TPS6589 Background: FLT3 mutations occur in 25-35% of AML and result from an internal tandem duplication (ITD) of amino acids in the juxtamembrane domain of FLT3 kinase or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased relapse, shorter remission, and decreased disease-free and overall survival. BMF-500 is a novel oral, highly potent and selective covalent inhibitor of FLT3 including wild-type (WT), ITD, TKD, and resistance mutations (e.g., gatekeeper F691). BMF-500 has high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing despite drug washout (Law et al., ASH 2022 Abst 2756). BMF-500 shows sustained tumor regression and improved survival in subcutaneous and disseminated xenografts of FLT3-m AML. Methods: COVALENT-103 (NCT05918692) is a multicenter, first-in-human study evaluating the safety, tolerability, and antileukemic activity of escalating doses of daily BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3-m. The trial has 2 arms that dose escalate in parallel: Arm A (without) and Arm B (with) concomitant use of a CYP3A4 inhibitor. Using an accelerated titration design (ATD), doses of BMF-500 are escalated in single-subject cohorts until one subject experiences ≥Grade 2 related adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may enroll up to 33% per arm. Treatment continues in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care, including hematopoietic stem cell transplant (HSCT). FLT3-positive AML patients must have received a FLT3 inhibitor approved for R/R FLT3-m AML. Additional inclusion criteria include ECOG PS ≤2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease, clinically significant cardiovascular disease, and WBC >50,000/µL (uncontrollable with cytoreductive therapy). The primary objective is to evaluate safety and tolerability and determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 monotherapy based on available pharmacokinetic/pharmacodynamic (PK/PD), safety and efficacy data. Secondary objectives include characterization of the PK/PD of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. The study was initiated in July 2023, is currently in dose escalation, and we plan to enroll approximately 110 patients total. Clinical trial information: NCT05918692 .
The combination of hypomethylating agent (HMA) azacytidine with venetoclax (HMA+Ven) was compared to azacytidine monotherapy in the recent multicentre phase III VIALE-A trial in patients with newly diagnosed acute myeloid leukaemia (AML) unfit for intensive chemotherapy either due to age (≥75 years) or comorbidities. The composite complete remission (CR) rate was 66·4% versus 28·3% in the study arm versus azacytidine alone (P < 0·001) with median overall survival (OS) of 14·7 versus 9·6 months (P < 0·001) in favour of the HMA+Ven arm. Based on these results, the combination of HMA+Ven is now United States Food and Drug Administration (FDA) approved for upfront treatment in the elderly AML population.1, 2 Given the inclusion criteria for enrolment on this study, patients were not eligible for allogeneic haematopoietic cell transplantation (allo-HCT), hence data regarding allo-HCT data after HMA+Ven induction is limited.3 We therefore analysed the clinical outcomes of 51 patients aged ≤74 years treated at our centre with HMA+Ven induction (2018–2020) to evaluate its performance in this age group and the clinical outcomes of patients, and evaluate the outcomes in patients who subsequently underwent HCT in remission. Response criteria from CR and CR without haematological recovery (CRi) were defined per standard International Working Group (IWG) AML response criteria.4 The primary end-point was defined as composite CR rate (cCR: defined as patients achieving CR +CRi). Minimal residual disease (MRD) assessment was done on post-induction bone marrow aspirate using multiparametric flow cytometric assessment with lower limit of sensitivity being 0·01%.5 The secondary end-point of OS, was defined as the time from the start of the therapy with either HMA+Ven to death and patients were censored if alive at the last follow-up. Leukaemia-free survival (LFS) among patients with CR/CRi was defined as the time interval from the date of response to relapse or death, whichever occurred first, and patients were censored at the last follow-up if still leukaemia free. Patients’ demographic, cytogenetic and molecular features are summarised in Table I. The majority of patients were European LeukemiaNET (ELN) adverse risk (69%; 35/51) and remaining (31%; 16/51) were good/intermediate risk. Physician rationale for choosing HMA+Ven were as follows: diagnosis of secondary AML (21 patients); age ≥70 years (nine); comorbid conditions at diagnosis (nine); poor performance status at diagnosis (six), concurrent second malignancy (five) and adverse risk cytogenetics (one). Among the nine patients with comorbidities at presentation, four had chronic kidney disease [including one with end-stage renal disease on dialysis], cardiac comorbidities (two), prior cerebrovascular accident (two) and one was intubated when induction chemotherapy with HMA+Ven was started. The cCR rate in patients treated with HMA+Ven was 68·6% (35/51), CR was seen in 21·5% (11/51) and CRi in 47% (24/51) of the patients (Table II). MRDneg remission was seen in 45% of the patients (23/51). With a median (range) duration of follow-up of 11·7 (0·6–40·6) months for all patients, the 1-year OS was 58% [95% confidence interval (CI) 43–70] and the median OS was 19·4 months (95% CI 6·8–26·2). The cCR rates were 55% in ELN adverse risk and 80% in ELN intermediate/good risk categories. In all, 16 patients presented with tumour protein p53 (TP53) mutation, of whom cCR was achieved in eight (50%). In patients with secondary AML (sAML), the cCR was 67% (21/31) with 48% (15/31) achieving MRDneg remission. In the de novo AML group (20 patients), the cCR was 65% (13/20) with MRD neg remission rate of 45% (nine of 20). A total of 25 patients (49%) eventually proceeded to allo-HCT after induction with HMA+Ven. This included 21 patients who achieved cCR with HMA+Ven and four who were refractory to HMA+Ven and received alternative salvage therapy and allo-HCT in remission (three) and one was transplanted with active disease on study. These four patients were excluded from final analysis. Of the 21 allo-HCT recipients 12 had sAML (38%; 12/31) and nine presented with de novo AML (45%; nine of 20). Pre-HCT MRDneg status was achieved in 71·4% of the patients (15/21). All patients received reduced-intensity conditioning with fludarabine and melphalan and received peripheral blood stem cells grafts from human leucocyte antigen matched unrelated donors. The median LFS for HCT patients was not achieved, compared to 7·8 months (95% CI 2·0–13·9) for non-HCT patients in cCR. The 1-year LFS in patients who underwent HCT (21 patients) was 67% (95% CI 41–84%) versus 33% (95% CI 10–57%) in non-HCT patients in cCR (14 patients). The 1-year OS for HCT patients (21 patients) was 85% (95% CI 61–95%) compared to 41% (95% CI 16–65%) in non-HCT patients in cCR (14 patients). The non-relapse mortality (NRM) at day 100 and 1 year was 12% (95% CI 4–35%). The reasons for not proceeding to allo-HCT in remission were advanced age (five patients, mean age 72·8 years), concurrent non-haematological cancer (four) and comorbidities (five). Poor outcomes were seen in patients who did not achieve remission with HMA+Ven or allo-HCT, the median follow-up was 3·5 months and the 1-year was OS 8% in this very high-risk group. Early mortality due to sepsis/infectious complications was seen in three patients, resulting in 28-day induction mortality rate of 5·8%. All three patients with induction mortality were included in the final analysis for the intent-to-treat analysis. On longer follow-up, 21 more patients died due to relapsed AML (nine patients), sepsis (five), fungal pneumonia (five), congestive heart failure (one) and unknown cause (one). In this retrospective analysis, we report the real-world outcomes in patients with AML who received treatment with HMA+VEN in the frontline setting followed by allo-HCT. In our study population, which was enriched for patients with adverse cytogenetic and molecular features, we saw a very promising cCR rate of 68% with median LFS not reached for CR1 patients, an OS of 19·4 months and low rate of induction mortality of 5·8%. MRDneg remissions of 45% in all patients and 71% in allo-HCT recipients consistent with the known mechanism of action of B-cell leukaemia/lymphoma 2 (BCL-2) inhibitors in targeting the leukaemia stem cell.6 In 41% patients who underwent allo-HCT, the NRM at day 100 was 12% and the 1-year LFS/OS was 67%/85% (Fig 1). In conclusion, our report shows that in patients with newly diagnosed AML, upfront treatment with HMA+Ven is associated with high cCR and low induction mortality and excellent post allo-HCT outcomes. This suggests that HMA+Ven may be an effective regimen prior to transplant in patients with AML. Amandeep Salhotra and Vinod Pullarkat designed the research study and wrote the manuscript. Ni-Chun Tsai and Jianying Zhang performed statistical analysis. Remaining authors (Dat Ngo, Ahmed Aribi, Karamjeet Sandhu, Brian Ball, Monzr Al-Malki, Haris Ali, Paul Koller, Andrew Artz, Stephen Forman, Ryotaro Nakamura, Anthony Stein, Guido Marcucci and Ibrahim Aldoss) critically reviewed the manuscript. All authors approve of the submitted final version. Amandeep Salhotra has research funding from Bristol Myers Sqibb and Advisor for Kadmon. Anthony Stein serves on the speaker bureau for Stemline, Amgen and Celgene, and on advisory boards for Stemline and Amgen. Guido Marcucci is a member of the speakers’ bureau for AbbVie and Novartis and serves on advisory board with Janssen Pharm. Vinod Pullarkat has served on the advisory boards for AbbVie and Jazz Pharmaceuticals and is member of speakers’ bureau for Jazz, Amgen, Novartis and AbbVie. Ibrahim Aldoss has served on advisory boards with AbbVie, Amgen, KiTE pharmaceuticals, Agios, consultant for Autolus and Amgen, speaker for Jazz Pharmaceuticals. The remaining authors have no relevant conflict of interest to declare.
The standard first-line treatment for acute graft-versus-host disease (aGvHD) is systemic, high-dose glucocorticoids which have historically had limited responses. Combined cytokine blockade therapy (CCBT) with the monoclonal antibodies infliximab (a TNF-α inhibitor) and basiliximab (an IL-2 receptor blocker) has had limited discussion in the literature.
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.
Abstract Allogeneic hematopoietic cell transplantation (alloHCT) is the only potentially curative modality for primary and secondary myelofibrosis (MF) due to other myeloproliferative neoplasms. However, alloHCT in MF is complicated by cardiopulmonary comorbidities that frequently exist in these patients, which in turn translates into higher non relapse mortality (NRM). We describe a syndrome of pulmonary infiltration and respiratory compromise (pulmonary engraftment syndrome, PES) that occurred at time of engraftment in patients undergoing alloHCT for MF. Eighteen of 83 (22%) patients experienced PES as defined and radiologic findings included ground glass opacities, consolidation or pulmonary nodularity. Only a third of patients had other features of engraftment syndrome. Pulmonary arterial hypertension was associated with occurrence of PES (Odds ratio 3.68 [95% CI 1.13,12; P = 0.04]). There was no association of PES with pre HCT pulmonary function testing or imaging. Hypoxemia occurred in 15 of 18 patients. Although 44% of the 18 patients who developed PES required intensive care and 40% required mechanical ventilation, all patients responded to supportive management and treatment with corticosteroids. Occurrence of PES did not adversely impact overall survival or NRM. PES is a distinct syndrome that occurs after alloHCT for MF and is associated with significant morbidity making its early recognition important.
Introduction Hemorrhagic cystitis (HC) is an early complication after hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy). Hyperhydration can reduce HC, but may lead to fluid overload (FO), which has been associated with higher non-relapse mortality (NRM) after HCT. Methods The objectives of this study were to grade FO between days 3 and 8 based on weight gain, diuretic therapy, and FO-related organ dysfunction and analyze the impact of FO on non-relapse mortality (NRM) and subsequently on overall survival (OS) of patients undergoing HCT with PTCy-based GvHD prophylaxis. Results Two hundred seventy-five patients who received PTCy at City of Hope from 2009 to 2018 were included. A majority, 270 (98%) patients were diagnosed with early FO from day 3-8 post HCT, of whom 248 (92%) experienced mild to moderate (grade 1-2) FO, and 22 (8%) experienced severe (grade 3-4) FO. Day 100 NRM was significantly higher in patients with grade 3-4 FO compared to patients with grade 0-1 (59.1 vs 1.7%, CI: 0.006-0.053p<0.001) and grade 2 (59.1 vs 8.8%, CI: 0.043-0.178, p<0.001) FO. At 2 years, OS and DFS were significantly lower in patients who experienced grade 3-4 FO compared to patients who had grade 0-1 FO (31.8% vs 68.2%, CI: 0.616-0.755, p<0.001) and grade 2 FO (31.8% vs 62.5%; CI: 0.527-0.741, p<0.001). Additionally, each 5% weight gain from baseline was associated with higher NRM (HR=1.91, 95%CI: 1.64-2.23, p<0.001). Conclusion Almost all patients undergoing hyperhydration for PTCy-induced HC will present with FO. Grade 3-4 FO is uncommon and associated with poor clinical outcomes. Weight gain could be used as an early and possibly modifiable indicator of FO.
