Baseline Cytopenias Research Articles

Infectious Complications in Patients with Relapsed or Refractory (R/R) Non-Hodgkin's Lymphoma (NHL) Treated with the Anti-CD20xCD3 Bispecific Antibody (BsAb) Mosunetuzumab

Introduction:NHL treatment with anti-CD20 antibodies is associated with an increased risk of infections. Mosunetuzumab (mosun) is a novel anti-CD20xCD3 BsAb that has been examined in clinical trials for different NHL subtypes and was recently approved for treating R/R follicular lymphoma. While the open-label clinical trial of mosun reported that 17% of the patients experienced infectious complications, a detailed analysis of the incidence and types of infections in patients receiving this treatment has not been reported. Methods: This is a single-center, IRB-approved, retrospective analysis of patients with R/R NHL receiving mosun, either on a study protocol (NCT02500407) at the recommended phase 2 dose or as commercial use. Patients who completed at least 1 treatment cycle and had at least 30 days of follow-up were included in this analysis. Patient demographics, information on the lymphoma, and infection variables were collected by chart review. All infection-specific variables were collected from the start of mosun therapy until the initiation of the next line of therapy or the last follow-up, whichever came first. The data cut-off was on 7/22/23. Infectious events were graded according to common terminology criteria for adverse events (CTCAE) version 5.0. Baseline characteristics were analyzed for infection risk by performing a Cox regression analysis. Results: Between October 2016 and July 2023, 48 patients were treated with mosun at our center, and 44 met the study inclusion criteria. Four patients had only received one dose or did not have sufficient follow at the time of the analysis. Baseline characteristics are summarized in Table 1. After a median follow-up of 6.8 months (range 0.7-59.7), we recorded 37 infection episodes in 16/44 patients (36.4%). Amongst these, the frequencies of viral, bacterial, and fungal infections were 54.1% (20/37), 43.2% (16/37), and 2.7% (1/37), respectively. The most common infection types were upper respiratory tract infections 42.1% (20/37), skin and soft tissue infections16.2% (6/37), including 3 shingles episodes), genitourinary infections 10.8% (4/37), and lower respiratory tract infections 10.8% (4/37). Of all the infections, 9/37 (24.3%) were Grade 3 or higher; of these, 2/37 (5.4%) were Grade 5 (1 biliary sepsis, 1 COVID pneumonia). The cumulative incidence of infection was 25% over the follow-up period (figure 1). The median time to the first infection was 144 days (range 29-1821). Among the patients who experienced infections, the infection rate was 1.54 every 100 days at risk within the first three months. The infection rate was 1.69 every 100 days at risk between three and six months and 0.37 every 100 days at risk beyond six months for patients with infection. We evaluated the type of lymphoma (i.e., aggressive vs. indolent), patients' age, number of prior therapies before BsAb administration, prior CAR-T therapy, prior autologous SCT, baseline hypogammaglobulinemia, and baseline cytopenia's as risk factors of infection with a univariate Cox regression analysis. We found that none of these characteristics were associated with the risk of infection with statistical significance. However, in a multivariate Cox regression analysis, patients who received CAR-T therapy before starting a BsAb were at a slightly higher risk of developing an infection (OR = 6.13; 95% CI: 0.90, 41.74, p = 0.063). Conclusion: Infection risk in patients with R/R NHL treated with mosun either on protocol or for commercial use appears to be higher than in the clinical trial experience reported in the literature. Viral infections were especially common, including respiratory infections and shingles episodes. Our findings highlight the need for careful monitoring and implementation of preventive strategies to decrease the infection burden in these vulnerable patients.

Anti-Leukemic Activity of Luveltamab Tazevibulin (LT, STRO-002), a Novel Folate Receptor-α (FR-α)-Targeting Antibody Drug Conjugate (ADC) in Relapsed/Refractory CBF2AT3::GLIS2 AML

Introduction: CBFA2T3::GLIS2 (CBF-GLIS) is an oncogenic fusion associated with a lethal and highly refractory childhood myeloid leukemia manifested by the RAM phenotype, uniquely expressed in infants and young children. Conventional chemotherapy and stem cell transplant (SCT) result in extraordinarily high rates of induction failure (>80%) and near uniform fatality with 2-year survival <15%. When conventional therapy fails, this leukemia is refractory to all reinduction therapies with post-relapse survival of nearly 0%. We have previously reported that FR-α is expressed on the surface of CBF-GLIS AML cells and that LT, an investigational ADC, demonstrated potent in vitro and in vivo anti-leukemia activity in CBF-GLIS AML cell lines and xenograft models (PMID: 36149945). LT has been provided under single patient IND to pts with CBF-GLIS AML. Herein, we update the clinical experience. Methods: All pts were required to demonstrate CBF-GLIS fusion by PCR or sequencing. Each investigator in consultation with Sutro Biopharma Inc. defined the treatment plan as to dose, schedule, and combination therapy administered. Results: Between August 2021 and March 2023, 25 pts with relapsed/refractory CBF-GLIS AML were treated with LT at doses of 4.3 or 5.2 mg/kg every 2-4 weeks (4 received smaller fractionated doses (FD) on days 1, 3, 5 per cycle). Median age at treatment was 2 years (range 0.7-8) with median number of prior therapies of 2 (range 1-7). 10 pts had relapsed after SCT. The remaining 15 had primary refractory, relapsed or MRD+ AML. Median time from initial diagnosis was 7.9 months (range 1.5-82.5). Of the 25 pts who received LT, 18 had ≥5% blasts (morphologic disease, MD) and 7 had <5% blasts (sub-morphologic disease, SMD). 21 pts initially received LT monotherapy (mono) (15 with MD and 6 with SMD), 9 of which went on to receive combination (combo) with additional therapies. The remaining 4 received LT in combo upfront. Morphologic or molecular/MRD- response was observed in 12/25 pts (48%). Among those with MD, 7/18 (39%) reached a CR/CRh (5 MRD-) and among those with SMD, 5/7 (71%) reached MRD- CR. Median number of doses received before response was 2. Responses were observed among patients receiving both mono and combo. Among the 11 MD pts treated with mono (excluding FD), 3 reached CR (27%). Among 10 pts with MD who received combo either initially or following mono, 4 reached CR/CRh (40%). Among the SMD pts, 4 reached MRD- with monotherapy and 1 with combo. Of the 10 pts with post-SCT MD relapse, 7 patients received non-fractionated LT either as mono or combo therapy. Of these, the CR rate was 71% (5/7). LT therapy enabled these children to receive potentially definitive therapy. Of the 7 pts with MD in CR, 4 proceeded to SCT, 2 received donor lymphocyte infusions and 1 received consolidation therapy. Of the 5 pts with SMD in MRD- CR, 1 proceeded to SCT, 2 received consolidation therapy in preparation for SCT, and 2 received LT maintenance therapy. In total, 12 pts remain on treatment. Of the 25 pts who received LT, 17 (63%) are alive, 7 died of progressive disease (5 with relapse post-SCT) and 1 died from SCT-related complications. Of the 10 pts who received LT (non-fractionated) post-transplant, 7 are alive (78%). Pt status and treatment are shown in Figure 1. LT was generally well tolerated. TEAEs reported at an incidence of ≥ 25% included decreased neutrophil, platelet, WBC, or lymphocyte count, anemia, increased AST or ALT, diarrhea, and pyrexia. Grade 3+ TEAEs (≥ 10%) included decreased neutrophil, platelet, WBC, or lymphocyte count, anemia, febrile neutropenia, ALT increased, vomiting and hypoxia. Observed cytopenias were often reported in pts with baseline cytopenia. Grade 5 SAEs were limited to fractionated dosing pts: apnea (n=1) and cardiopulmonary failure (n=1). Neither event was considered related to LT. The median duration of LT treatment was 9.1 weeks (2.1-60) and 60% of pts received ≥5 doses. While the initial dose was typically delivered inpatient, approximately 80% of subsequent doses were delivered outpatient. Conclusion: LT based therapy in CBF-GLIS AML provides clinical and laboratory responses that are highly unusual in this refractory patient population. LT has an acceptable safety profile and does not require inpatient delivery. Importantly, LT appears to be enabling these children to receive potential definitive therapy. These data support further characterization of this drug in pediatric CBF/GLIS AML.

Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma

Background: Teclistamab is a B-cell maturation antigen (BCMA) targeting bispecific T-cell engager approved in October of 2022 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) based on the results of the pivotal MajesTEC-1 trial. In this multicenter retrospective study, we evaluated the real-world safety and efficacy of teclistamab, highlighting patterns of utilization and outcomes, including patients who would have been considered ineligible for MajesTEC-1 trial. Methods: Five U.S. academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC), contributed data to this retrospective analysis, which included 102 patients with RRMM who received teclistamab as of 7/1/2023. Baseline characteristics were outlined by descriptive analysis. Teclistamab was administered in a step-up dosing manner as per the package insert. All patients had received at least the two step up doses and the first full dose of teclistamab. Patients received antimicrobial prophylaxis, supportive care, and toxicity management per institutional protocols. Responses to therapy including overall response rate (ORR), very good partial response (VGPR), and complete response or better (≥CR) were evaluated using the International Myeloma Working group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. The Kaplan-Meier method was used for progression free survival (PFS), duration of response (DOR), and overall survival (OS) calculation. Results: Of the 102 patients included in this analysis, 25% were non-Hispanic Black and 44% had extramedullary disease (EMD); the median number of prior LOT was 6 (range 4-17). More than 80% (83/102) of the patients would not have met the MajesTEC-1 eligibility criteria; main reasons for ineligibility included: prior BCMA-directed therapy (BDT) (55%), ECOG performance status ≥2 (28%), and baseline cytopenias: grade 3-4 anemia (26%), and grade 3-4 thrombocytopenia (20%). All patients were triple class exposed and 92% were triple class refractory, 78% were penta-class exposed and 67% were penta-class refractory. More than half of the patients (55%) were refractory to prior BDT. Baseline characteristics are summarized in Table 1. Cytokine release syndrome (CRS) was observed in 65% of patients, all of which, except one, were grade 1-2 events, while immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 15% of the patients, with three patients having grade 3-4 events. The most common grade 3-4 hematological toxicities were neutropenia (23%), leukopenia (18%), thrombocytopenia (17%), and anemia (17%). Infections occurred in 28% of the patients, half of which were characterized as severe. The vast majority (80%) of infections involved the respiratory tract and 7% of patients discontinued teclistamab permanently due to recurrent or severe infections. After a median follow up of 3.2 months, the ORR was 64% for the entire cohort; ORR was 57%, 66% and 45% for patients who were BDT-refractory, penta-refractory, or had EMD, respectively. Of those who did respond, responses were found to be deep (72% ≥VGPR; 45% ≥CR). Patients that would have been ineligible for the MajesTEC-1 trial had an ORR of 59%. Detailed responses for the groups of interest are reported separately in Table 1. The estimated 6-month PFS, DOR, and OS of the entire cohort were 38% (95% CI, 26-56), 54% (95% CI, 34-85) and 68% (95% CI, 58-80), respectively (Figure 1). No treatment-related mortality was observed, although 26% of the patients had died at the time of data cut-off, with 89% of the deaths attributed to disease progression. Conclusion: This is the largest real-world experience of the safety and efficacy of teclistamab for RRMM. Overall, teclistamab was well tolerated with no major safety concerns, despite worse performance status and cytopenias than the MajestTEC-1 trial population. Moreover, despite the increased incidence of high-risk features, including penta-refractoriness, BDT refractoriness, and presence of EMD in this heavily pre-treated RRMM patient population, early efficacy assessment of teclistamab in a real-world setting was encouraging.

Early Predictors of Severe Cytopenia Post CAR-T for Identification of Patients for Potential Stem Cell Collection

Background: Cytopenias are a common complication of and prolonged (beyond month 3 post CAR-T infusion), severe (grade 3 or higher) cytopenias can be difficult to manage. Stem cell boosts have been reported to restore hematopoiesis; however, stem cells would need to be available prior to CAR-T therapy for potential use post CAR-T. Most lymphoma patients and limited number of myeloma patients may have pre-collected stem cells in storage. Identifying patients at high risk for prolonged and severe cytopenia post CAR-T at the time of CAR-T evaluation (baseline), before leukapheresis, can help identify the patients for coordination of stem cell collection during CAR-T manufacturing and increase the likelihood that the collected stem cells would be used. In this study, we aim to identify clinical variables at the time of CAR-T evaluation, prior to leukapheresis, that are associated with severe cytopenias at month 3 post CAR-T infusion and identify patients who could be considered for pre-emptive stem cell collection prior to CAR-T therapy. Methods: We conducted a retrospective analysis of patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) who received CAR-T products at Mayo Clinic from 01/2016 to 06/2022. Patients with progressive disease in the first year post CAR-T were excluded from the analysis. Baseline (at CAR-T evaluation, prior to leukapheresis) variables were compared between those with and without severe cytopenia at month 3 post CAR-T. Severe cytopenias were defined as hemoglobin (Hg) < 8 g/dL, absolute neutrophil count (ANC) < 0.5 x 10 9/L, and/or platelet count (PLT) < 50 x 10 9/L. Statistically significant variables (p<0.05) by analysis were examined for statistical significance in multivariate analysis (MVA). Results: Among the 166 patients who received CAR-T (88 NHL, 78 MM) during the study period, 31 (18.67%) had a severe cytopenia at month . Twenty baseline variables were examined; HGB, PLT, ANC, and c-reactive protein (CRP) We devised a cytopenia risk score using 1 point each for Hg<10 or PLT<100k at baseline, with a range of 0 to 2. Demographics and clinical outcome by cytopenia risk score is shown in Table 1B. A higher percentage of patients with a score of 1 or 2 had a severe cytopenia at month 3 (Figure 1). In particular, there was a . In addition Conclusion: Baseline cytopenias before leukapheresis may identify patients with increased risk for severe cytopenias at month 3 post CAR-T. These patients can have continued slow hematopoietic recovery in the first year. Stem cell collection, if feasible, could be considered before CAR-T to alleviate post-CAR-T severe prolonged cytopenias.

An Analysis of Ruxolitinib Dosing for Myelofibrosis in Real-World Practice

Background: Myelofibrosis (MF) is a myeloid neoplasm characterized by splenomegaly, constitutional symptoms, and cytopenias. Notably, worsening cytopenias in MF patients is directly correlated with poor survival ( Coltro, et al. Blood Cancer J. 2022;12(8):116). The JAK1/2 inhibitor ruxolitinib (RUX) is effective in decreasing splenomegaly and improving symptom control at starting doses of 30-40 mg total daily dose (TDD), though drug-induced cytopenias often lead to significant dose reductions. Doses of ≤20 mg TDD are associated with decreased efficacy for spleen response, and doses of ≤10 mg TDD demonstrate minimal efficacy for spleen or symptom reduction ( Verstovsek, et al. Onco Targets Ther. 2014;7:13-21). Treating with less clinically effective doses may not be optimal in light of newer, less myelosuppressive JAK2 inhibitors that can be administered without dose reduction, regardless of baseline cytopenias. This study describes RUX dosing patterns in real-world community practice. Methods: This retrospective, observational study included deidentified data of adult patients from the IntegraConnect PrecisionQ database (~80% community practice) with MF treated with first-line RUX and with ≥2 office visits (with a criterion of 2 MF diagnosis codes reported within 180 days) from January 2016 to July 2022. Patients were stratified by baseline platelet count (PLT). Data on RUX TDD at initiation and at first dose modification were collected, with a focus on less clinically effective dosing of ≤20 mg TDD and ≤10 mg TDD. Results: Of 129 patients on RUX with a median age of 75 (range: 42-89) years, 61% (n=79) had PLT >200x10 9/L, 19% (n=24) had PLT 100-200x10 9/L, and 20% (n=26) had PLT <100x10 9/L. Across all PLT strata, 88% (n=114) were initiated on RUX at a TDD of ≤20 mg, and 51% (n=66) were started at a TDD ≤10 mg. Nearly half of patients with higher baseline platelet counts (>100 x 10 9/L) were started on doses ≤10 mg TDD (Fig 1). Among 79 patients with PLT >200x10 9/L, starting RUX TDD was ≤20 mg in 87% (n=69) and ≤10 mg in 43% (n=34). A total of 49 patients underwent subsequent dose modification (median time [min, max]: 47 days [10, 1336], with 19 dose increases vs 30 dose decreases. Of patients whose dose increased, only 4 escalated to a TDD >20 mg. Despite dose modification, RUX TDD remained ≤20 mg in 90% (44/49) and ≤10 mg in 43% (21/49) of patients. Similar to patients with baseline PLT >200x10 9/L, the majority of patients with PLT 100-200x10 9/L started on TDD ≤20 mg (87.5% [21/24]), with a high proportion on ≤10 mg (50% [12/24]). Among the 103 patients with PLT >100x10 9/L for whom a recommended starting dose is provided in the RUX package insert, 88% (91/103) initiated RUX below the recommended dose. Of the 61 patients who underwent subsequent dose modification (median time: 47 days [10, 1336], only 10% (6/61) were escalated to a dose recognized as clinically effective. Conclusions: These real-world data suggest that a majority of patients starting RUX, including those with PLT >200x10 9/L, are initiated on ≤20 mg TDD, and the majority of patients are not titrated up to the doses tested in the pivotal studies that led to RUX approval. These data suggest that clinicians are hesitant to prescribe RUX at doses known to be clinically effective. Together with the timing of dose modification, this suggests that there may be concerns related to toxicity or treatment-related cytopenias. Recognizing that JAK2 inhibition remains an important part of managing MF for patients, clinicians now have alternative treatment options. These newer treatments inhibit additional pathways (IRAK1/ACVR1), are less myelosuppressive, and can maintain dose intensity regardless of baseline platelet count. Study funded by CTI BioPharma Corp., a Sobi Company.

Ruxolitinib Promotes Clinical Responses in Large Granular Lymphocytic Leukemia Via Suppression of JAK/STAT-Dependent Inflammatory Cascades

Background: Large granular lymphocytic leukemias (LGL) are T or NK-cell lymphoproliferative disorders that are characterized by myelosuppression and frequent mutations in STAT3. Commonly used agents include low doses of methotrexate or cyclophosphamide. Among 5 patients (pts) with LGL treated on our phase II study of ruxolitinib in T-cell lymphoma (Moskowitz, et al. Blood 2021), 2 achieved partial response (PR) and 2 achieved stable disease, suggesting oncogenic dependence on JAK/STAT pathway activity in LGL. Methods: To further explore the efficacy and mechanism of JAK1/2 blockade in LGL, we expanded our phase II study to include 23 pts with relapsed/refractory LGL. This sample size was chosen to allow for narrowing of the 95% confidence interval to 54-87% (Wilson score method) if similar efficacy was observed. Pts received ruxolitinib 20mg PO BID continuously. Responses were assessed after cycles 2, 5, and every 3 cycles thereafter using the response assessment from the ECOG-5998 study for LGL. Furthermore, stable disease (SD) was defined as improvement in cytopenia(s) by 1 grade (without meeting criteria for PR) for a minimum of 6 months. Overall response rate (ORR) included complete response (CR) plus PR; clinical benefit rate (CBR) included ORR plus SD. In parallel, we performed single-cell RNA sequencing (scRNA-seq) on paired C1D1 and C1D8 peripheral blood mononuclear cells (PBMCs) from 7 patients (5 PR, 1 SD, and 1 non-responder) and plasma proteomic profiling on 5 patients (3 PR, 1 SD, and 1 POD). Results: Among 23 pts, median age was 58 (31-86), 13 (57%) were male, 19 (83%) were white, 1 (4%) was black. Median number of prior therapies was 2 (range 0-5). 12/22 (54%) had STAT3 mutations (of whom 1 also had a JAK1 mutation); 1 had a JAK2 mutation, 1 pt was missing sequencing. Baseline cytopenias included anemia (n=14, 61%), thrombocytopenia (n=12, 52%), and/or neutropenia (n=16, 70%). Among 20 pts evaluable for response (3 too early), there were 5 (25%) CRs, 6 (30%) PRs, and 4 (20%) SD. ORR and CBR were 55% and 75% respectively. Median event free survival (EFS) was not reached and was 68% (95% CI: 50-93) at 14 months ( Fig. 1A). STAT3 mutation status predicted for improved EFS (14-month EFS 100% vs 40%, p=0.007). After a median duration of treatment of 13.1 months, there were no unexpected toxicities. Severe adverse events included febrile neutropenia (n=3, 13%) and herpes zoster (n=1, 4%). To understand the mechanism by which ruxolitinib improved hematologic parameters in LGL, we performed unbiased proteomic analysis of peripheral blood plasma samples using the OLink 96 Inflammation and Immune Response Platforms. Ruxolitinib led to a decrease in several soluble mediators known to be driven by interferon-driven JAK/STAT activation, including CXCL9, CXCL10, and PD-L1, as well as TNF ( Fig. 1B). Several of these factors have been shown to suppress hematopoietic stem cell function, suggesting a JAK/STAT-dependent paracrine mechanism by which LGL leads to myelosuppression. ScRNA-seq of PBMCs identified LGL cells based on expression of cytotoxic genes, including NKG7, CST7, CCL5, GZMB and PRF1. Analysis of cell type proportions within the peripheral blood showed that patients achieving a PR to Ruxolitinib showed a decrease in the proportion of circulating myeloid cells. Gene set enrichment analysis (GSEA) of LGL cells revealed substantial downregulation of both JAK/STAT signaling and TNF signaling in LGL cells in PR but not SD patients, whereas persistently elevated TNF signaling was seen not only in LGL cells but also circulating myeloid and naïve T-cells in SD patients, suggesting that LGL cells might promote bone marrow suppression via paracrine effects on the bystander host immune system. Network analysis of LGL cells and non-malignant peripheral blood immune cells is ongoing. Conclusions: Ruxolitinib induced durable responses in pts with LGL and therefore may represent an option for pts requiring treatment. STAT3 mutation status was predictive of EFS and responses were associated with JAK/STAT pathway down-regulation, demonstrating on-target effects. Integrated immune profiling suggests that ruxolitinib may interrupt JAK/STAT-dependent paracrine inflammatory signals that promote bone marrow suppression. An ongoing phase II study of ruxolitinib in LGL will aid in clarifying optimal dosing and confirming both efficacy and mechanism of action (NCT05592015).

Tolerability of lutetium-177–PSMA-617 in men with prostate cancer and baseline cytopenia.

e17057 Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]

A phase I study of MEK inhibitor selumetinib in combination with azacitidine in patients with higher-risk chronic myeloid neoplasia.

TPS7084 Background: Myelodysplastic syndrome (MDS), Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes present significant clinical challenges for patients deemed transplant ineligible, and who are relapsed or refractory to conventional therapies. RAS-pathway activating mutations in myeloid malignancies are associated with a proliferative phenotype and contribute to disease progression. Cooperation between RAS-dependent signaling and epigenetic dysregulation provides the basis for rationally designed combination studies. Selumetinib (AZD6244) is a potent, selective, orally bioavailable, and non-ATP competitive small molecule inhibitor of MEK1/2, downstream of RAS. Methods: This is an investigator-initiated, Phase I, open-label dose-escalation study of selumetinib in combination with azacitidine for patients with higher risk MDS, MDS/MPNs, and myelofibrosis. The trial will enroll patients with high-risk myeloid neoplasms that meet disease-specific criteria for MDS or MPNs and who require treatment. This phase I study follows a 3+3 dose-escalation design, with three planned dose levels across two different cohorts (A and B). The dose of azacitidine 75 mg/m2 will remain stable, with three planned selumetinib dose levels (50 mg, 75 mg, and 100mg, respectively) across the two cohorts. Azacitidine will be given on days 1-7 followed by selumetinib from days 7-21 of 28 day cycles. Cohort A includes subjects with MDS with relapsed/refractory disease requiring therapy and MDS/MPN overlap syndromes; Cohort B includes subjects with myelofibrosis refractory or intolerant to JAK inhibitor therapy or ineligible for ruxolitinib treatment given baseline cytopenias (thrombocytopenia < 50,000/uL, anemia < 9 g/dL, and/or red cell transfusion dependent). The trial has an enrollment goal of 18 to 24 subjects, and treatment will continue indefinitely if the patient continues to derive benefit. Dose escalation will proceed independently within both cohorts. Cohort A is nearing completion of enrollment and cohort B is actively enrolling. The primary objective is to determine the maximum tolerated dose of selumetinib in combination with azacitidine. Select secondary and exploratory objectives include describing the preliminary clinical response rates and observing relationships between the presence of RAS activating mutations, RAS pathway activation, and clinical response. Clinical trial information: NCT03326310 .

Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma, a Real-World Single Center Experience

Introduction Belantamab mafodotin is an antibody drug conjugate targeting B-cell maturation antigen (BCMA) with single agent activity around 32% in the DREAMM2 phase II trial (Lonial et al, Cancer 2021). Side effects, including keratopathy and reduced best corrected visual acuity (BCVA), often necessitate dose reduction and dose delays which may limit efficacy. The aim of this study was to assess response rates, dose modifications, and frequency of ocular adverse events in patients treated with belantamab mafodotin in a real-world setting and in relation to prior treatment with BCMA targeted therapies. Methods All patients treated with at least one dose of commercial belantamab mafodotin at Memorial Sloan Kettering Cancer Center between October 1, 2020 and July 11, 2022 were included in the study. Descriptive statistics were used to assess patient characteristics, response rates, and rate of adverse events. Kaplan Meier curves were used to assess progression free survival (PFS) and overall survival (OS). Results Eighty-two relapsed/refractory multiple myeloma patients were included; 40 (49%) were women median age was 68 years, and 50 patients (61%) had high risk cytogenetics. Twelve patients were treated on the Expanded Access Program with belantamab mafodotin prior to receiving commercial drug. Patients had a median of 6 (range 2-14) prior lines of therapy, all had received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Sixteen patients (20%) had received one or more BCMA-targeted agents including a bi-specific antibody (N=5), chimeric antigen receptor (CAR) T cell (N=12), and trial therapy with belantamab mafodotin (N=1). Patients received a median of 4 cycles (range 1-31) of belantamab mafodotin. The majority, 96% (N=79), as single agent, while 3 patients were received belantamab mafodotin in combination with other anti-myeloma agents. The overall response rate (ORR) in all patients was 45%; 37/82 patients. Of these, 10 achieved a partial response (PR); 14 patients achieved a very good partial response (VGPR), and 13 patients achieved a complete response (CR) (Table). The median duration of response for patients in the ORR cohort was 11 months. Eighteen patients had stable disease (SD) and 27 patients had progressive disease (PD). The median PFS was 6 months and median OS was not reached. At the end of follow up, 19 patients continued belantamab mafodotin therapy and 28 patients had died. In a separate analysis of patients not included in the Expanded Access Program, the ORR was 43%; 8 had a PR, 13 had a VGPR, and 8 patients had a CR. Of the 16 patients who had prior exposure to BCMA targeted therapy, 5 patients had a PR or better (3 VGPR, 2 CR), 2 patients were in a VGPR/CR at start and continued to respond, 3 patients had SD while 6 patients had PD. The median PFS was similar in patients that were BCMA exposed and those that were BCMA naïve (Figure). Fifty-six patients (68%) had any grade of ocular toxicity per the Keratopathy and Visual Acuity (KVA) scale; 26 patients had grade 1, 15 grade 2, 12 grade 3, and 2 patients had grade 4 keratopathy, respectively. Twenty-six patients had presence of corneal microcysts (information missing in 11 patients). Forty-five patients experienced a decline in BCVA; 22 patients had grade 1, 13 had grade 2, 3 had grade 3, and 1 patient had grade 4 decline in BCVA, respectively (grade missing in 4 patients). The dose of belantamab mafodotin was reduced from 2.5 mg/kg to 1.92 mg/kg in 36 patients while 29 patients had dose delays, the majority due to ocular adverse events but also due to baseline cytopenia, infection, and patient preference. Most patients who had dose modifications due to ocular events were able to continue therapy on a lower dose with maintained response. Nine patients discontinued treatment due to keratopathy, 3 of whom had ongoing grade 1 keratopathy at the end of follow up. Conclusion In this heavily pre-treated multiple myeloma patient population, the ORR was 43-45% which is similar or better than the DREAMM2 phase II trial. The rate of ocular toxicity (68% keratopathy) was comparable to previous reports. Importantly, 5 of 16 patients with exposure to prior BCMA exposure achieved a PR or better while 5 had SD. The PFS was similar in BCMA exposed and BCMA naïve patients. These are encouraging outcomes for belantamab mafodotin in the real-world setting with responses and toxicities comparable to those reported in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Baseline blood count levels increase odds of cytopenia among CML patients in Kenya: a case control study

BackgroundImatinib is the gold standard for the treatment of all phases of Philadelphia positive Chronic Myeloid Leukemia (CML). During treatment, patients may develop cytopenia. We aimed to study the baseline characteristics and factors associated with cytopenia at a Nairobi Hospital.MethodsThis was a retrospective case-control study of patients aged ≥18 years on follow-up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. The cases consisted of CML patients on imatinib who developed cytopenia. The controls were CML patients on imatinib who did not develop cytopenia. Baseline socio – demographic, clinical, hematologic, and molecular data were retrieved from patients’ files. Chi square or fishers’ exact tests were used to analyze for differences between cytopenia and no cytopenia. Binary logistic regressions were employed to identify relationships. Univariate and multivariate analyses were done to identify independent predictors of cytopenia. Odds ratios (OR) were presented including the 95% confidence intervals and respective p values.ResultsA total of 201 patients were studied consisting of ninety-four (94) patients with cytopenia and 107 with no cytopenia. Among the entire population, males were 52, and 42% were aged 36–50 years. Sex, age, marital status, occupation and education level were similar between the cytopenia and no cytopenia groups.Among the 201 patients, 70% had symptoms for > 12 months before diagnosis, 78.6% had B symptoms at baseline, 80% had a moderate splenomegaly at baseline.Among patients with cytopenia, 40 and 37.4% developed cytopenia within 3 months and 3–6 months respectively after imatinib initiation. Baseline neutrophilia, neutropenia, anaemia, thrombocytosis, thrombocytopenia was found in 68, 11, 11, 23.5 and 11% respectively. Baseline hemoglobin, neutrophil and platelet level were significantly different between the cytopenia and the no cytopenia group. On univariable analysis, baseline anemia with hb < 7.9 g/dL (p = 0.002), neutropenia (p = 0.001), neutrophilia > 100,000/mm3 (p = 0.002) and thrombocytopenia (p = 0.001) increased the odds of developing cytopenia. On multivariable analysis, baseline anaemia (p value < 0.002), neutropenia (p value < 0.001), thrombocytopenia (p value, < 0.001) and thrombocytosis (p value, 0.033) increased the odds of developing cytopenia.ConclusionOdds of cytopenia were higher in presence of baseline cytopenia and thrombocytosis. Clinicians should have a high index of suspicion for these patients.

Peripheral Blood Cytopenia and Risk of Cancer Mortality

▪Introduction:Unexplained peripheral blood cytopenia remains a challenge in clinical practice which requires sorting through an array of etiologies from transient abnormalities to premalignant conditions. Clonal hematopoiesis has established an association between cytopenia and hematologic cancer, likely caused by inflammatory responses leading to hematopoietic stress. Similar mechanisms may occur in other organ systems and lead to neoplasia as the link between inflammation and solid tumors is well known. Thus, cytopenia may represent an early marker of serious conditions, including malignancy. Using the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study, we studied the association between cytopenia and cancer mortality.Methods:REGARDS prospectively enrolled 30,239 US black and white adults from 2003 to 2007 (41% black). Sociodemographic and medical data were obtained by phone interview, physical exam, and laboratory studies at enrollment (baseline CBC drawn after 8,000 people were recruited). Cancer death was identified via semiannual phone follow-up through 2018 to ascertain health events and linkage with Social Security Death and National Death Indexes. Cytopenia was defined as presence of 2 or more of the following: 1) hemoglobin below age, sex, and race-specific lowest 5th percentile, 2) white cell count below race-specific lowest 5th percentile, 3) platelet count below lowest 5th percentile, and 4) macrocytosis (MCV >98fL). Participants with baseline cancer, missing CBC, or lost to follow-up were excluded. Cox proportional hazards models were used to calculate hazard of cancer mortality associated with cytopenia, adjusting for demographics (Model 1), Model 1 + risk factors for cancer/anemia (Model 2), and Model 1 + socioeconomics (Model 3). Differences in the association of cytopenia and cancer death by race was tested by cross-product interaction terms and Inverse Odds Ratio Weighting (IORW) mediation analysis was conducted to study the effect of cytopenia as mediator in the race-cancer death interaction.Results:The analysis population included 19,028 participants, 62% were female and 60% were white. Median follow up was 9 years. There were 1112 (5.8%) cancer deaths and 3725 (19.6%) deaths from other causes. Cytopenia was present in 383 (2%) participants, of which 250 (65%) were white and 113 (35%) were black. Cytopenia prevalence increased by age and was higher in males (56%). Cytopenia was associated with increased risk of cancer mortality in all multivariate models adjusting for demographics (HR=1.60, 95%CI 1.16-2.21), cancer risk factors (HR=1.67, 95%CI 1.2-2.32), and socioeconomics (HR=1.58, 95%CI 1.12-2.23). Anemia and macrocytosis, but not leukopenia and thrombocytopenia, were hematologic parameters individually associated with risk of cancer death (Table 1). The 10-year cumulative incidence of cancer death was 13% for participants with baseline cytopenia vs. 6.5% for those without cytopenia (p<0.01, Figure 1). The race by cytopenia interaction term was significant with higher HR for cancer mortality in blacks compared to whites in all models: 2.01 vs 1.41, p=0.016 in model 1 (demographics), 2.12 vs 1.45, p=0.009 in model 2 (cancer risk factors), 1.82 vs 1.44, p=0.04 in model 3 (socioeconomics). Anemia and macrocytosis were individual hematologic parameters with higher HR for cancer death in blacks compared to whites and significant race by cytopenia interaction terms across all models (Table 2). Mediation analysis by IORW method showed that cytopenia was not a significant mediator in the pathway between the race and cancer death association (not shown).Discussion:In a large biracial prospective cohort, cytopenia was associated with increased risk of cancer mortality after adjusting for demographics, socioeconomics, and cancer risk factors. Cytopenia was a race-specific risk factor for cancer death affecting blacks more than whites, but not a mediator of the race and cancer death association. We conclude that 1) cytopenia is a risk factor for cancer death, with stronger association in blacks than whites, and 2) race is an effect modifier for the association of cytopenia with cancer death, but cytopenia is not a mediator of the black to white difference in cancer mortality. These results can inform further studies aimed at clarifying racial disparities in cancer death through theorized mechanisms such as clonal hematopoiesis. [Display omitted] DisclosuresGangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy.

Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma, a Real-World Experience

Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma, a Real-World Experience

Assessment of Venous Thromboembolism Risk Based on the Khorana Predictive Model and Compliance with Prophylactic Anticoagulation at a Regional Cancer Center- a Quality Improvement Study

Background:Malignancy is an independent risk factor for venous thromboembolism. Factors like site of the primary cancer, associated comorbidities, obesity, and baseline cytopenias play an important role in predicting the risk in cancer patients. Several risk assessments models have been proposed in the literature, however, the Khorana risk predictive model is the most favored tool used in the literature. Patient characteristics like site of primary, baseline hemoglobin/platelets/WBC and BMI are the main components of this scoring system. Patients are classified into low (0), intermediate (1-2) and high (> 3) risk groups. Low dose prophylactic anticoagulation (Apixaban 2.5 mg BID or Rivaroxaban 10 mg daily) for up to 6 months is indicated in patients with score 2 or higher.Methods:83 patients with a new cancer diagnosis in the years 2018 and 2019 who received chemotherapy and developed a venous thromboembolism (VTE) after the cancer diagnosis were identified from the cancer registry at Edwards Comprehensive Cancer Center. All the components of Khorana score including patient's baseline body mass index (BMI), white blood cell count (WBC), hemoglobin, platelet count and site of the primary were collected. Compliance with prophylactic anticoagulation (Khorana score =/>2) was evaluated.Results:Among 83 patients identified, 61 % and 39 % were female and males, respectively with a mean age of 59 years. The mean duration of onset of VTE was 18 months from the time of cancer diagnosis. The mean Khorana score was 1.1. 34 % of patients(n=28) were found to have a Khorana score of =/> 2 and prophylactic anticoagulation was indicated. Only 7 % of patients (n=2) received prophylactic anticoagulation. The reason for no prophylactic anticoagulation was not documented in all the cases.Conclusion:In patients with a higher risk of VTE, a very low compliance rates for prophylactic anticoagulation were found at our cancer center. Poor documentation and failure to address the risk of VTE are possible reasons for the low compliance rates. Necessary steps needed to improve the compliance rates are warranted including education of the healthcare providers about current available guidelines to decrease risk of VTE in cancer patients. Dedicated lectures and sessions will be organized and educational materials highlighting the importance of VTE risks and prophylactic anticoagulation will be provided to the healthcare providers at the cancer center. DisclosuresNo relevant conflicts of interest to declare.

Rituximab and High-Dose Methylprednisolone for the Initial Treatment of Chronic Lymphocytic Leukemia Is Associated with Promising Clinical Activity and Minimal Hematologic Toxicity

Myelosuppression is associated with significant morbidity and mortality in chronic lymphocytic leukemia (CLL) and is often exacerbated by currently available treatments for this disease. Myelosuppression often requires dose reductions in cytotoxic agents, delays in therapy, truncated treatment courses, or the exclusion of elderly or infirmed individuals from receiving standard chemoimmunotherapy.High-dose methylprednisolone (HDMP) and the anti-CD20 mAb rituximab (Rituxan), each is non-myelotoxic and can induce partial remissions when used alone to treat patients with CLL. However, complete remissions (CRs) in CLL patients are rarely observed following treatment with either agent. Recently, we reported the use of the combination of HDMP and rituximab in fludarabine-refractory patients [Castro Leukemia 2008]. The promising clinical activity and tolerability of this regimen in the refractory setting led to the evaluation of this regimen for the initial treatment of patients with CLL. To mitigate toxicity associated with use of HDMP, we employed a 40% reduction in the dose of HDMP by administering solumedrol at 1 gm/m2 for 3 instead of 5 days during each 4-week treatment cycle. Rituximab was given weekly for 12 weeks at 375mg/m2 or at 750mg/m2 in 9 doses over the 12 weeks of treatment to chemotherapy na·ve CLL patients with an NCI-WG indication for treatment. Objectives were to determine the response rate, safety, and toxicity of this regimen. PFS, overall survival (OS), hematologic, and immune parameters were also evaluated. We enrolled 28 patients who had a median age 65 years (range 48–80), 29% of whom were at least 70 years old. Forty-six were high risk by modified Rai classification, 39% had unfavorable cytogenetic features, and 64% had CLL cells that used unmutated IgVH region genes or exhibited high expression levels of ZAP-70. Patients received the full course of treatment without dose reductions or delays and the treatment well tolerated. Overall response rate was 96% with complete remission achieved in 32% of patients, 22% of whom had no detectable minimal residual disease (MRD) by sensitive 4-color flow cytometry capable of detecting residual CLL cells when present in marrow mononuclear cells at levels of more than 0.01%. Those patients over age 70 had an ORR of 100% with 38% CR, and 11% MRD-negative CR. There was a non-significant trend towards those receiving rituximab at 750mg/m2 being more likely to achieve a CR to treatment (Odds Ratio (OR) = 4.3, p-value 0.09). Individually, both beta-2-microglobulin (p=0.04) and splenomegaly palpable to at least 5 cm below the left costal margin (p<0.01) were associated with failure to achieve a CR to HDMP and rituximab. However, multivariable logistic regression analysis identified only splenomegaly as being significantly associated with failure to achieve a CR (OR = 0.096, p value = 0.03) to this regimen.The majority of adverse events were grade I/ II (80%) and hematologic toxicity was minimal. During the course of treatment, we noted resolution of thrombocytopenia or anemia. (See Figure) A total of 81 cycles of treatment were administered and only one red cell transfusion and no platelet transfusions were required. Serum immunoglobulins decreased with therapy and a low threshold was used to initiate intravenous gammaglobulin for those patients with experiencing recurrent infections. Percent of CD4 T cell counts increased significantly from median 2% (+/−4% 95% CI) to 32% (+/−8%) (Student t-test p < 0.0001). All patients had a CD4 count of greater than 200 cells/μl (median 848 cells/ul) two months after the completion of treatment.Six patients received consolidation with alemtuzumab at least 4 months following initial therapy and 83% of these patients became MRD negative. The CR and MRD negative CR rate following HDMP and Rituximab with 6 patients receiving consolidation were 43% and 25% respectively. With over three years of follow-up (36.3 mo) median PFS and time to requiring additional therapy have not been reached and OS is 96%. Achieving a MRD negative response was associated with significantly prolonged PFS and time to requiring additional therapy over all other responses (log-rank test p= 0.036 and 0.016 respectively).In summary, the combination of HDMP and rituximab is an effective non-myelotoxic treatment regimen for patients with CLL. Treatment was well tolerated, notably in elderly patients and those with baseline cytopenias making this regimen an effective and safe alternative for frontline therapy. [Display omitted]

Impact of Red Blood Cell Transfusion Intensity on Progression-Free Survival in Lower-Risk MDS Patients Included in the European Leukemianet MDS Registry

Abstract Background Progression-free survival (PFS) of lower-risk (LR) MDS patients treated with red blood cell transfusions (RBCT) is usually reduced, but whether the RBCT intensity is important for prognosis is unknown. The EUMDS Registry contains data on 2,192 newly diagnosed LR-MDS patients from 16 European countries and Israel, collected at diagnosis and at 6 months intervals.The aim of this analysis is to assess the effect of RBCT intensity on PFS of patients with LR-MDS in a prospective, observational setting. MethodsData on the number of RBCT units received during each visit-interval were analyzed using proportional hazards regression with time-varying co-variates. The cumulative dose received at the end of each interval was divided by the time since the beginning of the interval in which the first RBCT was received rather than for each visit-interval, to give an overall dose density. Dose density rises over time when RBCT intensity increases over time, but declines when patient becomes RBCT independent after treatment. In Cox regression with time-varying covariates, PFS was adjusted by relevant confounders, including age, gender, patient condition (proxied by EQ-5D index), and number of cytopenias at diagnosis. We analyzed a cohort of 1,509 patients with at least 3 visit reports available. Within this group 476 patients have died and 118 patients have progressed to higher-risk MDS or AML, which were defined as events. ResultsPatients with ring sideroblastic MDS (RS-MDS) received more frequently RBCT after diagnosis compared to non-RS-MDS (60% vs 54%). Very low-risk patients according to IPSS-R received RBCT less often compared to intermediate risk patients (35% vs 69%). Age, gender, presence of co-morbidities, and countries influenced RBCT dependency and RBCT rate. The transfused patients were subdivided in 3 groups according to the maximum RBCT rate over time: low rate ( 2 units/month) in order to analyse the impact of the RBCT rate in more detail (figure A). Unadjusted overall PFS stratified this way, is shown in figure B. Univariate analysis of the 404 patients transfused at a high rate showed a strong association of age (p ConclusionThe negative effect of RBCT treatment on PFS already occurs at low RBCT densities below 2 units/month and before 25 units of RBCT have been transfused. This indicates that the RBCT dependency, even at relatively low intensities, may be considered as an indicator of poor prognosis for survival. Download : Download high-res image (93KB) Download : Download full-size image Figure . Disclosures Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sanz: Gamida Cell: Research Funding. Germing: Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Almeida: Servier: Consultancy; Alexion: Honoraria; Novartis: Consultancy; Celgene: Consultancy; Bristol Meyer Squibb: Honoraria. Itzykson: Janssen: Research Funding; Novartis: Research Funding. Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira/Pfizer: Research Funding; Celgene: Research Funding. de Witte: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Cilag: Research Funding.

Chimeric Antigen Receptor Induced Cytopenia Differs from Chemotherapy Induced Myelosuppression

▪Background: Cytopenias are a potential complication of chimeric antigen receptor (CAR) therapy. The specific degree, duration, or implication of these cytopenias is not well established, and is further confounded by baseline cytopenias in heavily pre-treated patients with active leukemia. Preclinical models suggest that these cytopenias may be due to a cytokine rich milieu which may contribute to nonspecific suppression of marrow progenitors-independent of the CAR target (Sauter, ASH 2016, abstract 3357); which differs from standard cytotoxic chemotherapy based myelosuppression. We systematically analyzed CAR-related cytopenias on our phase I dose-escalation study of CD22 CAR.Design: Children and young adults with relapsed/refractory CD22+ acute lymphoblastic leukemia (ALL) treated on our phase I dose escalation anti-CD22 CAR therapy protocol (NCT02315612) were evaluated for time to neutrophil and platelet recovery (defined by absolute neutrophil count (ANC) of > 500 k/mcL x 3 days and achievement of transfusion independent platelet count > 20 k/mcL, respectively). All patients had bone marrow evaluations by morphology and flow cytometry at baseline, prior to lymphodepleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR. Infections were closely monitored for. All patients were on anti-fungal prophylaxis and were empirically treated for fever during periods of neutropenia.Results: From December 2014 to July 2017, 30 patients with ALL were treated on study at 3 dose levels. All patients had active bone marrow involvement at baseline with the majority (n=21) having an M2 marrow (>5% blasts) or higher. Twenty-six patients had prior transplants, and 21 patients had prior CD19-directed CAR therapy. Cytokine release syndrome (CRS) was seen in 24/30 (80%), with most patients having grade 1-2 CRS. 18/30 patients (60%) attained a complete remission following CD22 CAR therapy. Baseline hematologic parameters for responders prior to lymphodepletion included grade 2-4 neutropenia and grade 2 and 3 thrombocytopenia, with five patients requiring platelet transfusions (Table 1). Amongst complete responders, the bone marrow at day 28 demonstrated a median cellularity of 28% with trilineage hematopoiesis noted in 16/18 patients. The median CAR T cell % in bone marrow at 1 month was 30%. The median time to ANC nadir was 15 days post CAR infusion (range:10-23 days).17/18 patients had ANC recovery >500 k/mcL, at a median of 22 days post-infusion (range: 15-44 days). One patient had ANC recovery to 260 k/mcL but subsequently developed disease relapse. Eight patients received intermittent GCSF, with clinically relevant responses seen in seven of these patients with a median increase in ANC of 2,180 k/mcL (range: 850-4,100 k/mcL) with limited dosing. The median number of days of GCSF administration to time of ANC recovery was 4, with 3 patients requiring only 1 injection to achieve robust ANC response. Interestingly, only 1/18 patient (6%) had a new onset of infection (clostridium difficile colitis) during the period of CAR associated neutropenia, which was confounded by administration of intravenous antibiotic therapy for fevers that was initiated 24 hours prior to onset of diarrhea. There was no new development of fungal infections or worsening of any pre-existing infections. Platelet recovery to > 20 k/mcL was at a median of 36 days (range: 21-55) post-CAR and was seen in 16 of 18 responders. Two patients who remained platelet transfusion dependent post-CAR included one patient who was later found to have donor-cell monosomy 7 MDS and another patient whose disease relapsed prior to recovery.Conclusion: In contrast to chemotherapy associated myelosuppression, CAR-therapy associated peripheral blood cytopenias existed despite evidence for trilineage hematopoiesis on the bone marrow. Although the period of CAR associated neutropenia is substantial, with prophylactic antifungals and intermittent growth factor support, this heavily pre-treated population was not at an increased risk of developing serious bacterial or fungal infections over baseline. The rapid response to G-CSF is suggestive of an alternative modality of bone marrow inhibition distinct from chemotherapy induced cytotoxicity. Further evaluation in the context of multiple CAR targets and constructs are needed to further explore this complication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies

AbstractFactors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had “recovered” (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell–associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies.

Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL

A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL