Litzow, Mark R.

Background: The addition of midostaurin (M), an oral multi-kinase inhibitor, to intensive chemotherapy (IC) prolongs survival in newly diagnosed (ND) FLT3 mutated (m) AML. It is not known if there is a benefit to more potent and selective FLT3 inhibitors. Among these is Gilteritinib (G), now approved as a single agent in relapsed/refractory FLT3m AML. Combined with IC, G also leads to high measurable residual disease (MRD)negative (-) composite complete remission (CRc) in FLT3 Internal Tandem Duplication (ITD)m AML. The aim of the PrECOG 0905 study was to compare FLT3m clearance and CRc rates of G vs M with IC in adults with ND FLT3m AML. Methods: We conducted a randomized, open-label, phase 2 trial comparing G to M in combination with IC during induction and consolidation in ND AML pts with centrally PCR detected FLT3 ITD or TKD mutations. Pts age 18-70 with non M3 AML and no known core binding factor rearrangement were eligible. Pts were stratified by mutation type (TKD only vs. ITD (+/- TKD)), NPM1 mutation status, and FLT3-ITD allelic ratio. Induction consisted of cytarabine 100 mg/m2 by continuous infusion daily, on day (d) 1-7 and daunorubicin 90 mg/m2 IV on d 1-3. G 120 mg daily or M 50 mg twice daily was given orally on d8-21. Consolidation (up to 4 cycles) began within 60 d of induction with Cytarabine (1.5-3 g/m2 IV) X 6 doses and G or M (as per randomization) on d8-21. Pts could proceed to transplant (HCT) at any time. Maintenance was not included. The primary outcome was FLT3m MRD (-) CRc after induction. MRD for TKD mutations was tested by PCR (sensitivity 10-2); ITD MRD was tested by amplicon-based NGS (sensitivity 10-4). Safety and efficacy were analyzed in all eligible pts who received treatment. Secondary endpoints included comparison of CRc, MRD by flow cytometry (sensitivity 10-3), and survival. Results: From 11/2019 to 11/2022, 722 pts were screened at 37 centers, 180 pts randomized, and 177 pts (58% female, 77% white, 8.5% black, 8.5% hispanic) treated on the G (n=90) or M (n=87) arm. Median age was 54, with 27.7% > age 60. FLT3-ITD was present in 80% in the G arm and 78.2% in the M arm. Of those with FLT3-ITD, NPM1 was detected in 56.9% pts in G arm and 58.8% in M arm. 24.4% G and 20.7% M pts had co-occuring FLT3-ITD, NPM1 and DNMT3A mutations. Adverse karyotype was seen in 3.4% G and 9.3% M while 10% G and 13.8% M were ELN 2022 adverse risk. For pts on G arm, 85.6% achieved CRc compared to 72.4% for M (p=0.042). 5 (5.6%) pts on G arm and 6 (6.9%) on M arm received 2 cycles in induction. Post induction, the FLT3m- CRc rate was 40% for G vs 47.1% for M (p=0.366). FLT3-TKD only mutated pts achieved CRc in 88.9 % with G and 63.2% with M and FLT3m- CRc in 72.2% and 63.2% respectively. FLT3-ITDm (+/- TKDm) pts achieved CRc/FLT3m- CRc in 84.7%/31.9% with G and 75%/42.6% with M, respectively. In pts with FLT3-ITD, NPM1 and DNMT3A mutations, 95.5% G and 72.2% M achieved CRc and 50% G vs 33.3% on M achieved FLT3m- CRc. Flow cytometry MRD negative CRc was documented in 64.4% on G arm and 59.8% on M arm after induction (p=0.539). On G arm 67 (74%) patients received at least one cycle of consolidation compared to 53 (61%) pts on M arm. On exploratory analysis, 54 (66%) G and 40 (46%) M were reported to proceed to HCT in first remission. FLT3m testing was done post consolidation cycle 1 in 27 pts in FLT3m+ CRc after induction and 15/18 (83%) on G and 4/9 (44.4%) on M converted to FLT3m-. On multivariate logistic regression analysis for FLT3m-CRc post-induction, FLT3-ITD allelic ratio, NPM1m, WBC and hemoglobin at baseline were significant at the 0.10 two-sided level, while treatment arm, and 2017 ELN risk were not. There were no deaths from treatment-related (TR) adverse events (TRAEs) while grade >=3 TRAE was reported in 73%G vs 70% M during induction and 79%G vs 73%M pts during consolidation. Conclusion: Induction therapy with daunorubicin 90 mg/m2 X 3 days, cytarabine 100 mg/m2 and gilteritinib results in an excellent CRc rate with no TR deaths in pts with ND FLT3m AML up to age 70. Compared to M, G increased the CRc but not the FLT3m- CRc rate after induction. More post induction FLT3m+CRc pts who received G became FLT3m- after consolidation cycle 1 and more G pts succeeded in proceeding to HCT. Future survival data will help evaluate the clinical impact of G and MRD assessments in ND FLT3mAML. Larger studies will be needed to establish most predictive timing of MRD and for definitive comparisons of these drugs in patients with specific mutation profiles ( ie TKD, ITD/NPM1/DNMT3).

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by providers and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases, or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE 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. METHODS 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. RESULTS The literature search identified 52 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS 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 .

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

AbstractVenetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real‐world data published on HMAs plus VEN have been either single‐center studies or using community‐based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real‐world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85–13.5), with OS significantly worse among patients with TP53‐mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30‐day and 60‐day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE‐A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Abstract A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Abstract Venetoclax + hypomethylating agent (Ven‐HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND‐AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND‐AML was to identify molecular predictors of treatment response to Ven‐HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, “favorable” predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and “unfavorable” TP53 (40% vs. 67%), FLT3‐ ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy‐related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow‐up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5–4.8), adverse karyotype (1.6, 1.1–2.6), TP53 mutation (1.6, 1.0–2.4), and absence of IDH2 mutation (2.2, 1.0–4.7); these risk factors were subsequently applied to construct an HR‐weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low ( n = 130; median survival 28.9 months), intermediate ( n = 105; median 9.6 months), and high ( n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3‐tiered, CR/CRi‐based, and genetics‐enhanced survival model for AML patients receiving upfront therapy with Ven‐HMA.