Exagamglogene Autotemcel for Severe Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. METHODS: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. RESULTS: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred. CONCLUSIONS: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).

Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified ß-globin gene, which produces an antisickling hemoglobin, HbAT87Q. METHODS: In this ongoing phase 1-2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of four severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least four vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up. RESULTS: As of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAT87Q contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells. Hemolysis markers were reduced. Among the 25 patients who could be evaluated, all had resolution of severe vaso-occlusive events, as compared with a median of 3.5 events per year (range, 2.0 to 13.5) in the 24 months before enrollment. Three patients had a nonserious adverse event related or possibly related to LentiGlobin that resolved within 1 week after onset. No cases of hematologic cancer were observed during up to 37.6 months of follow-up. CONCLUSIONS: One-time treatment with LentiGlobin resulted in sustained production of HbAT87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events. (Funded by Bluebird Bio; HGB-206 ClinicalTrials.gov number, NCT02140554.).

Betibeglogene Autotemcel Gene Therapy for Non-ß0/ß0 Genotype ß-Thalassemia.

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent ß-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the ß-globin (ßA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent ß-thalassemia and a non-ß0/ß0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-ß0/ß0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).

Defining curative endpoints for sickle cell disease in the era of gene therapy and gene editing.

A growing number of gene therapy- and gene editing-based treatments for patients with sickle cell disease (SCD) are entering clinical trials. These treatments, designed to target the underlying cause of SCD, have the potential to provide functional cures, which until now were possible only through allogeneic hematopoietic stem cell transplant. However, as these novel approaches advance from early- to late-stage clinical trials, it is essential to identify physiologically and clinically relevant endpoints that can demonstrate the achievement of a functional cure for SCD. Here, we present an overview of the pathophysiology of SCD and current treatment options, review ongoing SCD clinical trials using gene therapy or gene editing approaches, and identify the most relevant endpoints for demonstrating the attainment of a functional cure for SCD.

Defining curative endpoints for transfusion-dependent ß-thalassemia in the era of gene therapy and gene editing.

ß-thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion-dependent ß-thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life-long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end-organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing-based treatments for patients with TDT with the potential to provide a one-time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.

Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study.

lovo-cel (bb1111; LentiGlobin for sickle cell disease [SCD]) gene therapy (GT) comprises autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified ß-globin gene (ßA-T87Q ) to produce anti-sickling hemoglobin (HbAT87Q ). The efficacy and safety of lovo-cel for SCD are being evaluated in the ongoing phase 1/2 HGB-206 study (ClinicalTrials.gov: NCT02140554). The treatment process evolved over time, using learnings from outcomes in the initial patients to optimize lovo-cel's benefit-risk profile. Following modest expression of HbAT87Q in the initial patients (Group A, n = 7), alterations were made to the treatment process for patients subsequently enrolled in Group B (n = 2, patients B1 and B2), including improvements to cell collection and lovo-cel manufacturing. After 6 months, median Group A peripheral blood vector copy number (≥0.08 c/dg) and HbAT87Q levels (≥0.46 g/dL) were inadequate for substantial clinical effect but stable and sustained over 5.5 years; both markedly improved in Group B (patient B1: ≥0.53 c/dg and ≥2.69 g/dL; patient B2: ≥2.14 c/dg and ≥6.40 g/dL, respectively) and generated improved biologic and clinical efficacy in Group B, including higher total hemoglobin and decreased hemolysis. The safety of the lovo-cel for SCD treatment regimen largely reflected the known side effects of HSPC collection, busulfan conditioning regimen, and underlying SCD; acute myeloid leukemia was observed in two patients in Group A and deemed unlikely related to insertional oncogenesis. Changes made during development of the lovo-cel treatment process were associated with improved outcomes and provide lessons for future SCD GT studies.

Who Places High Value on the Uterus? A Cross-sectional Survey Study Evaluating Predictors for Uterine Preservation.

STUDY OBJECTIVE: To determine predictors for placing high value on the uterus in patients who no longer desire fertility. The secondary objective was to identify reasons for placing high value on the uterus. DESIGN: Cross-sectional survey study. SETTING: Three hospitals within a large healthcare system in the United States. PATIENTS: New patients ≥45 years old seeking care for benign gynecologic conditions, including abnormal uterine bleeding, uterine myomas, pelvic organ prolapse, endometriosis, or pelvic pain. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the summative score of the validated Value of Uterus (VALUS) instrument for measuring value placed on the uterus and the validated visual analog scale with the question "how important is it to you to keep your uterus when you have a gynecologic condition?" A total of 163 surveys were returned for analysis (79.2%). Using the VALUS cutoff, 64 patients (45.7%) were considered to have low value for their uterus (VALUS score <14), whereas 76 patients (54.3%) were considered to have high value for their uterus (VALUS score ≥14). The adjusted odds of placing high value for the uterus was 5.06 times higher among those who wanted to be sexually active in the future than those who do not desire to be sexually active (95% confidence interval, 1.55-16.52, p = .01). Patients who are sexually active have 3.94 higher adjusted odds of placing high value on the uterus than those who are not sexually active and do not desire to be (95% confidence interval, 1.36-11.43; p = .01). Race, religion, and personal history of cancer were not statistically significant. CONCLUSION: Patients who highly value the uterus were highly motivated by the desire to be sexually active. Nonwhite race, religion, and personal history of cancer were not predictors for placing high value on uterine preservation.

Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease.

We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.

Development and validation of the Value of Uterus instrument and visual analog scale to measure patients' valuation of their uterus.

BACKGROUND: Currently, there are no clear frameworks or tools to objectively or subjectively evaluate patient attitudes toward uterine preservation and how they influence the decision to proceed with hysterectomy vs uterine preservation when undergoing prolapse surgery. OBJECTIVE: This study aimed to develop a reliable and valid instrument to measure patients' valuation of their uterus. STUDY DESIGN: The Value of Uterus instrument was developed on the basis of existing literature and created with structured patient-reported outcome measurement development methodology. An initial 14-question instrument was administered to 152 patients, and the instrument was revised on the basis of an analysis of internal consistency. The resulting Value of Uterus instrument has 6 items and includes a visual analog scale for the question "How important is it to you to keep your uterus when you have a gynecologic condition?" To validate the instrument, we recruited 51 patients aged >45 years with uterovaginal prolapse who presented to the urogynecology department and were scheduled to undergo vaginal surgery with or without hysterectomy. Internal reliability of the instrument was measured with Cronbach alpha. For known-groups validity, Value of Uterus summary scores were compared between women who underwent hysteropexy and those who underwent hysterectomy using the t test. Intraclass correlation coefficient was used to assess test-retest reliability with Value of Uterus administered to women twice. Lastly, a receiver-operating characteristic curve analysis was conducted to identify a cutoff Value of Uterus and visual analog scale score for predicting whether a woman would undergo hysteropexy (vs hysterectomy). RESULTS: A total of 51 patients were recruited (26 patients in the hysterectomy and 25 in the hysteropexy group), with a mean age of 64±10 years; 87.8% of patients self-identified as White. There were no differences in demographics between the groups. Cronbach's alpha was 0.94, suggesting excellent internal consistency of the items in the Value of Uterus instrument. The Value of Uterus instrument was highly correlated with the visual analog scale question, with r=0.82 (95% confidence interval, 0.69-0.89; P<.001). Patients in the hysteropexy group had significantly higher Value of Uterus scores (indicating greater value placed on the uterus) than women who underwent hysterectomy (20.8 vs 12.2; P<.001). Receiver-operating characteristic curve analysis identified a Value of Uterus cutoff score ≥14, with good accuracy for predicting hysteropexy (area under the curve, 0.87; sensitivity, 92.0%; specificity, 68%). CONCLUSION: Value of Uterus is a reliable and valid 6-item instrument that measures patients' valuation of the uterus and preferences for uterine preservation when undergoing surgery for pelvic organ prolapse. Value of Uterus and visual analog scale were shown to reliably predict whether a patient undergoes uterine-preserving prolapse surgery. The Value of Uterus instrument and visual analog scale tool can be useful tools to ensure that the patient's preferences are included in the medical decision-making. Value of Uterus may be useful for future research in other gynecologic conditions where uterine preservation is an option.

Intermediate term outcomes after transvaginal uterine-preserving surgery in women with uterovaginal prolapse.

INTRODUCTION AND HYPOTHESIS: There is growing interest in and performance of uterine-preserving prolapse repairs. We hypothesized that there would be no difference in pelvic organ prolapse (POP) recurrence 2 years following transvaginal uterosacral ligament hysteropexy (USLH) and sacrospinous ligament hysteropexy (SSLH). METHODS: This is a retrospective cohort study with a cross-sectional survey of women who underwent transvaginal uterine-preserving POP surgery from May 2016 to December 2017. Patients were included if they underwent either USLH or SSLH. POP recurrence was defined as a composite of subjective symptoms and/or retreatment. A cross-sectional survey was used to assess pelvic floor symptoms and patient satisfaction. RESULTS: A total of 47 women met the criteria. Mean age was 52.8 ± 12.5 years, and all had a preoperative POP-Q stage of 2 (55.3%) or 3 (44.7%). Thirty (63.8%) underwent SSLH and 17 (36.2%) underwent USLH. There were no differences in patient characteristics or perioperative data. There was no difference in composite recurrence (26.7% [8] vs 23.5% [4]) and retreatment (6.7% [2] vs 0%) retrospectively between SSLH and USLH groups at 22.6 months. Survey response rate was 80.9% (38) with a response time of 30.7 (28.0-36.6) months. The majority of patients (84.2%) reported POP symptom improvement, and both groups reported great satisfaction (89.5%). In respondents, 13.2% (5) reported subjective recurrence and 5.3% (2) underwent retreatment, with no differences between hysteropexy types. There were no differences in other pelvic floor symptoms. CONCLUSIONS: Although 1 in 4 women experienced subjective POP recurrence after transvaginal uterine-preserving prolapse repair and <5% underwent retreatment at 2 years, our results must be interpreted with caution given our small sample size. No differences in outcomes were identified between hysteropexy types; however, additional studies should be performed to confirm these findings. Both hysteropexy approaches were associated with great patient satisfaction.

Gene Therapy in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent ß-thalassemia. After previously establishing that lentiviral transfer of a marked ß-globin (ßA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with ß-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent ß-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent ß-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. RESULTS: At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-ß0/ß0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a ß0/ß0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS: Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe ß-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).

A randomized controlled noninferiority trial of reduced vs routine opioid prescription after prolapse repair.

BACKGROUND: Given the accelerating opioid crisis in the United States and evidence that patients use fewer opioid tablets than prescribed, surgeons may choose to decrease prescribed quantities. The effect this may have on patient satisfaction with pain control after hospital discharge is unknown. OBJECTIVE: The primary objective of this study was to compare patient satisfaction with postoperative pain control between patients receiving a routine or reduced quantity opioid prescription after prolapse repair. Secondary objectives included a comparison of opioid-related side-effects, the number of opioid tablets used, and the number of excess tablets prescribed between these groups. STUDY DESIGN: This was a single-center, unmasked, 2-arm, randomized controlled noninferiority trial of women who underwent a prolapse repair with a planned overnight hospitalization. Patients were assigned randomly to 1 of 2 study arms: routine (28 tablets of oxycodone 5 mg) or reduced (5 tablets) prescription of opioid tablets. Patients were eligible if they were at least 18 years of age and undergoing a prolapse repair with an anticipated overnight hospital stay. Exclusion criteria included a history of chronic pain, preoperative opioid use, intolerance to study medication, or a score of ≥30 on the Pain Catastrophizing Scale. In addition to their opioid prescription, all patients received multimodal pain medications at discharge. Patients were asked to complete 6 weeks of diaries to record pain and medication use. The primary outcome (patient satisfaction) was collected as part of a postoperative survey completed at patients' routine postoperative visit 6 weeks after surgery. The sample size for noninferiority was calculated at 59 patients per group for a total of 118 patients. RESULTS: One hundred eighteen patients were assigned randomly; the primary outcome was available for 116. The majority of patients were white, postmenopausal, and nonsmokers; the mean age was 62±10.4 years. The most common surgery was a hysterectomy with native tissue repair (n=71; 60%). One hundred ten patients (93%) were satisfied with postoperative pain control. Statistical analysis constructed for noninferiority showed that the difference between the groups was <15% (93% vs 93%; P=.005). Subjects in the reduced arm reported requiring an additional opioid prescription more frequently than in the routine arm (15% vs 2%; P=.01). Patients in the routine arm used more opioid tablets than the reduced arm (median, 3 [interquartile range, 0-14] vs 1 [interquartile range, 0-3]), but overall opioid utilization was low. As such, patients in the routine arm had significantly more unused opioid tablets (median, 26 [interquartile range, 15-28] vs 4 [interquartile range, 2-5]). CONCLUSION: Patient satisfaction with pain control was noninferior in patients who received a reduced quantity of opioid tablets after prolapse repair compared with those who received a routine prescription. A large quantity of excess opioid tablets was seen in both groups. Surgeons should consider prescribing 5-10 opioid tablets after prolapse repair surgery and consider applying these findings to postoperative prescribing after other gynecologic procedures.

Pelvic organ prolapse recurrence in young women undergoing vaginal and abdominal colpopexy.

INTRODUCTION AND HYPOTHESIS: While pelvic organ prolapse (POP) recurrence is believed to increase over time, outcomes of young women who undergo POP surgery are unclear. We hypothesized POP recurrence incidence among women <49 years would be higher after vaginal versus abdominal colpopexy. METHODS: This is a retrospective cohort study with a cross-sectional survey of women 18-49 years who underwent primary POP surgery from January 2003 to September 2013. Patients were identified by CPT codes for vaginal and abdominal colpopexy. POP recurrence was defined as vaginal bulge symptoms, POP retreatment (pessary or surgery) or both. Validated questionnaires were used to assess pelvic floor symptoms, patient satisfaction and improvement. RESULTS: Three hundred thirty-three women met the criteria. Mean age was 43 (+ 5.3) years; 29.1% (97) had an abdominal colpopexy and 70.9% (236) had a vaginal colpopexy. The recurrence incidence overall was 32.0% (31) in the abdominal group and 24.2% (57) in the vaginal group (p = 0.15), with a 10.3% (10) retreatment incidence in the abdominal group and 5.9% (14) in the vaginal group (p = 0.16). Forty-five percent (149) responded to the survey at a median time of 7.9 (3.1-15.2) years since surgery. The overall recurrence incidence in respondents was 13.7% (7) in the abdominal group and 15.3% (15) in the vaginal group (p = 0.80), with a retreatment incidence of 5.9% (3) in the abdominal and 5.2% (5) in the vaginal group (p = 0.85). CONCLUSIONS: One in four young women experienced subjective POP recurrence and/or retreatment, but only 5-10% underwent retreatment. There does not appear to be a difference in the incidence of recurrence between vaginal and abdominal colpopexy.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study.

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m2 ) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).

Intraoral Digital Impression Technique for a Neonate With Bilateral Cleft Lip and Palate.

OBJECTIVE: Dental casts are an important aspect in the treatment planning, documentation, and analysis of the dental arch forms of infants with cleft lip and palate (CLP). Impression taking in a neonate is a technique-sensitive procedure, which can result in foreign body dislodgement and carries a small risk of aspiration and airway obstruction. The advent of digital dental technologies and intraoral scanning may facilitate safer, more effective, and accurate impressions for CLP infants. DESIGN: A digital intraoral scan of a 3-month-old with bilateral CLP (BCLP) was compared with a conventional alginate impression taken prior to primary lip repair. SETTING: Princess Margaret Hospital for Children. MAIN OUTCOME MEASURES: To test the applicability and accuracy of digital impression taking for a neonate with BCLP and palate using digital morphometrics. RESULTS: The average deviation of points ranged above and below the plane of superimposition from +0.78 mm to -0.42 mm with a maximum range of +2.80 mm to -2.80 mm and standard deviation of 0.88 mm. The premaxillary segment showed the greatest degree of variation. CONCLUSIONS: This is to our knowledge the first report that illustrates the use of a digital impression system to scan the oral structures of a neonate with BCLP. Digital scanning was found to be fast, accurate, and safe, when compared to a conventional alginate impression technique.

Late Effects Screening Guidelines after Hematopoietic Cell Transplantation (HCT) for Hemoglobinopathy: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT.

Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms in hemoglobin disorders, including sickle cell disease (SCD) and thalassemia major. Managing the residual manifestations of pre-HCT disease complications and the long-term effects of HCT requires systematic monitoring, follow-up and intervention when indicated. Late complications vary with age and disease status at HCT and with transplant variables such as preparative regimen, donor source and compatibility, and immune reconstitution. An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium in May 2016 entitled "Late Effects Screening and Recommendations Following HCT for Immune Deficiency and Nonmalignant Hematologic Disorders" focused on follow-up after HCT for hemoglobinopathy. An earlier publication from experts who participated in this session described the pathophysiology and spectrum of complications that HCT recipients experience after HCT for SCD and thalassemia major. This companion publication summarizes the consensus reached by this group of experts about long-term follow-up guidelines after HCT for hemoglobinopathy. In addition, these guidelines might also be included in studies of novel curative therapies such as autologous HCT after hematopoietic progenitor stem cell gene modification.

Unrelated Donor Transplantation in Children with Thalassemia using Reduced-Intensity Conditioning: The URTH Trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n = 1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.