History Of Hematopoietic Cell Transplantation Research Articles

Venetoclax-Based Therapy before Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Introduction The BCL-2 inhibitor venetoclax (VEN) is effective in older patients with untreated acute myeloid leukemia (AML). Few reports exist on the use of VEN as a bridging therapy for allogeneic hematopoietic cell transplantation (HCT) for AML. Previous studies have shown that NPM1 and IDH2 gene mutations are associated with high response rates to VEN therapy. We performed a retrospective cohort study to analyze the efficacy of VEN-based bridging therapy before HCT. Methods We included 46 patients who were eligible for HCT and received bridging therapy combined with VEN between April 2021 and June 2023 at our center. We evaluated response rates to VEN and HCT outcomes. None of the patients received VEN prior to the study. The response rate to VEN was evaluated using the 2022 European LeukemiaNet (ELN) criteria. We estimated overall survival (OS) using the Kaplan-Meier method, log-rank test, and Gray's test for univariate analysis of cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). We used the Cox proportional hazards model for a multivariate analysis of OS. We extracted DNA from the bone marrow or peripheral blood, and analyzed gene mutations using next-generation sequencing (NGS), targeting 70 genes known to be recurrently mutated in myeloid malignancies. Results Of the 46 patients, 32 had de novo AML, 7 had de novo MDS/AML, 5 had secondary AML, 1 had secondary MDS/AML, and 1 had myeloid sarcoma. The median age was 59 (21-70) years. Nineteen were women and 7 had a history of HCT. The regimens combined with VEN were azacitidine in 39 cases and low-dose cytarabine in 7. According to the 2022 ELN risk classification by genetics at diagnosis, 7 were favorable, 11 were intermediate, and 27 were at adverse risk. Nine patients were in hematological complete remission (CR) / CR with incomplete count recovery (CRi) while 37 were not, when VEN was initiated. The maximum response rates among the patients who started VEN treatment in the non-CR group were: 18 with CR/CRi (49%) and no response in 19 (51%). The median time from the first dose of VEN to HCT was 70 (27-315) days. Forty-one patients underwent HCT and 19 (43%) were in CR/CRi at HCT. The reasons for discontinuation of VEN were HCT in 34 cases, failure in 9, and adverse events in 4 (hematological toxicity in 3 cases and infection in 1). Sixteen patients died due to primary disease (n=9), infection (n=5), thrombotic microangiopathy (n=1), and multi-organ failure (n=1). The median post-HCT observation period of survivors was 156 (25-775) days, and at 1-year after HCT, OS was 49.6% (95% CI: 28.0-67.9), CIR was 40.6% (95% CI: 24.1-56.6) and NRM was 15.2% (95% CI: 5.5-29.5). At 1-year after HCT, outcomes of the patients who were in CR/CRi at HCT was better than that of those who were not (OS, 80.8% vs. 26.4%, p=0.002; CIR, 13.4% vs. 61.8%, p<0.01; NRM, 0% vs. 26.7%, p<0.05). In 35 of the patients who underwent the first HCT, the 1-year OS was 88.9% in those who were in CR and 36.5% in those who were not (p=0.015). Thirty cases were non-CR at the start of the VEN regimen prior to their first HCT. This group had a 1-year OS of 57.8% (95% CI, 27.4-79.3). In 11 patients who achieved CR before HCT and 18 others who did not, the 1-year OS rates were 83.3% and 39.9%, respectively (p=0.10). Genetic analysis was performed by NGS in 37 patients before starting VEN, revealing mutations in TP53 (n=9), RUNX1 (n=7), IDH1 (n=6), ASXL1 (n=6), and DNMT3A (n=6) (Fig. 1A). Alterations in MDS-related genes (n=20) and kinase-related genes ( KIT, PTPN11, FLT3, KRAS, n=11) were frequent. Among the patients receiving their first HCTs, the 1-year OS was 0% in the group with TP53 mutations, and 63.9% in the wild-type TP53 group (p=0.04). The OS was worse in patients with mutated TP53 or kinase-related genes (n=19) than those without either mutation (n=15) (Fig. 1B, 1-year OS 28.7% vs. 72.9%, p=0.029). A multivariate analysis of OS revealed that patients who were not in CR at HCT (HR, 25.01 [95% CI, 2.406-259.9], p=0.007), those who previously underwent HCT (HR, 36.81 [95% CI, 4.599-294.7], p=0.035), and those with TP53 or kinase-related gene mutations (HR, 6.311 [95% CI, 1.137-350.0], p=0.035) had significantly lower OS rates. There was no significant difference in OS between the different ELN risk categories. Conclusions Non-CR at the time of HCT, a history of HCT, and mutations in TP53 or kinase-related genes were found to be independent poor prognostic factors for OS after VEN-based bridging treatment followed by HCT.

#46 A Multicenter Study Exploring the Epidemiology and Outcomes of COVID-19 Among Pediatric Hematopoietic Cell Transplant, Cellular Therapy and Solid Organ Transplant Recipients: Preliminary Results from the Pediatric COVID-19 U.S. Registry.

BackgroundWhile most pediatric patients with COVID-19 experience mild disease, children with a history of hematopoietic cell transplant or cellular therapy (HCT/CT) or solid organ transplant (SOT) may be at increased risk for severe disease. Despite this, there is a dearth of data from multicenter studies examining COVID-19 outcomes among pediatric HCT/CT and SOT recipients. We present descriptive results from the Pediatric COVID-19 U.S. registry to characterize COVID-19 illness among pediatric HCT/CT and SOT recipients across the United States.MethodDemographic, medical history, and COVID-19 related data were extracted from HCT/CT and SOT recipient medical records and submitted to the Pediatric COVID-19 U.S. Registry, a passive surveillance registry of pediatric patients less than 21 years old diagnosed with COVID-19 between March 2020 and April 2021. Participating US centers (n=170) submitted de-identified information for inpatients and outpatients at 7- and 28-days post COVID-19 diagnosis via a publicly available REDCap electronic survey. Data were summarized descriptively to characterize COVID-19 hospitalizations among HCT/CT and SOT recipients.ResultsOf the 13,140 registry COVID-19 cases, a total of 202 (1.5%) were patients with history of HCT/CT (n=58) or SOT (n=144). Median age at COVID-19 diagnosis among HCT/CT was 9.5 years (range 0.66 to 18) and SOT was 13.5 years (range 1 to 20). Over half of HCT (64%) and SOT (53.8%) patients were White/Caucasian and 26% of HCT and 39% of SOT here Hispanic/Latino. Hospitalizations among HCT/CT and SOT accounted for approximately 12% of all hospitalizations reported to the registry (n = 1683). Almost half of the reported HCT/CT (48%) and SOT (44%) cases were hospitalized. In those hospitalized, 11 (19%) HCT and 18 (12.5%) SOT cases required ICU admission. Half (50%) of HCT hospitalized cases received oxygen support and 3 (11%) required mechanical ventilation while only 2 (0.6%) SOT cases received oxygen support, and none required mechanical ventilation. The majority of HCT/CT cases (64%) were hospitalized between Days 100 and 365 post-transplant. Approximately half (48%) of the HCT cases had received an allogenic HCT. Myeloablative conditioning was the most common regimen reported (48%) among hospitalized HCT cases. Approximately half of SOT hospitalized cases had received a kidney transplant (48%) followed by liver (30%) and heart (19%). Of the 63 hospitalized SOT cases, the majority (87%) were receiving tacrolimus at COVID-19 diagnosis. One SOT death related to COVID-19 was reported, while no related deaths were reported in the HCT/CT group.ConclusionAlthough HCT/CT and SOT cases were low in comparison to all cases submitted to the registry, almost half of these cases required hospitalization. Only one COVID-19 related death was reported (SOT group); however, up to 20% of cases received ICU care. This data may aid clinicians developing future prospective studies examining COVID-19 risk mitigation and effective treatment strategies among this increased-risk population.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

Taking a Closer Look: Clinical and Histopathological Characteristics of Culture-Positive versus Culture-Negative Pulmonary Mucormycosis.

The cultural recovery of Mucorales from hyphae-laden tissue is poor, and the clinical implications of culture positivity are scarcely studied. Therefore, we compared clinical and histopathological characteristics of culture-positive and culture-negative histology-proven pulmonary mucormycosis cases among cancer patients. Histology specimens were blindly reviewed by a thoracic pathologist and graded on four histopathologic features: hyphal quantity, tissue necrosis, tissue invasion, and vascular invasion. Twenty cases with a corresponding fungal culture were identified; five were culture-positive, and fifteen were culture-negative. Although no statistically significant differences were found, culture-positive patients were more likely to exhibit a high burden of necrosis and have a high burden of hyphae but tended to have less vascular invasion than culture-negative patients. In terms of clinical characteristics, culture-positive patients were more likely to have acute myeloid leukemia (60% vs. 27%, p = 0.19), a history of hematopoietic cell transplant (80% vs. 53%, p = 0.31), severe lymphopenia (absolute lymphocyte count ≤ 500/µL, 100% vs. 73%, p = 0.36), and monocytopenia (absolute monocyte count ≤100/µL, 60% vs. 20%, p = 0.11). Forty-two-day all-cause mortality was comparable between culture-positive and culture-negative patients (60% and 53%, p = 0.80). This pilot study represents the first comprehensive histopathological scoring method to examine the relationship between histopathologic features, culture positivity, and clinical features of pulmonary mucormycosis.

Cholecystectomy in patients with hematologic malignancies

BackgroundCholecystectomy in patients with hematologic malignancies remains poorly understood. MethodsWe retrospectively evaluated patients with hematologic malignancies who underwent cholecystectomy at a single institution. ResultsOf 313 patients who presented for evaluation of abdominal pain, 64 underwent cholecystectomy for acute cholecystitis (34.4%), gangrenous cholecystitis (21.9%), chronic cholecystitis (23.4%), and cholelithiasis (20%). Most had a history of hematopoietic cell transplantation (62.5%) and/or immunosuppressive medication within 30 days of consultation (82.8%). Ultrasound had a 39% false-negative rate for acute nongangrenous cholecystitis. Operative time was 92 ± 39 min, 7 were performed open, 10 had intraoperative transfusions, and 4 had grade 3+ complications. Intraoperative transfusion was associated with increased postoperative length of stay (p = 0.03). Open procedure, operative time, estimated blood loss, intraoperative transfusion, and complications were not associated with timing of surgery. ConclusionsPatients with hematologic malignancies can safely undergo cholecystectomy. Length of postoperative stay for inpatients is associated with intraoperative blood transfusion.

Seroprevalence of Measles and Mumps Antibodies Among Individuals With Cancer

Although patients with cancer are at an increased risk of infection-related complications, few studies have characterized their vulnerability to measles and mumps. Given the recent outbreaks and increased community vaccine hesitancy, understanding measles and mumps immunity within this population is vital. To identify a point prevalence estimate of protective measles and mumps antibodies among ambulatory patients with cancer. In this cross-sectional study, residual clinical plasma samples were obtained from consecutive patients with cancer at Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center in Seattle, Washington, in August 2019. These samples were tested for measles and mumps IgG using a commercial enzyme-linked immunosorbent assay. Patients without cancer were excluded from the analysis. Patient age, sex, self-reported race and ethnicity, primary disease, receipt of chemotherapy in the past 30 days before sample collection, hematopoietic cell transplant (HCT) history, and date of most recent intravenous immunoglobulin treatment were abstracted from electronic medical records. Measles and mumps IgG seroprevalence, defined as the proportion of patients with positive antibody test results, was measured overall and among the subgroups. Of the 959 patients included in the analysis, 510 (53%) were male individuals and the mean (SD) age at sample collection was 60 (15) years. Most patients (576 [60%]) had a malignant solid tumor, and 383 patients (40%) had a hematologic malignant neoplasm; 146 patients (15%) had an HCT history. Overall, the seroprevalence of measles antibodies was 0.75 (95% CI, 0.72-0.78), and the seroprevalence of mumps antibodies was 0.62 (95% CI, 0.59-0.65). The lowest seroprevalences were among patients with a hematologic malignant neoplasm (0.63 for measles and 0.48 for mumps), those with a history of HCT (0.46 for measles and 0.29 for mumps), and those aged 30 to 59 years (0.49-0.63 for measles and 0.41-0.58 for mumps). In this study, 25% of ambulatory patients with cancer lacked protective antibodies for measles and 38% lacked protective antibodies for mumps. Deficits in protective antibodies underscore patients' increased risk during outbreaks and emphasize the need for community-based efforts to increase herd immunity to protect this population.

Utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML).

Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

We performed a multicenter retrospective cohort study of children with 14 days to 18 years of age in the United States from 2011 to 2016 with cancer or hematopoietic cell transplant (HCT) who were supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared the outcomes of children with oncological diagnoses or HCT supported with V-V ECMO to other children who have received V-V ECMO support. In this cohort of 204 patients supported with V-V ECMO, 30 (15%) had a diagnosis of cancer or a history of HCT. There were 21 patients who had oncological diagnoses without HCT and 9 children were post-HCT. The oncology/HCT group had a higher overall ICU mortality (67% vs. 28%, P < 0.001), mortality on ECMO (43% vs. 21%, P < 0.01), and ICU mortality among ECMO survivors (35% vs. 8%, P < 0.01). The oncology/HCT group had a higher rate of conversion to veno-arterial (V-A) ECMO (23% vs. 9%, P = 0.02) (RR, 2.5; 95% CI, 1.1-5.6). Children with cancer or HCT were older (6.6 vs. 2.9 years, P = 0.02) and had higher creatinine levels (0.65 vs. 0.4 mg/dL, P = 0.04) but were similar to the rest of the cohort for other pre-ECMO variables. For post-HCT patients, survival was significantly worse for those whose indication for HCT was cancer or immunodeficiency (0/6) as compared to other nonmalignant indications (3/3) (P = 0.01).

History of hematopoietic cell transplantation: challenges and progress.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.

Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders

To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.

Risk of Mortality in Immunocompromised Children With Severe Sepsis and Septic Shock.

To assess the prevalence of immunocompromised diagnoses among children with severe sepsis and septic shock, and to determine the association between immunocompromised diagnoses and clinical outcomes after adjustment for demographics and illness severity. Retrospective multicenter cohort study. Eighty-three centers in the Virtual Pediatric Systems database. Children with severe sepsis or septic shock admitted to a participating PICU between January 1, 2012, and December 31, 2016. None. Across 83 centers, we identified 10,768 PICU admissions with an International Classification of Diseases, 9th Revision, Clinical Modification code for severe sepsis or septic shock; 3,021 of these patients (28%) had an immunocompromised diagnosis. To evaluate variation across centers and determine factors associated with PICU mortality, we used mixed-effect logistic regression models. Among patients without hematopoietic cell transplant, congenital immunodeficiency (adjusted odds ratio, 1.90; 95% CI, 1.24-2.92), multiple prior malignancies (adjusted odds ratio, 1.86; 95% CI, 1.15-2.99), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 3.09; 95% CI, 1.91-4.98) were associated with an increased odds of PICU mortality. Among patients with prior hematopoietic cell transplant, liquid malignancy (adjusted odds ratio, 3.15; 95% CI, 2.09-4.74), congenital immunodeficiency (adjusted odds ratio, 6.94; 95% CI, 3.84-12.53), multiple prior malignancies (adjusted odds ratio, 3.54; 95% CI, 1.80-6.95), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 2.79; 95% CI, 1.36-5.71) were associated with an increased odds of PICU mortality. PICU mortality varied significantly by center, and a higher mean number of sepsis patients per month in a center was associated with lower PICU mortality (adjusted odds ratio, 0.94; 95% CI, 0.90-0.98). PICU resource utilization varied by immunocompromised diagnosis and history of hematopoietic cell transplant, and among survivors immunocompromised patients have shorter median PICU length of stay compared with patients without immunocompromised diagnoses (p < 0.001). Immunocompromised diagnoses are present in 28% of children with severe sepsis or septic shock. Multiple prior malignancies, hemophagocytic lymphohistiocytosis, congenital immunodeficiency, and hematopoietic cell transplant are independently associated with an increased odds of PICU mortality in children with severe sepsis or septic shock. Significant variation exists in PICU mortality among centers despite adjustment for immunocompromised diagnoses, known risk factors for sepsis-related mortality, and center-level sepsis volume.

Clinical Experience of CAR T Cell Immunotherapy for Relapsed and Refractory Infant ALL Demonstrates Feasibility and Favorable Responses

Background: The youngest patients referred for CAR T cell therapy are those with relapsed or refractory (R/R) KMT2A-rearranged infant B-ALL. Infants with relapsed ALL following Interfant-99 therapy have a dismal reported 3-yr OS of 20.9%, indicating the need for novel therapies. Smaller patient size, heavily pre-treated disease and high leukemia burden are often characteristics of this subgroup of patients that pose unique challenges to apheresis and manufacture of a T cell product. Additionally, reports of KMT2A-rearranged leukemia undergoing lineage switch following CD19-targeting pressure raises concern for an increased risk of myeloid leukemia relapses after B-lineage targeted CAR T cell therapy in this population. Here we report our experience using CAR T cell immunotherapy for patients with R/R infant ALL enrolled on clinical trials PLAT-02 (NCT02028455) and PLAT-05 (NCT03330691). Methods: PLAT-02 is a phase 1/2 trial of CD19-specific (FMC63scFv:IgG4hinge:CD28tm:4-1BB:ζ) CAR T cells. PLAT-05 is a phase 1 trial of CD19xCD22 dual specific CAR T cells, transduced with two separate lentiviral vectors to direct the co-expression of the CD19-specific CAR above and a CD22-specific CAR (m971scFv:IgG4hinge-CH2(L235D)-CH3-CD28tm:4-1BB:ζ). Eligible subjects on both studies have R/R B-ALL, an absolute lymphocyte count ≥100 cells/µL, and were at least 1 year of age. In addition, subjects on PLAT-02 were ≥ 10kg, and ≥ 8kg on PLAT-05. For cell manufacture, apheresis products were immuno-magnetically selected for CD4 and CD8 cells. Selected T cells were activated with anti-CD3/CD28 beads, transduced, and grown in culture with homeostatic cytokines to numbers suitable for clinical use. Infant ALL subjects received a range of 5x105 to 10x106 CAR+ T cells/kg following lymphodepleting chemotherapy. Disease response assessments were required at Day 21 and Day 63 following CAR T cell infusion. Adverse events were graded according to CTCAEv4, except CRS which was graded according to 2014 Lee criteria. Results: Eighteen subjects with R/R infant ALL have enrolled on PLAT-02 (n=14) or PLAT-05 (n=4), with a median age of 22.5 months at enrollment (range: 14.5 - 40.1 months). Of these, 2 (11.1%) had primary refractory disease, 8 (44.4%) were in 1st relapse, 7 (38.9%) were in 2nd relapse and 1 (5.6%) was in 3rd or greater relapse. Ten subjects (55.6%) had an M2 marrow or greater at enrollment prior to apheresis, and 9/18 had a history of hematopoietic cell transplant (HCT). The mean ALC was 1309 cells/µL (range 253-6944). Successful CAR T cell products were manufactured in 17/18 subjects, including in 9/9 subjects with no prior history of HCT. Of these, 16/17 subjects with available products were infused, with a median follow up of 26.9 months. One subject died of disease complications prior to CAR T cell infusion. Of the 16 treated subjects, 1 is pending disease and toxicity assessments. The maximum grade of CRS was 3 and occurred in two of 15 evaluable subjects (13%) and neurotoxicity was limited to a maximum grade of 2. Fourteen of 15 (93.3%) achieved an MRD negative complete remission (MRD-CR) by Day 21. Of the 14 subjects with an MRD-CR, 6 went on to HCT with 1 subsequent CD19 negative relapse. Of the 8 subjects who did not proceed to HCT, 1 developed lineage switch at one month following CAR T cells, and 1 died of infectious complications with aplasia. A "wait and watch" approach was taken for the remaining 6 subjects, and 2 developed CD19+ relapse. The incidence of lineage switch among the infant ALL group was 1/15 (6.7%). The estimated 1-year LFS was 66.7% and 1-year OS was 71.4%. Conclusion: This is the largest reported cohort to date of R/R infant B-ALL subjects treated with CAR T cell therapy. We report successful manufacture and administration of a CAR T cell product in the significant majority of infant subjects. Toxicity and MRD-CR rates are comparable to that of non-infant ALL subjects. In our experience, subjects with R/R infant ALL are not at increased risk for lineage switch relapse compared with the entire study populations following B-antigen targeting CAR T cell immunotherapy. Numbers in this report are too small to make definitive conclusions about the value of consolidative HCT. However, the LFS of this cohort is remarkably higher when compared with historical controls. Future work is focused on overcoming feasibility issues for the smallest of subjects, to enable a larger number of these cases to access CAR T cell therapy. Disclosures Pulsipher: Amgen: Other: Lecture; Bellicum: Consultancy; Miltenyi: Research Funding; Medac: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Wayne:AbbVie: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding; Servier: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding. Gardner:Novartis: Honoraria.

Improved Overall Survival with Enasidenib Compared with Standard of Care Among Patients with Relapsed or Refractory Acute Myeloid Leukemia and IDH2 Mutations: A Propensity Score Matching Analysis Using Data from the AG221-C-001 Trial and Two Data Sources from France and Germany

Improved Overall Survival with Enasidenib Compared with Standard of Care Among Patients with Relapsed or Refractory Acute Myeloid Leukemia and IDH2 Mutations: A Propensity Score Matching Analysis Using Data from the AG221-C-001 Trial and Two Data Sources from France and Germany

Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated robust responses in refractory/relapsed subjects with CD19+ acute lymphoblastic leukemia (ALL). Our Phase 1 clinical trial demonstrated a minimal residual disease (MRD) negative complete remission (CR) rate of 93% at 21 days following SCRI-CAR19v1 (a CD19 specific CAR T cell product) infusion (PMID: 29171004). Though remission is frequently attained, approximately half of patients recur. Controversy exists regarding the benefit of hematopoietic cell transplant (HCT) following CD19 CAR T cell therapy. Although not mandated by the study, our current institutional recommendation for relapsed/refractory patients without a history of allogeneic HCT is to undergo a HCT once in remission following SCRI-CAR19v1. Additionally, we have recommended HCT to those who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of prior HCT status. We report here the leukemia free survival (LFS) of subjects who proceeded to HCT following remission after SCRI-CAR19v1 infusion.Methods/Results: We analyzed the first 64 subjects on our Phase 1/2 trial, PLAT-02 (NCT02028455), with follow-up of ≥1 year to evaluate the potential benefit of consolidative HCT. We excluded subjects that did not respond (n=5) or relapsed prior to day 63 (n=9). Thirty-two of the evaluated subjects were treated on the Phase I dose finding portion of the study and 18 were treated on the Phase 2 portion at dose level of 1x106cells/kg. Of the 50 evaluable subjects, 33 had a history of at least one prior HCT, whereas 17 had no history of HCT. Figure A demonstrates the LFS for patients that did and did not undergo HCT following SCRI-CAR19v1.There is a trend towards improved LFS (p-value 0.057; Figure B) in patients who underwent first HCT following SCRI-CAR19v1. Of the 17 patients without a history of HCT, 3 did not pursue HCT following CAR therapy. Of those 3 subjects, only 1 remains in remission at 28 months. The other 2 subjects relapsed at 6 and 7 months with CD19+ and CD19- disease, respectively. Of the 14 patients that underwent first HCT after SCRI-CAR19v1, 2 relapsed following HCT. One had evidence of MRD by flow at the time of HCT and the other subject relapsed with CD19- disease. The role of second HCT following CAR therapy remains unclear. Of the 33 subjects with a history of HCT, 10 underwent a second HCT following SCRI-CAR19v1 infusion, and 5 are alive and remain in remission. The recurrences included 2 lineage switches and 2 CD19+ (1 was MRD positive by deep sequence prior to HCT), and one transplant related mortality (TRM). Of the 23 subjects that did not undergo a second HCT, 8 remain in remission (p-value not significant (NS); Figure C).We previously reported that subjects with a short duration of B cell aplasia (BCA) ≤63 days following SCRI-CAR19v1 have an increased risk of relapse. Here we show that subjects with short BCA who attained a CR and did not relapse prior to day 63 demonstrate a clear benefit of consolidative HCT (p-value 0.007; Figure D). Of the 15 subjects with short BCA (regardless of HCT history), 6 did not pursue HCT and all recurred (5 CD19+, 1 CD19-). Of the short BCA subjects that underwent HCT, 1 subject died of TRM (2ndHCT for this subject) and 2 subjects relapsed following HCT (1 was MRD positive prior to HCT).All events in the consolidative HCT group have occurred by 20 months following SCRI-CAR19v1. However, we continue to see late relapses following CAR T cell therapy in the group who did not proceed with HCT. Three subjects have relapsed beyond 2 years: 1 with CD19+ disease at 27months, 1 with CD19- disease at 41 months, and 1 patient with lineage switch AML at 38 months. Further analysis is needed to understand the continued long-term risk of relapse following CD19 CAR T cell therapy and the potential role and timing for consolidative HCT in patients with a previous HCT.Conclusions: We demonstrate a trend towards improved LFS for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T cell therapy on PLAT-02. In addition, HCT appears to benefit subjects who attain a CR but are at increased risk of relapse with short-term BCA. Currently, the benefit of second HCT following CD19 CAR T cell therapy is unclear and may be restricted to those that have short functional persistence of SCRI-CAR19v1. Late relapses after SCRI-CAR19v1 have only occurred in those without consolidative HCT, but longer follow up is needed to confirm these findings. DisclosuresJensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Clinical characteristics and outcomes of varicella zoster virus infection in children with hematologic malignancies in the acyclovir era.

BackgroundAlthough intravenous acyclovir therapy is recommended for varicella zoster virus (VZV) infection in immunocompromised children, the clinical characteristics and outcomes of VZV infection in the acyclovir era have rarely been reported.MethodsThe medical records of children diagnosed with varicella or herpes zoster virus, who had underlying hematologic malignancies, were retrospectively reviewed, and the clinical characteristics and outcomes of VZV infection were evaluated.ResultsSeventy-six episodes of VZV infection (herpes zoster in 57 and varicella in 19) were identified in 73 children. The median age of children with VZV infection was 11 years (range, 1-17), and 35 (46.1%) episodes occurred in boys. Acute lymphoblastic leukemia was the most common underlying malignancy (57.9%), and 90.8% of the episodes occurred during complete remission of the underlying malignancy. Acyclovir was administered for a median of 10 days (range, 4-97). Severe VZV infection occurred in 16 (21.1%) episodes. Although the finding was not statistically significant, a previous history of hematopoietic cell transplantation (HCT) appeared to be associated with the development of more severe episodes of herpes zoster (P=0.075).ConclusionClinical characteristics of VZV infection in immunocompromised children were not significantly different from those without it, and clinical outcomes improved after the introduction of acyclovir therapy. However, risk factors for severe VZV infection require further investigation in a larger population and a prospective setting.

Physical Activity, Fitness, and Cardiometabolic Risk Factors in Adult Survivors of Childhood Cancer with a History of Hematopoietic Cell Transplantation

Along with other childhood cancer survivors (CCS), hematopoietic cell transplantation (HCT) survivors are at high risk of treatment-related late effects, including cardiovascular disease and diabetes. Cardiometabolic risk factor abnormalities may be exacerbated by inadequate physical activity (PA). Relationships between PA and cardiometabolic risk factors have not been well described in CCS with HCT. PA (self reported), mobility (timed up and go test), endurance (6-minute walk test), handgrip strength, and cardiometabolic risk factors were measured in 119 HCT survivors and 66 sibling controls ages ≥18 years. Adjusted comparisons between HCT survivors and controls and between categories of low and high PA, mobility, endurance, and strength were performed with linear regression. Among HCT survivors, the high PA group had lower waist circumference (WC) (81.9 ± 2.5 versus 88.6 ± 3.1 cm ± standard error (SE), P = .009) than the low PA group, whereas the high endurance group had lower WC (77.8 ± 2.6 versus 87.8 ± 2.5 cm ± SE, P = .0001) and percent fat mass (33.6 ± 1.8 versus 39.4 ± 1.7% ± SE, P = .0008) and greater insulin sensitivity (IS) (10.9 ± 1.0 versus 7.42 ± 1.14 mg/kg/min ± SE via euglycemic insulin clamp, P = .001) than the low endurance group. Differences were greater in HCT survivors than in controls for WC between low and high PA groups, triglycerides between low and high mobility groups, and WC, systolic blood pressure, and IS between low and high endurance groups (all Pinteraction <.05). Higher endurance was associated with a more favorable cardiometabolic profile in HCT survivors, suggesting that interventions directed to increase endurance in survivors may reduce the risk of future cardiovascular disease.