John Reynolds

In randomized studies, addition of FLT3 inhibitors failed to improve survival in older patients with FLT3-ITD AML unfit for intensive chemotherapy. Although hypomethylating agents or low-dose cytarabine combined with venetoclax is standard, FLT3-ITD is an important mechanism of resistance and a barrier to improved survival. Recent studies show promise for the addition of gilteritinib or quizartinib to less intensive venetoclax-based therapy, however resulting marrow toxicity requires substantial reductions to administered treatment. The INTERVENE study (Investigating Novel Triplets to Extend Remission with VENetoclax in Elderly AML) (ACTRN12619001655134) examined the role of midostaurin (M) administered sequentially after low-dose cytarabine (L) combined with venetoclax (V) in patients with newly diagnosed AML ≥60 years with non-adverse karyotype. After a run-in phase (n=18) established that LDAC combined with venetoclax from days 1-28 and midostaurin from days 11-28 was tolerable, 120 patients were randomized 2:1 to receive either LVM or LV. For the primary endpoint, LVM did not improve composite complete remission (CRc), compared to LV (72% vs 68%). Combining midostaurin with LV enhanced CRc among the sub-group of patients (n=29) with FLT3-ITD (82% vs 57%, difference = 25%, 0.85 posterior probability true difference > 5%, 95% CrI: -10 to 59%) and improved FLT3-ITD clearance as measured by ultrasensitive NGS (65% vs 0%), resulting in longer OS (median 24.2 vs 8.8 months, HR=0.34, 95% CrI: 0.071 to 0.960), compared to LV. In conclusion, midostaurin combined with low-dose cytarabine and venetoclax is well-tolerated and may have a role in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.

Nonrelapse mortality (NRM) in allogeneic haemopoietic stem cell transplantation (alloHSCT) is driven by acute graft-versus-host disease (aGVHD) and infection. The MAGIC algorithm probability (MAP) composite biomarker score is based on serum ST2 and REG3a levels at day (D)7 after transplantation and predicts aGVHD-related mortality. Although changes in MAP score predict aGVHD treatment response, their posttransplant predictive value and association with infection-related NRM (iNRM), independent of GVHD, are unclear. We evaluated the association of D0 to D21 MAP change (MAPΔ) vs D7 MAP with 6-month NRM (6mNRM) and developed a risk stratification model using random forest analysis and recursive partitioning. We prospectively enrolled 101 adult alloHSCT recipients from 2022 to 2024. Serum was collected weekly from D0 to D21 to derive MAPΔ. Associations with 6mNRM were assessed using generalized linear and random forest modeling. 6mNRM was 14.8%, with 80% (12/15) of deaths attributed to infection without prior aGVHD. Both MAPΔ ≥0.055 and D7 MAP ≥0.16 were significantly associated with 6mNRM (P< .0001), with MAPΔ showing superior predictive accuracy (receiver operator characteristic area under the curve 0.934 vs 0.779). In multivariable analysis, MAPΔ (odds ratio, 45; 95% confidence interval, 10.6-318; P = .01), but not D7 MAP, was an independent predictor of 6mNRM. A classification tree incorporating MAPΔ, D7 MAP, and age-adjusted comorbidity index stratified patients into low, intermediate, and high-risk groups. MAPΔ was a powerful, independent predictor of 6mNRM, which was driven by infection rather than aGVHD in this cohort. We propose a tool based on MAPΔ to assess iNRM, which may guide interventions and clinical trial design. Further validation in larger cohorts is warranted.

Acute myeloid leukemia (AML) is a polyclonal malignancy marked by high relapse rates despite initial morphologic remission. Although measurable residual disease (MRD) is an established prognostic tool, increasing evidence supports a role for preemptive, MRD-directed therapy. AML monitoring is hampered by the absence of a universal MRD marker, necessitating a more personalized approach. NPM1 is suited to an MRD-directed strategy because the mutation is AML defining and the monitoring methods are highly sensitive. Critically, rising NPM1mut levels portend clinical relapse with high fidelity, and recent studies demonstrate that venetoclax-based regimens induce rapid and deep MRD responses in a high proportion of patients with NPM1mut MRD relapse. The range of MRD-directed treatment options is expanding and includes FLT3 and menin inhibitors for MRD relapse driven by FLT3-ITD, NPM1mut and KMT2A rearrangements, respectively. To overcome the logistical issue of multiple MRD markers and associated therapies, we have developed a multitarget, multiarm platform trial named INTERCEPT. Novel features include the potential to adaptively expand the range of MRD markers and directed therapies, seamless transition of patients from a local to centralized MRD monitoring framework, a clinical decision rules approach to allocate treatment in a hierarchical and prespecified manner, creation of parallel protocol appendices to enable multiple industry partners to coexist with commercial independence, and development of approaches to minimize the time interval from “MRD relapse to treatment.” The future success of MRD-directed therapy will depend on rapid diagnostic turnaround, coordinated logistics, and innovative clinical trial designs able to keep pace with advances in MRD detection technologies and associated targeted therapies.

The purpose of this study was to explore and determine the optimal landmark for defining complete remission after intensive induction therapy that best correlates with long-term survival outcome among patients with newly diagnosed acute myeloid leukemia.

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients aged ≥65 years. In this final analysis, 85 patients (median age, 71 years) were followed up for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg and 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematologic recovery after consolidation was ameliorated by omitting idarubicin from postremission therapy. The overall response rate (ORR; complete response [CR] + CR with partial hematologic recovery + CR with incomplete count recovery) was 75%, with a median overall survival (OS) of 19.3 months (95% confidence interval [CI], 11.1-31.3). Among de novo AML, ORR was 88% and median OS was 33.1 months (95% CI, 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median, 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit, older patients with AML. This trial was registered at https://www.anzctr.org.au as #ACTRN12616000445471.

The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid and IV arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in patients with APL in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both IV and oral ATO 0.15 mg/kg per day, with exposure to oral ATO restricted to the first week in 2 of 4 ATO cycles. The primary end point was bioequivalence of area under the curve from 0 to 24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary end point. The 90% confidence intervals (CIs) around point estimates of the geometric means of the oral-to-IV ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral-to-IV ratios and 90% CIs for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral-to-IV ratio, 0.966 [0.879-1.063]). The adverse event profiles of oral and IV ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with IV ATO and offers a convenient alternative for patients with APL. This trial was registered at www.anzctr.org.au as #ACTRN12616001022459.

Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).

PURPOSE: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse. METHODS: Patients with either MRD (≥1 log₁₀ rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort. RESULTS: Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log₁₀ rise in IDH1/ 2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log₁₀ reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts. CONCLUSION: For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.

Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive, and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial–based economic evaluation from the Australian health care system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig vs prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: (1) cost-utility analysis to assess the incremental cost per quality-adjusted life year (QALY) gained; and (2) cost-effectiveness analysis to assess the incremental cost per serious infection prevented (grade ≥3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference, AU$29 140; P < .001). Most patients received IVIg, which was the main cost driver; only 2 patients in the intervention arm received subcutaneous Ig. There were nonsignificant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio of Ig vs antibiotics was AU$111 262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared with prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered at the Australian and New Zealand Clinical Trials Registry as #ACTRN12616001723471.