Prior Hematopoietic Cell Transplantation Research Articles

Rapid identification of early infections in febrile patients after CD19 target CAR-T cell therapy for B-cell malignancies

BackgroundCD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies.MethodsIn this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson’s Chi-square test, t-test, Mann–Whitney U-test, Kaplan–Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression.ResultsIn this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262–15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577–5.345], P < 0.001) and severe infection (9.040 [2.256–36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy.ConclusionsCRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.

Safety and efficacy of chimeric antigen receptor T-cell therapy for acute myeloid leukemia: A subgroup based meta-analysis

IntroductionAcute myeloid leukemia (AML) is a significant hematological malignancy in the United States, with a high mortality rate and limited treatment options. CAR T-cell therapy, a new and promising treatment, is being investigated for its efficacy and safety in AML. This meta-analysis aims to assess the safety and efficacy of CAR T-cell therapy in AML, considering various subgroups such as study location, study design, prior transplantation status, conditioning regimen, and CAR T-cell source. MethodsWe conducted a comprehensive literature review across multiple databases, adhering to PRISMA guidelines and focusing on studies concerning CAR T-cell therapy in AML. We included original articles in English and excluded non-original reviews, abstracts, and non-English studies. The risk of bias was assessed using the Cochrane ROBINS-I tool. Statistical analysis involved meta-analysis with Cochrane’s Q-test and I² statistic, using both fixed-effect and random-effects models, and assessed for publication bias. ResultsOur search yielded studies encompassing 57 AML patients treated with CAR T-cell therapy. The meta-analysis revealed a 48% incidence of complete remission with CAR T-cell therapy, varying significantly across subgroups based on study design, location, prior transplantation, conditioning regimen, and CAR T-cell source. The highest complete remission rates were observed in patients from China, those who had undergone prior hematopoietic cell transplantation, and those treated with fludarabine and cyclophosphamide conditioning regimen. Adverse events included graft-versus-host disease (7%) and cytokine release syndrome (53%). ConclusionsThis meta-analysis highlights the potential of CAR T-cell therapy in AML treatment, especially when integrated with certain prior treatments and conditioning regimens. The findings suggest a higher efficacy in patients with previous hematopoietic cell transplantation and specific conditioning regimens. Further large-scale, randomized trials are essential to confirm these findings and establish CAR T-cell therapy as a standard treatment for AML.

Post Hematopoietic Cell Transplantation Maintenance Therapy with Low-Dose Azacitidine in a Pediatric Population with High-Risk Myeloid Neoplasms

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT) remain at risk for relapse. Children with relapsed AML and high-risk features including prior HCT, early relapse, and high-risk cytomolecular features experience survival of ≈30%. Given the even more dismal survival and limited therapy options for post-HCT relapse, azacitidine (aza) has been explored as post-HCT maintenance therapy based on potential disease targeting activity and enhancement of graft versus leukemia. Studies to date suggest that this approach is safe with signals of favorable survival. A phase 3 trial in adults did not show a survival benefit, although results were confounded by a high rate of withdrawal and a minority of patients received all intended cycles. We performed a descriptive analysis of all patients with high-risk myeloid neoplasms who underwent allogeneic HCT at Seattle Children's Hospital (SCH) from November 2017 to January 2023 and received post-HCT maintenance aza. Patients were considered high-risk if they had undergone prior HCT, measurable residual disease at HCT, ≥CR2, or high-risk cytomolecular features. Patients received myeloablative conditioning according to standard protocols. All patients were in remission prior to aza initiation. Aza 36-50 mg/m 2 was administered as IV or subcutaneous infusions daily for 5 consecutive days on a 28-day cycle with intention to continue therapy with cycles beginning through 1-year post-HCT. Nineteen patients began aza therapy at a median of 109 days (range 66-263) post-HCT. Demographics and disease information plus the primary high-risk feature for consideration of post-HCT aza are reported in Table 1. Following aza initiation, 9 (47.4%) patients continued subsequent aza cycles at their referring institution with concurrent remote management by SCH as needed. Median post-HCT follow-up was 30.4 months (range 7-66). The median number of completed aza cycles was 8 (range 3-12) and 14 (73.7%) patients received all intended cycles through 1 year following HCT. In 3 patients, aza cycles were delayed &amp;gt;4 weeks due to non-neutropenic fever or infection; de-escalation to 36 mg/m 2 for subsequent courses in the 2 patients who were receiving 50 mg/m 2 led to no further delays. There were no delays due to marrow suppression, no increased transfusion needs, and no hospitalizations attributed to aza. Fourteen (73.7%) patients had grade II acute graft versus host disease (GVHD) prior to initiation of aza. Two (10.5%) of these patients subsequently developed chronic oral GVHD, 1 diagnosed incidentally during their last aza cycle and 1 diagnosed after completion of aza. Two (10.5%) patients experienced ≤ grade II acute GVHD flares while tapering systemic immunosuppressive treatment (IST) and receiving aza, prompting escalation of same systemic IST (n=1) or addition of topical IST (n=1). Seventeen of 18 patients who were in remission at 1-year post-HCT were tapering or off IST. Five (26.3%) patients discontinued aza before 1 year post-HCT: 2 due to relapse, 2 per family preference, and 1 for inflammatory process with persistent dual chimerism from double cord HCT. Three-year estimates for overall and relapse free survival were 92% (95% CI 54-99) and 76% (95% CI 46-91), respectively, and cumulative incidence of relapse was 24% (95% CI 7-48) (Figure 1). The 6 patients with history of prior HCT are all are alive with ongoing remission at ≥3 years following second HCT with aza maintenance. Our experience demonstrates that post-HCT maintenance therapy with low-dose aza for high-risk pediatric AML/ MDS is tolerable with limited toxicity and without significant impact on marrow suppression or GVHD. The ability to successfully implement a post-HCT aza regimen in partnership with local institutions allowed families to return home, potentially reducing emotional hardship and financial toxicity due to travel/ housing and supporting feasibility. Outcomes in this cohort were improved compared to historical controls; this was especially notable in patients undergoing 2 nd HCT and in patients ≥CR2. Our findings suggest a potential role for post-HCT low-dose aza in children with high-risk AML/ MDS but further prospective pediatric studies are needed to define optimal dosing and evaluate for benefit.

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan &amp; US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of &amp;gt; 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

A Phase 2 Trial of SCRI-CAR19 Demonstrates Favorable Leukemia-Free Survival (LFS), with a Pilot Study of CD19-Expressing T-Cell Antigen Presenting Cells (CD19t T-APCs) Demonstrating Safety and Tolerability

The value of CD19 directed CAR T cell therapy for relapsed, refractory B-ALL has been well established. Iterative and complementary clinical trials have identified subgroups with improved outcomes, including those with low disease burden at the time of treatment as well as those with prolonged CAR T cell in vivo persistence. PLAT-02 was a phase 1/2 study of SCRI-CAR19, a 2 nd generation murine CAR with 41BB co-stimulation. Phase 1 previously reported 1 year LFS, event-free (EFS) and overall survival (OS) of 55%, 51.2%, and 69.5%. Subjects with low CD19 antigen burden in the bone marrow (&amp;lt;15%) prior to lymphodepletion (LD) and those with a rapid contraction of CAR T cells between Day 10 and 14 (ratio ≥1.5) were at higher risk of early loss of persistence. Phase 2 of PLAT-02 was a multisite trial along with a single site pilot study, PLAT-03, to explore administration of exogenous CD19 antigen designed to boost CAR T cell engraftment in subjects at high risk of early loss of persistence. PLAT-02 (NCT02028455) enrolled subjects 1-26 years of age with relapsed, refractory CD19+ B-ALL. The primary efficacy cohort was defined as those who received fludarabine/cyclophosphamide (flu/cy) LD and were infused with CAR19. PLAT-03 (NCT03186118) was a pilot study of CD19t T-APCs (manufactured T cells with CD19 tag) administered at doses of 10x10 6/kg or flat dosing of 5x10 8 for subjects &amp;gt;25kg every 4 weeks up to 6 total doses. Cohort A included subjects with low CD19 antigen burden, and cohort B included those with rapid early contraction of CAR19. 88 subjects with B-ALL were enrolled on PLAT-02 with plans for treatment at the recommended phase 2 dose (RP2D) of 1x10 6 CAR+ T cells/kg. Eighty-six percent had at least one prior relapse and 42% had undergone prior hematopoietic cell transplant (HCT). The feasibility of manufacturing was 98%. 71 subjects were in the primary efficacy cohort with an 89% minimal residual disease negative complete remission (MRDneg CR) rate. EFS and OS probability estimates with 95% CI at 1 year following CAR19 were 0.65 (0.53, 0.75) and 0.76 (0.64, 0.84). LFS at 1 year from entering MRDneg CR was 0.71 (0.58, 0.81). Cytokine release syndrome (CRS) was grade (Gr) 1 (53%), Gr 2 (26%), Gr 3 (10%), and Gr 4 (3%). Neurotoxicity occurred in 53%: Gr 1 (24%), Gr 2 (13%), Gr 3 (15%), and Gr 5 (1%). 25 subjects were treated on PLAT-03, 10 as cohort A (10 received CAR19 on PLAT-03, 9 received T-APCs), and 11 as cohort B (5 received CAR19 on PLAT-02, 6 received CAR19 on PLAT-03, and 9 total received T-APCs). One was cohort C (retreatment) and 3 were cohort D (no T-APCs). A total of 72 infusions of T-APCs were administered, with no occurrence of CRS or neurotoxicity. Two subjects had grade 3 toxicities related to T-APCs, 1 febrile neutropenia and 1 infusion related reaction. EFS and OS probability estimates at 1 year following CAR19 were 0.67 (0.43, 0.83) and 0.95 (0.71, 0.99). Overall LFS at 1 year was 0.63 (0.38, 0.80); by cohort: cohort A, 0.44 (0.13, 0.72) and cohort B, 0.80 (0.41, 0.95). Median duration of persistence, as determined by cumulative incidence using B cell aplasia (BCA) as a surrogate, among all subjects who received RP2D of CAR19 with flu/cy LD across PLAT-02 and PLAT-03, engrafted and achieved MRDneg CR, was 12.9 months (m). For subjects who did not receive T-APCs, the median persistence was 12.1m. Impact of antigen burden prior to LD was again observed; those with &amp;gt;15% CD19 antigen burden had persistence of &amp;gt;12.1m vs. 3.9m in the low antigen burden group. For subjects treated with T-APCs, the median persistence was 16m; 9.9m in cohort A and &amp;gt;16m in cohort B. The improvement in LFS after SCRI-CAR19 in phase 2 compared to phase 1 is likely multi-factorial, with contributing factors including earlier treatment, uniform use of LD, enhanced persistence, and better allocation of patients who benefit from consolidative HCT. The use of T-APCs was well tolerated without recurrent CAR T cell mediated toxicity. Although not directly comparable, there did appear to be enhancement of CAR T cell persistence with the use of T-APCs in populations predicted to have inferior persistence, including those with low antigen burden. There was not a clear improvement of LFS in those who received T-APCs. However, subjects were not randomized to receive T-APCs and those enrolled on PLAT-03 were more heavily treated and more likely to have received a prior HCT. Further exploration of T-APCs is warranted to define and evaluate their impact on persistence and durable responses.

2711. Viral encephalitis after chimeric antigen receptor (CAR)-modified T-cell therapy: A Retrospective Cohort Study

Abstract Background Central nervous system (CNS) symptoms are frequent after chimeric antigen receptor T-cell therapy (CARTx) and usually attributed to immune effector cell-associated neurotoxicity syndrome (ICANS). Cerebrospinal fluid (CSF) testing to rule out CNS infection is not routinely performed, although ICANS and viral encephalitis have overlapping presentations. Reports of viral encephalitis after CARTx are increasing, but no cohort studies have been performed to understand its epidemiology. Methods This retrospective cohort study included all adults receiving first CARTx for B-cell malignancies at Fred Hutch Cancer Center from July 2013 to December 2022. We computed the cumulative incidence of CSF testing for viruses within 56 days after CARTx. Results 626 patients received CARTx during the study period; 552 (88.2%) received CD19 or CD20-targeted CARTx and 74 (11.8%) BCMA-targeted CARTx. Median age was 60.4 (IQR: 50.9–67.6) years, 232 (37.1%) identified as female, and 216 (34.5%) received prior hematopoietic cell transplantation. Thirty-four patients had CSF tested for viruses with PCR in the context of CNS symptoms for a cumulative incidence of 5.7% (95% confidence interval, 4.0–7.8) (Figure 1). ICANS was diagnosed in 29 (85.3%) of these 34 patients (ICANS grade ≥ 3 in 14), and 26 patients received immunosuppressive treatment. In the remaining five tested patients, the cause of CNS symptoms was vascular (n=1), CNS progressive disease (n=2), metabolic encephalopathy (n=1) or unknown (n=1). CSF testing practices evolved overtime, and testing was performed more frequently before 2018 (Figure 2); after 2018, all tested patients had ICANS grade ≥ 3. Four patients had a positive CSF PCR test for EBV (n=3) occurring 8–39 days post-CARTx or HHV-6 (n=1) on day 32 post-CARTx. EBV detection in CSF was low-level, of unclear clinical significance, and not treated; all three patients were treated for ICANS. The patient with HHV-6 had low-level detection in CSF and blood; HHV-6 encephalitis was considered, but no antiviral therapy was administered, and symptoms resolved with treatment for ICANS grade 4. Conclusion CSF testing for infection early after CARTx was rarely performed, and the incidence of viral encephalitis appears to be low in this population. Disclosures Cameron J. Turtle, MBBS, PhD, Allogene: Advisor/Consultant|Allogene: Ad hoc advisory boards/consulting|ArsenalBio: Advisor/Consultant|ArsenalBio: Scientific Advisory Board, stock options|ArsenalBio: Stocks/Bonds|Caribou Biosciences: Advisor/Consultant|Caribou Biosciences: Stocks/Bonds|Century Therapeutics: Advisor/Consultant|Century Therapeutics: Ad hoc advisory boards/consulting|Eureka Therapeutics: Stocks/Bonds|Fred Hutchinson Cancer Center: CJT has the right to receive payment from Fred Hutchinson Cancer Center as an inventor on patents related to CAR-T-cell therapy|Juno Therapeutics/BMS: Grant/Research Support|Kyverna: DSMB member|Legend Bio: Advisor/Consultant|Legend Bio: Ad hoc advisory boards/consulting|Myeloid Therapeutics: Advisor/Consultant|Myeloid Therapeutics: Scientific Advisory Board, stock options|Myeloid Therapeutics: Stocks/Bonds|Nektar Therapeutics: Advisor/Consultant|Nektar Therapeutics: Grant/Research Support|Prescient Therapeutics: Advisor/Consultant|Prescient Therapeutics: Ad hoc advisory boards/consulting|Sobi: Advisor/Consultant|Sobi: Ad hoc advisory boards/consulting|Syncopation Life Sciences: Advisor/Consultant|Syncopation Life Sciences: Ad hoc advisory boards/consulting|T-CURX: Advisor/Consultant|T-CURX: Scientific advisory board Mazyar Shadman, MD, AbbVie: Advisor/Consultant|AbbVie: Grant/Research Support|ADC therapeutics: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|BeiGene: Advisor/Consultant|BeiGene: Grant/Research Support|BMS: Advisor/Consultant|BMS: Grant/Research Support|Eli Lilly: Advisor/Consultant|Fate Therapeutics: Advisor/Consultant|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|Genmab: Advisor/Consultant|Genmab: Grant/Research Support|Kite: Advisor/Consultant|MorphoSys/Incyte: Advisor/Consultant|MorphoSys/Incyte: Grant/Research Support|Mustang Bio: Advisor/Consultant|Mustang Bio: Grant/Research Support|Nurix and MEI Pharma: Advisor/Consultant|Pharmacyclics: Advisor/Consultant|Pharmacyclics: Grant/Research Support|Regeneron: Advisor/Consultant|TG Therapeutics: Grant/Research Support|Vincerx: Grant/Research Support Brian Till, MD, Juno Therapeutics/BMS: Grant/Research Support|Mustang Bio: Grant/Research Support|Mustang Bio: patents/royalties|Mustang Bio: Consulting|Proteios Technology: Advisor/Consultant Ryan D. 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Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192). Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat. Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes. As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5). Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE). Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption. Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.

Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a leading treatment for relapsed or refractory aggressive and indolent lymphomas. One major adverse effect of CAR T-cell therapy is prolonged risk for infection. To quantify infectious risk after CAR, we performed a single center analysis of patients after anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel, n=78) and compared these with chemo-responsive lymphoma patients concurrently undergoing autologous hematopoietic cell transplant (HCT) with cyclophosphamide, carmustine, and etoposide conditioning (n=61). Methods: All 139 patients were treated between 09/2017 and 10/2021, with 37/78 CAR and 32/61 HCT patients treated after the first report of COVID-19 in California (02/2020). Median follow up was 718 days (range 175-1650 days). We included only patients without documented relapse of their lymphoma to avoid the confounding impact of lymphoma relapse on study endpoints. There was no significant difference in age or sex between groups. The CAR-treated cohort had fewer non-CAR prior lines of therapy (mean 3.0 vs mean 3.6, p=0.014, Wilcoxon rank sum test). Nearly all patients in the CAR group (76/78) were treated for large B-cell lymphoma (LBCL) entities, with 2/78 having follicular lymphoma with a prior LBCL history. Similarly, a minority of patients in the HCT group were treated for mantle cell lymphoma (4/61) and follicular lymphoma (5/61). Of the CAR patients 19/78 had an HCT prior to CAR, and 1/61 HCT patients had prior CAR treatment. For each patient we catalogued and graded post-treatment infections after day +30 (D+30) to focus on post-discharge events. Endpoints analyzed were any infection as well as severe infections (grade ≥3). Death and treatment for a second malignancy were considered competing events. We additionally catalogued blood count measurements including hemoglobin, platelets, white blood cell count (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at regular intervals from pre-treatment through D+800. There was no difference in baseline WBC or ANC between groups. CAR-treated patients had a higher baseline ALC and hemoglobin while HCT-treated patients had higher baseline platelets (p<0.05 for all values, Wilcoxon rank sum test). Results: There was no difference in overall survival between groups (p=0.18, log-rank test). We performed cumulative risk regression considering infections for 1200 days starting at D+30. When considering all infections there was no significant difference in the total incidence of infections between the CAR and HCT group. However, there was increased risk in CAR-treated patients for severe (grade >= 3) infections (Figure 1A, HR 2.4, CI 1.2-4.78, Gray's p=0.013). The increased risk for severe infection was sustained when considering only infections that occurred greater than one-year post-transplant (HR 3.06, CI 1.14-8.21, Gray's p=0.021). The increased risk for severe infection in the CAR-treated cohort remained if patients with prior HCT were excluded, or if COVID-19 cases were excluded. We used linear mixed effects modeling to assess cytopenic risk longitudinally from D+28 to D+800. Age, sex, and non-CAR lines of therapy were also included in the multivariate model. CAR-treated patients demonstrated significantly reduced WBC, ANC, and ALC relative to patients treated with HCT (Figure 1B, p-value <5E-7, <0.05, and <5E-5 respectively, restricted maximum likelihood with t-test using Satterthwaite's approximation). These values remained significant if CAR patients with prior HCT were excluded from analysis. WBC and ANC were significantly reduced relative to pre-lymphodepletion baseline through D+365 (p<0.05, Wilcoxon signed-rank test). There was no difference in hemoglobin level in CAR-treated vs HCT patients using the same methods. Platelet counts in CAR-treated patients resolved to the same level as following HCT by the end of the follow up period. Conclusion: Lymphoma patients without relapse after axi-cel CAR T-cell therapy have greater risk for severe infections than a concurrent group of patients treated with autologous HCT. This risk is associated with prolonged reduction in WBC, ANC, and ALC but not platelets or hemoglobin. Clinical surveillance for infections in these immune compromised CAR-treated patients therefore remains critical, with role of additional prophylaxis strategies needing further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with variable clinical course. The disease is characterized by presence of t(11;14) and bright CD20 expression. While frontline immunochemotherapy plus autologous hematopoietic cell transplant (HCT) has improved progression-free survival, invariably MCL patients (pts) relapse. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL provides durable disease control but is limited by high rates of Grade 3+ cytokine release syndrome (CRS) and neurological events with 15% and 31% of pts experiencing such toxicities. We hypothesized that bispecific, tandem, lentiviral CAR-T cell targeting both CD20 and CD19 B-cell antigens (LV20.19 CAR) with 4-1BB co-stimulatory signaling will improve clinical outcomes in R/R MCL and that expansion in IL7 and IL15 would produce less "exhausted” CAR product with more durable clinical activity. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report below outcomes from a Phase 1/2 cohort of MCL pts. LV20.19 CAR T-cells were manufactured onsite in the CliniMACS Prodigy device with IL7+15 for cell expansion with goal of fresh infusion at varying lengths of manufacturing (8 vs 12 days). After safety run-in, we opened a 14 patient single stage Phase II arm with flexible 8/12-day manufacturing with fresh infusion for MCL pts. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via log-rank test. Results: To date, 10 MCL pts have received LV20.19 CAR T-cells at the specified dose of 2.5x10e6 cells/kg (Phase 1=3 pts and Phase 2=7 pts). 8 of 10 pts received 8-day manufactured CAR-T cells whereas two pts received a 12-day product in the Phase 1 cohort. Manufacturing was successful in 100% of pts and all received a fresh (non-cryopreserved) product. Median age was 62 years and median prior lines of therapy were 4 (range: 3-8). Three pts progressed after prior autologous HCT and 2 pts progressed after prior allogeneic HCT. Eight of 10 pts had progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had additionally progressed on a non-covalent BTKi (pirtorbrutinib) administered on a clinical trial (Table 1). LV20.19 CAR T-cells produced in the CliniMACS Prodigy with IL-7/IL-15 had robust expansion with mean 5.4x10e8 CAR T-cells obtained on Day 7 of manufacturing. CAR T-cells from pts mostly consisted of central-memory and effector-memory phenotype T-cells with robust in-vivo expansion typically starting Day +4 after infusion. The Day 28 ORR was 100% (CR=60% and PR=40%). 7 of 9 pts with MRD assessed between Day 28-60 post CAR were negative. No patient has relapsed with a median follow-up of 18 months of among surviving pts. Regarding toxicity, all 10 pts (100%) had Grade 1-2 CRS (no grade 3+ events). Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 2 pts with one patient experiencing Grade 2 and the other Grade 3 toxicity. The patient with Grade 3 ICANS experienced a non-relapse mortality event due to gram negative sepsis after Day 28 evaluation. At 1-year the cumulative incidence of relapse and NRM were 0% and 10%, respectively while the 1-year PFS and OS were 90% each (Figure 1). Conclusions: Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R MCL with ORR 100%, no relapses with a median follow-up of >1.5 years, and no Grade 3+ CRS and low rates of Grade 3+ ICANS (10%). All pts on the Phase II arm had CAR T-cells manufactured on-site utilizing an 8-day platform with fresh CAR T-cell infusion and lymphodepletion starting during manufacturing. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Avascular Necrosis and Minimal Trauma Bone Fractures in Patients with Dyskeratosis Congenita

Introduction: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) result from germline variants in genes required for telomere maintenance. DC is traditionally characterized by a triad of nail dysplasia, oral leukoplakia, and reticular skin pigmentation. Significant complications include bone marrow failure (BMF), pulmonary fibrosis, liver disease, and hematologic and solid organ malignancies. Previous reports described avascular necrosis (AVN) of the femoral head or humerus in DC/TBD. However, these findings were limited to a few individual case reports. Herein, we present a study of AVN and minimal trauma fractures (MTF) in a large cohort of patients with DC/TBD. Methods: We reviewed medical records of all patients with a confirmed diagnosis of DC/TBD enrolled in the IRB-approved Inherited Bone Marrow Failure Syndromes study (NCT00027274) between 2002 - 2019 for the history of AVN and/or MTF. Data were compiled on DC/TBD characteristics, treatments, as well as body mass index (BMI), lipid profile, bone mineral density (BMD), and 25-hydroxyvitamin D (25[OH]D) levels. We used stratified random sampling to match DC/TBD patients with AVN and/or MTF by age, gender, inheritance pattern and genotype with a control group of DC/TBD patients with no AVN/MTF. Distributional variance was assessed for all t-tests and two-sided p values <0.05 were considered significant. Statistical analysis was carried out using RStudio (Ver 1.4.1106). Results: Forty-two of 233 patients (18%) with DC/TBDs experienced at least one AVN and/or MTF at a median age of 21.9 years (range 4 to 58.7); 15/42 were females (Table 1). Twenty-three patients had AVN alone, 6 had MTF alone, and 13 developed both AVN and MTF (Figure 1). The median age at first AVN was 24.1 years (range 6.3 - 58.7) and at first MTF 13.6 years (range 4 - 44.3). AVN was more common in patients with autosomal recessive/X-linked recessive (AR/XLR)/TINF2 DC (n=20, 21.3%) and developed at a younger age (median 18.8 years, range 6.3 - 47.8) than in patients with autosomal dominant (AD) disease (12.5%; median age 29.9 years, range 11.1 - 58.7); p=0.013. MTF occurred almost exclusively in patients with AR/XLR/TINF2 DC (n=17, 19%) compared with AD DC/TBD (n=1, .9%); p<.0001. There were 68 AVN events in 36 patients (median 2 events/patient, range 1 - 5). The most frequent sites were femoral heads (33/36) followed by humeral heads (5/36) and knees (3/36); 22/33 had bilateral femoral head AVN (Figure 1). Twenty-two of 26 patients with severe BMF received androgen/steroids within 5 years of AVN and 8 received hematopoietic cell transplantation (HCT). Compared with the matched control group, significantly more DC patients with AVN had severe BMF and received androgen/corticosteroids (p<0.02). Importantly, 12/36 DC/TBD patients (33%) developed AVN without prior HCT, corticosteroid, or androgen treatment. 24/36 patients received treatment for AVN, including total hip arthroplasty (n=15) and core decompression (n=5) or other medical intervention (n=4). Median time from diagnosis with AVN to treatment was 0.81 years (range 0.03 - 2.7). We identified 38 MTF events in 19 DC patients; the most frequent fracture site was the femoral diaphysis (11 events in 8 patients) (Figure 1). Fractures occurred spontaneously or during routine activities such as entering a vehicle, running in the playground, or low-impact dancing as per patient reports. Seventeen patients (89%) with MTF had severe BMF, 12 (63%) had received HCT (7 had taken androgens/steroids). Compared with matched controls, significantly more DC patients with MTF had received HCT (p=0.02). Other factors such as BMD, elevated cholesterol, overweight/obesity, and 25[OH]D levels were not significantly associated with AVN or MTF in our cohort. Conclusions: AVN and MTF are highly prevalent in patients with DC/TBDs. AVN developed across the entire DC/TBD spectrum but was significantly associated with severe BMF and AR/XLR/TINF2 DC. MTFs occurred almost exclusively in young patients with severe disease indicated by AR/XLR/TINF2 mode of inheritance. Improved screening and effective clinical management of symptoms for patients at higher risk of developing AVN/MTF is needed. Furthermore, these findings signal the need for future research exploring the mechanism underlying AVN and MTF in patients with DC/TBDs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I Safety and Feasibility Study to Evaluate Motixafortide (CXCR4/SDF-1 Inhibition) and Natalizumab (VLA-4/VCAM-1 Inhibition) As a Novel Regimen to Mobilize CD34+ Hematopoietic Stem Cells for Gene Therapy in Sickle Cell Disease

Background: Sickle cell disease (SCD) is one of the most common genetic diseases globally. Clinical manifestations of SCD commonly include anemia, pain, vaso-occlusive events and cumulative end organ damage leading to significant morbidity and mortality. Historically, allogeneic hematopoietic cell transplantation (HCT) represented the only curative therapy for SCD, but is associated with significant HCT-related morbidity and mortality which limit its use (PMID: 8663884, PMID: 20007560). Autologous hematopoietic stem cell (HSC) -based gene therapies now offer curative potential with decreased toxicity (PMID: 28249145). However, effective HSC-based gene therapy depends on collection of sufficient HSCs (ideally >10x106 CD34+ cells/kg), typically from peripheral blood (PB) (PMID: 33956057). G-CSF and CXCR4 inhibition (CXCR4i) with plerixafor are the most widely used mobilization strategies (PMID: 19363221, PMID: 19720922). However, G-CSF is associated with risk of fatal vaso-occlusive events in SCD (PMID: 9734950, PMID: 11368061, PMID: 19513902). Meanwhile, short-acting CXCR4i with plerixafor alone does not reliably yield optimal HSC numbers for gene therapy applications (PMID: 30282642, PMID: 29419425, PMID: 29472357). Therefore, developing novel HSC mobilization regimens to rapidly and reliably mobilize optimal CD34+ HSCs for gene therapy in SCD represents an unmet need. Motixafortide (M) is a high-affinity, long-acting CXCR4 inhibitor. The recent Phase III, randomized, controlled GENESIS Trial demonstrated combination M+G-CSF resulted in 88.8% of patients collecting ≥6x106 CD34+ cells/kg (median 10.8x106) within 1 leukapheresis (LP) for HCT. This compares favorably to historical data with plerixafor+G-CSF where 54.2% collected to goal in 1 LP. Motixafortide also mobilized more immunophenotypically primitive HSCs and multi-potent progenitors compared to plerixafor. Meanwhile, transcriptional profiling by single-cell RNA sequencing revealed HSCs mobilized with M have gene expression profiles associated with enhanced regeneration and self-renewal, compared to G-CSF or plerixafor (DOI: 10.1182/blood-2021-144296). Motixafortide alone also mobilized an average of 11.6×106 CD34+ cells/kg in healthy volunteers, while mobilizing 91.6% of allogeneic HSC donors to goal in ≤2 LPs (median 6.07x106) (DOI: 10.1182/blood-2018-99-109701, PMID: 28835380). Natalizumab (N) is a monoclonal antibody to the a4 integrin subunit of a4b1 (VLA-4) capable of VLA4 inhibition (VLA4i). In mice and primates, N led to an ~8-fold increase in PB CD34+ HSCs in 24 hrs (PMID: 7692447). In humans, a single N infusion resulted in a 5- to 6-fold increase PB CD34+ HSCs. Meanwhile, the average PB CD34+ HSC levels after a single dose were similar to levels with repeated doses, indicating rapid mobilization of maximal PB HSCs by 24 hrs after N infusion (PMID: 18195093). Combination CXCR4i and VLA-4i has been well-tolerated and resulted in synergistic mobilization of HSCs in preclinical studies (PMID: 21886173). Therefore, we hypothesize that combination CXCR4i and VLA-4i with M+N represents a safe and effective strategy for robust, rapid and synergistic mobilization of HSCs to PB in patients with SCD. Study Design and Methods: This is a single center, single-arm, dose de-escalation, Phase 1 safety and feasibility study. Key eligibility criteria include patients with SCD (SS or Sβ0) age 18-35 years receiving automated RBC exchanges. Patients with prior HCT or gene therapy will be excluded. We estimate 5 patients in this pilot feasibility study will provide sufficient safety and preliminary efficacy data to guide further development of this novel mobilization strategy. All patients will have baseline labs prior to M (1.25mg/kg, subcutaneous), N (300mg, IV) and M+N dosing. Each patient will then undergo mobilization and LP (1 blood volume), per protocol (see Figure 1). The primary outcome will be to assess the safety and tolerability of M, N and M+N in each SCD patient, defined by dose-limiting toxicities and maximum tolerated dose. Key secondary outcomes include: kinetics of CD34+ HSC mobilization to PB (CD34+ cells/uL), number of CD34+ HSCs collected via LP (CD34+ cells/kg/L), incidence of AEs, pharmacokinetics and the recommended phase 2 dose. Correlative studies include immunophenotypic and single cell transcriptional profiling of CD34+ HSCs from LP product mobilized with M, N and M+N. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Revised Prognostic Index for Patients with Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms in First Relapse

Introduction: Though many patients with acute myeloid leukemia (AML) will achieve a first complete remission (CR1), most patients will relapse. A previous analysis from HOVON on 667 consecutive AML patients in first relapse identified four key predictors for achieving a second CR (CR2), which improved overall survival (OS): age at relapse, CR1 duration, cytogenetic risk, and prior receipt of hematopoietic cell transplant (HCT), thereby developing a scoring system to aid in therapeutic decision making (Breems, JCO 2005). Since this original publication, other predictors of relapse have emerged, most notably measurable residual disease (MRD), and cytogenetic/molecular risk stratification has been refined in the form of ELN2017 (Dohner, Blood 2017). We hypothesize that incorporation of MRD and ELN2017 categorization into a risk stratification model will improve our ability to predict CR2 likelihood and OS after relapse. Methods: Eligible patients included those ≥18 years (yrs) old who received treatment (tx) at our center for AML or other high-grade myeloid neoplasms (≥10% marrow/peripheral blasts at diagnosis) between January 2008 and July 2019, who later relapsed. Using our IRB-approved institutional AML database, we obtained the following demographic and outcome parameters: age; gender; new diagnosis (ND) type (AML vs. other; de novo vs. secondary); ECOG performance status; TRM score; ELN2017 risk; CR1 date; CR1 details [CR vs. CR with incomplete hematologic recovery (CRi) and MRD status]; initial tx intensity [low being hypomethylating agents (HMA); intermediate being 7+3 or similar; high being FLAG-ida/CLAG-M or similar]; cycles to CR1; prior HMA before relapse; prior HCT before relapse; relapse date; relapse salvage tx type and intensity; response to salvage (CR vs. CRi + MRD status); CR2 date; subsequent HCT; and death date or date of last contact. We fit multivariable (MV) models for OS after first relapse (Cox) and CR2 after first relapse (logistic). A score for each respective outcome was developed by rounding the coefficients from the models. C-statistics (Cox) and area under the receiver operating characteristic curve (AUC; logistic) were also calculated. Results: We identified 315 eligible patients who achieved CR1 and relapsed. Among these, 266 received subsequent tx and were included in our analysis: the median age at relapse was 63 yrs (range 20-85); 40% (n=106) were female; 56% (n=148) received high-intensity tx for ND; 47% (n=125) had secondary AML at ND; 28% (n=75) had received prior HCT before relapse; 36% (n=95) had received prior HMA before relapse. For initial tx of first relapse, 52% (n=138) received high-intensity tx; 5% (n=13) received HCT; 12% (n=31) received intermediate-intensity tx; and 32% (n=84) received low-intensity tx. Overall, 60% (n=160) achieved a subsequent CR2. Significant covariates in the CR2 MV model were CRi following ND tx (odds ratio [OR] 0.85; 95% confidence interval [CI] 0.73-0.99), ≥2 cycles to CR1 (OR 0.86; CI 0.75-0.99), CR1 7-18 m (OR 1.22; CI 1.07-1.38), CR1>18 m (OR 1.31; CI 1.12-1.53), post-relapse HCT (OR 1.43; CI 1.1-1.86), and low-intensity tx post-relapse (OR 0.77; CI 0.68-0.87). Significant covariates leading to improved OS in the MV model were CR1 duration of 7-18 m (hazard ratio [HR] 0.5; 95% CI 0.36-0.69), CR1 duration >18 m (HR 0.36; CI 0.24-0.55); and post-relapse HCT (HR 0.49; CI 0.26-0.91). We derived scoring systems from these MV models (Table 1). A positive score indicates a favorable prognosis (median OS of 13.6 m); a score of 0 (median OS 6.5 m) or below (median OS 5.6 m) indicates a poor prognosis (Figure 1). When the Breems scoring system for OS was applied to our dataset, the C-statistic was 0.55; our score improved to a C-statistic of 0.61. The AUC for the CR2 score from our model was 0.69. Conclusions: The Breems system was not well-calibrated to our dataset, underscoring the need to develop an updated scoring model for OS and CR2 in relapsed AML patients. Surprisingly, factors such as CR1 MRD status and ELN2017 risk did not appear to be significant in MV analyses. Efforts are underway to update this dataset to include additional contemporary patients; we hope to enhance the prognostic scoring algorithm by capturing the effect of specific mutational profiling (e.g. TP53, FLT3, and others). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Trial of CD8-Depleted Human Leukocyte Antigen (HLA) Mismatched Unrelated Donor Lymphocyte Infusion (DLI) to Achieve Remissions in Myelodysplastic Syndrome (MDS) and Secondary Acute Myeloid Leukemia (sAML)

Background Hypomethylating agents (HMAs) are the standard of care in higher risk MDS, yielding a median survival of 12-18 months. After HMA failure or progression to sAML. median survival is only 4-6 months. We developed a novel cellular therapy using HLA mismatched, unrelated, CD8-depleted, CD4+ DLI to induce remission in patients with MDS and sAML who have not previously undergone allogeneic hematopoietic cell transplant (HCT). The DLI is intentionally class II HLA mismatched to activate donor CD4+ T cells which then provide immunologic "help" to reverse recipient immune exhaustion and, thus, promote a potent antitumor response (Symons. BBMT. 2008). Further, HLA mismatched donors are easily identified and allow the potential for an "off the shelf" product. By depleting CD8+ T cells, it is intended that the DLI does not engraft, thus negating the risk of graft-versus-host disease (GVHD). Instead, this therapy is intended to induce remission as a bridge to curative allogeneic HCT. Methods This completed phase I trial enrolled patients with MDS refractory to at least 4 cycles of HMA or sAML at the Moffitt Cancer Center from 2020-2022. Patients who received prior allogeneic HCT were excluded. DLI donors were selected from a pre-existing pool of unrelated donors at the New York Blood Center (NYBC) on the basis of class II HLA mismatch, CMV compatibility, and ABO compatibility. Patients were treated with induction chemotherapy as chosen by their primary physician. In parallel, donors underwent leukapheresis at the NYBC and the cell product was shipped to the Moffitt Cancer Center. The DLI was depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent in the Moffitt Cell Therapy Laboratory. HLA-mismatched CD4+ DLI was infused fresh within 24-36 hours after completing induction chemotherapy. The trial followed a 3+3 design to determine the recommended phase II dose (RP2D) of DLI where dose level (DL) 1 was 1x106 CD4 cells/kg, DL2 was 1x107 CD4 cells/kg, and DL3 was 5x107 CD4 cells/kg. Dose limiting toxicities (DLTs) were defined as grade 2-4 acute GVHD, grade 3-4 cytokine release syndrome (CRS), grade 2-4 infusion reactions, aplasia beyond 56 days in the presence of detectable donor chimerism, or grade 4 organ toxicity by CTCAE 5.0. Mechanistic studies were pursued to evaluate markers of immune tolerance, cytokine profiles, and confirm the DLI did not engraft. Results Nine patients (8 sAML, 1 MDS) were treated. All patients had progressed through at least one prior line of therapy (Table 1). The median age was 66. All AML patients had adverse risk disease by ELN risk stratification including 4 patients with TP53 mutation and complex cytogenetics. The MDS patient had very high-risk disease by R-IPSS. A suitable donor was identified for all patients despite a donor pool of only 30 donors. Cell collections, shipments, and processing for all patients were successful with all products achieving <3% CD8+ T cells and >70% cell viability. No patients experienced DLTs at any dose level. One patient at DL3 experienced grade 2 CRS that resolved with tocilizumab. There were no cases of grade 3-4 CRS nor GVHD (Table 2). Complete remission (CR) was achieved in 2/3 (66%) patients at DL3, 1/3 (33%) patients at DL2, and 0/3 (0%) patients at DL1. All 3 patients who reached CR proceeded to allogeneic HCT. At the time of marrow recovery post-treatment, donor DNA in the blood and marrow was no longer detectable in any of the patients. Patients who achieved CR (n=3) had significantly higher levels of IL6 on day +1 (p=0.01) and a trend towards higher levels of IL2, IL15, IFN-gamma, and TNF-alpha in the first 7 days after DLI compared to patients who did not achieve CR. Conclusions Induction chemotherapy followed by CD8-depleted HLA mismatched, unrelated donor DLI was feasible and well tolerated with no DLTs, confirming the RP2D of 5x107 CD4 cells/kg. At DL3, 2 of 3 patients achieved CR, including one with TP53 mutation and complex cytogenetics, which is generally resistant to induction chemotherapy and compares favorably to 20-30% historical CR rates with chemotherapy alone in those pts. Mechanistic studies correlated increased post-treatment cytokine levels with depth of remission. Assessment of markers of immune tolerance are pending and will be presented at the conference. Based on these promising results, this novel cellular therapy is being investigated now in a phase II clinical trial at the Moffitt Cancer Center. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept for the Prevention of Gvhd in Pediatric and Adult Patients Receiving 7/8 HLA-Mismatched Unrelated Transplant for Hematologic Malignancies: A Real-World Analysis

Background: Recipients of HLA mismatched unrelated donor (MMURD) hematopoietic cell transplant (HCT) are at increased risk for severe acute graft versus host disease (aGVHD) and treatment related mortality (TRM). Abatacept, CTLA4-Ig was granted FDA approval for the prevention of aGVHD in patients receiving unrelated donor HCT in part based on results of ABA2, a phase II trial evaluating abatacept in addition to standard immunoprophylaxis (calcineurin inhibitor (CNI)/ methotrexate (MTX) for GVHD prevention in either 8/8 MUD or 7/8 MMURD HCT (Watkins et al., 2021). The 7/8 MMURD cohort from ABA2 showed a significant reduction in grade III-IV aGVHD compared with a matched cohort from the CIBMTR receiving CNI/MTX alone (2.3% vs 30.2%, P<0.001). The lower rates of severe aGVHD translated into significant improvements in TRM and overall survival (OS) at 2 years for patients receiving abatacept. While ABA2 included pediatric and adult patients in the analysis, outcomes were not reported separately. Furthermore, there may be selection bias associated with study eligibility and participation that could result in benefits that may not translate into everyday clinical practice. Objectives: To determine the real-world impact of abatacept combined with CNI/MTX on the development of acute and chronic GVHD, survival, and relapse in pediatric and adult patients with hematologic malignancies receiving of 7/8 MMURD HCT as standard of care (off-study). Methods: We conducted a multi-center retrospective analysis of outcomes for pediatric and adult patients receiving a 7/8 MMUD HCT (bone marrow (BM) or peripheral blood stem cells (PBSC)) for hematologic malignancies and received GVHD prophylaxis with abatacept (4 doses on days -1, +5, +14, and +28) combined with CNI/MTX between January 2015 and December 2021. Patients were excluded if they were on ABA2, not in remission at time of HCT, received a prior HCT, or required additional GVHD prophylaxis. The analysis included consecutive adult patients transplanted at Emory University and pediatric patients transplanted at Children's Healthcare of Atlanta and Boston Children's Hospital. Data were analyzed for all patients and for pediatric and adult patients as separate cohorts. Results: A total of 50 consecutive patients (27 pediatric patients and 23 adult patients) met inclusion criteria. Median follow up was 759 days. Twenty-five of 27 pediatric patients received BM grafts while 20 out of 23 adult patients received PBSC. Grade II-IV aGVHD at day 180 was 40%, 48% and 28% for all patients, pediatric patients and adult patients, respectively. Grade III-IV aGVHD at day 180 was 10%, 5% and 15% for all, pediatric and adult patients respectively. Moderate-severe chronic GVHD (cGVHD) at 1 year was 49%, 56% and 42% for all, pediatric and adult patients respectively. TRM at day 180 was 8%, 7% and 9% for all, pediatric and adult patients respectively. OS at 1 year was 82%, 85% and 78% for all, pediatric and adult patients respectively. Relapse at 1 year was 16%, 15% and 17% for all, pediatric and adult patients respectively Disease-free survival (DFS) at 1 year was 73%, 77% and 70% for all, pediatric and adult patients respectively. Grade III-IV aGVHD free, severe cGVHD free, relapse free survival at day 180 was 74%, 70% and 78% for all, pediatric and adult patients respectively. Conclusion: Our real-world results using abatacept prophylaxis for 7/8 MMUD HCT compared favorably with ABA2 results with low incidence of grade III-IV aGVHD and TRM and encouraging DFS. These results are promising given that our off-study patients had more advanced disease compared to the patients on ABA2 (27% vs 13%). This was especially true in our adult patients where 50% had advanced disease and almost all received PBSC grafts. This study was the first to analyze and report outcomes separately for pediatric and adult patients receiving abatacept for GVHD prophylaxis. Our results indicate that both pediatric and adult patients had favorable outcomes with abatacept. Similar to results from ABA2, cGVHD rates were not reduced with the 4 dose abatacept regimen and further studies are needed to evaluate the efficacy of extended dosing abatacept to mitigate this risk. Our real-world results mirrored the results from ABA2 and suggest that the addition of abatacept to standard immunoprophylaxis for our highest risk patients can be effective at substantially improving aGVHD related transplant outcomes in MMUD recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Introduction The 2021 European LeukemiaNet (ELN) recognizes MRD relapse as ≥1 log rise confirmed on repeat testing (Heuser Blood 2021). Molecular MRD relapse (e.g. NPM1mut) precedes clinical relapse by ~3-4 months (Ivey NEJM 2016) and provides a window of opportunity for pre-emptive therapy to be delivered prior to clinical relapse. Venetoclax (VEN)-based low intensity therapy is associated with rapid achievement of clinical response in older patients (pts) with AML (DiNardo NEJM 2020 and Wei Blood 2020) but only has modest activity in relapsed/refractory AML. We hypothesized that VEN-based therapy initiated at the time of MRD relapse could be associated with improved clinical response and longer clinical benefit. We therefore conducted a prospective study to explore the efficacy of low dose ara-C (LDAC) + VEN in pts with AML and MRD relapse (ACTRN12619000746134). Methods This multicenter phase 2 study stratified pts into either oligoblastic relapse (marrow blasts 5-15%; Group A), or molecular MRD relapse (Group B). Pts received VEN 600 mg (days 1-28, without dose ramp-up for Group B) and LDAC 20 mg/m2 sc (days 1-10). Primary objectives were morphologic or MRD response (≥1 log reduction) in groups A and B, respectively. Key secondary objectives were realization of allogeneic hematopoietic cell transplantation (HCT), relapse-free (RFS) and overall survival (OS). The study was approved by Alfred Health ethics committee (196/19). NPM1mut and other fusions (per 100 ABL1) from bone marrow were analyzed by RT-qPCR, and IDH1/2mut by Bio-RadTM droplet digital PCR. Results A total of 48 pts were recruited (median age 67; range 18-80). Cytogenetic risk was intermediate in 91%, favorable in 4.5% and adverse in 4.5%. Most (94%) had received prior intensive chemotherapy and only 2 (4%) had received prior HCT in first remission. The median interval from AML diagnosis to study entry was 13.7 months (IQR 9, 23). At the time of study screening, 22 (46%) pts had oligoblastic disease and 26 (54%) MRD relapse. Oligoblastic relapse included pts with early progression not captured by interval MRD surveillance. Pts received a median of 3 cycles (range 1-21+) of VEN-LDAC (ongoing in 11). Reasons for treatment cessation in 37 pts were: HCT (n=19, 51%), treatment failure (n=11, 30%), adverse events (n=3), donor lymphocyte infusion (DLI, n=2) or death before response assessment (n=2). One patient (Group B, NPM1mut) was deemed not evaluable for response assessment after only receiving 9 days of therapy but included in the survival analysis. Among 22 pts with oligoblastic disease, CR/CRi was achieved in 17 (77%). Two additional pts achieved morphologic leukemia-free state and 1 had stable disease. MRD response (≥1 log reduction) among those with an evaluable marker (N=8; all NPM1 mutated) was achieved in 8/8 (100%), with MRD negative in 6/8 (75%) (Figure). Among 25 evaluable pts with MRD relapse, MRD response (≥1 log reduction) was observed in 68% and MRD negative in 52%. Of patients with NPM1mut AML treated at MRD relapse, 13/19 (68%) achieved an MRD response and 10/19 (53%) an MRD negative response (Figure). An MRD response was observed in 2/3 with IDH1/2mut, 1/2 with core-binding factor and 1/1 with KMT2A::MLLT3. Bridging to HCT or DLI (median time 4 months) was successful in 18/27 (67%) pts ≤70 years. With a median follow up time of 14.4 months, the median RFS was 21.5 months and not reached for OS. The estimated 18-month RFS was 63.3% (95% CI, 48.0-83.5) and OS 71.1% (95% CI, 56.5-89.4). Similar outcomes were observed for Groups A and B. Subsequent HCT (as a time-dependent covariate) was the only significant factor for RFS (HR 0.13, 95% CI 0.03-0.61) but not OS (HR 0.48, 95% CI 0.13-1.75) in a multivariate Cox regression model that included age, features at original diagnosis (NPM1, FLT3-ITD and ELN 2017 risk), time since AML diagnosis, and study cohort (A vs B). FLT3-ITD was detected in 3/7 (43%) of relapsed pts. Conclusions In this prospective study of pts with early relapsing AML (oligoblastic or MRD relapse), VEN in combination with LDAC induced a high rate of molecular MRD response, resulting in excellent RFS and OS outcomes. Follow-up is ongoing to determine the durability of response. This novel MRD-targeting approach is being further investigated in a multi-arm, precision-based platform trial ( INTERCEPT: Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML; ACTRN12621001265864). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplantation for Patients with Relapsed Acute Promyelocytic Leukemia

Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P=.014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P=.013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P=.085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P=.001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.

The Use and Duration of Preintubation Respiratory Support Is Associated With Increased Mortality in Immunocompromised Children With Acute Respiratory Failure.

To determine the association between preintubation respiratory support and outcomes in patients with acute respiratory failure and to determine the impact of immunocompromised (IC) diagnoses on outcomes after adjustment for illness severity. Retrospective multicenter cohort study. Eighty-two centers in the Virtual Pediatric Systems database. Children 1 month to 17 years old intubated in the PICU who received invasive mechanical ventilation (IMV) for greater than or equal to 24 hours. None. High-flow nasal cannula (HFNC) or noninvasive positive-pressure ventilation (NIPPV) or both were used prior to intubation in 1,825 (34%) of 5,348 PICU intubations across 82 centers. When stratified by IC status, 50% of patients had no IC diagnosis, whereas 41% were IC without prior hematopoietic cell transplant (HCT) and 9% had prior HCT. Compared with patients intubated without prior support, preintubation exposure to HFNC (adjusted odds ratio [aOR], 1.33; 95% CI, 1.10-1.62) or NIPPV (aOR, 1.44; 95% CI, 1.20-1.74) was associated with increased odds of PICU mortality. Within subgroups of IC status, preintubation respiratory support was associated with increased odds of PICU mortality in IC patients (HFNC: aOR, 1.50; 95% CI, 1.11-2.03; NIPPV: aOR, 1.76; 95% CI, 1.31-2.35) and HCT patients (HFNC: aOR, 1.75; 95% CI, 1.07-2.86; NIPPV: aOR, 1.85; 95% CI, 1.12-3.02) compared with IC/HCT patients intubated without prior respiratory support. Preintubation exposure to HFNC/NIPPV was not associated with mortality in patients without an IC diagnosis. Duration of HFNC/NIPPV greater than 6 hours was associated with increased mortality in IC HCT patients (HFNC: aOR, 2.41; 95% CI, 1.05-5.55; NIPPV: aOR, 2.53; 95% CI, 1.04-6.15) and patients compared HCT patients with less than 6-hour HFNC/NIPPV exposure. After adjustment for patient and center characteristics, both preintubation HFNC/NIPPV use (median, 15%; range, 0-63%) and PICU mortality varied by center. In IC pediatric patients, preintubation exposure to HFNC and/or NIPPV is associated with increased odds of PICU mortality, independent of illness severity. Longer duration of exposure to HFNC/NIPPV prior to IMV is associated with increased mortality in HCT patients.

A Phase I Study to Determine the Maximum Tolerated Dose of ex Vivo Expanded Natural Killer Cells Derived from Unrelated, HLA-Disparate Adult Donors

The administration of allogeneic natural killer (NK) cells following a lymphodepleting chemotherapy regimen is emerging as a well-tolerated therapeutic approach in the management of various malignancies. Contrary to the expected complications of allogeneic T cell therapy, there remains no evidence of graft-versus-host disease (GVHD) mediated by NK cells in numerous clinical trials. On the contrary, preclinical and clinical studies suggest that NK cells do not induce GVHD and in fact may prevent its development following allogeneic hematopoietic cell transplantation (HCT). In this study, we sought to determine the maximum tolerated dose of non-HLA-matched donor NK cells derived from peripheral blood and ex vivo expanded using a novel feeder cell platform. In a single-center Phase I clinical trial using a 3×3 design, 9 subjects each received 2 infusions of NK cells 2 weeks apart following a preparative regimen of cyclophosphamide (60 mg/kg i.v.) and fludarabine (25 mg/m2/day i.v for 5 days). No exogenous cytokines were administered. NK cells were administered at 3 dose levels: 1×107/kg, 2.5×107/kg, and 5×107/kg. Three subjects had myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), and the other 6 subjects had colorectal carcinoma. Recipients were monitored over a 4-week period for GVHD as well as other adverse events and for persistence of donor NK cells in systemic circulation. Disease assessment was started at 28 days following the first NK cell infusion and continued until postinfusion day 100 or disease progression. In all 9 study subjects, there was no occurrence of GVHD and no dose-limiting toxicities that would warrant cohort expansion at any of the 3 planned cell dose levels. Low-level donor NK cell persistence was observed up to 4 weeks after the first NK cell infusion at all dose levels. The best observed response was a complete response with incomplete platelet recovery in a MDS subject who experienced disease relapse after prior allogeneic HCT. Other responses were stable disease in 1 subject with MDS and 2 subjects with colorectal cancer up to postinfusion day 100. This off-the-shelf, third-party NK cell product can be administered safely without inducing GVHD and exhibits in vivo persistence promoted by preparative lymphodepletion alone. The observed clinical responses could be enhanced by administration of exogenous cytokine support, as well as complementary approaches that promote NK cell function in the tumor microenvironment.

Sub-myeloablative Second Transplantations with Haploidentical Donors and Post-Transplant Cyclophosphamide have limited Anti-Leukemic Effects in Pediatric Patients

Pediatric patients with high-risk hematologic malignancies who experience relapse after a prior allogeneic hematopoietic cell transplant (HCT) have an exceedingly poor prognosis. A second allogeneic HCT offers the potential for long-term cure but carries high risks of both subsequent relapse and HCT-related morbidity and mortality. Using haploidentical donors for HCT (haploHCT) can expand the donor pool and potentially enhance the graft-versus-leukemia effect but is accompanied by a risk of graft-versus-host disease (GVHD). The goal of this protocol was to intensify the antileukemia effect of haploHCT for pediatric patients with hematologic malignancies that relapsed after prior allogeneic HCT, while limiting regimen-associated toxicities. This phase II clinical trial evaluated a sub-myeloablative preparative regimen consisting of anti-thymocyte globulin, clofarabine, cytarabine, busulfan, and cyclophosphamide, in combination with plerixafor to sensitize leukemic blasts. Participants received a mobilized peripheral blood unmanipulated haploidentical donor graft with one dose of post-transplant cyclophosphamide as GVHD prophylaxis, followed by natural killer (NK) cell addback. Here we report the clinical outcomes and immune reconstitution of 17 participants treated on the study and 5 additional patients treated on similar single-patient treatment plans. Of the 22 participants analyzed, 12 (55%) had active disease at the time of HCT. The regimen provided robust immune reconstitution, with 21 participants (95%) experiencing neutrophil engraftment at a median of 14 days after HCT. In this high-risk population, the overall survival was 45% (95% confidence interval [CI], 24%-64%), with a 12-month event-free survival of 31% (95% CI, 14%-51%) and cumulative incidence of relapse at 12 months of 50% (95% CI, 27%-69%). Four participants (18%) remain in remission at >5 years follow-up. Expected HCT-related organ-specific toxicities were observed, and 13 participants (59%) experienced acute or chronic GVHD. This intensified but sub-myeloablative regimen, followed by a high-dose unmanipulated haploidentical graft, post-transplantation cyclophosphamide, and NK cell infusion, resulted in adequate immune reconstitution but failed to overcome the elevated risks of relapse and treatment-related morbidity in this high-risk population.

Allogeneic Stem Cell Transplantation with Sequential Melphalan-Based Conditioning in AML: Residual Morphological Blast Count Determines the Risk of Relapse.

IntroductionAllogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia.MethodsWe retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia.ResultsMedian bone marrow blast count prior to conditioning was 10% (range, 0–96%). Four year probabilities of EFS and OS were 34% (95% CI, 28–43%) and 43% (95% CI, 36–52%), respectively. In multivariate analysis, blast count >20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy.ConclusionAllogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.