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Background: Aberrant overexpression of pro-survival Bcl-2 family proteins is one mechanism by which leukemic cells circumvent apoptosis. BCL-2 overexpression is common in various subtypes of B-acute lymphocytic leukemia (ALL), including Philadelphia (Ph)-like ALL. Ph-like ALL is a chemotherapy-resistant disease associated with higher rates of induction failure and persistent measurable residual disease (MRD), and poor overall survival (OS) outcomes with frontline chemotherapy regimens, compared to other subtypes. Venetoclax (VEN) is a selective BCL2 inhibitor, and its addition to pediatric-type frontline regimens could improve response and long-term outcomes for B-ALL, including Ph-like subtype.

Background

Background:Mutations in FLT3 (FLT3m), either internal tandem duplication (ITD) or tyrosine kinase domain (TKD) are found in approximately 25% of AML patients. The current standard of care for eligible patients is induction chemotherapy with 7 + 3 regimen with the addition of multikinase inhibitor midostaurin, based on CALGB 10603 which enrolled patients up to 59 years of age (Stone et al; NEJM 2017). Quizartinib recently demonstrated improved overall survival (OS) compared to placebo when combined with standard 7+3 induction in patients up to 75 years of age, although the benefit in patients 60 and above was less clear (Erba et al; Lancet Oncol 2023). We sought to review the clinical outcomes among patients 60 years of age or greater at our institution for who received midostaurin with 7+3 for newly diagnosed (ND) FLT3m AML.

Background

INTRODUCTION:Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively.

Relapse of primary hematologic malignancy remains the leading cause of treatment failure afterallogeneic Hematopoietic cell transplantation (allo-HCT). Multiple studies have shown that presence of measurable residual disease (MRD), at the time of HCT, irrespective of the detection method, is associated with lower overall survival (OS) and relapse-free survival (RFS). In a recent meta-analysis of 11,151 patients with AML, Short et al., reported 5-year disease-free survival (DFS) of 25% for patients who have detectable MRD pre -HCT, compared to 64% for those without MRD. The 5-year OS was 34% and 68% for patients with or without MRD at HCT (JAMA Oncology 2020). In AML patients with genomic evidence of MRD before allo-HCT, myeloablative conditioning (MAC) regimens result in improved survival when compared to reduced intensity conditioning (RIC); (Hourigan et al, JCO 2020). Our center has pioneered and developed Total marrow and lymphoid irradiation (TMLI) that allows for delivery of higher dose of radiation to the sites with high disease burden (bone marrow and lymphoid organs), while sparing healthy tissues. In an ongoing Phase 2 trial (NCT02094794), we delivered TMLI (20Gy) with high dose chemotherapy to patients with high-risk leukemias (ALL or AML) undergoing allo-HCT from an HLA matched or mismatched donor. Here, we report on the results of our prospective analysis on a subset of patients of NCT02094794 who underwent allo-HCT with morphologic remission but had detectable MRD status in their pre HCT bone marrow biopsy (n=30).

Background

Background

Introduction:Fludarabine/melphalan (F/M) conditioning is associated with superior disease-free survival (DFS) compared to busulfan-based reduced-intensity conditioning (RIC) regimens in patients with AML/MDS undergoing allogeneic hematopoietic cell transplantation (alloHCT). A recent CIBMTR analysis in AML patients reported 5-year OS, cumulative incidence of Relapse (CIR) and NRM of 29%, 36% and 36% respectively after F/M conditioning when Tac/MTX was used for graft-vs-host disease (GVHD) prophylaxis (Blood Adv 2020). At City of Hope (COH), tacrolimus and sirolimus (T/S)-based GVHD prophylaxis has been used in patients undergoing HLA-matched sibling and unrelated donor alloHCT, based on the results of a phase 2 study by Rodriguez et al (Blood 2010). Here, we retrospectively reviewed clinical outcomes of 409 consecutive AML patients who underwent RIC alloHCT at COH from 2008-2019 with F/M conditioning and T/S-based GVHD prophylaxis. The primary objective was to assess long term survival outcomes and associated risk factors adjusted for secular trends in patient demographics undergoing alloHCT over time.

Background:CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase Polo-like kinase 4 (PLK4), a unique Polo-like kinase family member, that is a conserved upstream regulator of centriole duplication. Dysregulation of PLK4 expression causes loss of centrosome numeral integrity, promotes genomic instability and also potentially enables cancer cells to tolerate genomic instability (Mason et al, Cancer Cell 2014). Its inhibition likely causes mitotic catastrophe. An investigator-initiated study (IIS) demonstrated clinical activity in relapsed/refractory AML with adverse cytogenetics. Dose limiting toxicity was colitis, sepsis and the RP2D 96 mg, three CR's (9 evaluable pts) across 2 dose levels were observed [Data on File, Murphy et al]. We report updated data on a company sponsored study (TWT-202; NCT04730258).

Background

Background: Ph-like ALL is a high-risk subset of B-lineage ALL that responds poorly to standard chemotherapy regimens. While allogeneic hematopoietic cell transplantation (HCT) is routinely recommended for patients with Ph-like ALL, large multicenter data addressing its role is limited. Here, we conducted a multicenter study to evaluate the role of HCT in adolescent and young adult (AYA) and adult patients (pts) with Ph-like ALL and compare their outcomes to pts with Ph-pos and Ph-neg (non-Ph-like) ALL.

Introduction:CD19-targeted chimeric antigen receptor (CD19CAR) T cell therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR T cell therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). However, available data for post CAR T alloHCT in r/r B-ALL are limited, especially for the role of the second alloHCT post CAR T response among patients (pts) who relapsed following their first alloHCT.

Background

INTRODUCTION:Tuspetinib is a potent once daily oral myeloid kinase inhibitor of SYK, FLT3, JAK1/2, RSK1/2, mutant KIT, and TAK1-TAB1 kinases that mediate dysregulated cellular proliferation in AML. In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib is being evaluated clinically as monotherapy (TUS) and in combination (VEN/TUS) in a global Phase 1/2 trial of patients with R/R AML.

Background:FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival.

Background:Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curable treatment option for several hematological malignancies. Preparative and graft-versus-host disease (GVHD) prophylactic regimens combined with graft-versus-leukemia effect (GVL) are important in preventing graft rejection, disease relapse and GVHD; and subsequently impact the success of this life saving procedure. Choice of regimen depends on patient, donor/graft source and disease characteristics.

Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR] = 3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR = 2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR = 0.55; 95% confidence interval [CI] = 0.28-1.06, P = .08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR = 0.56; 95% CI = 0.25-1.22, P = .19). Cumulative incidences of day 100 acute GvHD grades II-IV (P = .97) and grades III-IV (P = .47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P = .05). Rates of NRM (P = .66), relapse (P = .83), disease-free survival (P = .86), and overall survival (P = .73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

Post-transplantation cyclophosphamide (PTCy) has improved hematopoietic stem cell transplantation outcomes for patients with major HLA disparities. Although PTCy in combination with calcineurin inhibitors is a successful graft-versus-host disease regimen, giving high doses of cyclophosphamide may cause hemorrhagic cystitis (HC). The strategies used to prevent HC are adapted from published data in the pre-transplantation conditioning setting. However, there is no consensus on what the optimal strategy is to prevent PTCy-associated HC. This review provides a summary of the different preventative strategies used in this setting. Based on the results published in current literature, hyperhydration is an effective preventative strategy, but it may cause fluid overload and other complications. Additionally, mesna at least 100% of the PTCy dose should be administered as a continuous infusion or frequent intermittent bolus infusion. More comparative studies between these strategies are needed to provide a definitive solution for preventing HC associated with PTCy.

Presents a letter to the editor about access arrangements for public exams in Great Britain.