Advanced Hematologic Malignancies Research Articles

Hematopoietic Stem-Cell Transplantation: Exploring the Latest Advances and Gaps in Disparities, Psychosocial and Symptom Management Interventions, and Chronic Graft-Versus-Host Disease Care.

Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure or immunodeficiency syndromes, it is an intensive treatment and accompanied by short- and long-term physical and psychological symptoms requiring specialized care. With substantial advances in therapeutic approaches for HCT and supportive care, HCT survivors experience less morbidity and mortality. However, disparities in both HCT access and outcomes persist, and HCT survivors and their caregivers often lack access to much-needed psychosocial care. Additionally, more medical and psychosocial resources are needed to holistically care for HCT survivors with chronic graft-versus-host disease (GVHD). Hence, this chapter focuses on three areas pertaining to advances and gaps in HCT care: disparities in access to and outcomes of HCT, psychosocial and physical symptom management with supportive care interventions, and GVHD prevention and management.

Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells

BackgroundImmune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting.MethodsWe utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release.ResultsIn ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models.ConclusionsAPG-1387 has the potential to turn “cold tumors” into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).Graphic abstract

Palliative Care for Patients With Cancer: ASCO Guideline Update.

To provide evidence-based guidance to oncology clinicians, patients, nonprofessional caregivers, and palliative care clinicians to update the 2016 ASCO guideline on the integration of palliative care into standard oncology for all patients diagnosed with cancer. ASCO convened an Expert Panel of medical, radiation, hematology-oncology, oncology nursing, palliative care, social work, ethics, advocacy, and psycho-oncology experts. The Panel conducted a literature search, including systematic reviews, meta-analyses, and randomized controlled trials published from 2015-2023. Outcomes of interest included quality of life (QOL), patient satisfaction, physical and psychological symptoms, survival, and caregiver burden. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. The literature search identified 52 relevant studies to inform the evidence base for this guideline. Evidence-based recommendations address the integration of palliative care in oncology. Oncology clinicians should refer patients with advanced solid tumors and hematologic malignancies to specialized interdisciplinary palliative care teams that provide outpatient and inpatient care beginning early in the course of the disease, alongside active treatment of their cancer. For patients with cancer with unaddressed physical, psychosocial, or spiritual distress, cancer care programs should provide dedicated specialist palliative care services complementing existing or emerging supportive care interventions. Oncology clinicians from across the interdisciplinary cancer care team may refer the caregivers (eg, family, chosen family, and friends) of patients with cancer to palliative care teams for additional support. The Expert Panel suggests early palliative care involvement, especially for patients with uncontrolled symptoms and QOL concerns. Clinicians caring for patients with solid tumors on phase I cancer trials may also refer them to specialist palliative care.Additional information is available at www.asco.org/supportive-care-guidelines.

Impact of Palliative Care Referrals on End-Of-Life Outcomes in Patients with Advanced Hematologic Malignancies

Impact of Palliative Care Referrals on End-Of-Life Outcomes in Patients with Advanced Hematologic Malignancies

Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome

AbstractIvosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor and has shown efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia populations. We report final data from a phase 1 single-arm substudy of patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Oral ivosidenib was taken once daily on days 1 through 28 in 28-day cycles. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion–dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant by data cutoff. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in patients with mIDH1 R/R MDS. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study

CD123 “expression” is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin’s lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

Metronomic chemotherapy in hematology: Lessons from preclinical and clinical studies to build a solid rationale for future schedules

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.

Abstract CT160: A phase I trial to evaluate allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells in subjects with advanced solid tumors or hematological malignancies (the ANGELICA Trial)

Abstract Background: Adoptive cellular therapy (ACT) has been transformative in the treatment of hematological malignancies. Limitations of ACTs include difficulty identifying suitable tumor antigens for solid tumors, the ability to target only one antigen per construct which commonly results in secondary resistance due to antigen escape, and largely autologous approaches which are challenging in heavily pre-treated patients with poor marrow function and those with rapidly progressive disease who may not receive their personalised cellular products in time. This is a phase I study evaluating a novel off-the-shelf allogenic mRNA-electroporated NKG2D ligand-targeting CAR-grafted γδ T cell therapy. NKG2DLs are a group of 8 types of stress-induced cancer antigens which are preferentially and widely expressed on tumor cells from diverse tissue origins but are not typically present on normal tissue. NKG2DL-targeting γδ T cells will be manufactured from peripheral blood mononuclear cells isolated from healthy donors enrolled on the donor protocol of the ANGELICA trial. ANGELICA is a phase I study evaluating the safety, tolerability and recommended phase 2 dose (RP2D) of NKG2DL-targeting CAR-grafted γδ T cells in patients with treatment refractory tumors. Methods: Patients will be enrolled in a 3+3 design. Dose escalation will be performed at 3 dose levels: 1x108, 3x108 and 1x109 per infusion (adjusted for body weight). Lymphodepletion with fludarabine 25mg/m2/day and cyclophosphamide 250mg/m2/day will given for 3 days and completed at least 2 days prior to the first cycle of treatment. Patients will receive 4 doses of weekly infusions for the first cycle, with up to 5 subsequent infusions every 2 months as maintenance. Patients will receive intravenous zoledronic acid 1mg prior to each cellular infusion and subcutaneous IL-2 1x106 IU/m2 within 2 hours of each cellular infusion as pre-clinical data demonstrated cancer cell sensitisation and prolonged γδ T cell survival with these adjuncts. Dose-limiting toxicities will be assessed over the first 8 weeks. Adverse events, response rates (RECIST v1.1), survival outcomes and immunomonitoring (immune cell phenotyping and serum cytokine analysis) will be assessed. The trial is currently enrolling healthy donors; enrolment of patients at the first dose level will begin in February 2024. NCT05302037 TABLE 1: NAND Dose Level and Schedule Dose Level Dose per infusion Infusion schedule Number of patients 1 Weight 65kg and above: 1x108.Weight less than 65kg: 1.5x106. Cycle 1: weekly x 4 infusions. Maintenance phase: 2-monthly x 5 infusions. 3-6 2 Weight 65kg and above: 3x108.Weight less than 65kg: 4.6x106. 3-6 3 Weight 65kg and above: 1x109.Weight less than 65kg: 1.5x107. 3-6 Citation Format: Joan Choo, Wee Kiat Tan, Lucas Luk, Jieming Zeng, Teck Guan Soh, Sou Yen Soon, Jedidah Lieow, Calista Wong, Mei Yan Pang, Sudipto Bari, Michelle Poon, Liang Piu Koh, Wee Joo Chng, Anand Jeyasekharan, Lip Kun Tan, Esther Chan, Raghav Sundar. A phase I trial to evaluate allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells in subjects with advanced solid tumors or hematological malignancies (the ANGELICA Trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT160.

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

Palliative care for patients with hematologic malignancies in Germany: a nationwide survey on everyday practice and influencing factors from the perspective of treating physicians

Integrating palliative care into the treatment of patients with advanced hematological malignancies (HM) remains challenging. To explore treating physicians’ perspectives on current palliative care practice and to evaluate factors influencing integration, we conducted a nationwide online survey. Based on literature and expert review, the survey addressed the importance of palliative care, communication about life-threatening conditions, challenges in establishing goals of care, and factors influencing the integration of palliative care. 207 physicians treating patients with HM in Germany participated. We used standard descriptive statistics to analyze quantitative data and a content structuring approach. Most physicians considered palliative care in HM to be very important (60.6%) and discussed life-threatening conditions with more than half of their patients (52%), especially when goals of care were changed (87.0%) or when patients raised the topic (84.0%). Disease-related factors, different professional perspectives on prognosis, and patient hopes were the main barriers to changing goals of care, but collaboration with colleagues and multidisciplinary teams provided important support. Time constraints were identified as the main barrier to integrating palliative care. The majority worked well with palliative care teams. Referral processes and conditions were perceived as minor barriers. The study highlights the need to address barriers to integrating palliative care into the management of patients with advanced HM. Future research should aim at optimizing palliative care for patients with HM.

Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPα That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies.

Increasing the phagocytotic capabilities of tumor-associated macrophages by modulating macrophage-tumor cell surface signaling via the CD47-SIRPα axis is a novel strategy. Molecules targeting CD47 have potential but its ubiquitous expression necessitates higher therapeutic doses to overcome potential antigen sink effects. The restricted expression pattern of SIRPα may limit toxicities and lower doses of the SIRPα antibody BMS-986351 may overcome target mediated drug disposition while maintaining the desired pharmacology.

The experience of patients with hematological malignancy in their terminal stage: a phenomenological study from Jordan’s perspective

BackgroundPatients diagnosed with hematological malignancies residing in low-middle-income countries undergo significant physical and psychological stressors. Despite this, only 16% of them receive proper care during the terminal stages. It is therefore crucial to gain insight into the unique experiences of this population.AimTo have a better understanding of the needs and experiences of adult patients with advanced hematological malignancy by exploring their perspectives.MethodsA qualitative interpretive design was employed to collect and analyze data using a phenomenological approach. The study involved in-depth interviews with ten participants aged between 49 and 65 years, utilizing a semi-structured approach.ResultsTwo primary themes emerged from the participants’ experiences of reaching the terminal stage of illness: “Pain, Suffering, and Distress” and “Spiritual Coping.” The first theme encompassed physical and emotional pain, suffering, and distress, while the second theme was centered on the participants’ spiritual coping mechanisms. These coping mechanisms included seeking comfort in religious practices, relying on spiritual support from family and friends, and finding solace in their beliefs and faith.ConclusionPatients with hematological malignancies in the terminal stages of their disease experience severe pain, considerable physical and psychosocial suffering, and spiritual distress. While they require support to cope with their daily struggles, their experiences often go unnoticed, leading to disappointment and loss of dignity. Patients mainly rely on their spirituality to cope with their situations. Healthcare providers must acknowledge these patients’ needs and provide more holistic and effective care.

Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021

IntroductionHematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. Material and methodsThis retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. ResultsOur study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). ConclusionDonor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.

Identification of triciribine as a novel myeloid cell differentiation inducer.

Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and tolerance development of ATRA need to be improved, we searched for another efficient myeloid differentiation inducer. Kinase activation is involved in leukemia biology and differentiation block. To identify novel myeloid differentiation inducers, we used a Kinase Inhibitor Screening Library. Using a nitroblue tetrazolium dye reduction assay and real-time quantitative PCR using NB4 APL cells, we revealed that, PD169316, SB203580, SB202190 (p38 MAPK inhibitor), and triciribine (TCN) (Akt inhibitor) potently increased the expression of CD11b. We focused on TCN because it was reported to be well tolerated by patients with advanced hematological malignancies. Nuclear/cytoplasmic (N/C) ratio was significantly decreased, and myelomonocytic markers (CD11b and CD11c) were potently induced by TCN in both NB4 and acute myeloid leukemia (AML) M2 derived HL-60 cells. Western blot analysis using NB4 cells demonstrated that TCN promoted ERK1/2 phosphorylation, whereas p38 MAPK phosphorylation was not affected, suggesting that activation of the ERK pathway is involved in TCN-induced differentiation. We further examined that whether ATRA may affect phosphorylation of ERK and p38, and found that there was no obvious effect, suggesting that ATRA induced differentiation is different from TCN effect. To reveal the molecular mechanisms involved in TCN-induced differentiation, we performed microarray analysis. Pathway analysis using DAVID software indicated that "hematopoietic cell lineage" and "cytokine-cytokine receptor interaction" pathways were enriched with high significance. Real-time PCR analysis demonstrated that components of these pathways including IL1β, CD3D, IL5RA, ITGA6, CD44, ITGA2B, CD37, CD9, CSF2RA, and IL3RA, were upregulated by TCN-induced differentiation. Collectively, we identified TCN as a novel myeloid cell differentiation inducer, and trials of TCN for APL and non-APL leukemia are worthy of exploration in the future.

Abstract B002: Pharmacodynamics and antitumor mechanism of the BRG1/BRM (SMARCA4/2) inhibitor FHD-286 in a Phase 1 study in subjects with AML or MDS

Abstract BRG/Brahma-associated factors (BAF) chromatin remodeling complexes are critical to the regulation of cellular differentiation and are implicated in cancer and other diseases. FHD-286 is a first-in-class dual inhibitor of the BAF catalytic subunits BRM and BRG1 (SMARCA2/4) that is being developed for the treatment of advanced hematologic malignancies. We previously reported that extended exposure of acute myeloid leukemia (AML) cells to FHD-286 led to upregulation of the myeloid maturation marker CD11b, downregulation of BRG1, and decreased cell proliferation. Morphologic features of differentiation were also observed, suggesting that BAF functions to maintain AML cells in an undifferentiated state and that FHD-286 may inhibit AML cell growth by overcoming this differentiation block. Biomarkers identified from these nonclinical studies were analyzed in a Phase 1 dose escalation study of FHD-286 monotherapy in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS) (Study FHD-286-C-002). Flow cytometric analysis was performed on serially collected peripheral blood mononuclear cells (PBMCs) from a total of 31 subjects across 4 dose cohorts (2.5, 5, 7.5 and 10 mg once-daily). Peripheral blasts showed time- and dose-dependent upregulation of myeloid maturation markers, including CD11b and CD64, and concomitant decreases in BCL2, CD34, and BRG1. At the highest dose, substantial biomarker modulation was evident beginning at Cycle 1 Day 15 (C1D15), whereas significant modulation was not observed before C2D1 at the lower dose levels. Single cell RNA sequencing of bone marrow aspirates revealed distinct populations of blasts expressing leukemic stem cell (LSC) markers versus those expressing myeloid differentiation markers. In the majority of on-treatment bone marrow samples, blast populations expressing LSC markers were reduced, while populations expressing myeloid differentiation markers were expanded in a generally dose-dependent manner. Evidence of differentiation was also observed by morphological assessment of patient bone marrow samples. Importantly, these effects were observed in subjects with a wide range of mutation profiles, including those considered high risk. In summary, analysis of patient samples from Study FHD-286-C-002 revealed dose-dependent impacts on stemness and maturation markers in peripheral and bone marrow blasts. These results suggest that FHD-286 forces stem-like blasts to mature, possibly reducing their capacity for self-renewal, and leading to a gradual reduction in circulating blasts. Consistent with this, decreases in bone marrow and peripheral blast counts were observed across cohorts. These findings suggest combining FHD-286 with cytoreductive agents may be a promising strategy to target both LSC-like and proliferative blasts, which is supported by nonclinical data showing enhanced antitumor activity with various combination partners. Citation Format: Mike Collins, Astrid Thomsen, GiNell Elliott, Jessica Wan, Kim Horrigan, Laure Delestre, Virginie Penard-Lacronique, Stephane De Botton, Warren Fiskus, Kapil N. Bhalla, Courtney DiNardo, Samuel Agresta, Jessica Piel, Martin Hentemann. Pharmacodynamics and antitumor mechanism of the BRG1/BRM (SMARCA4/2) inhibitor FHD-286 in a Phase 1 study in subjects with AML or MDS [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B002.

Abstract A013: Leukemic stem cell differentiation visible at single-cell resolution in AML patients treated with BRG1/BRM inhibitor FHD-286

Abstract BAF chromatin remodeling complexes are critical to the regulation of cellular differentiation and are implicated in cancer as well as other diseases. FHD-286 is a first-in-class dual inhibitor of the BAF catalytic subunits BRM and BRG1 (SMARCA2/4) that is being developed for the treatment of advanced hematologic malignancies. We previously reported that exposure of acute myeloid leukemia (AML) cells to pharmacologically relevant concentrations of FHD-286 led to downregulation of leukemic stem cell (LSC) marker CD34, and upregulation of the myeloid maturation marker CD11b. Morphologic features of differentiation were also observed, suggesting that BAF functions to maintain AML cells in an undifferentiated state, and that FHD-286 may inhibit AML cell growth by reducing their capacity for stem cell renewal. Using single-cell transcriptomic data, we further assessed the impact of FHD-286 on differentiation markers of tumor cells from clinical AML patients. scRNA-seq data was obtained for 26 bone marrow aspirate samples from 11 AML and 2 myelodysplastic syndrome (MDS) patients from the Phase 1 clinical study evaluating FHD-286. Non-tumor cell types (T-cells, erythroid, B cells, megakaryocytes) were identified using published gene markers and removed from the dataset, leaving only tumor cells enriched for either LSC markers (CD34, CD123) or CD11b. We next identified differentially expressed genes between patient LSCs and CD11b+ cells. The top 50 genes associated with each cell group were taken as signature markers of stemness or differentiation, and their mean expression used as phenotypic scores for all patient tumor cells. Clustering analysis of the patient single-cell data showed that cells grouped according to cell type, treatment timepoint, and patient identity. Tumor cells expressing LSC markers CD34 and CD123 clustered separately from those expressing differentiation marker CD11b, and the relative percentage of CD11b+ tumor cells increased on treatment for 8 out of 12 patients dosed at &amp;gt;=5mg, consistent with preclinical AML models. Differential expression analysis revealed additional genes upregulated in either LSCs or CD11b+ cells, which were identified in literature as markers of stemness or myeloid differentiation, respectively. Single-cell LSC and differentiation signature scores showed a strongly statistically significant shift away from LSC identity and toward differentiation for 10 out of 12 patients. Single-cell RNA data from AML patients validates the preclinical observation that FHD-286 treatment induces changes in LSCs resembling differentiation towards a terminal myeloid cell state. This dataset further indicates that nearly all patients undergo some degree of tumor cell differentiation after treatment, suggesting broad on-target activity of FHD-286. Citation Format: GiNell Elliott, Jessica Wan, Kim Horrigan, Mike Collins, Astrid Thomsen, Ashley K Gartin, Ammar Adam, David L Lahr, Gabriel Sandoval, Sameul Agresta, Jessica Piel, Martin Hentemann. Leukemic stem cell differentiation visible at single-cell resolution in AML patients treated with BRG1/BRM inhibitor FHD-286 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A013.

Results from the Cohort-Expansion Stage of a Phase I Trial of Tinostamustine Monotherapy in Advanced Hodgkin Lymphoma (HL), Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) (NCT02576496)

Background Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Tinostamustine was well tolerated, with signals of efficacy, during the dose-escalation stage of a Phase I study in patients with relapsed/refractory (R/R) haematological malignancies (Zinzani et al. HemaSphere 2019;3(S1):102:PF300) and for patients with HL in the cohort-expansion stage (Ghesquières et al. Blood 2021;138(S1):2472; Sureda et al. Blood 2022;140(S1):3696). Aims We report safety and efficacy findings from patients with advanced haematological malignancies including HL, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), T-cell prolymphocytic leukaemia (T-PLL) and MM treated with tinostamustine in the expansion cohorts of a Phase I study. Methods Patients with advanced haematological malignancies, for whom no standard treatment with proven clinical benefit was available or recommended, were recruited to receive the recommended Phase II dose of tinostamustine. Patients with HL must have received ≥2 lines of prior therapy, CTCL 1-4 prior standard systemic therapies, PTCL &amp;gt;1 prior line of combination therapy, T-PLL ≥1 prior line of therapy and MM ≥1 prior systemic therapy. Adverse events (AEs) were assessed for severity using US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03, June 2010; for QTc prolongations CTCAE version 5.0 was used). Treatment-related AEs, fatal AEs, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Primary efficacy objectives were to estimate the overall response rate (ORR; complete response [CR] + partial response [PR]) and clinical benefit rate (CBR; CR + PR + stable disease ≥4 cycles [SD]) for each cohort and to evaluate the safety of tinostamustine. Secondary efficacy variables included progression-free survival (PFS) and overall survival (OS); all outcomes were evaluated from Cycle 3 until progression or toxicity. Results 48 patients with advanced haematological malignancies were enrolled to the study and received treatment with tinostamustine (HL, n=20; CTCL, n=13; PTCL, n=8; T-PLL, n=1; MM, n=6; Table). Patients with HL, CTCL, PTCL and T-PLL received 50 mg/m 2 (1 patient), 80 mg/m 2 (7 patients) and 100 mg/m 2 (34 patients) over 60 minutes on Day 1 of a 21-day cycle; patients with MM: 60 mg/m 2 over 60 minutes on Day 1 and Day 15 of a 28-day cycle. Patients received a median of 3.5 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed. Treatment-emergent AEs (TEAEs) occurred in 46/48 (95.8%) patients (500 events), with 28 patients experiencing 90 events ≥Grade 3. Gastrointestinal AEs were observed in 33/48 patients, the majority of which were nausea or vomiting. Haematological AEs, including thrombocytopenia, anaemia and neutropenia, occurred in 27/48 patients. Serious TEAEs considered related to tinostamustine occurred in 11 patients with HL or CTCL ( Table) and included thrombocytopenia (n=3) and infusion-related reaction (n=1); one patient with CTCL experienced a fatal TEAE of decreased appetite. Overall, 22/48 (45.8%) patients discontinued due to progressive disease and 13/48 (21.6%) discontinued due to AEs. In the 46 patients included in the efficacy analysis, ORR was 30.4% (95% confidence interval [CI]: 17.7%, 45.8%) and CBR 52.2% (95% CI: 36.9%, 67.1%). 4 patients achieved a CR (2 patients with HL, 2 CTCL), 10 a PR (5 HL, 4 CTCL, 1 PTCL) and 14 SD (4 HL, 4 CTCL, 3 PTCL, 3 MM). Median PFS was 4.3 months (95% CI: 2.7, 6.6 months; HL, 3.8 [2.2, 9.4] months; CTCL, 7.3 [3.2, not estimable (NE)] months; PTCL, 2.6 [1.4, NE] months; T-PLL, 0.5 [NE, NE] months; MM, 2.4 [1.4, NE] months;). Median OS was 10.3 (95% CI: 2.2, NE) months for PTCL, 5.6 (95% CI: NE, NE) months for T-PLL and not estimable for HL, CTCL and MM. Conclusions Results from expansion cohorts further demonstrate that tinostamustine has manageable tolerability in patients with advanced haematological malignancies with no unexpected AEs. The principal TEAEs were haematological and gastrointestinal. An ORR of 30.4% and a median progression-free survival of 4.3 months were observed, revealing signals of efficacy in this heavily pre-treated patient population for whom no other standard therapy with proven clinical benefit was available or recommended. Funding: Mundipharma Research Limited and Purdue Pharma, LP

A Novel PI3K γ/δ and DNA-PK Triple Inhibitor, BR101801, for r/r PTCL: A Phase 1a/b, Multi-Center, Open-Label Clinical Trial

Background BR101801, a triple inhibitor of PI3Kγ/δ and DNA-PK, inhibits not only the signal affecting cell growth caused by PI3Kγ/δ but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation, with this triple target inhibition it decreases the stability of oncogenic protein, c-Myc (AACR2020 abstract #655). BR101801 is currently being evaluated in a phase 1a/b study in advanced hematologic malignancies. In phase 1a study, BR101801 exhibited evidence of clinical activity and was established at 200mg orally once daily 28-day cycle (RP2D) in patients with r/r PTCL (ASCO2023 abstract #7551). Methods This is a phase 1, open-label, multi-center, dose escalation (1a), and expansion (1b) study of BR101801 in adult patients with advanced hematologic malignancies (NCT04018248). In the phase 1a study, Dose was escalated at 50, 100, 200 and 325 mg QD. PTCL-NOS, AITL, FTCL and Nodal PTCL with TFH phenotype were determined as target indications for phase 1b with the RP2D. Results As of Jul 19, 2023, a total of 26 patients were enrolled in dose-escalation phase (n=12) and dose-expansion phase (n=14). The median age was 66 years (range of 30-83). Histological subtypes include PTCL-NOS (n=11, 42%), AITL (n=11, 42%), DLBCL (n=2, 8%), MZL (n=1, 4%) and MF (n=1, 4%). The majority of patients had stage III or IV (92%). In the phase 1a study, Dose limiting toxicity (DLT) occurred at 325 mg; thus, 200 mg QD was determined as the maximum tolerated dose (MTD) and RP2D. Of 19 evaluable patients with r/r PTCL (PTCL-NOS and AITL) in the phase 1 study. Patients' stage was III or IV (100%) with 47.4 % of patients having received three or more prior systemic therapies. The ORR was 31.6% (95% CI, 12.6-56.6) with 4 CRs (21.1%) and 2 PRs (10.5%), CBR was 47.4% (95% CI, 24.5-71.1). In median follow-up duration of 12.9 months, the median PFS was 7.5 months (95% CI, 1.7-NC), median OS and DoR (range of 1.9+-31.8+) has not reached. Currently, 5 patients still remain on treatment. Safety analysis was conducted for the 26 patients; 23 patients (88.5%) experienced adverse events (AEs). The most common (≥ 20%) AEs were Rash (23.1%), AST increased (23.1%), ALT increased (23.1%) and Cough (23.1%). Grade 3/4 ADRs occurred in 12 patients (46.2%) and those were (≥ 10%, frequency) AST increased (19.2%), ALT increased (15.4%), Neutropenia (15.4%). There were no treatment related mortality observed. Conclusion BR101801, the triple inhibitor of PI3K γ/δ and DNA-PK, demonstrated as a promising therapeutic option for r/r PTCLs patients. Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial

Background: Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419). Methods: Module 1, Part A of NIMBLE is a dose-escalation study of AZD0466 monotherapy investigating its preliminary safety and tolerability, pharmacokinetics (PK), and preliminary efficacy. Dose escalation and de-escalation of AZD0466 follow a modified toxicity probability interval (mTPI-2) design. Eligible pts are ≥18 years old with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome. AZD0466 is administered IV with a dose ramp-up on Days (D) 1, 4, and 8, reaching the target dose on D8 of Cycle 1, with weekly administrations thereafter. Cycle duration is 35 days for Cycle 1 and 28 days for subsequent cycles. Pts remain on study until disease progression, unacceptable toxicity, or withdrawal of consent. Resul ts: As of May 31, 2023, 31 pts (n=25 AML, n=6 ALL; median age 69 years) had received ≥1 dose of AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), 1200 mg (n=7), 2400 mg (n=5), 3600 mg (n=9), and 5400 mg (n=2). Median treatment duration was 4.1 weeks (range 0.1−29.6). Twenty-two pts (71%) had prior VEN and 11 (35%) had prior hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of any grade reported in &amp;gt;10% of pts are displayed in Table 1. One Grade 5 intracranial hemorrhage unrelated to AZD0466 was reported. Four pts experienced a serious adverse event (SAE) possibly related to AZD0466 (alanine aminotransferase [ALT] increase, pneumonia, troponin T increase, and uncoded SAE). Grade ≥3 TEAEs possibly related to AZD0466, reported in 12 pts (39%), included febrile neutropenia (n=3), platelet count decrease (n=2), diarrhea, thrombocytopenia, ALT increase, blood creatinine phosphokinase increase, pneumonia, gamma-glutamyltransferase increase, lipase increased, and troponin T increase (n=1, each). DLTs of asymptomatic troponin increase were observed in two pts (3600 mg [n=1], 5400 mg [n=1]). Evaluation of maximum concentration and area under the concentration-time curve revealed dose-proportional exposure to AZD4320. Released AZD4320 represented 1-5% of total AZD4320 and had a longer half-life than total AZD4320. Preclinical modeling and PK data predicted that 5400 mg may be required to drive efficacy. As a surrogate of BCL-xL on-target activity, transient aggravation of thrombocytopenia post-dosing was observed across all dose cohorts followed by platelet recovery prior to the next dose. Platelet reduction was in line with preclinical models showing a substantial reduction at lower doses with a ceiling effect at higher doses. As of July 6, 2023, no complete responses have been observed. However, preliminary bone marrow (BM) blast reductions of &amp;gt;50% were observed in four pts (1200 mg [n=1], 2400 mg [n=2], 3600 mg [n=1]), indicating antileukemia activity of AZD0466. Conclusions: Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of &amp;gt;24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.