higher CD34+ doses were not associated with increased NRM (p = .59). Stratification of CD34+ dose by quartile did not reveal any statistically significant differences between quartiles for 3-year PFS (p = .66), OS (p = .29), risk of relapse (p = .57), or EIC (p = .87). There were no significant differences in patient outcomes based on TNC, and those receiving a TNC >4.4 × 108/kg did not experience superior PFS (p = .26), superior OS (p = .14), reduced risk of relapse (p = .37), or reduced NRM (p = .25). Children with medulloblastoma had superior PFS (p < .001), OS (p = .01), and relapse rates (p = .001) compared to those with other CNS tumor types. Median time to neutrophil engraftment was 10 days versus 12 days in the highest and lowest infused CD34+ quartiles, respectively. For children undergoing autologous HSCT for CNSTs, increasing CD34+ cell dose was associated with significantly improved OS and PFS, and lower relapse rates, without increased NRM or EICs.

Early post-induction augmented therapy improves outcome in children and adolescents with T-cell acute lymphoblastic leukemia.

INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all newly diagnosed ALL in children and adolescents and is associated with worse outcomes compared to pre-B ALL. We aimed to decrease T-ALL relapses by intensifying our regimen. METHODS: Patients with T-ALL were treated using two different regimens; before September 2014, patients were treated per St. Jude Total XV protocol; subsequently, a major change was adopted by adding two intensive blocks: FLAG and Reintensification. Cranial radiation was limited to patients with WBC ≥ 100 k/µl at diagnosis and/or patients with CNS2/CNS3 status. RESULTS: Between June 2005 and April 2020, a total of 100 patients (76 males) were treated and followed up for a median of 70 months (range 14-181). Median age at diagnosis was 9 years (range 0.5-17.8). Forty-eight patients were diagnosed after September 2014 and received the augmented regimen; their median follow up was 46 months (range 14-74). The 5-year-EFS estimates for patients who received the augmented regimen versus standard regimen were 87% ± 4.9% versus 67% ± 6.8% (p = .03); and the 5-year-OS estimates were 87% ± 5.1% versus 71% ± 6.3% (p = .06), respectively. Treatment related mortality (TRM) was reported in two patients treated per standard regimen but none for patients who received the augmented regimen. CONCLUSIONS: We implemented a novel approach with early intensification added to a backbone of modified St. Jude Total-XV regimen for patients with T-ALL that resulted in improved outcome with no treatment related mortality.

Expanded HCT-CI Definitions Capture Comorbidity Better for Younger Patients of Allogeneic HCT for Nonmalignant Diseases.

Allogeneic hematopoietic cell transplantation (HCT) can cure many nonmalignant conditions, but concern for morbidity and mortality remains. To help physicians estimate patient-specific transplant mortality risk, the HCT comorbidity index (HCT-CI) is used. However, pediatric physicians use the HCT-CI less frequently than adult counterparts. We used the Center for International Blood and Marrow Transplant Research database to expand the HCT-CI comorbidity definitions to be more inclusive of children and adolescent and young adult (AYA) patients, adding history of mechanical ventilation, history of invasive fungal infection, assessment of chronic kidney disease (CKD) by estimated glomerular filtration rate, expanding the definition of obesity, and adding an underweight category. A total of 2815 children and AYAs (<40 years old) who received first allogeneic HCT for nonmalignant diseases from 2008 to 2017 were included to create an expanded youth nonmalignant HCT-CI (expanded ynHCT-CI) and a simplified non-malignant (simplified ynHCT-CI) HCT-CI. The expanded comorbidities occurred frequently-history of mechanical ventilation (9.6%), history of invasive fungal infection (5.9%), mild CKD (12.2%), moderate/severe CKD (2.1%), obesity (10.9%), and underweight (14.5%). Thirty-nine percent of patients had an increase in their comorbidity score using the expanded ynHCT-CI, leading to a redistribution of scores: ynHCT-CI score 0 (35%), 1-2 (36.4%), and ≥3 (28.6%). Patients with an increase in their comorbidity score had an increased hazard of mortality compared to those whose score remained the same (hazard ratio = 1.41; 95% confidence interval, 1.01-1.98). Modifications to the HCT-CI can benefit children and AYA patients with nonmalignant diseases, creating a risk assessment tool that is clinically relevant and better captures comorbidity in this younger population.

Adapting the HCT-CI Definitions for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation is a curative procedure for hematologic malignancies but is associated with a significant risk of non-relapse mortality (NRM). The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) is a prognostic tool that discriminates this risk in all age groups. A recent survey of transplant physicians demonstrated that 79% of pediatric providers used the HCT-CI infrequently, and most reported concerns about its applicability in the younger population. We conducted a retrospective study using the Center for International Blood and Marrow Transplant Research database to examine the impact of expanded HCT-CI definitions on NRM in pediatric and young adult patients with hematologic malignancies. We included 5790 patients <40 years old receiving allogeneic transplants between 2008 and 2017 to examine broader definitions of comorbidities in the HCT-CI, including history of mechanical ventilation and fungal infection, estimated glomerular filtration rate, and body mass index (BMI) percentiles. Multivariable Fine-Gray models were created to determine the effect of each HCT-CI defining comorbidity and its modification on NRM and were used to develop 2 novel risk scores. We next developed the expanded HCT-CI for children and young adults (youth with malignancies; expanded ymHCT-CI), where 23% patients had an increased comorbidity score, compared to the HCT-CI. Comorbidities with hazard ratio < 1.2 were then removed to create the simplified HCT-CI for children and young adults (youth with malignancies; simplified ymHCT-CI), which demonstrated higher scores corresponded to a greater risk of NRM (P < .001). These novel comorbidity indexes with broader definitions are more relevant to pediatric and young adult patients, and prospective studies are needed to validate these in the younger patient population. It remains to be seen whether the development of these pediatric-specific and practical risk indexes increases their use by the pediatric transplant community.

Allogeneic Hematopoietic Cell Transplantation for Patients With Deficiency of Adenosine Deaminase 2 (DADA2): Approaches, Obstacles and Special Considerations.

Deficiency of adenosine deaminase 2 (DADA2) is an inherited autosomal recessive disease characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages, end organ vasculitis), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure. Allogeneic hematopoietic cell transplantation (HCT) is curative for DADA2 as it reverses the hematological, immune and vascular phenotype of DADA2. The primary goal of HCT in DADA2, like in other non-malignant diseases, is engraftment with the establishment of normal hematopoiesis and normal immune function. Strategies in selecting a preparative regimen should take into consideration the specific vulnerabilities to endothelial dysfunction and liver toxicity in DADA2 patients. Overcoming an increased risk of graft rejection while minimizing organ toxicity, graft-versus-host disease, and infections can be particularly challenging in DADA2 patients. This review will discuss approaches to HCT in DADA2 patients including disease-specific considerations, barriers to successful engraftment, post-HCT complications, and clinical outcomes of published patients with DADA2 who have undergone HCT to date.

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy.

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P = .38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Noninfectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation.

Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Surgical management of cervical kyphosis in larsen syndrome. Case report and review of literature.

INTRODUCTION: and importance: Larsen syndrome is a rare genetic disorder that is characterized by multiple joint dislocations, flat faces that can also be referred to as "dish face", kyphoscoliosis, and anomalies of the vertebrae. Patients with this syndrome frequently develop various spinal deformities, one of them being kyphosis of the cervical spine. This deformity can lead to serious health manifestations if not surgically treated. CASE PRESENTATION: We report a case of a 6-month-old female, diagnosed with Larsen syndrome. She presented with progressive upper and lower limbs spasticity, flexed neck, and bilateral resistant developmental dysplasia of the hip. A C3 corpectomy with iliac crest allograft was done and 2.7 plates with screws in C2 and C4 were placed. An abduction brace (Pavlik harness) was used for 3 months after the surgery to prevent early collapse. CLINICAL DISCUSSION: Our patient was the youngest patient reported in the literature to be operated on. Although the type of surgery for patients with Larsen who suffer from spinal deformities is dictated by the severity of the deformity; the literature agrees that surgical intervention is the most important step in its management. CONCLUSION: If cervical kyphosis in a patient with Larsen syndrome is left untreated; the progression of the condition can eventually lead to paralysis. Early surgical correction can spare the patient future deterioration due to chronic cord compression.

En-plaque sphenoid wing grade II meningioma: Case report and review of literature.

INTRODUCTION AND IMPORTANCE: En-plaque-meningioma (EPM) is characterized by its flat growth along the bony contour. It accounts for 2-9% of all meningiomas. Very few grade II or III EPM cases were reported. Surgical resection of sphenoid wing EPM is especially challenging as the tumour tends to invade the cavernous sinus, and/or the orbit, and their neurovascular structures. Consequently, tumours in such locations have a higher rate of recurrence. We report the clinical course and management of a patient suffering a second recurrence of grade II EPM. The clinical course of grade II EPM, and the management of multiple recurrences of EPM are scarcely reported in the literature. CASE PRESENTATION: A 53-year-old male with a history of three previous surgeries for EPM presented with decreased vision in the right eye. Brain magnetic resonance imaging (MRI) showed progression of a sphenoid wing meningioma invading the left optic nerve, indicating a second recurrence of the tumour. CLINICAL DISCUSSION: We reviewed the literature discussing the clinical course of grade II EPM, and cases suffering multiple recurrences. Only a few cases were found with varying clinical course and management. In our case, surgical intervention was necessary to save the patient's vision. A modified orbitozygomatic craniotomy was performed. A small residual tumour invading the cavernous sinus was left for treatment with stereotactic radiosurgery. CONCLUSION: Sphenoid wing EPM is challenging pathology to manage, especially grade II tumours which are rarely encountered. Multimodality treatment with surgery and radiotherapy offers EPM patients the best chance of treatment.