CD19-directed therapy remains the mainstay treatment for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, treatment patterns and outcomes following CD19-negative (CD19-) relapse remain poorly defined. We retrospectively analyzed 65 adult patients with ALL who developed CD19-relapse after CD19-directed therapy. TP53 mutations and BCR::ABL1-like ALL were each identified in 27.7% (n = 18) of patients. Forty-six patients (70.8%) received one CD19-targeted therapy, whereas 19 patients (29.2%) received ≥ 2 prior to CD19-relapse. Overall, 60 patients (92.3%) received blinatumomab, and 23 (35.4%) received CAR T-cell therapy. The median time from the initiation of the most recent CD19-targeted therapy to CD19-relapse was 155 days (range, 13-1946). The median follow-up of the entire cohort was 32.7 months (IQR, 15.1-90.3). The median event-free and overall survival (EFS and OS) was 3.1 months (95% CI, 2.5-4.5) and 9.9 months (95% CI, 6.8-24.7), respectively. In multivariate analysis, receipt of ≥ 2 CD19-directed therapies was associated with both inferior EFS and OS, HR 2.17 (95% CI, 1.10-4.29; p = 0.03) and HR 3.05 (95% CI, 1.40-6.62; p = 0.005). The complete remission rate following first salvage therapy was 47.5% and 72.1% any time following CD19-relapse. Sixteen (34.8%) of 46 patients evaluated had subsequent CD19 re-expression, 5 of whom subsequently received CD19-directed therapy, and all 5 patients responded. Patients with ALL who develop CD19-relapse after CD19-directed therapy have poor outcomes and limited therapeutic options. However, since this study lacked a comparator cohort of patients with CD19-positive relapse, the independent prognostic impact of CD19 negativity could not be determined.

We report a phase 1 study assessing safety and efficacy of CD19 chimeric antigen receptor (CAR) T cells as definitive consolidation in older adults (≥55 years) with B-cell acute lymphoblastic leukemia (B-ALL) in first complete remission (CR1) (ClinicalTrials.gov identifier: NCT05707273). Eighteen patients received lymphodepletion followed by infusion of memory-enriched CD19 CAR T cells. The median age was 64 years, and all patients were measurable residual disease (MRD)-negative pre-lymphodepletion. There were no dose limiting toxicities, grade ≥2 cytokine release syndrome or any grade immune effector cell-associated neurotoxicity syndrome. Estimated 18-month event-free and overall survival were 84% and 100%, respectively. CAR T cells expanded in blood and cerebrospinal fluid despite patients' MRD-negative status. Comparing clinical samples from patients with relapsed/refractory (R/R) B-ALL from our historical trial (NCT02146924) and patients in CR1, we found that the blood and CAR T cell products from R/R patients were hyper-inflammatory and hyper-immunometabolic, respectively. First line CAR T cell therapy was safe, well-tolerated, and potentially extended remission in patients in MRD-negative CR1. These findings support further investigation of early use of CAR T cell therapy for B-ALL.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of B-cell ALL associated with poor response to induction chemotherapy, suboptimal measurable residual disease (MRD) clearance, and inferior survival outcomes compared to non-Phlike subtypes. We retrospectively analyzed 140 consecutive adult patients with Ph-like ALL treated at our institution. The median age was 33.5 years, and the majority harbored CRLF2 rearrangements (85%). IKZF1plus deletion and JAK mutations were identified in 26% and 37% of patients, respectively. The majority (75%) received pediatric-inspired regimens (PIR), which were associated with higher complete remission (CR) rates (p=0.034), reduced risk of relapse (p.

We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the "gatekeeper" Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of "canonical" miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via "non-canonical" mechanisms of miRNA biogenesis.

Manufacturing schema for the clinical trial

Persistence of Tcm-derived CD19-CAR T cells

Extramedullary disease at time of lymphodepletion

Toxicity management algorithms

Exploratory Analysis - Landmark at Day 28 Univariate Cox Proportional Hazards Models for Relapse-Free Survival

T cell subset analysis pre and post CAR T cell manufacturing

AbstractPurpose: A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Patients and Methods: In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II. Results: The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22–72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05–0.48; P = 0.001). Conclusions: Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694

AL amyloidosis, a plasma cell disorder caused by extracellular deposition of misfolded proteins, is a rare disease with an estimated incidence of 12 to 14 cases per million person-years.1 Patients with early-stage disease have a relatively high survival rate, with nearly 80% of patients alive 5 years after diagnosis.2 However, delayed diagnosis reduces the survival rate substantially; patients diagnosed at stage IIIB have 5-year overall survival of about 10%.3 Early diagnosis of AL amyloidosis is often delayed due to the non-specificity of early symptoms and rarity of the condition.4 In a retrospective study of ~1500 patients with newly diagnosed AL amyloidosis, the median time from sign or symptom onset to diagnosis was 2.7 years.5 Electronic health records (EHRs) present an avenue for identifying patients with suspected AL amyloidosis based on their symptoms, which could enable earlier diagnosis and treatment. EHRs are especially useful for investigating rare diseases because of difficulties in recruiting sufficient patients for prospective clinical trials. EHRs contain a wealth of clinical insight across the structured tables (e.g., diagnosis codes, medications, and laboratory results) and unstructured free text (e.g., admission/discharge summaries, physician notes, and descriptions of conditions), which can be used collectively to identify early indications. The goal of this study was to compare three different methods for identifying 15 signs and symptoms of AL amyloidosis from EHRs in a study population of 1223 patients with biopsy-confirmed systemic AL amyloidosis diagnosis. Patients were diagnosed between January 1, 2010, and August 31, 2019, according to a research registry from Mayo Clinic Rochester, and had research authorization available. If patients had no data in the Mayo EHR within 90 days of their diagnosis date, they were excluded from the analysis. Demographics and clinical characteristics of the study population are summarized in Table S1. We considered 15 signs and symptoms: ascites, atrial fibrillation or flutter, autonomic neuropathy, carpal tunnel, congestive heart failure, dyspnea, edema, fatigue, lightheadedness, proteinuria, orthostatic hypotension, paresthesia, pericardial effusion, peripheral neuropathy, and pleural effusion. These were selected because they are characteristic of AL amyloidosis, present in the registry, and relatively common in patients (>3% prevalence). We considered signs and symptoms around the time of diagnosis since longitudinal data were not available for many patients, and we did not consider post-diagnosis signs and symptoms since they could be secondary to treatment. Three data sources were used for identifying signs and symptoms: (1) a manually curated registry, (2) structured diagnosis codes, and (3) unstructured clinical notes curated with a natural language processing (NLP) algorithm. The registry was made by the abstraction of signs and symptoms from the EHR's unstructured notes. Conditions not attributed to AL amyloidosis were not entered into the registry, and only signs and symptoms recorded in the registry prior to initiation of treatment were considered in this analysis. International Classification of Disease (ICD)-9-CM and ICD-10-CM diagnosis codes from a structured table in the EHR provided another data source. Lists of codes were generated and reviewed for clinical relevance by the hematologist (A. Dispenzieri) who trained the data abstractors who created the registry (Table S2). The notes, which we automatically curated with a neural network-based NLP algorithm, were the third data source.6 The algorithm classifies a sign/symptom synonym and its surrounding text fragment with one of the following labels: “Yes”-confirmed, “No”-ruled-out, “Maybe”-suspected, or “Other”-alternate context (e.g., family history of sign or symptom; Figure S1).6 This data source is referred to as “augmented curation”. Lists of synonyms for each sign and symptom (Table S3) were curated with input from the hematologist (A. Dispenzieri) to ensure alignment with categories in the registry. Synonyms classified with a “Yes” sentiment were counted as a record, while other classifications were not. ICD codes and notes timestamped 1 year before to 90 days after AL amyloidosis diagnosis and prior to initiation of treatment were considered. For a patient to be counted as having a sign/symptom according to a given data source, the patient needed at least one record of the sign/symptom in that data source. The number of cases identified from each data source and the overlap across data sources are reflected in Euler diagrams (Figure 1). Congestive heart failure (38.5%) and pleural effusion (32.3%) had the highest levels of concordance across all data sources (Figure 1 and Table S4). Lightheadedness (3.8%), atrial fibrillation/flutter (5.3%), and paresthesia (8.6%) had the lowest concordance across the data sources. There was relatively high concordance between augmented curation and the registry for the most prevalent signs and symptoms: edema (520/876 patients; 59.4%), dyspnea (375/770 patients; 48.7%), fatigue (307/786 patients; 39.1%), and proteinuria (230/712 patients; 32.3%). Relatively few of these cases were also captured by ICD codes (Table S4). We evaluated the accuracy of each data source for proteinuria by deriving a “gold standard” patient set based on laboratory data. For this, we considered all patients with at least one laboratory measurement for urine protein occurring 1 year before to 90 days after the AL amyloidosis diagnosis date and prior to initiation of treatment, followed by a clinical note within 0 to 15 days, which was 974 patients (of 1223 in the study population). Individuals who had at least one measurement ≥0.5 grams of urine protein/24 hours during the study period were counted as positive for laboratory test-derived proteinuria, which was 423 patients. Using this “gold standard” patient set, we computed specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) metrics for patient sets identified by each data source. Augmented curation and registry yielded similar results in terms of specificity (67.2% and 66.4%, respectively), sensitivity (73.2% and 75.1%, respectively), PPV (76.5% and 76.5%, respectively), and NPV (63.2% and 64.6%, respectively; Table S5). ICD codes had higher specificity (91.9%) and PPV (85.3%), but substantially lower sensitivity (32.2%) and NPV (48.1%), affirming that ICD codes miss many true positive cases. For each of the signs and symptoms, we further investigated a random sample of 10 cases (150 cases in total) identified by augmented curation alone. We manually reviewed all notes containing a mention of the sign/symptom in the observation window, and then assigned one of the following labels for each patient-symptom pair: “Present, attributed to AL amyloidosis”, “Present, attributed to another condition/treatment”, “Present, no attribution”, or “Not present”. Of the 150 cases reviewed, the symptom was confirmed to be present in 141, while 9 were false positives (Figure S2). Of the 141 cases, the symptom was not attributed to any condition in 90, attributed to another condition or treatment in 25, and attributed to AL amyloidosis in 26. Symptoms most commonly attributed to conditions other than AL amyloidosis included peripheral neuropathy (5), proteinuria (4), congestive heart failure (3), and dyspnea (3). Peripheral neuropathy was attributed to diabetes, trauma/overuse from long-distance running, and vincristine. Proteinuria was attributed to chronic kidney disease, glomerulonephritis, and diuretics. Congestive heart failure was attributed to heart attack, mild hypertension, hyperlipidemia, and as an adverse event of pomalidomide for treating multiple myeloma. Dyspnea was attributed to cerebrovascular disease, depression, fatigue, and promethazine and fentanyl for treating abdominal pain. Overall, augmented curation was highly accurate in identifying conditions experienced by patients, but these conditions were often not explicitly linked to AL amyloidosis in the clinical notes. Alternatively, the registry dataset was manually curated to include signs and symptoms attributed to AL amyloidosis exclusively. To develop screening algorithms that facilitate earlier diagnosis, symptoms identified via augmented curation may be more useful, since they capture symptoms noted at their earliest manifestation and do not rely upon a suspected diagnosis of AL amyloidosis from the clinician. These findings demonstrate that an NLP-based approach is valuable for the comprehensive capture of signs and symptoms of AL amyloidosis from EHRs. The NLP-based method matches the quality of manual curation, but it is significantly more time-efficient and cost-effective. This analysis had several limitations. First, the lists of synonyms and ICD codes may not fully capture all terms and codes used to record the signs and symptoms. Second, this analysis only considered EHR data from a single healthcare system, and further validation studies are needed to determine if these NLP algorithms can be directly used in other healthcare systems. Going forward, an NLP method for identifying signs and symptoms from clinical notes could be integrated as part of an AL amyloidosis screening / early identification tool. These tools could reduce the time between the initial presentation of AL amyloidosis to treatment of the disease. Medical writing and editorial support were provided by Lisa Shannon, PharmD, of Lumanity Communications Inc., and were funded by Janssen Global Services, LLC. This analysis was sponsored by Janssen Research & Development, LLC. ES, CP, and VS are employees of nference and have financial interests in the company. LH, BK, SK, NT, and NK are employees of Janssen R&D, LLC. ER was an employee of nference at the time of the study. FB has nothing to disclose. EM received honorarium from Janssen and consultation fees from Protego (fee paid to institution). MG reports personal fees from Ionis/Akcea, Prothena, Sanofi, Janssen, Aptitude Healthgrants, Ashfield, Juno, Physicians Education Resource, AbbVie (for Data Safety Monitoring board), Johnson & Johnson, Celgene, Research to Practice, and Sorrento; and development of educational materials for i3Health. AD served on an advisory board and independent review committee for Janssen, served on a data monitoring safety committee for Oncopeptides and Sorrento and received research funding from Alnylam, Pfizer, Takeda, and Bristol Myers Squibb. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. These data were made available by Mayo Clinic for the current study and are not publicly available due to the inclusion of protected health information (PHI). To request data from this study, researchers should contact the corresponding author and follow Mayo Clinic's standard IRB process for such requests. Table S1. Patient demographics and clinical characteristics. Table S2. ICD-9 and ICD-10 diagnosis codes used to identify signs and symptoms of AL amyloidosis. Table S3. Synonyms used for identifying signs and symptoms of AL amyloidosis in the clinical notes. Table S4. Prevalence counts and proportions of AL amyloidosis signs and symptoms across the registry, ICD codes, and augmented curation of clinical notes data sources, along with intersections. Table S5. Performance metrics of proteinuria diagnoses from augmented curation, manual abstraction of the EHR registry, and ICD codes compared to laboratory test-derived “gold standard.” For each data source, we define TP as the number of patients with proteinuria based on both laboratory tests and the data source, TN as the number of patients without proteinuria based on both laboratory tests and the data source, FN as the number of patients with proteinuria based on laboratory tests but not based on the data source, and FP as the number of patients with proteinuria based on the data source but not based on laboratory tests. Figure S1. Overview of the study design. (A) Illustration of the inclusion criteria for the study population. (B) Description of the three different sign and symptom extraction methods, along with the time windows considered for each extraction method. (C) Summary of the comparison and evaluation of the three data extraction methods. Figure S2. Stacked horizontal bar chart depicting results of a manual review of signs and symptoms identified exclusively by augmented curation of clinical notes. For each sign or symptom, we show the manual review results from 10 randomly selected patients who had the sign/symptom determined by the augmented curation method but not by ICD codes or registry data sources. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for acute lymphoblastic leukemia (ALL), yet large amounts of data describing alloHCT outcomes in Philadelphia (Ph)-like ALL are lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n = 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Fusions associated with Ph-like ALL were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r. Compared with other non-Ph-like ALL (n = 71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P = .008), were less likely to carry high-risk cytogenetics (P < .001), and were more likely to receive blinatumomab prior to HCT (P = .019). With the median followup of 3.5 years, patients with Ph-like ALL fusions had comparable posttransplant outcomes compared with other B-cell ALL: 3-year relapse-free survival (RFS) (41% vs 44%; P = .36), overall survival (OS) (51% vs 50%; P = .59), and relapse (37% vs 31%; P = .47). In multivariable analysis, age (P = .023), disease status at the time of transplant (P < .001), and donor type (P = .015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P < .001) and conditioning regimen intensity (P = .014). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL.

PURPOSE Hematopoietic stem-cell transplantation–associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

Background: AL amyloidosis is a rare disorder in which deposition of insoluble amyloid fibrils composed of misfolded light chains in vital organs, such as the heart or kidney, leads to serious and life-threatening organ dysfunction. Cardiac involvement is the primary determinant of clinical outcomes for patients with AL amyloidosis, and survival expectations decrease with increasing cardiac stage. Subcutaneous DARA (DARA SC) in combination with VCd recently became the first and only approved treatment for newly diagnosed AL amyloidosis based on results of the phase 3 ANDROMEDA study. In the ANDROMEDA study, a higher hematologic complete response rate was consistently achieved with D-VCd versus VCd in patients with newly diagnosed AL amyloidosis, regardless of baseline cardiac stage (Kastritis E, et al. N Engl J Med. 2021;385[1]:46-58). However, cardiac involvement leads to challenges in the attribution of cardiac events to underlying disease and/or treatments. Additionally, among patients randomized to receive D-VCd in the ANDROMEDA study, 15.4% were Asian, 4.6% were Hispanic or Latino, and 3.1% were Black or African American, limiting the interpretation of safety, efficacy, and pharmacokinetic results among patients of different racial and ethnic backgrounds. Therefore, the ongoing phase 2 AQUARIUS (AMY2009) study will characterize the cardiac safety of different D-VCd treatment regimens in patients with newly diagnosed AL amyloidosis with cardiac involvement to identify potential mitigation strategies for cardiac toxicity, as well as better characterize the safety, efficacy, and pharmacokinetics of D-VCd among racial and ethnic minorities. Study Design and Methods: This ongoing multicenter, multicohort, open-label phase 2 study will enroll ~150 patients aged ≥18 years with newly diagnosed systemic AL amyloidosis and measurable disease from ~45 sites across 10 countries. Patients in Cohort 1 (n = ~120) will have cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ involvement. Patients in Cohort 2 (n = ~30) will be of racial or ethnic minority (including ≥15 Black or African American patients) and have ≥1 organ affected by systemic AL amyloidosis. Patients in Cohort 1 will be stratified by baseline cardiac stage (Stages II and IIIa) and randomly assigned (2:1) to receive DARA SC plus immediate VCd (Arm A) or DARA SC plus deferred VCd (Arm B; Figure 1). In both arms, DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) will be administered QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter until a maximum of 24 cycles or the start of subsequent therapy. In Arm A, starting at Cycle 1 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. In Arm B, starting at Cycle 4 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. Patients in Cohort 2 will receive DARA SC plus immediate VCd. Several unique initiatives were incorporated into the study to enhance enrollment of patients of racial or ethnic minority in Cohort 2, including selecting sites from the ANDROMEDA study that enrolled racially/ethnically diverse patients, targeting new sites in diverse communities, raising awareness of AL amyloidosis and the AQUARIUS study among minority patients at the local and national levels, and educating sites on engagement of patients from diverse backgrounds. The first primary endpoint is incidence of any toxicity grade cardiac events for the different D-VCd treatment regimens (DARA SC + immediate VCd and DARA SC + deferred VCd). The second primary endpoint is trough serum concentration (C trough) of DARA at the end of QW dosing (Cycle 3 Day 1 predose). Efficacy evaluations include assessment of hematologic response and organ response. Data will be summarized using descriptive statistics. The first patient was enrolled on March 17, 2022. As of July 10, 2023, the study has enrolled 75 patients; 71 in Cohort 1 and 4 in Cohort 2. In the US, 2 of the 8 patients enrolled were of racial minority ( Figure 2). Efforts to increase enrollment of minorities continue to be optimized and new collaborative initiatives explored to ensure representative and diverse enrollment in clinical trials. The ClinicalTrials.gov Identifier is NCT05250973.

This phase 1 b study evaluated the safety, efficacy, and pharmacokinetics of atezolizumab in combination with guadecitabine in patients with relapsed/refractory (R/R) or first-line acute myeloid leukemia (AML). Patients received atezolizumab 840 mg (days [D] 8 and 22) and guadecitabine 60 mg/m(2) (D1 and D5) over 28-day cycles. Sixteen patients (median age 73.0 years) enrolled (R/R cohort, n = 11; first-line cohort, n = 5). All patients reported at least 1 AE; 15 patients (93.8%) reported grade >= 3 AEs, and 15 patients (93.8%) reported SAEs. Fourteen of the 16 patients (87.5%) died during the trial period due to disease progression (8/14) or AEs (6/14), hence the study was terminated early. One patient (from the R/R AML cohort) achieved a response (CR with incomplete platelet recovery) with a DOR of 27.8 months at study termination. Atezolizumab plus guadecitabine had limited clinical activity in AML and an overall unfavorable benefit-risk profile at the investigated dose levels.