Prolonged Pancytopenia Research Articles

CTNI-30. A PHASE 2 DOUBLE-BLIND, RANDOMIZED, PROSPECTIVE, PLACEBO CONTROLLED STUDY OF NANO₂TM COMBINED WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA: RESTORE

Abstract INTRODUCTION Glioblastoma (GBM) commonly has extensive hypoxic regions, possibly due to thrombosis from tumor-produced pro-coagulant factors. Radiation-induced cell death relies on oxygen free radicals and oxygen fixation of DNA-strand breaks. In the absence of oxygen tumor cells can repair the DNA strand breaks leading to treatment resistance. Hypoxic cells also exhibit chemoresistance due to decreased drug efficacy, limited drug diffusion, and poor delivery to distant cells. This study hypothesizes that increasing oxygen delivery to hypoxic GBM tissue using NanO₂ (2% w/v dodecafluoropentane emulsion) infusion will enhance the effectiveness of radiation therapy (RT) and chemotherapy (CT). METHODS Patients diagnosed with GBM per CNS5-WHO criteria receive standard chemoradiation: 30 fractions of focal RT with 60 Gy, delivered as 2 Gy fractions five days per week for six weeks with concurrent oral TMZ at 75 mg/m²/day for six weeks. Patients are randomized in a 1:2 ratio to receive either a placebo (0.9% Sodium Chloride) or NanO₂ infusion administered immediately prior to each RT dose. Patients continuously breathe oxygen during infusion and RT. Following six weeks of RT with temozolomide, patients have a four-week break before starting adjuvant temozolomide. RESULTS Ten patients have been enrolled in the RESTORE trial. Seven continue to be followed through maintenance treatment and long term follow up. There have been 23 non-hematologic adverse events described as CTCAE severity grade 3 and above. Grade 4, hematologic toxicity occurred in two patients, with one patient experiencing prolonged pancytopenia necessitating hematologic support and discontinuation of temozolomide. Two patients discontinued therapy due to early tumor progression. CONCLUSION This study is ongoing, assessing the safety and potential efficacy of NanO₂ in improving treatment outcomes for GBM by enhancing oxygen delivery to hypoxic tumor regions.

Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies

AbstractWe report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37–treated patients than in both cytopenic and noncytopenic cohorts of CAR-19–treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275.

Management of children and adolescents receiving CAR-T cell therapy for acute lymphoblastic leukemia

Tisagenlecleucel, a commercially available CD19-targeted CAR-T cell product, has dramatically changed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel infusion has been linked to distinct acute adverse events, including cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis and prolonged pancytopenia, which are rare with cytocidal chemotherapy. In addition, recent retrospective studies have revealed pre-infusion prognostic factors including high tumor burden (bone marrow leukemia cell fraction ≥5%) and non-response to blinatumomab, another CD19-targeting agent. Not only physicians providing CAR-T cell therapy but also those referring patients for this therapy should thoroughly understand the indications and limitations, characteristic acute complications, pre-treatment factors affecting prognosis, and late complications. This article outlines the current understanding regarding the use of tisagenlecleucel in children and adolescents with B-ALL.

Phase 1/2 Dose-Escalation/Dose-Expansion Study of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (T-ALL/LBL)

T-ALL/LBL are challenging hematologic cancers with high rates of relapse and mortality in both children and adults. Despite success in B-cell malignancies, development of CAR-T cell therapy for T cell malignancies has been complicated by induction of fratricide and risk of malignant cell contamination of the drug product in the autologous setting. WU-CART-007 is a CD7-targeted CAR-T cell products with CRISPR/Cas9 deletion of CD7 and T-cell receptor alpha constant (TRAC), to prevent fratricide and enable the use of healthy donor allogeneic T-cells, respectively (Leedom et al. ASH 2021). This off-the-shelf allogeneic CAR-T cell product is being developed for the treatment of CD7 + malignancies. WU-CART-007 1001 (NCT04984356) is a global first-in-human, Phase 1/2 single-agent study of WU-CART-007 in patients (pts) with R/R T-ALL/LBL. The recommended Phase 2 dose (RP2D) of WU-CART-007 is 900 million (M) cells administered on day 1 following lymphodepleting chemotherapy (LDC). Two different LDC regimens have been tested: standard LDC (fludarabine 30 mg/m 2/day x 3 days and cyclophosphamide 500 mg/m 2/day x 3 days), and enhanced LDC (eLDC; fludarabine 30 mg/m2/day x 4 days and cyclophosphamide 1000 mg/m2/day x 3 days).Disease response is assessed by Day 28 bone marrow (BM) aspirate/biopsy, and CT/PET, if applicable, per NCCN Guidelines Version 2.2022; Pharmacokinetics (PK) are measured by ddPCR; samples are collected for immunophenotyping by flow cytometry (FACS). As of July 21, 2023, 18 pts have been dosed with WU-CART-007(n = 11 T-ALL, n = 7 T-LBL); 3 with 100M (DL1), 3 with 300M (DL2), 6 with 600M (DL3), and 6 with 900M (DL4/RP2D) cells in a single infusion. A total of 15 pts received standard LDC while 3 received eLDC at the DL4/RP2D. Median age is 33.5 years (range 20-68). Pts were heavily pretreated with a median of 4 prior lines of therapy (range 2 - 7), 28% (5/18) relapsed following an allogeneic HSCT. Disease burden at baseline consisted of extramedullary disease (EMD) in 28% (5/18) of pts, and a median BM blast count of 60% (range 5-98%) in pts with BM disease (13/18). Overall WU-CART-007 demonstrated manageable safety profile; treatment-related adverse events of ≥ G3 were observed in 8/18 (44%) pts. Cytokine release syndrome (CRS) was observed in 14/18 (78%) pts. Most (72%; 13/18) pts had G1-2 CRS events; a single G3 CRS event was reported which resolved within 72 hours after receiving tocilizumab, dexamethasone, and low-dose vasopressors. Grade 1 ICANS was reported in one patient at DL3, which resolved spontaneously. No GvHD, prolonged T-cell aplasia, or prolonged pancytopenia in the absence of disease were observed. One unrelated DLT lead to cohort expansion at DL3. The majority of deaths were due to disease progression. There were two Grade 5 events not attributed to WU-CART-007, both due to fungal infection. WU-CART-007 showed dose-dependent anti-tumor activity with no responses seen at DL1. In evaluable patients at DL≥ 2 (n=12) Composite Complete Remission Rate (CRc; CR + CRi + CRh): 58% (86% MRD neg), median duration of response 12.3 weeks (1.1 - 29.4); two patients successfully received a consolidating allogeneic-HSCT. At the RP2D, the CRc rate was 60% (3/5; 2 CR, 1CRi). Molecular expansions of CAR-T cells peaked on day 10 in peripheral blood (mean 66,069 copies/ug DNA) and persisted out to day 56. Of all pts tested (n=15), none developed novel anti-HLA antibodies against the donor, and no anti-drug antibodies against the CAR-construct were detected. Phenotypic analysis revealed in vivo WU-CART-007 cells expressed activation markers (KI67, CD38, HLA-DR) and were largely an effector memory CD45RA + (EMRA) CM phenotype (CD45RA +, CD197 +). WU-CART-007 has demonstrated an acceptable safety profile and preliminary evidence of anti-leukemic activity. This program advances CAR-T cell therapy in heavily pre-treated patients with R/R T-ALL/LBL. Enrollment is ongoing.

Prolonged fever, pancytopenia, and splenomegaly - is it sarcoidosis?

Prolonged fever, pancytopenia, and splenomegaly - is it sarcoidosis?

Cytokine profiles are associated with prolonged hematologic toxicities after B-cell maturation antigen targeted chimeric antigen receptor–T-cell therapy

Background aimsThe considerable efficacy of B-cell maturation antigen–targeted chimeric antigen receptor (CAR)–T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. MethodsThis retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR–T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). ResultsAmong 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR–T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR–T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. ConclusionsOur findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies.

Predictors for Survival and Relapse in Patients (pts) with Diffuse Large b-Cell Lymphoma (DLBCL) Treated with Anti-CD19 CAR T-Cell Therapy: A Case for Early Intervention in High-Risks Pts Assessed By Day 30

Purpose: Despite the success of CAR T-cell therapy in pts with relapsed/refractory (R/R) DLBCL, some pts still fail treatment, and their prognosis is dismal. Our aim is to elucidate factors that govern the clinical performance of CAR T therapy given as standard of care (SOC) for R/R DLBCL at a single institution and to recognize the group of pts who are at risk for relapse after CAR T as early intervention may help improve the outcomes. Methods: We performed a retrospective study of R/R DLBCL pts treated with CAR T-cell as SOC at our center between Jan 2018 and Feb 2021. Disease characteristics, ferritin and CRP levels were collected pre-treatment initiation; CBC data were collected at time of apheresis. The study was IRB-approved at our center. Results: Characteristics of the pts at pre-conditioning for CAR T are listed in Table 1. Of 201pts, 190 (94.5%) received axicabtagene ciloleucel, and 11 (5.5%) received tisagenlecleucel. Median time from apheresis to infusion was 29 days (range, 20-111). Regarding adverse events of special interest, 6% had cytokine release syndrome of > grade 3 and 38.8% had neurotoxicity > grade 3. Day 30 death rate was 4.5%. Nine (4.68%) pts developed AML/MDS and 3 (1.56%) additional pts had prolonged pancytopenia. Sixty (29.8%) pts died post Day 30 [42 of progressive disease (PD); PD/AML =3; PD/Infection =2; PD/Toxicity =2; Infection =9; unknown=2). Four pts lost follow-up after PD. With a median follow-up from infusion of 16.86 (0.92-38.7) months, the 12-months overall survival (OS) rate was 55.48 %(95%CI:49-63); 12-months relapse-free survival (RFS) was 34.57% (95% CI: 28-42). In multivariate analysis, the factors with independent influence on both RFS and OS were serum ferritin, > 2 extra-nodal sites of disease involvement, glomerular filtration rate pre-conditioning and Hb level at apheresis (Table 2, Figure 1a). Salvage therapies were received by 38 pts with PD after CAR T (median 1, range 1-6 lines of therapies), including 9 pts who received an allogeneic stem cell transplant. Only 5 (13%) of these 38 pts achieved CR. Therefore, we assessed response by day 30 to predict which pts were at risk for relapse prior experiencing an actual progression. We found a significant difference in OS and RFS in patients who were in CR vs PR/SD after CAR T. The 12-months OS rates were 75.52% and 54.38%, respectively (P<0.001). The RFS rates were 65.4% vs 16.56%, respectively (P<0.001, Figure 1b). In multivariate analysis, the factors with independent influence on RFS in Day 30 PR/SD pts were serum ferritin level pre-conditioning, histology (primary mediastinal vs DLBCL), and WBC at apheresis (figure 1c). Conclusions: Predictors of outcomes after CAR T cell therapy are multifactorial. However, we found that simple clinical tools by Day 30 (pts not achieving CR by imaging, ferritin level pre-CAR T infusion, WBC at apheresis) are associated with outcomes. Studies are needed to study whether integration of CAR T with innovative therapies in such high-risk patients may improve survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infectious Disease Antimicrobial Prophylaxis Strategies in Children with Severe or Very Severe Aplastic Anemia: A North American Pediatric Aplastic Anemia Consortium (NAPAAC) Study

Introduction: Pediatric Severe Aplastic Anemia (sAA) results in severe and prolonged pancytopenia that may increase the risk for infections. Infections from bacterial, viral, and fungal etiologies remain a leading cause of mortality, prompting an interest in the development of infectious disease (ID) supportive care guidelines. However, institutional clinical practice guidelines (CPG) to-date are often extrapolated from adult studies or providers experiences with other oncologic diagnoses given the paucity of sAA-specific data to inform best practices. Objective: Evaluate current antimicrobial prophylaxis practices in individuals with sAA or very severe aplastic anemia (vsAA) receiving care at hematology centers participating in the North American Pediatric Aplastic Anemia Consortium (NAPAAC). Method: A RedCap survey was created and electronically distributed to the 53 NAPAAC institutions querying ID antimicrobial prophylaxis practices in pediatric patients with sAA /vsAA. Pediatric patients were defined as individuals 0 to 18 years of age who had not received a hematopoietic cell transplant (HCT) and met diagnostic criteria for sAA/ vsAA. Standard immunosuppressive therapy (IST) agents included anti-thymocyte globulin, calcineurin inhibitors, alemtuzumab, eltromobag (not monotherapy), and systemic corticosteroids. Each institution was asked to submit one collective survey response from June 1, 2022 to July 16, 2022. Results: In total 43 (81%) NAPAAC sites completed the survey. The participant demographics were as follows: 68% (N=29) hematologists, 30% (N=13) HCT specialists, 2% (N=1) practiced as both. Most centers diagnosed 0 to 5 new sAA/vsAA cases/ year (N=28, 65%), 3 (7%) centers diagnosed ≥11/yr. Centers reported having a written CPG for bacterial (N=11; 26%), viral (N=11; 26%), fungal (N=19; 44%), and Pneumocystis (PCP) prophylaxis (N=17; 41%). Respondent opinions regarding strength of data to inform and prescribe ID prophylaxis are summarized in Table 1. Less than half of respondents felt there was sufficient data to inform the decision to prescribe antimicrobial prophylaxis. In the 44% of centers that prescribe antibacterial prophylaxis, absolute neutrophil count (ANC) threshold of 500 was the most frequent criterion used to start and stop prophylaxis. The preferred antibacterial prophylaxis agent was levofloxacin (N=29, 91%) among centers regardless of beta-lactam allergy and the majority of centers did not use IVIG (N=37, 86%). Thirty-four (79%) centers perform antiviral testing at diagnosis and 43% reported prescribing antiviral prophylaxis, preferentially initiating acyclovir in HSV or VZV seropositive patients who receive IST. Twelve (28%) centers routinely performed viral PCR monitoring (frequency of twice weekly to monthly) for CMV. Eighty-one percent of institutions prescribe fungal prophylaxis, most frequently with mold active agents (N=24, 62%) over fluconazole (N=12, 31%). Among mold-active agents, voriconazole was preferentially prescribed (N=19, 79%); dosing was below the recommended maintenance amount of 8-9 mg/kg/dose in 65% of prescribing centers. Criteria to discontinue antifungal prophylaxis included a combination of time after IST completion (0-3 months) and ANC ≥ 500 (N=22, 51%) or ALC > 1000 (N=5, 12%). Eighty-eight percent of centers prescribe PCP prophylaxis with IV pentamidine (N=12, 32%), aerosolized pentamidine (N=10, 26%), or TMP/S (N=11, 29%) based primarily on initiation IST, less on ALC. Cessation of PCP prophylaxis was variable with 60% either stopping 3 or 6 months after completion of IST; ANC or ALC contributed less frequently to the decision to stop PCP prophylaxis. Conclusion: This study evaluated current antimicrobial prophylaxis practices from multiple NAPAAC institutions, highlighting the degree of practice variation across centers caring for pediatric patients with sAA or vsAA. Interestingly, the majority of centers do not have written ID prophylaxis guidelines in place and in centers with a prophylaxis CPG for this population, practice variability persists regarding type of prophylaxis, preferred agents, and criteria to start and stop prophylaxis. This study underscores the need for sAA/vsAA-specific data to inform national guidelines regarding optimal antimicrobial prophylaxis strategies in these high-risk children. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transient Responses and Significant Toxicities Due to Cytopenias and Rashes with Anti-CD30 CAR T Cells for CD30-Expressing Lymphomas: Results of a Phase I Clinical Trial

Although several effective therapies are available for Hodgkin lymphoma (HL), new treatments are needed, especially for chemotherapy-refractory HL. We developed a novel anti-CD30 CAR, designated 5F11-28Z, with a human antibody-derived binding domain, CD28 hinge, transmembrane, and costimulatory domains, and a CD3-ζ domain (Choi et al., Hum Gene Ther 2021; 32(13-4): 730-43). T cells expressing 5F11-28Z are designated 5F11-28Z-T; 5F11-28Z-T exhibited a full range of T-cell functions in vitro and eradicated tumors from mice. Safety and feasibility of 5F11-28Z-T were evaluated in a phase I clinical trial for patients (Pts) with CD30-expressing lymphomas (NCT03049449). Pts were divided into 2 cohorts with separate dose escalations based on prior allogeneic stem cell transplant status and received 5F11-28Z-T on one of 4 dose levels (Table). The treatment protocol was 300 mg/m2 or 500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5 to -3 followed by infusion of 5F11-28Z-T on day 0. Normal organ function and absence of baseline Grade (Gr) 3-4 cytopenias were required for eligibility. Twenty-one Pts received 5F11-28Z-T infusions, 20 with HL and 1 Pt with anaplastic large cell lymphoma (Table). The median prior lines of therapy was 7 (4-15). Forty-three percent of Pts (9 of 21) obtained a response of partial remission or better with one (4.8%) obtaining a complete remission. The median event-free survival was 13 (4-22) weeks. Eleven Pts (52%) had cytokine release syndrome (CRS): 4 (19%) with Gr 1, 6 (29%) with Gr 2, 1 (4.8%) with Gr 3, and no Pts had grade 4-5. Two Pts (9.5%) received tocilizumab; no Pts received corticosteroids for CRS. Neurologic toxicity possibly related to CAR T cells (graded by CTCAE v 5) occurred at Gr 2 in 5 (24%) Pts, with no Gr 3-4 events. There were no treatment related deaths. Nine Pts (43%) had new onset maculopapular or pustular rashes after 5F11-28Z-T infusion (Figure). Rashes occurred a median of 11 (7-55) days after 5F11-28Z-T infusion and lasted at Gr of 2 or higher for a median of 7 (3-39) days. Six Pts had Gr 2 rashes; 3 Pts had Gr 3 rashes. Two Pts with Gr 3 rashes lasting 29 and 39 days received systemic corticosteroids for management of rash. One Pt received phototherapy. Nineteen Pts (90%) had Gr 3-4 neutropenia; 5 (24%) had Gr 3-4 thrombocytopenia; and 6 (29%) had Gr 3-4 anemia. Three Pts (14%) had Gr 3-4 cytopenias lasting more than 30 days. Two Pts had prolonged pancytopenia, lasting 77 and > 82 days; both Pts had infections requiring intensive care while neutropenic. Three Pts received eltrombopag; 2 Pts received corticosteroids for management of prolonged cytopenias. Eleven bone marrow (BM) biopsies were performed for 5 Pts to evaluate cytopenias. All biopsies showed hypocellularity; 10/11 (4 Pts) showed trilineage or myeloid hypoplasia, 4/11 (2 Pts) showed fibrosis, 1 showed stromal gelatinous changes, and none showed HL or dysplasia. Blood 5F11-28-T were detected in all 15 patients assessed so far. A median of 2.2% (range 0.1-29.4%) of peripheral blood mononuclear cells contained the CAR gene. An immunohistochemical stain for CAR+ cells was performed with an antibody against the CAR linker. Seven Pts had technically adequate tumor biopsies within 30 days following 5F11-28Z-T; infiltrating CAR+ cells were not detected in any of these biopsies. For comparison, post-treatment tumor biopsy specimens from Pts with B-cell lymphoma were collected within 30 days after infusion of anti-CD19 CAR T-cells (Brudno et al., Nat Med 2020; 26: 270-80). These specimens were stained for CAR+ cells with the same antibody used to stain for 5F11-28Z-T. Two of 5 Pts (40%) had one or more tumor biopsy samples with detectable CAR+ cells. Four Pts with rashes after 5F11-28Z-T had skin biopsies, which showed a spongiotic dermatitis. CD30 was detected on mononuclear cells in 2 biopsies (2 Pts). Of 3 evaluable skin biopsies, 1 performed at Day 7 had detectable CAR+ cells in the dermis; none from later time points had CAR+ cells. Three Pts with Gr 4 cytopenias had 5 evaluable BM biopsies after 5F11-28Z-T. The earliest biopsy, performed at Day 16, had CAR+ cells. In conclusion, 5F11-28Z-T cells have limited anti-malignancy efficacy. Severe toxicities from rashes and myelosuppression may be due to CD30 expression on dermal mononuclear cells and on hematopoietic stem cells (Hombach et al., Mol Ther 2016; 24(8):1423-34). These toxicities along with limited anti-lymphoma activity prompted us to end this clinical trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ongoing Risk of Unrelated Donors Testing Positive for COVID-19 Following Medical Clearance and Impact on Operations: A Report from the National Marrow Donor Program

The global demand for hematopoietic stem cell grafts from unrelated donors (URD) continues to grow despite the COVID-19 pandemic (WMDA report 2021). The pandemic has challenged URD registries to adapt to the changing landscape of SARS-CoV-2 variants. While travel logistics have improved, the Omicron surge, particularly with the BA.5 subvariant, continues to place donors and patients at risk of developing COVID-19. The National Marrow Donor Program (NMDP) and other registries mandated cryopreservation at the beginning of the pandemic and reinstituted a mandate in January 2022 in response to the Omicron surge. NMDP removed the mandate in March 2022 but has continued to strongly recommend cryopreservation for patient safety. In this analysis, we sought to quantify the risk of donors becoming infected with COVID-19 from May 2021, when we began collecting more detailed information, to present (data cutoff 6/30/22). We quantified the total number of donors testing positive following medical clearance (Table 1). In aggregate, we observed a 2.4-fold increase in the absolute number of donors testing positive following clearance over the first half of 2022, compared to the previous first half of 2021 (53 versus 22). We next analyzed numbers based on age of intended recipients (pediatric vs adult) and graft sources (bone marrow, BM vs. peripheral blood, PB). 57 and 19 donors tested positive prior to planned collection for adults and pediatric recipients, respectively. For BM and PB, the absolute numbers were 22 and 54, respectively. Given that requests for a fresh product may place recipients at risk for prolonged pancytopenia if a donor tests positive following the initiation of conditioning but prior to graft collection, we quantified the number of donors testing SARS-CoV-2 positive based on whether the transplant center (TC) requested a fresh or cryopreserved URD graft. 33 donors who tested SARS-CoV-2 positive prior to a planned fresh product, compared to 43 donors when cryopreservation was planned. Donor SARS-CoV-2 positivity led to HCT postponement for all patients who had not yet started conditioning. 20 recipients of planned fresh products had already initiated conditioning at the time the donor tested SARS-CoV-2 positive. Of these 20 recipients, 9 eventually received a transplant with the same URD, 1 received a different URD provided by another registry, 1 received a cord blood unit, 4 received a different, but similar in match (8/8 or 7/8) URD, and 5 cases are open (i.e., infusion status unknown/pending). Realizing donor and staff safety is paramount, NMDP conducted a survey of our network apheresis centers (ACs) and BM collection centers posing a hypothetical question: "Would you collect a SARS-CoV-2 positive donor who was asymptomatic if the recipient had already started conditioning?" Of the 45 ACs responding to the survey, 65% replied no. Of the 32 responding BM collection centers, 50% replied no. Thus, in the majority of cases, an asymptomatic URD would not be collected. Overall, requests to NMDP for a cryopreserved URD product have varied over the course of the pandemic based on periodic mandates, TC preference, and requested graft source (Figure 1). While <10% of NMDP products were cryopreserved prior to the pandemic, >90% of products have been cryopreserved during the mandate periods (3/23/2020-8/10/2020 and 1/17/2022-3/14/2022). Rates have also varied by graft source: 68% PB products and 27% BM products are currently being cryopreserved. We analyzed practice patterns by TC to determine the degree of variation in requests for fresh versus cryopreserved products. While the median request rate for cryopreserved NMDP products throughout the pandemic is 58%, the lowest quartile included 10 TCs who requested >20 products over the course of the pandemic with cryopreservation request rates ranging from only 19-33%. In conclusion, the COVID-19 pandemic continues to pose logistical challenges to the NMDP and other global URD registries, particularly during the most recent Omicron subvariant BA.5 surge. TCs ordering fresh products for infusion following initiation of conditioning should be aware of and discuss with patients and inpatient teams the ongoing risk of patients undergoing conditioning without an URD product available for infusion on the day of intended transplantation. These sites should have in place a viable back-up donor plan or stem cell source in the event the intended donor tests positive. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ODP442 Posaconazole-induced Pseudohyperaldosteronism (PIPH) in Patient Treated for Acute Myeloid Leukemia

Abstract Case summary A 62-year-old Caucasian female presented to our institute with mechanical fall complicated by cervical spine fracture. She had known history of essential hypertension and recently diagnosed acute myeloid leukemia with myelodysplasia related changes (AML-MRC). She had undergone induction chemotherapy with combination of daunorubicin and cytarabine, resulting in chemotherapy induced prolonged pancytopenia. She was initially started on primary prophylaxis with fluconazole, but was switched to voriconazole due to persistent neutropenia. Patient then developed bilateral upper and lower extremity erythematous popular rash on voriconazole. Decision at that time was to switch to Posaconazole 300 mg orally daily. Three months after initiating Posaconazole, patient presented with severe hypokalemia (2.1 mmol/L) and hypertension. Previously her blood pressure was under control with amlodipine, lisinopril and nadolol. Hypokalemia persisted despite aggressive oral and intermittent intravenous potassium replacement therapy. No sources of potassium loss were identified on clinical history. She had persistently elevated blood pressure (systolic blood pressure of 150-180 mmHg) despite being on her home anti-hypertensive regimen. Further work up showed undetectable plasma aldosterone of less than 1 ng/dL (normal &amp;lt; 28 ng/dL) and plasma renin activity level was suppressed to 0.14 ng/mL/h (normal 0.25–5.82 ng/mL/h) with concurrent potassium of 2.9 mmol/L (normal 3.5-5.3 mmol/l). Diagnosis of pseudohyperaldosteronism was made at this time. Posaconazole gradually stopped and eplerenone 25 mg daily was commenced to selectively block mineralocorticoids receptors to control blood pressure. Subsequently hypokalemia resolved after stopping posaconazole and blood pressure normalized with her original home anti-hypertensive regimen. Eplerenone was eventually stopped. Her potassium level and blood pressure remained normal 2 weeks after discharge. Discussion Recent studies have shown the presentation of hypokalemia and hypertension in nearly a quarter of patients on Posaconazole. The clinical presentation of hypokalemia and hypertension with apparent mineralocorticoid excess was evident in our patient and was consistent with posaconazole-induced pseudohyperaldosteronism (PIPH). Posaconazole interference with the steroid synthesis pathway has been described in various literature. Both cortisol and aldosterone activate aldosterone receptors. In the case of posaconazole, excess mineralocorticoid effect is due to relative selectivity of posaconazole for 11ΒHSD2 inhibition. 11ΒHSD2 inhibition causes increased serum cortisol level by preventing the conversion to inactive cortisone. The high cortisol level cross-reacts with the mineralocorticoid receptor leading to apparent mineralocorticoid excess with low serum aldosterone level and low plasma renin activity. The degree of pseudohyperaldosterone effect on systolic blood pressure and hypokalemia has been strongly associated with serum posaconazole level in some studies. Our patient had resolution of uncontrolled hypertension and hypokalemia after withholding the posaconazole and short term treatment with selective mineralocorticoid receptor blocker. Conclusion Early diagnosis and to allow for early intervention with cessation of the offending agent or treatment with mineralocorticoid antagonists, such as spironolactone and eplerenone is necessary in PIPH. Presentation: No date and time listed

Recurrent macrophage activation syndrome due to hyperimmunoglobulin D syndrome: a case-based review.

Hyperimmunoglobulin D syndrome (HIDS) is a hereditary autoinflammatory disease characterized by recurrent inflammatory attacks with fever, abdominal pain, lymphadenopathy, aphthous stomatitis, and skin lesions. There are few reports on HIDS patients complicated with macrophage activation syndrome (MAS); however, to our knowledge, there is no case of HIDS with recurrent MAS attacks. We report two pediatric patients initially diagnosed as Kawasaki disease and systemic juvenile idiopathic arthritis presented with recurrent MAS episodes with prolonged fever, skin rash, hepatosplenomegaly, cervical lymphadenopathy, aphthous stomatitis, headache, pancytopenia, hyperferritinemia, and hypofibrinogenemia, finally diagnosed as HIDS with a documented homozygous MVK gene mutation. This is the first report on recurrent MAS attacks due to HIDS in pediatric patients who were successful treated with corticosteroids and anti-IL-1 therapies. Thus, clinicians should be vigilantly investigated signs of autoinflammatory diseases in patients with recurrent MAS attacks during their disease course, and HIDS should be considered an underlying disease for triggering recurrent MAS attacks. We have also reviewed the current literature regarding HIDS cases complicated with a MAS attack and summarized their demographic, treatment, and outcome characteristics. Key points • Hyperimmunoglobulin D syndrome should be considered in differential diagnosis in patients who experienced recurrent macrophage activation syndrome attacks.

P351: DOSE-ADJUSTED EPOCH + INOTUZUMAB OZOGAMICIN (DA-EPOCH-INO) IS SAFE AND ACTIVE IN ADULTS WITH RELAPSED/REFRACTORY (R/R) B LYMPHOBLASTIC LEUKEMIA (B-ALL): INITIAL RESULTS OF A PHASE I TRIAL

Background: Despite new drugs, survival with R/R B-ALL remains poor. Combination therapies may improve outcomes, but none are proven superior, and toxicities may pose limits. InO has been added to low-intensity chemotherapy, but the risks/benefits of such combinations are poorly defined. As we recently found DA-EPOCH to be effective for untreated ALL, we here tested the addition of InO to DA-EPOCH (#NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible adults had R/R CD22+ B-ALL with ≥5% blasts in blood/marrow or ≥1 site of extramedullary disease [EMD] ≥1.5 cm in diameter. No history of sinusoidal obstructive syndrome (SOS) or chronic liver disease was allowed. Other key eligibility criteria included bilirubin ≤1.5x upper limit of normal (ULN), AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN, QTc ≤500 msec, and ECOG 0-2. All patients (pts) gave written informed consent. DA-EPOCH was given on Days 1-5 with G-CSF. Three dose levels (DL) of InO given on Days 8 and 15 were studied in 28-day cycles: DL1, 0.3 and 0.3 mg/m2; DL2, 0.6 and 0.3 mg/m2; and DL3, 0.6 and 0.6 mg/m2 (respectively). In Cycles 2+, EPOCH was dose-adjusted based on the hematologic nadir from the prior cycle. Up to 4 cycles were permitted. Hepatic prophylaxis with ursodiol and CNS-directed therapy with intrathecal chemotherapy was recommended. MTD was the dose of InO yielding a true dose-limiting toxicity (DLT) rate of 33%. Initial dose-escalation plan for InO was a 6 + 6 design, but after 5 pts enrolled, this was modified to Bayesian Optimal Interval Design (BOIN) with target accrual of 24 pts. Secondary objectives were descriptions of treatment-related adverse events (TRAEs) per NCI CTCAE v5; efficacy by rate of complete remission without or with incomplete hematologic recovery (CR/CRi) and response at EMD sites per NCCN; measurable residual disease negativity (MRD-) by multiparameter flow cytometry (MFC) and high-throughput sequencing (HTS; clonoSEQ) of bone marrow aspirate; and survival. Results: To date, 17 pts have been enrolled (Table). All are evaluable for DLT. 5 pts were treated at DL1; then per BOIN, 3 pts at DL2, and 9 pts at DL3. Median number of cycles given was 2 (range, 1-3). There have been 4 DLTs: 1 at DL2 (20%; grade 4 sepsis) and 3 at DL3 (33%; grade 4 hyponatremia, grade 4 SOS, and prolonged pancytopenia). The single case (6%) of SOS occurred after allografting and is ongoing. There have been no treatment-related deaths. Grade 3+ non-heme TRAEs were seen in 13 pts (76%). Those seen in >1 pt were infections (5 pts; 8 events), neutropenic fever (5 pts; 5 events), oral mucositis (3 pts; 4 events), and increased ALT (2 pts; 3 events); all these events resolved. Other hepatic toxicity was generally mild. Of 10 pts who received ≥2 cycles, 5 (50%) escalated the dosing of EPOCH, while 2 (20%) de-escalated. 17 pts are evaluable for response. Of 13 with >5% blasts, 12 (92%; 90% confidence interval 68-100%) achieved CR/CRi, 10 (77%) after 1 cycle. MRD- by MFC was achieved in 9 (75%); 1 had prior InO. In the 5 pts with EMD, 4 (80%) responded including 3 CRs. To date, 6 pts (35%) have undergone allograft post-study. Median follow-up of survivors is 7 mo, with 7 pts in ongoing remission beyond 6 mo. Image:Summary/Conclusion: DA-EPOCH-InO has a manageable toxicity profile with infrequent DLTs and only 1 case of SOS in heavily pre-treated adults with B-ALL. Nearly all pts with >5% blasts at enrollment achieved CR, with most being MRD- by MFC. Responses in EMD were common. Enrollment is ongoing. Updated follow-up and responses by HTS will be presented.

Phase 1 Study of CD37-Directed CAR T Cells in Patients with Relapsed or Refractory CD37+ Hematologic Malignancies

Phase 1 Study of CD37-Directed CAR T Cells in Patients with Relapsed or Refractory CD37+ Hematologic Malignancies

Umbilical Cord Blood Transplantation after Graft Failure from a Previous Hematopoietic Stem Cell Transplantation

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). The incidence of GF after HCT using human leukocyte antigen (HLA) matched donors is lower than 5%; however, a higher incidence is observed when considering HLA mismatched donors or alternative donor sources and the use of reduced intensity conditioning (RIC) regimens.In the absence of autologous recovery, a second HCT is necessary to attempt preventing death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after a GF with different types of donor sources report a wide range of overall survival (OS) and transplant related mortality (TRM), however studies including a large number of patients receiving a second transplant with umbilical cord blood (UCB) are scarce.In this retrospective study, using registry data from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT), we report the outcomes of 247 umbilical cord blood transplants (UCBT) performed after GF following a previous HCT. Data were analyzed separately for patients with malignant (n=141) and non-malignant diseases (n=106). UCB was the most frequent stem cell source that resulted in GF (65.0% and 68.9%, for malignant and non-malignant diseases, respectively), and most of the reported GF occurred within 100 days after HCT (92.3% and 85.9%). The most frequent diagnosis in malignant diseases was acute leukemia (64.5%), mainly acute myeloid leukemia (AML). In non-malignant diseases, the diagnoses most often reported were inborn error of metabolism (IEM) (37.7%), followed by bone marrow failure syndrome (BMF) (34.0%) and primary immune deficiency (PID) (21.7%). In malignant and non-malignant diseases, we observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% CI 51.4- 67.9%) and 60.4% (95% CI 51.7- 70.6%), in a median time of 23 and 24 days, and a 3-year OS of 28.9% (95% CI 21.8- 37.3%) and 49.1% (95% CI 39.5- 58.8%). TRM at 100 days and at 3 years for malignant diseases was 39.9% (95%CI 32.5 - 49.1%), and 57.5% (95%CI 49.4 - 66.8%). In multivariate analyses, none of the characteristics were statistically significantly associated with engraftment or overall survival.Although survival for patients requiring a second transplant is not optimal, UCB remains a valid life-saving option for some patients with GF as it is an immediately available source of stem cells in severely ill patients. The most appropriate stem cell source for salvage transplants remains controversial, as it depends on multiple factors including center choice, donor availability, underlying disease and existing comorbidities. DisclosuresPeffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

Umbilical Cord Blood Transplantation after Graft Failure from a Previous Hematopoietic Stem Cell Transplantation

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). In the absence of autologous recovery, a second HCT is necessary to attempt to prevent death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after GF with different types of donor sources report wide ranges of overall survival (OS) and transplantation-related mortality (TRM); however, studies including a large number of patients undergoing a second HCT with umbilical cord blood (UCB) as the graft source are scarce. This retrospective registry-based study examined data extracted from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT) databases to evaluate outcomes of 247 UCBTs performed in EBMT transplant centers after GF following a previous HCT. Data were analyzed separately for patients with malignant diseases (n=141) and those with nonmalignant diseases (n=106). The most frequent HCT that resulted in GF was also UCBT (65.0% for patients with malignant diseases and 68.9% for those with nonmalignant diseases), and most GFs occurred within 100 days after transplantation (92.3% and 85.9%, respectively). The median follow-up was 47 months for surviving patients with malignant diseases and 38 months for those with nonmalignant diseases. We observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% confidence interval [CI], 51.4% to 67.9%) and 60.4% (95% CI, 51.7%-70.6%), respectively, at a median time of 23 days and 24 days, correspondingly. The 3-year OS was 28.9% (95% CI, 21.8% to 37.3%) in the malignant disease group and 49.1% (95% CI, 39.5%-58.8%) in the nonmalignant disease group. In patients with malignancies, TRM was 39.9% (95% CI, 32.5% to 49.1%) at 100 days and 57.5% (95% CI, 49.4%-66.8%) at 3 years. In multivariate analyses, none of the characteristics studied was statistically significantly associated with engraftment or OS. Although survival is not optimal in patients requiring a second HCT, UCBT remains a valid life-saving option for patients with GF.

Use of a Hemoglobin Substitute (HBOC-201) to Treat Acute Anemia in a Leukemic Patient with Anti-Vel Antibodies

BackgroundThe Vel-negative blood type is a rare autosomal recessive trait, occurring in 1 in 4000 persons. It is extremely difficult to supply blood to patients with anti-Vel antibodies, and the situation is even more challenging for Vel-negative patients with leukemia who may have high transfusion needs. There are case reports of treatment with hemoglobin substitutes in Jehovah's Witnesses and surgical patients. To the best of our knowledge, we report the first use of a hemoglobin substitute, HBOC-1201 (HemoPure) to treat a patient with refractory acute myeloid leukemia (AML) and anti-Vel antibodies.Case ReportOur patient is a 67-year-old Caucasian man with a one-year history of acute myeloid leukemia, refractory to multiple hypomethylator- and chemotherapy-based regimens. History is also significant for coronary artery disease with type 2 NSTEMI due to severe anemia. He has experienced prolonged pancytopenia due to leukemia and chemotherapy and required blood transfusions approximately weekly. Anti-Vel antibodies make transfusion of compatible blood challenging, and we utilized a hemoglobin transfusion threshold of 5 g/dL. Working with the American Red Cross and the American Rare Donor Program (ARDP), we transfused 44 units of Vel-negative blood over a one-year period, depleting the available Vel-negative units in North America. He presented to the hospital with productive cough and dyspnea. Initial labs revealed acute on chronic anemia with hemoglobin 3.5 g/dL. CT of the chest revealed right lower lobe pneumonia. Given critical anemia in the setting of pneumonia and possible sepsis, the patient needed immediate blood transfusion. Compatible Vel-negative blood was not available in North America. While awaiting availability of international blood units through the Red Cross and ARDP, we considered the choices of 1) transfusing incompatible blood or 2) administering a blood substitute. Because individuals with anti-Vel antibodies may develop severe acute hemolytic transfusion reactions when transfused incompatible blood, we chose to treat with HBOC-1201 (Biopure Corporation, Cambridge, MA), a bovine hemoglobin polymer that lacks a red blood cell membrane and thus red cell antigens such as Vel. We obtained an emergency IND from the FDA and local IRB approval. Three 32-gram units of HBOC-1201 were successfully transfused, with hemoglobin rise from 3.5 to 4.5 g/dL. Common adverse effects associated with the use of acellular hemoglobin substitutes include increase in concentration of methemoglobin and vasopressor effects leading to elevated blood pressure, fluid overload, and myocardial infarction. Our patient was monitored closely and tolerated the transfusion without any apparent adverse events.ConclusionDuring a challenging clinical situation, we successfully treated severe acute anemia in a patient with refractory AML and anti-Vel antibodies, using the acellular bovine hemoglobin-based blood substitute HBOC-1201, when compatible blood was not available. The infusion was tolerated without complications. Hemoglobin substitutes may be considered as bridging treatments in critically anemic patients such as those with hematologic malignancies when red blood cell transfusion is not an option. DisclosuresNo relevant conflicts of interest to declare.

Pretransplant bone marrow cellularity and blood count recovery are not associated with relapse or survival risk following allogeneic stem cell transplant for AML in CR.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. Median follow-up was 33months. Overall survival (OS) for the whole cohort was 55.8% at 2years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P<2.6e-8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II-IV GvHD, and moderate-severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. Neither ELNr status nor pretransplant BMC influenced relapse post-HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post-HCT outcomes of AML.

Pancytopenia and Progressive Splenomegaly in Patient with Disseminated Histoplasmosis

Disseminated histoplasmosis is a severe manifestation of fungal infection caused by Histoplasma capsulatum. It usuallyoccurs in a patient with an immunodeficiency state. With the increase of HIV infection and the use of immunosuppressantdrugs lately, its prevalence also increases. A case of 43 years old female with prolonged fever, pancytopenia, and massiveprogressive splenomegaly. The diagnosis of disseminated histoplasmosis and the secondary hemophagocytic syndromewas made based on bone marrow examination that showed increased hemophagocytic processes and multipleintracytoplasmic H.capsulatum. She had been treated with Itraconazole 200 mg for three months. In the first month'sevaluation, her complete blood count improved without any transfusions, and the size of her spleen size decreased. She hadbeen fully recovered after the completion of 3-month treatment.

Therapy Related Acute Myeloid Leukemia in Solid Tumors: Two Pediatric Case Reports and Review of the Literature

Introduction: Therapy-related acute myeloid leukemia is devastating late effects in solid tumors. The most frequent and lethal secondary malignancy is secondary acute myeloid leukemia t-AML. t-AML is a sequel of specific chemotherapeutic agents, specifically alkylating agents, and topoisomerase II inhibitors, commonly used in treating solid tumors. t-AML is relatively rare with a poor prognosis. Case reports: We are reporting two cases of t-AML. Case 1: A 13-year-old girl presented with left hand swelling in 2014. Biopsy confirmed the diagnosis as Ewing sarcoma. She started a chemotherapy regimen that contained alkylating agents and epipodophyllotoxins. In 2017, local recurrence occurred, and she received salvage chemotherapy (ifosfamide, carboplatin, and etoposide) followed by amputation of the left 4th finger. In 2020, she had a second local recurrence with unexplained prolonged neutropenia. Diagnosis of t-AML was confirmed by bone marrow aspiration. Case 2: A 5-years-old boy presented with an abdominal mass in July 2006. It was diagnosed as rhabdomyosarcoma and treated with alkylating agents. He showed a good response to the treatment initially. In September 2007, prolonged pancytopenia, neutropenia, and thrombocytopenia occurred. Diagnosis of t-AML was confirmed by bone marrow aspiration as it showed mild dysplastic, moderate marrow fibrosis. Conclusion: t-AML is of growing interest to the pediatric oncologist and requires further studies to develop pathways for leukemogenesis. We discussed two cases to highlight the importance of designing treatment regimens for solid tumors associated with t-AML.