About
Rafael Madero Marroquin is an Assistant Professor of Medicine in the Department of Medicine at The University of Chicago. His professional role involves research and academic responsibilities within the department, contributing to the university's medical and scientific community. He is associated with the university's research network and maintains a profile for further information. His contact email is gvk7643@uchicago.edu, and he is based at the university's main medical campus located at 5841 South Maryland Avenue, MC 6092, Chicago, IL 60637.
Research topics
- Internal medicine
- Medicine
- Oncology
Selected publications
Blood · 2025-11-03
articleOpen accessAbstract Introduction and Rationale Philadelphia-chromosome negative (Ph-) myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders typified by activation of the JAK/STAT pathway along with single or multi-lineage cellular hyperplasia. Ph- MPNs also have a variable propensity to evolve into acute leukemia; a blast percentage of ≥5% in the blood or bone marrow is associated with a high risk of progression to blast phase (≥20% blasts) and poor long-term outcomes (Patel et al, CLML 2023). Standard acute myeloid leukemia (AML)-based therapies have limited efficacy, with a median overall survival of less than 1 year (Patel et al, Blood Adv 2024). Mutations in IDH1 and IDH2 are enriched in accelerated/blast-phase MPNs (MPN-AP/BP), with the incidence of IDH1 mutations being 12-13%. Ivosidenib, a small-molecule inhibitor of the IDH1 mutant enzyme, has provided a new treatment paradigm for IDH1-mutated AML and myelodysplastic syndrome (MDS). While there are limited prospective clinical trial data of IDH inhibition in advanced-phase MPNs, several retrospective studies have highlighted the efficacy of IDH inhibition including patients with responses of ≥ 1 year (Patel et al, BJH 2020; Chifotides et al, Blood Adv 2020; Gangat et al, BJH 2023). Of note, IDH inhibition addresses the blast component of the disease but the chronic-phase MPN typically persists (Patel et al, SOHO 2020). Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, is approved for use in both polycythemia vera (PV) and myelofibrosis (MF). It has also been investigated in a variety of combinatorial approaches for both chronic-phase MPNs and accelerated/blast-phase MPNs. Work in murine models has demonstrated that concurrent JAK2 and IDH1/2 mutations initiate and propagate the proliferative process within long-term hematopoietic stem cells. In addition, there is expansion of a blast population and impaired differentiation of these cells, allowing for leukemic transformation. Of note, synergism was demonstrated with combined JAK2/IDH inhibition in these models with resultant reduction in spleen size, reduction in leukemic blasts, and reduction in the mutant variant allele frequency (McKenney et al, JCI 2018). We therefore, seek to determine the safety and preliminary efficacy of ruxolitinib in combination with ivosidenib in IDH1-mutated advanced phase MPNs, based on the hypothesized synergism in this context. (NCT06291987). Study Design and Methods This study is an investigator-initiated, Phase 1b study to establish the maximum tolerated dose (MTD) of ivosidenib in combination with ruxolitinib. Eligible patients must have a IDH1-mutated Ph- MPN or MDS/MPN overlap syndrome with ≥5% blasts. Patients with IDH1-mutated chronic-phase MF and ≤5% blasts with an inadequate response to JAK inhibitor therapy are also eligible. Other pertinent inclusion criteria include age ≥18 years, ECOG ≤2, and a platelet count ≥50 x 109/L for patients with MF and ≤5% blasts. Relevant exclusion criteria include prior treatment with ivosidenib. This study will follow a Rolling 6 design. Cycles are 28 days. Enrollment will begin at dose level (DL) 1 (ivosidenib 500mg daily, ruxolitinib 10mg twice daily), with a planned escalation to DL2 (ivosidenib 500mg daily, ruxolitinib 20mg twice daily) or de-escalation to DL-1 (ivosidenib 500mg daily, ruxolitinib 5mg twice daily) based on an assessment of DLTs. The primary endpoint is to establish the MTD of the combination. At the DL designated to be the MTD, defined as a DL where <2/6 DLTs are observed, we will plan to expand enrollment to have 12 patients in total treated at that dose to better characterize safety and efficacy. Total accrual is anticipated to be 18 patients. Secondary endpoints include overall survival, overall response rate, and time to response. For patients with ≥5% blasts the response will be characterized using 2012 MPN-BP criteria (Mascarenhas et al, Leuk Res 2012); for patients with MF and ≤5% blasts the response will be characterized using 2013 International Working Group-Myelofibrosis Research Treatment/European LeukemiaNet revised response criteria. Exploratory endpoints include characterization of co-occurring pathogenic mutations, evaluation of measurable residual disease (MRD status) via error-corrected next generation sequencing, assessment of the proportion of patients going onto allogeneic stem cell transplant, and assessment of clonal dynamics under combined IDH1/JAK2 inhibition.
Blood · 2025-11-03 · 2 citations
articleAbstract Background: The 4-gene molecular prognostic risk score (mPRS) improves overall survival (OS) prediction in patients (pts) with newly diagnosed AML (ND-AML) treated with hypomethylating agents (HMA) and venetoclax (VEN). Yet given the broad clinical and molecular heterogeneity of AML, risk stratification remains suboptimal. We consolidated a large international cohort of ND-AML pts treated with lower-intensity regimens including HMA or low-dose cytarabine (LDAC) plus VEN to improve OS prognostication. Methods: We analyzed 2,273 ND-AML adult pts who received frontline VEN with HMA (n=2,222) or LDAC (n=51) at an academic medical center in the US, UK, France, Germany, or Italy who had complete clinical, cytogenetic, and molecular data. An initial set of 1,974 patients were split into a training (TC, N=1,339) and internal validation (VC, N=635) cohorts, stratifying on key clinical variables (de novo vs. secondary AML, TP53 and IDH2 mutations, hematopoietic cell transplantation [HCT], death). An additional N=299 patients, acquired later, were utilized as an external validation set. OS was measured from therapy start, estimated with Kaplan-Meier curves, and compared across risk groups using the log-rank test. HCT was considered a time-dependent covariate. OS discrimination was estimated by Harrell's C-index (C). Clinical and genomic features (with a frequency ≥ 4% required for nominal features) were included in model development. Cox L1-penalized regression of OS applied to 1,000 bootstrap samples from the TC was used to identify stable features (selected with a consistent direction in ≥75% of bootstrap iterations). These features were entered into a robust Cox model. Non-significant genes “ResMut” were grouped according to their directional effect on OS to create “ResMut-fav” denoting the presence of ≥1 mutation in a favorable set of residual genes. The final robust Cox model beta coefficients were added to calculate patient-specific risk PRISM scores. Quartiles of PRISM scores defined four clinical PRISM risk groups: low (L), moderate (M), high (H), and very-high (VH). Results: In the TC, median pt age was 74 years; 61% were male. 41% had secondary AML (sAML), arising from an antecedent hematologic disorder (sAML-AHD) in 33% (11% with treated AHD) and from prior therapy in 8%. The mPRS distribution was 56% higher-, 22% intermediate-, and 22% lower-benefit. HCT rate was 12%. The final PRISM model included age, sex, sAML-AHD, ELN 2022 complex karyotype and other adverse-risk cytogenetic abnormalities, and adverse mutations in KRAS, PTPN11, FLT3-ITD, JAK2, ASXL1, and TP53. Favorable features included diploid karyotype, mutations in RUNX1 or IDH2, and ResMut-fav (comprising CEBPA, BCOR, IDH1, SF3B1). For TC pts, at median follow-up of 20.8 months (mo), median OS (mOS) was 12.2 mo (95% CI: 10.9–13.6). Higher PRISM scores were associated with worse OS (1-unit increase HR: 2.50; 95% CI: 2.21–2.82; C: 0.654). Median OS by PRISM risk group L/M/H/VH was 29.6, 17.6, 11.3, and 5.6 mo (C: 0.641; p<0.001). PRISM risk groups improved OS discrimination vs. mPRS (C: 0.641 vs. 0.583, p<0.001), with similar benefit after adjusting for HCT (C: 0.650 vs. 0.594, p<0.001). There were no significant differences in considered variables between the TC and VC. In the VC, median follow-up was 24.4 mo and mOS 13.0 mo (95% CI: 11.5–14.8). The PRISM score was significantly associated with OS (1-unit increase HR: 2.28; 95% CI: 1.91–2.71; C: 0.653). Median OS by PRISM group L/M/H/VH was 24.4, 15.0, 11.7, and 5.8 mo, similar to rates observed in the TC. PRISM risk groups outperformed mPRS (C: 0.648 vs. 0.613, p=0.002), including after adjusting for HCT (C: 0.659 vs. 0.629, p=0.018). The external validation cohort was marginally older (median age 75 years) with fewer HCT recipients (8%) compared to the initial TC/VC. Higher PRISM scores remained highly associated with OS (1-unit increase HR: 2.49, 95% CI: 1.92-3.24; C: 0.661). Median OS by PRISM group L/M/H/VH was 28.8, 13.9, 12.5, and 6.3 mo. PRISM risk groups had better OS discrimination than mPRS (C: 0.648 vs. 0.584, p=0.010), including after adjusting for HCT (C:0.662 vs. 0.607, p=0.004). Conclusions: Integration of prognostically relevant clinical and genomic features into the PRISM score and subsequent PRISM risk groups enables improved discrimination of survival following lower-intensity HMA/LDAC+VEN therapy in patients with ND-AML compared to current risk classification frameworks.
Blood · 2025-11-03
articleOpen accessAbstract Introduction Acute leukemia (AL) is a life-threatening hematologic malignancy that often necessitates urgent hospitalization and rapid initiation of intensive, frequently toxic, therapies within hours to days of diagnosis. AL carries a markedly higher acuity than most cancers and presents with great variability in illness trajectories, treatment paradigms, and potentials for cure – even in the relapsed and refractory settings. The unique clinical dynamics of AL care often disrupt multiple domains of quality-of-life (QOL), including psychosocial, physical, emotional, and spiritual well-being. Patients with newly diagnosed AL are often confronted with multiple time-sensitive, complex decisions which can lead to profound spiritual distress as they navigate the emotional and existential impact of their illness. While increased spiritual wellness (SW) has been associated with improved physical functionality and QOL in patients with advanced cancers, particularly at the end-of-life, its role remains poorly understood in the distinct context of newly diagnosed AL. To address this gap, we conducted a prospective observational multi-methods study at the University of Chicago using patient-reported outcome measures (PROMs) to evaluate SW and QOL among adults with newly diagnosed AL receiving initial therapy. We evaluated early changes in PROMs and investigated the relationship between SW and QOL in this population. Methods Adult patients with newly diagnosed AL were prospectively enrolled and completed validated PROMs assessing SW (FACIT-Sp12) and QOL (FACT-Leu) within 7 days of AL diagnosis and again 30 days later. Five additional free-response questions exploring areas of spiritual practices, coping mechanisms, community support, and changes in outlook were asked at both time points and coded thematically using an open, double-coded approach. PROM changes over time were assessed via paired t-tests. The relationship between PROMs were assessed with Pearson correlation coefficients. Patients' SW scores were then stratified categorically into low, average, or high spirituality levels based on established national data (Munoz et al., Cancer, 2015). Chi-square tests examined associations between patients' spirituality levels and selected sociodemographic or biologic factors at both time points. Results Thirty patients were enrolled and completed all assessments. The median age was 52 years (range 21-93), 60% were female, and 53% had acute myeloid leukemia. All patients received disease-specific therapy during hospitalization. Qualitative analysis revealed 3 core themes: personal practice, community support, and perceived growth. Personal practices most commonly included prayer, meditation, and positive thinking. Community support ranged from spouses and family members to friends and religious/spiritual groups. Finally, 53% (16/30) reported a positive change in outlook, comfort, or hope between baseline and day 30. While the mean SW score did not significantly increase from enrollment to day 30 (36.5 vs 37.8, p = 0.31), QOL scores did significantly improve over the same period (111.3 vs 129, p = 0.022). SW had moderate, significant positive correlations with QOL at both enrollment (r = 0.47, p = 0.012) and day 30 (r = 0.43, p = 0.022). The distribution of patients' spirituality levels was 13.3% low, 76.7% average, and 10% high at enrollment; and 13.3%, 73.3%, and 13.3%, respectively, at day 30. Four patients (13%) demonstrated an increase in spirituality level between enrollment and day 30 (2 from low to average and 2 from average to high). Patients in the low spirituality level at enrollment were significantly more likely to have higher household income (50% with $100,000 or more, p = 0.044). No other sociodemographic or biologic factor differed significantly by spirituality level at either time point. Conclusions While SW is significantly correlated with QOL, only QOL significantly improved in the first 30 days following AL diagnosis and treatment initiation. This finding suggests that QOL in this population could improve further through a multidisciplinary care model that actively supports SW. During hospitalization for AL, many personal and community-based sources of encouragement, hope, and strength are often disrupted, which can contribute to spiritual distress. Integrating spiritual care into AL treatment paradigms has the potential to enhance patient-centered care and improve patient-reported outcomes.
Imetelstat: drugging telomerase in transfusion-dependent low- and intermediate-1–risk MDS
Blood Advances · 2025-01-07
articleOpen accessConceptTelomerase maintains telomere length at the terminal strands of DNA to protect adjacent coding regions during cell replication. 1etelstat is a 13-mer oligonucleotide and first-in-class telomerase inhibitor (see figure), initially studied in early-phase trials, that achieved red blood cell transfusion independence (RBC-TI) end points in lower-risk myelodysplastic syndrome (MDS; LR-MDS). 2
Blood · 2025-11-03
articleOpen access1st authorCorrespondingAbstract Introduction: Clinical outcomes for patients (pts) with Philadelphia chromosome positive (Ph+) B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) have significantly improved with the incorporation of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the incidence of central nervous system (CNS) relapse in Ph+ B-ALL is rare, it has become an emerging challenge with chemotherapy-free approaches. While IKZF1, CDKN2A/B and emergence of T315I kinase domain mutations in ABL1 have been associated with worse outcomes (Foà R, JCO, 2024),further characterization of patients with CNS relapse could prove useful in risk stratification and optimizing treatment intensification. Currently, high white blood cell count (WBC) is being assessed as a marker to identify pts who may benefit from addition of CNS penetrant chemotherapy (ex. cytarabine or high-dose methotrexate (HD-MTX)) to TKI and immunotherapy protocols (Short NJ, J Hematol Oncol, 2025). Methods This is a multicenter retrospective study of relapsed/refractory Ph+ B-ALL pts under the COMMAND consortium. Age, gender, induction regimen and TKI of choice during induction were descriptively reported for the entire cohort. Categorical variables were compared, using Fisher's exact test, between pts with CNS relapse and pts with systemic relapse. Variables of interest were the presence of IKZF1 or CDKN2A/B alterations, emergence of T3151 mutation, CNS disease at diagnosis (dx), WBC >70K/microliter at dx, use of high-dose methotrexate (HD-MTX) during induction or consolidation, and use of TKI as part of the induction regimen. Odds ratio (OR) and 95% confidence intervals (CI) were reported for each variable. Results A total of 654 Ph+ B-ALL pts were initially identified across multiple centers in the United States, of whom 20 (3%) experienced a CNS relapse and 157 (24%) experienced a systemic relapse on median follow up of 29 months (range, 0-207). A total of 15 pts with CNS relapse and 114 pts with systemic relapse were used for this analysis after exclusion of pts without molecular data. The median age for the 129 pt cohort was 55 years (range 22-85), of whom 65 pts (50%) were male. Induction regimens used were intensive chemotherapy (IC)+TKI for 79 pts (61%), low-intensity chemotherapy or steroids (LDC-S)+TKI for 40 pts (31%), IC without TKI during induction for 5 pts (4%) and blinatumomab+TKI for 1 pt (1%). TKI of choice during induction included second-generation TKIs (dasatinib, nilotinib) for 77 pts (60%), imatinib for 30 pts (23%), ponatinib for 15 pts (12%) and none during induction for 5 pts (4%). CNS disease at dx was found in 6/15 pts (40%) with CNS relapse and 9/114 pts (8%) with systemic relapse, which was a statistically significant difference (p=0.002, OR= 7.57, 95% CI= 1.81 - 31.08). The systemic treatment regimens for the 15 pts with CNS disease at x were IC+TKI for 10 pts (66%) and LDC-S+TKI for 5 pts (33%), 9 of the pts (60%) received HD-MTX during induction. Intrathecal (IT) chemotherapy administration data at dx was available for 8 pts (53%) with CNS disease at dx, of whom 2 pts received <9 doses, 4 pts received 9-12 doses and 2 pts received >12 doses of IT chemotherapy. Although not statistically significant, pts with CNS relapse were more likely to have IKZF1 or CDKN2A/B alterations (p = 0.648, OR= 1.44, 95% CI= 0.14-7.78), WBC >70K/mcl (p = 0.472, OR= 1.73, 95% CI= 0.34-7.41), emergence of T3151 mutations (p = 0.123, OR= 2.54, 95% CI= 0.72-8.84) and use of HD-MTX during induction or consolidation (p = 0.262, OR= 2.15, 95% CI= 0.61-8.61); while they were less likely to have received a TKI during induction (p = 0.106, OR= 0.18, 95% CI= 0.02-2.34). Conclusion This data confirms that the presence of CNS disease at dx is associated with CNS relapse. Despite recent incorporation into clinical trials, WBC≥70K/mcl and omission of HD-MTX were not seen more frequently in pts with CNS relapse in this cohort. However, this analysis is limited by the small number of pts who experienced CNS relapse. With the rising use of chemotherapy-free regimens, prospectively trialing treatment intensification, such as with additional IT chemotherapy or HD-MTX, could be prospectively trialed in pts with CNS disease at dx to potentially improve outcomes for this subset of pts. The impact of increasing IT chemotherapy doses or additional cycles of systemic chemotherapy in this pt population is yet to be elucidated.
British Journal of Haematology · 2025-10-26 · 1 citations
articleOpen accessRearrangements of the lysine methyltransferase 2A gene (KMT2Ar) and mutations in nucleophosmin 1 (NPM1m) are among the most common genetic aberrations in acute leukaemia, with KMT2Ar seen in both acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) and NPM1m present in ~30% of AML cases.1 Historically, outcomes in relapsed/refractory (R/R) acute leukaemia with KMT2Ar or NPM1m have been poor, with a median overall survival of 6 months or less.2, 3 Both KMT2Ar and NPM1m acute leukaemia harbour leukaemogenic pathways dependent on aberrant transcription and differentiation blocks due to the protein menin. Revumenib, an oral selective menin inhibitor, disrupts leukaemogenesis in both KMT2Ar and NPM1m acute leukaemias.4 The phase 1/2 AUGMENT-101 trial of revumenib in patients with R/R KMT2Ar and NPM1m acute leukaemia demonstrated a complete remission (CR) or complete remission with partial haematological recovery (CRh) rate of 22.8% among patients with KMT2Ar and a CR + CRh rate of 23.4% in those with NPM1m.5, 6 While the single-agent efficacy of revumenib in the R/R setting is promising, the duration of response has been limited; the median overall survival (OS) was 8 months for patients with R/R AML with KMT2Ar and 4 months for those with NPM1m AML.5, 6 Currently, there are limited data regarding outcomes of subsequent therapies in patients already treated with revumenib. We sought to analyse the outcomes of patients with R/R acute leukaemia after receiving revumenib and the efficacy of subsequent treatment lines. Adult patients with R/R acute leukaemia treated with revumenib monotherapy at the University of Chicago between 22 January 2020 and 22 May 2025 were studied as part of a single-centre, retrospective cohort analysis. Patients were identified through the University of Chicago leukaemia registry and pharmacy records. Institutional review board approval was obtained. Diagnosis, relapse and disease status were confirmed according to the International Consensus Classification of myeloid neoplasms and acute leukaemias.7 Risk classification and response assessment for patients with AML utilized the European LeukemiaNet (ELN) 2022 criteria for intensive chemotherapy.8 Response assessments for patients with ALL and mixed-phenotype acute leukaemia (MPAL) utilized the ELN 2024 adult ALL criteria.9 Descriptive statistics were utilized for baseline patient characteristics. A response was defined as achieving a CR, CRh or CR with incomplete count recovery (CRi); overall response rate (ORR) was defined as CR + CRh + CRi. OS was estimated using the Kaplan–Meier method. We evaluated 26 patients treated with revumenib monotherapy for R/R acute leukaemia in our analysis. Twenty patients (76.9%) received revumenib as part of a clinical trial, 4 (15.4%) as part of an expanded access protocol and 2 (7.7%) as a commercial drug. Most patients (73%) had AML; the remainder had B-ALL (15%) or rare subtypes (12%). Demographic and biological characteristics are presented in Table 1. Fifteen patients (58%) received revumenib for KMT2Ar, 10 (38%) for an NPM1m and 1 (4%) for a KMT2A partial tandem duplication (PTD) (Figure S1A,B). The patient with KMT2A-PTD previously received all available standard therapies and was therefore treated with revumenib given preclinical rationale for menin inhibition.10 Twenty patients had a comprehensive molecular evaluation at initial diagnosis. Aside from KMT2Ar and NPM1m, common pathogenic mutations at diagnosis included fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (5/20, 25%), neuroblastoma RAS viral oncogene homolog (NRAS) (5/20, 25%), Kirsten rat sarcoma viral oncogene homolog (KRAS) (4/20, 20%), tet methylcytosine dioxygenase 2 (TET2) (4/20, 20%) and tumor Protein P53 (TP53) (2/20, 10%) (Figure S1A). Responses to revumenib are summarized in Table 1; the ORR rate was 42% (11/26). Fifteen patients received additional treatment after revumenib (post-revumenib treatment). Of the 11 patients who did not receive post-revumenib treatment, 10 (91%) died either while taking revumenib, after cessation due to no response, or due to other complications of their leukaemia, while 1 (9%) remained on revumenib at the time of data cut-off (Figure 1B). The median OS of the 26-patient cohort from the time of revumenib initiation was 7.3 months (95% confidence interval (CI) [2.5, 14.4]). Fourteen patients had repeat molecular assessments via next-generation sequencing (NGS) at the time of no response or progression on revumenib (Figure S1C), of which 5 (36%) developed a multiple endocrine neoplasia 1 (MEN1) mutation, a known driver of resistance to revumenib.11 Of the 5 patients who developed MEN1 mutations, 3 (60%) had NPM1m and 2 (40%) had KMT2Ar. Of the 15 patients who received post-revumenib treatment, 5 (33%) had an NPM1 mutation, 9 (60%) had KMT2Ar and 1 (7%) had a KMT2A-PTD. Twelve patients (80%) received one or two lines of treatment following revumenib, and three patients (20%) received ≥3 lines of treatment (Table S1). As the first line of post-revumenib treatment, 6 (40%) received a hypomethylating agent (HMA) + venetoclax (ven), 5 (33%) received intensive chemotherapy (IC) + ven, 2 (13%) with FLT3 mutations received gilteritinib-based therapy, 1 (7%) with B-ALL received CD19-directed chimeric antigen receptor T-cell (CAR T) therapy and 1 (7%) received revumenib again after previously achieving a CR on revumenib, undergoing allogeneic haematopoietic stem cell transplant (allo-HSCT), and having another relapse of disease. Of the 26 patients, 18 (69%) received ven prior to revumenib. Of these, five (28%) achieved a response to revumenib. Nine patients (50%) went on to receive post-revumenib therapy. Seven of the nine patients (78%) were retreated with ven-containing regimens post-revumenib. Two of seven patients (29%) achieved a response to a ven-containing regimen post-revumenib. Following the first line of post-revumenib treatment, 8 patients (53%) had no response. Of these, 5 (62.5%) had KMT2Ar, 2 (25%) had NPM1 mutations and 1 (12.5%) had a KMT2A-PTD. Three patients achieved a CR while four achieved a CRi for an ORR of 47% (Table S1). Among these 7 patients who achieved a response, 3 (42.8%) received HMA + ven, 2 (28.8%) received IC + ven, 1 (14%) received gilteritinib-based therapy and 1 (14%) received CAR-T therapy. Among the seven patients with a response after the first line of therapy post-revumenib, three (43%) had KMT2Ar and four (57%) had an NPM1 mutation. Among the four patients with an NPM1 mutation who achieved a response after their first line of post-revumenib therapy, NPM1 measurable residual disease (MRD) status was assessed via NGS assay with 10−5 sensitivity. Two patients (50%) were MRD positive at assessment post-revumenib, and 2 (50%) achieved and maintained MRD-negative status. Of the two patients with MRD-positive disease, one patient switched to HMA therapy and has not had subsequent NPM1 MRD assessments at the time of data cut-off, and the other patient died prior to repeat MRD assessment. Four patients who received post-revumenib therapy had a MEN1 mutation. Two of these patients had NPM1m disease and received HMA + ven; both patients achieved a response. Two patients had KMT2Ar and received HMA + ven but did not have a response. Among the 15 patients who received post-revumenib treatment, the median OS was 7.5 months (95% CI [2.3, NA]) from the time of first post-revumenib treatment and was 8.3 months (95% CI [7.8, NA]) in the seven patients who achieved a CR/CRi to their first post-revumenib treatment (Figure 1A). Of the 15 patients, 7 (47%) received additional treatment lines beyond the first line of post-revumenib therapy; their courses are summarized in the swimmer plots (Figure 1A). Of the post-revumenib treatment cohort, four patients (27%) were still alive at the time of data cut-off (Figure 1A). Of the 15 patients who received post-revumenib therapy, 6 (40%) subsequently underwent allo-HSCT; three patients died from relapsed disease and three are still alive at the time of data cut-off. The median OS from the time of allo-HSCT was 8.8 months (95% CI [4.8, NA]). In summary, this analysis characterized the clinical outcomes of 26 patients with R/R acute leukaemia treated with revumenib. The ORR was 47% in the 15 patients who received post-revumenib therapy, with most patients receiving ven-containing regimens (n = 11) as the next line of treatment. Responses were seen in patients with KMT2A aberrations (3/10), NPM1 mutations (4/5) and MEN1 mutations (2/4), suggesting that additional therapy may be effective across the common aberrations seen after relapse/progression on revumenib. Of the 15 patients who received post-revumenib therapy, 6 were able to proceed to an allo-HSCT. Prior work has demonstrated that responses to menin inhibitors in the R/R setting are typically limited in duration and that if MRD-negative status can be achieved, patients benefit from proceeding to transplant promptly.5, 6, 12 Limitations of our analysis include the small sample size. Many patients received revumenib through a clinical trial or through an expanded access programme. Therefore, our findings may not reflect the broader population which has more limited access to such resources. Nevertheless, our study provides insight into potential therapeutic strategies for revumenib-exposed patients. To our knowledge, this is the first report describing outcomes of subsequent therapies after revumenib exposure in a real-world cohort. We found that post-revumenib therapies, particularly venetoclax-based approaches, can induce responses across mutational subsets including MEN1. In addition, consolidation with allo-HSCT is feasible in eligible patients who achieve a response. Prospective studies evaluating therapies, including other menin inhibitors, in patients already treated with revumenib will be critical to understand how to improve outcomes in this group.13 As menin inhibitors are investigated in the front-line setting, similar studies might inform combinatorial trial designs and identify effective treatments after menin inhibitor therapy.14, 15 Miles Thomas was responsible for project design, data collection, data analysis and manuscript creation. Hannah Johnston was responsible for project design, data collection, data analysis and manuscript creation. Emily Dworkin was responsible for manuscript creation. Austin Wesevich was responsible for manuscript creation. Gregory W. Roloff was responsible for manuscript creation. Caner Saygin was responsible for manuscript creation. Mariam T. Nawas was responsible for manuscript creation. Michael W. Drazer was responsible for manuscript creation. Adam S. DuVall was responsible for manuscript creation. Satyajit Kosuri was responsible for manuscript creation. Michael J. Thirman was responsible for manuscript creation. Olatoyosi Odenike was responsible for manuscript creation. Wendy Stock was responsible for manuscript creation. Richard A. Larson was responsible for manuscript creation. Rafael Madero-Marroquin was responsible for project concept and design, data collection, data analysis and manuscript creation. Anand A. Patel was responsible for project concept and design, data collection, data analysis and manuscript creation. The authors would like to thank the patients whose data are represented in the study below. Anand A. Patel is supported by the NCI Early Career Investigator Award (3P30CA014599-49S1). Miles Thomas: No conflicts of interest to disclose. Hannah Johnston: No conflicts of interest to disclose. Emily Dworkin: Honoraria from AbbVie. Austin Wesevich: Honorarium from Amgen. Gregory W. Roloff: Advisory boards for Autolus Therapeutics and Kite/Gilead. Caner Saygin: No conflicts of interest to disclose. Mariam T. Nawas: No conflicts of interest to disclose. Michael W. Drazer: Scientific advisory board for Argenx. Adam S. DuVall: Speaker for CE Concepts. Satyajit Kosuri: No conflict of interest to disclose. Michael J. Thirman: Has acted as a consultant or advisor to AbbVie, AstraZeneca, Celgene, Janssen, Pharmacyclics and Roche/Genentech. Research funding from AbbVie (Inst), Gilead Sciences, Janssen, Merck, Nurix, Pharmacyclics, Syndax and TG Therapeutics. Olatoyosi Odenike: Institutional research funding by AbbVie, Astra Zeneca, Celgene, Curis, Incyte, Shattuck Lab and K-group alpha; scientific advisory board participant for AbbVie, Celgene/BMS, Novartis, Incyte, Kymera therapeutics, Servier and Rigel; service on data safety board for Treadwell therapeutics. Wendy Stock: Advisor for Kura, Servier, Newave and Asofarma. Richard A. Larson has acted as a consultant or advisor to Ariad/Takeda, CVS/Caremark, Epizyme/Ipssen and Novartis and has received clinical research support to his institution from Astellas, Biomea, Cellectis, Daiichi Sankyo, Forty Seven/Gilead and Novartis and royalties from UpToDate. Rafael Madero-Marroquin: No conflicts of interest to disclose. Anand A. Patel: Honoraria from AbbVie, Amgen, Astellas, Jazz, Sobi, Syndax; research funding (institutional) from Pfizer, Incyte, Servier and Sumitomo. Informed consent was waived as per institutional review board approval due to the retrospective nature of the study. Those seeking to reproduce material from this manuscript should reach out to the corresponding author for permission. The data used for this study can be made available in its de-identified form at the request of the corresponding author upon reasonable request and following institutional data sharing practices. To protect the confidentiality and security of individual health records, these data will not be made publicly available. Figure S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Blood · 2025-11-03
articleOpen accessAbstract Background Mutated nucleophosmin-1 (NPM1m) is present in ~ 30% of patients (pts) with newly-diagnosed acute myeloid leukemia (ND-AML). A subset of pts with NPM1mhave improved overall survival (OS) following venetoclax (VEN) combined with hypomethylating agents (HMA; azacitidine or decitabine) or low-dose cytarabine (LDAC) treatment. Yet outcomes of pts with NPM1m AML treated with VEN-based therapy are highly dependent on co-mutations whereby the presence of signaling pathway mutations associate with worse OS (Döhner et. al. Blood 2024; Othman et. al. Blood 2024). Current mutational subgroup analyses are limited by sample size. Which co-occurring mutations best stratify outcomes in NPM1m AML following VEN-based lower intensity therapy is unclear. We hypothesized that studying pts with NPM1m AML who experienced poor clinical outcomes would better identify those who benefit most from investigational therapies. Methods We assembled a cohort of 2,089 pts withND-AML receiving frontline VEN+HMA (n=2,057) or LDAC (n=32) at academic medical centers in the US, UK, France, or Germany with available clinical, cytogenetic, and molecular data. OS was measured from therapy start, estimated with Kaplan-Meier curves, and compared using the log-rank test. Categorical features were compared using the Fisher Exact test. Multivariable analysis utilized AIC-based backwards selection of variables with allogeneic hematopoietic cell transplantation (HCT) included as a time-dependent covariate. Results 301 (14%) pts had NPM1m AML. Median age was 74 years (range: 20-93). Most (91%) received HMA-based therapy and had de novo AML (79%), while 21% had secondary AML including 14% arising from an antecedent hematologic disorder. 63/172 pts (37%) with available data had monocytic AML. Hematopoietic cell transplantation (HCT) was performed in 24 (8%) pts. Frequent co-mutations included DNMT3A (33%), TET2 (27%), FLT3-ITD (26%), IDH2 (22%), SRSF2 (16%), NRAS (14%), IDH1 (12%), FLT3-TKD (12%), and PTPN11 (8%). 4-gene classifier/molecular prognostic risk (mPRS) was higher in 60%, intermediate in 39%, and lower-benefit in 2%. A diploid karyotype was most common (70%), followed by other ELN 2022 intermediate-risk cytogenetic abnormalities (19%). ELN 2022 adverse-risk cytogenetics (1%) and complex karyotype (1%) were uncommon. After median follow-up of 22 months, median OS (mOS) was 22 months (95% CI: 14.4-29.6). No OS difference was observed in pts receiving HMA vs. LDAC+VEN (p=0.89). OS varied across mPRS higher, intermediate, and lower-benefit groups with mOS of 26.6, 13.8, and NR (24-month OS: 53%)(p=0.40). Co-occurring mutations in IDH1/2 associated with a reduced risk (HR: 0.62, 95% CI: 0.42-0.89, p=0.011) while mutations in FLT3-ITD (HR: 1.42, 95% CI: 0.99-2.04, p=0.055) and TET2 (HR: 1.76, 95% CI: 1.24-2.50, p=0.002) associated with an increased risk of death. Median OS in pts with vs. without triple-mutant NPM1/DNMT3A/FLT3-ITD (n=33) was 10.9 vs. 26.6 months (p=0.010). Other signaling pathway variants demonstrated no significant impact on OS including NRAS (p=0.73), PTPN11 (p=0.218), KRAS (p=0.69), or FLT3-TKD (p=0.91). When stratifying pts with mutated IDH1/2 and wild-type signaling pathway genes (FLT3-ITD, N/KRAS, PTPN11) (n=66) vs. mutated signaling pathway genes (n=133) vs. other mutations (n=102), mOS was 45 vs. 16.1 vs. 14.7 months (p=0.20). Backward AIC-based selection of gene mutations identified in ≥10% of the study population identified FLT3-ITD (p=0.04) and TET2 (p=0.004) as the top candidate predictors of OS in NPM1m AML. When dichotomized into NPM1-low (n=164; FLT3-ITD and TET2 wild-type) vs. NPM1-high (n=137; FLT3-ITD or TET2 mutated) risk groups, mOS was 43 vs. 11.5 months (HR: 0.53, p < 0.001), with consistent effects observed after inclusion of HCT (HR: 0.54, p < 0.001), and IDH1/2 mutation status (HR: 0.59, p=0.003). Pts with NPM1-high AML had a mOS similar to NPM1 wild-type AML (11.5 vs. 11.7 months, p=0.46). NPM1-low vs. high was associated with differences in complete response/complete response with incomplete count recovery rates (CR/CRi; 80% vs. 69%, p=0.028), and MRD-negative remissions measured via NPM1 qPCR (n=49; 63% vs. 38%, p=0.13). Conclusion Survival outcomes following lower-intensity venetoclax-based therapy in NPM1m AML are highly dependent upon co-occurring mutations. Development of risk stratification tools may identify patients who experience sub-optimal outcomes and benefit most from alternative therapeutic approaches.
eJHaem · 2025-06-01 · 1 citations
articleOpen access1st authorBackground: Outcomes for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that have progression after treatment with hypomethylating agent (HMA) and venetoclax (VEN) are poor. However, data for chemotherapy and VEN (C+VEN) therapy after prior treatment with HMA+VEN are limited. Methods: We identified 18 patients with AML or MDS/AML who received C+VEN after prior HMA+VEN. Results: Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 7 patients (39%) and 6 patients (33%) proceeded to allogeneic hematopoietic stem cell transplantation. Conclusion: This study shows suggests that C+VEN could be a viable option in a subset of patients after HMA+VEN.
Blood · 2025-11-03
articleOpen accessAbstract Background and significance: T-lineage acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for 15% of pediatric and 25% of adult ALL cases. Precursor T-ALL and its more immature subset, early T precursor (ETP) ALL, have limited treatment options after first-line chemotherapy. Due to this unmet need, long-term survival for relapsed/refractory (R/R) T-ALL is <10%. During normal T-cell development in thymus, early precursor cells first rearrange T-cell receptor β chain (TCRβ), which pairs with an invariant surrogate pre-Tα chain to create pre-TCR signaling complex. Pre-TCR signaling promotes cell survival, proliferation and differentiation in a ligand-independent manner. We and others have shown that in T-ALL, oncogenic mutations frequently hijack this pathway, leading to constitutive activation of downstream signaling cascades. We discovered that the inhibition of pre-TCR (LCK) signaling leads to induction of apoptosis in T-ALL, and BCL-2/BCL-xL inhibitors which activate suicide pathways can synergize with LCK inhibitors (Saygin, Clin Cancer Res 2023). LP-118 is an oral dual BCL-2/BCL-xL inhibitor, with a modified structure and fine-tuned BCL-xL activity to minimize platelet toxicity. Based on our preclinical work showing the synergy between LP-118 and ponatinib (pre-TCR signaling inhibitor), we designed the phase 1/2 LPVd trial combining LP-118 and ponatinib (LCK inhibitor) with low-intensity chemotherapy backbone (Vd: vincristine, dexamethasone) in patients with R/R T-ALL/LBL (NCT06207123). The trial was activated at the University of Chicago in September 2024, and we plan to open it at four additional sites. Study design and methods: Adult patients (≥18 years) with R/R T-ALL/LBL, defined as bone marrow or blood involvement with ≥5% lymphoblasts, or measurable residual disease (MRD) with >10-4 level detected by multiparameter flow cytometry or NGS-based MRD, or patients with isolated extramedullary disease that is measurable by CT scan are eligible. Participants should otherwise have good performance status (ECOG 0-2), adequate organ function, and no active infections. In phase 1, a standard 3+3 design is implemented to test the combination of different dose levels of LP-118 with low-intensity chemotherapy (Vd) at dose levels 1 (100 mg), 2 (200 mg) and 3 (300 mg), followed by the addition of ponatinib 30 mg to different dose levels of LP-118 at levels 4 (100 mg), 5 (200 mg) and 6 (300 mg). Ponatinib dose reduction to 15 mg is allowed for participants who experience toxicity or achieve MRD-negative remission. The primary objective of the phase 1 portion is to identify the recommended phase 2 dose (RP2D) of this novel-novel combination therapy. The primary endpoint is dose limiting toxicity (DLT), defined as a grade ≥3 non-hematologic toxicity related to the study drugs, except for the following which will not be considered DLT: grade 3 fatigue, asthenia, fever, anorexia, constipation; grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral nutrition or hospitalization; infection, bleeding or other expected direct complication of cytopenias due to active underlying leukemia. The maximum tolerated dose is the dose such that <33% of patients (<2 of 6) experience DLT. At the time of this submission, 9 patients have been enrolled. After identifying the RP2D from the phase 1 portion, we will do a phase 2 dose expansion by enrolling 12 additional patients at this dose level to investigate the efficacy of LPVd. R/R T-ALL is a rare disease for which large phase III studies are rarely conducted. Primary endpoint of the phase 2 portion is complete remission (CR). The CR rate with re-induction chemotherapy in patients with R/R T-ALL is 10%. A previous phase 1b/2 study of venetoclax, navitoclax and chemotherapy in R/R T-ALL showed 50% CR rate. Therefore, we anticipate a CR rate of 30% in our study, which combines LP-118 with similar chemotherapy backbone. A total of 18 patients are needed to achieve 80% power under one-sided alpha= 0.10. We will include 6 patients from phase 1 portion in our efficacy analysis. Several correlative studies are planned to identify biomarkers of response and resistance, including BH3 profiling, molecular genetic profiling (DNA- and RNA-seq), and pre-TCR signaling activity in baseline vs relapse samples. This investigator-initiated trial is funded by the Leukemia Lymphoma Society Academic Clinical Trials grant.
Blood · 2025-11-03 · 1 citations
articleOpen accessAbstract Introduction: Amongst patients (pts) ≥ 50 years old diagnosed with B-ALL, half have Ph+ ALL. Achieving a BCR::ABL1 qRT-PCR of <0.1% (MR3) or <0.01% (MR4) with TKI-based therapy correlates with excellent long-term survival in Ph+ ALL (Short et al. Blood 2016). Tyrosine kinase inhibitor (TKI) + blinatumomab regimens have demonstrated high MR4 rates and favorable overall survival (OS); however, these regimens include up to 5 courses of blinatumomab which is a continuous 28-day infusion (Kantarjian et al, JCO 2024; Foa et al, JCO 2024). The anti-CD22 antibody drug conjugate inotuzumab ozogamicin (InO) has efficacy in both relapsed/refractory Ph+ ALL and newly diagnosed B-ALL (Stock et al, Cancer 2021; Wieduwilt et al, JCO 2023). We hypothesized that TKI + InO-based therapy for newly diagnosed Ph+ ALL would achieve high rates of MR3 or better (MR3+) while minimizing cytotoxic chemotherapy, prolonged antibody-based treatment, and inpatient administration of treatment. Methods: The primary endpoint of this investigator-initiated, Phase 2 study was MR3+ rate after 2 courses. Eligibility criteria includes newly diagnosed Ph+ ALL, age ≥ 18, ECOG ≤2, CD22+ on ≥20% blasts, and no central nervous system (CNS) disease. Schema 1 was as follows; Course (C) 1 was (28 days) dasatinib (DAS) 140mg daily, dexamethasone (dex) 10mg/m2 D1-7 & D15-21, and InO 0.8mg/m2 D8, 0.5mg/m2 D15 and D22. C2 was (28d) DAS 140mg daily + InO 0.5mg/m2 on D1, D8, D15. C3 was TKI + POMP (84d), C4 was TKI + InO (28d), and C5-7 were (84d each) 3 cycles of TKI + POMP. If MR4 was not achieved by end of C2 (EOC2), DAS was switched to ponatinib (PON). Dose limiting toxicity (DLT) window was C1. There were no DLTs, however, a planned interim analysis after 7 pts led to an amended schema (#2) due to the occurrence of veno-occlusive disease (VOD) after the DLT period in 2 pts. Schema 2 is the following: C1 (28d) DAS 140mg daily, dex 10mg/m2 D1-7 & D15-21; C2 (28d) InO 0.5mg/m2 on D1, D8, D15; C3 (84d) TKI + POMP; C4 (28d) TKI (InO added if no MR4); C5-7 (84d each) TKI + POMP. DLT window was C1 + C2 along with continuous VOD monitoring. CNS prophylaxis was 15 doses of intrathecal chemotherapy. Fourteen pts were treated on Schema 2. MR3+ rate of ≥ 64% by EOC2 would meet the efficacy endpoint. Results: Twenty-one pts were enrolled. Median age was 60 (range 21-79) and 57% were female. Race/ethnicity distribution was 53% non-Hispanic (NH) White, 24% NH Black, 14% Hispanic, and 10% not reported. Fourteen pts had p190 transcript, 6 had p210, and 1 had an atypical transcript. Three pts had IKZF1plus. Among all 21 pts, the EOC2 MR4 rate was 62% and another 19% achieved MR3; 4 pts had complete remission without MR3+. Pts (n=8) who did not achieve MR4 at EOC2 switched TKI to PON. The end of C3 (EOC3) MR4 rate was 90%. For the 3 pts with IKZF1plus, MR4 rate was 67% at EOC2 and 100% at EOC3. One pt had a WBC ≥70 at diagnosis and achieved MR4 by EOC2. For Schema 2 (n=14), the EOC2 MR4 rate was 57% and MR3 rate was 14%; the EOC3 MR4 rate was 93%. Measurable residual disease (MRD) was also assessed with next-generation-sequencing (NGS) (sensitivity 10-6); MRD negative (MRD-) rate was 62% by EOC2 and 90% by EOC3. By EOC3, all pts achieved either a MR4 or MRD- disease by NGS. Median follow-up was 1.66 years (range, 0.19-3.85). Estimated 2-year OS was 79% (95% CI, 62%-100%). No pts received allogeneic transplant and there have been no CNS relapses. One pt died in remission while on study (respiratory failure during C5), 3 pts died in remission after going off study (2 sepsis, 1 gastrointestinal (GI) bleed), and 1 pt had a CD19+/CD22- systemic relapse with acquisition of an ABL1 T315I mutation after completing protocol therapy. Two of the first 7 pts on Schema 1 developed VOD; one pt completed protocol therapy with the omission of InO moving forward while the other came off study upon development of VOD. No VOD or DLTs have occurred on Schema 2. Grade 3-4 adverse events with incidence ≥10% were COVID-19 (19%), dyspnea (19%), anemia (14%), and fatigue (14%). Conclusion: TKI + InO-based therapy for newly diagnosed pts with Ph+ ALL has an MR3+ rate of 81% within 2 courses and 100% of pts achieved MR4 and/or NGS MRD- disease by EOC3. No cases of VOD were seen with Schema 2. Given the excellent rates of MR3+ with limited cycles of InO, further development of this induction approach is warranted. Longer follow-up will be necessary to better understand the risk of post-protocol relapse.
Frequent coauthors
- 16 shared
Lukasz P. Gondek
Johns Hopkins Medicine
- 16 shared
Lin Zhao
Sichuan Academy of Traditional Chinese Medicine
- 14 shared
Amy E. DeZern
Johns Hopkins University
- 10 shared
Akhilesh Pandey
- 8 shared
Bryan C. Hambley
University of Cincinnati Medical Center
- 8 shared
Ben Ho Park
- 8 shared
Christopher D. Gocke
Johns Hopkins University
- 8 shared
Richard J. Jones
Johns Hopkins University
Labs
- Resume-aware match score
- Save to shortlist
- AI-drafted outreach
See your match with Rafael Madero Marroquin
PhdFit ranks faculty by your research interests, methods, and publications — grounded in their actual work, not templates.
- Free to start
- No credit card
- 30-second signup