Mascarenhas, John

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

Abstract Background: The functional importance of bone marrow adipocytes (BMA) is frequently overlooked even though they are critical components of the BM (bone marrow) microenvironment. BMA have been proposed to play a supportive role within the hematopoietic niche and to directly sustain hematopoietic stem cell (HSC) survival as well as to preferentially support leukemia cell survival and proliferation (Sabbah Cell Commun Signal 2023). Although significant ex-vivo data implicates direct and indirect crosstalk between BMA and neoplastic HSCs (Venti Front Endocrinol 2022), the possible role of BMA in myeloproliferative neoplasms and their dynamics following therapy have yet to be characterized. Adiponectin, an anti- inflammatory adipokine that maintains metabolic homeostasis through regulation of insulin sensitivity, lipid metabolism and pro-inflammatory signaling is low in MPN patients and increases with IFN-α therapy (Avcu Int J Hematol. 2006). IFN-α has also been implicated in inhibiting adipogenesis via JAK-STAT1 signaling (Lee Biochim Biophys Act. 2016). A single institutional study of IFN-α in patients with essential thrombocythemia (ET) and polycythemia vera (PV) confirmed the potential for BM histopathologic responses and a correlation with molecular responses (Masarova Exp Hematol Oncol 2017). The aim of this analysis was to characterize the change in BM cellularity and fat composition with pegylated IFN α-2a (Pegasys; PEG) and the relationship with both hematologic and molecular response from tissue collected in prospective, global clinical trials of PEG in patients with ET/PV. Methods: A total of 24 subjects from the phase 2 MPN-RC 111 (Yacoub Blood 2019) salvage PEG study and 16 subjects from the MPN-RC 112 (Mascarenhas Blood 2022) phase 3 study comparing PEG to HU with available clinical, BM H&E slides, laboratory and molecular data were included in this retrospective analysis of prospective clinical trial data. We assigned a semi-quantitative score for changes in cellularity, fat distribution, and megakaryocyte (MK) histo-topography for changes from baseline, at 12, 24 and 36 months when available. Changes in BMA content and para-trabecular distribution were assessed on whole slide digital images with machine learning models. BMA content was quantified with a QuPath pixel classifier that distinguished adipocytes from other marrow components (Bankhead Scientific Reports 2017). Para-trabecular adipocyte distribution was assessed by leveraging UNI2-h, a self-supervised Vision Transformer (ViT-H/14) model and successor to UNI (Mahmood Nature 2024). UNI2-h was pre-trained on 200 million image tiles from over 300,000 H&E and IHC slides. In this study, UNI2-h was adapted to distinguish between high and low para-trabecular adiposity using image tiles centered on trabeculae. Trabeculae with a surrounding layer of adipocytes were labeled as ‘high’ adiposity, while ‘low’ para-trabecular fat distribution was defined by the direct contact of cellular marrow with trabeculae, lacking surrounding adipocytes. Results: A total of 40 PEG-treated ET (n=18) and PV (n=22) patients were included in this analysis with a median age of 64 years (26-85), 77% JAK2V617F+, 23% CALRmut+, and 40% treatment-naïve. The median JAK2V617F variant allele fraction (VAF) was 26% (range 3-96%). A complete hematologic response (CHR) was obtained with PEG in 58%, 61% attained >20% reduction in driver VAF and 48% attained a >50% reduction in VAF (MR) within 24 months of baseline. We observed an increase in BMA content and notable increase in para-trabecular distribution (confirmed by morphology and ML, independently) in 93% and 53% of PEG treated patients attaining a MR versus only 31% and 6% who did not attain MR, respectively (P Value=0.0004). There was more notable improvement towards normalization of MK histo-topography and orderly erythropoiesis in MR (86.6%) than in non-MR (31.2%) (P value=0.001). Increase in BMA content, BMA para-trabecular distribution, or improvement in MK histo-topography were not associated with achievement of CHR or changes in CALR VAF in this small cohort. Cytokine correlation with BMA dynamics is currently ongoing and will be reported at the meeting. Conclusion: Treatment of MPN patients with IFN-α resulted in reproducible changes in BM cellularity including MK histo-topography, erythropoiesis, BMA number and distribution. Changes in BMA were closely associated with reduction in JAK2V617F VAF following PEG treatment.

Abstract Background/rationale Primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia (Post-PV/ET MF) (collectively termed MF) are chronic hematopoietic malignancies with progressive bone marrow collagen fibrosis, peripheral cytopenias, extramedullary hematopoiesis, splenomegaly, debilitating constitutional symptoms and heightened risk of transformation to acute leukemia. The only currently approved therapies for MF are JAK inhibitors (JAKi) which can provide significant improvements in splenomegaly and systemic symptoms but do not fundamentally change the pathogenesis of the disease. As a result, additional non-JAKi therapies for patients with MF after JAKi failure represent an important translational focus. Reparixin is a novel, potent and specific inhibitor of the chemokine CXCL8 (IL)-8. IL-8 is a member of a class of cytokines involved in leukocyte recruitment and activation in tissues. There are two known types of CXCL8 receptors – CXCR1 and CXCR2, which are expressed in neutrophils (Baggiolini M, Adv Immunol 1994). IL-8/CXCR1/2 signaling has been shown to be a key mediator of inflammatory signaling in MF patients. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an exogenous CXCL8 ligand in vitro. Genetic deletion or a small molecule inhibitor of CXCR2 in MF mouse adoptive transfer models ameliorates fibrosis, extends overall survival and improves hematologic parameters (Dunbar A, Blood 2023). This pre-clinical data validates targeting this pathway in clinical investigations. Study design This is an open-label, phase II study assessing the efficacy, safety, and tolerability of reparixin in patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-2, or high-risk PMF, post ET/PV MF either after prior treatment with, or those who are ineligible for treatment with a JAKi. Patients will receive oral reparixin 1200 mg three times daily on a four-week cycle for a core study period of 24 weeks. Patients who achieve at least clinical improvement (CI) or stable disease (SD) with one grade improvement in bone marrow fibrosis by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria at the Cycle 7 response assessment may continue receiving reparixin until loss of response, disease progression, unacceptable toxicity, patients/physician withdrawal, or termination of study by sponsor. The study monitors both efficacy and toxicity using a Bayesian Optimal Phase 2 (BOP2) design. If response is observed in at least one patient out of 10 and safety is confirmed at the interim analysis, the trial will proceed to full enrollment of 26 patients. If more than three responses are observed in the total cohort, then a signal of activity is confirmed. Primary Objective: To estimate the efficacy of reparixin treatment in DIPSS intermediate-2 or high-risk subjects with PMF, post PV-MF, or post ET-MF. Secondary Objectives: To assess the efficacy of reparixin as determined by response assessment using IWG-MRT/ELN criteria at the end of Cycle 6 and Cycle 12. To assess the change in bone marrow fibrosis grade at the end of Cycle 6 and Cycle 12 with reparixin. To assess the safety of reparixin as measured by the adverse event profile of Common Terminology Criteria for Adverse Events v5.0. To assess spleen volume reduction by imaging after Cycle 6 and Cycle 12 as compared to baseline spleen volume. Key Exploratory Objectives: To evaluate changes in quality of life and patient-reported outcomes To conduct correlative studies to measure biomarkers of reparixin activity, such as Vascular Endothelial Growth Factor (VEGF) levels, bone marrow microvessel density, megakaryocyte number and peripheral blood CD34+ cell number, and patients with and without IL-8 secretion. Key inclusion criteria: Have a pathologically confirmed diagnosis of PMF, post-ET-MF, or post-PV-MF as per the WHO diagnostic criteria with intermediate-2 or higher risk disease by DIPSS Be refractory/resistant to or intolerant of/inappropriate for JAKi therapy Have adequate liver and kidney function Platelet count ≥ 25 x 109/L Bone marrow and peripheral blood blast count < 10% ANC ≥ 1000 mm3. MPN Research Consortium (MPN-RC) 120 is currently enrolling patients through the MPN-RC clinical sites throughout the United States. Clinical Trial Identifier NCT05835466

Abstract Background Myeloproliferative neoplasms (MPNs) can progress from chronic phase to accelerated or blast phase (MPN-AP/BP), a transition with poor prognosis and limited treatment options. While some abnormalities have been described, the genomic and clonal drivers of transformation remain poorly defined. We characterized mutational and structural alterations in MPN-AP/BP, leveraging paired samples to trace clonal evolution. Methods We profiled 186 samples from 160 individuals, including 159 MPN-AP/BP and 27 chronic-phase MPN samples (26 MF, 1 PV), using targeted sequencing of a 588 gene panel (mean depth: 709x). Paired pre- and post-transformation samples were available for 26 patients (n= 52). A consensus pipeline was used to detect somatic mutations, copy number variations (CNVs), and copy-neutral loss of heterozygosity (cnLOH). Clinical cytogenetic data were integrated when available. Single-cell validation is ongoing. Results Genomic complexity was widespread: 99% of patients harbored ≥1 oncogenic mutation (median 4; range 1–10). In total, 859 mutations were identified, most commonly in JAK2 (68%), ASXL1 (28%), TET2 (26%), SRSF2 (24%), TP53 (22%), and RUNX1 (22%). 684 structural alterations were identified in 86% of patients (median 3; range 1-20), including arm-level (22.5%), segmental (>5 Mb; 60%), and focal (<2 Mb; 9%) alterations. Recurrent events included 9p cnLOH (16%), del(5q) (13%), del(17p) (10%), and focal deletion of 21q22.12 involving RUNX1 (10%). Complex karyotypes (≥3 abnormalities) were observed in 55% of patients. Biallelic mutations accounted for 21% (183/859) of mutations, affecting 58% of patients across 21 genes, most frequently JAK2 V617F (28%), TP53 (17%) and TET2 (14%). Patients with biallelic mutations in these genes had significantly higher blast percentages compared to those with monoallelic mutations (p<0.05), highlighting an association with aggressive disease. In 26 patients with longitudinal samples (chronic phase MPN and MPN-AP/BP), 87% (125/144) of mutations were already detectable during the chronic phase, on average more than 7 years prior to transformation. Only 11% (16/144) of mutations were newly acquired, including additional RUNX1 and TP53 hits, or structural changes that converted pre-existing JAK2 V617F and TP53 R248Q mutations from monoallelic to biallelic via 9p cnLOH or 17p loss, respectively. These findings suggest transformation is often driven by outgrowth of pre-existing high-risk clones, indicating that these clones likely have a competitive advantage and that the mutations within these clones have a cooperative biological interaction which underlies this competitive advantage. To investigate this hypothesis, we examined whether patterns of recurrent co-mutations were identifiable in this cohort. We identified recurrent co-occurring mutations in SRSF2-IDH2, ASXL1-SRSF2, and ASXL1-EZH2, which were enriched at transformation (p < 0.05; Fisher exact test). Importantly, presence of these co-mutations was consistently associated with a higher transformation risk in two independent cohorts of MF patients from Mayo Clinic (n= 405) and University of Florence (n= 518). Clonal architecture analysis revealed that these co-mutations frequently arose within the same malignant clone: 100% for SRSF2-IDH2, 80% for ASXL1-SRSF2, and 85% for ASXL1-EZH2, and are often within the dominant clone. Prior studies have demonstrated mechanistic interplay between SRSF2 and IDH2 (Yoshimi et al.), as well as ASXL1 and SRSF2 (Sui et al.) mutations in myeloid malignancies. We assessed functional synergy of ASXL1-EZH2 using a murine model and identified that dual deletion caused a rapidly fatal myeloid neoplasm with shorter survival than single-gene loss. These results reinforce that functional synergy emerges within a shared cellular context, supporting clonal co-dependence as a driver of progression. Single-cell RNA sequencing of ASXL1-EZH2 mutant cases is ongoing and will be presented. Conclusions Transformation to MPN-AP/BP is driven by gradual clonal remodeling and expansion of pre-existing high-risk abnormalities. Biallelic and multi-hit alterations in TP53, JAK2, TET2, and RUNX1 promote clonal dominance and blast progression. Recurrent co-mutations such as IDH2-SRSF2 and ASXL1-EZH2 arise within the same clone, exhibit functional synergy, and are linked to poor outcomes. These findings support the clinical utility of early clonal and co-mutational profiling to guide risk-adapted intervention.

Abstract Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have a propensity to transform to an accelerated or blast phase (MPN-AP/BP). The resulting disease has clinically similar manifestations to Acute Myeloid Leukemia (AML) but worse clinical outcomes. Here we present the first comprehensive description of the transcriptomic characteristics of MPN-AP/BP. Our analysis incorporates data from 261 patients of the BeatAML cohort and 56 MPN-AP/BP patients, 11 of whom had paired samples from before and after transformation. We establish that transformed MPN is a transcriptionally distinct entity from de novo AML and chronic phase MPNs. Genomic pathways traditionally associated with MPN pathogenesis, such as IL2/STAT5 signaling and IL6/JAK/STAT3 signaling were enriched in chronic-phase MPNs but are absent in transformed disease, suggesting JAK2 directed therapy may be less effective in this disease phase. We also discovered that gene expression signatures associated with doxorubicin resistance are highly enriched in transformed MPNs, which may explain the lack of efficacy of standard AML therapies. In addition, we identify that lineage composition at the time of transformation may define distinct subsets of MPN-AP/BP patients, which may assist in the future development of novel treatment strategies.

Abstract Most myelofibrosis (MF) drug approvals by Health Authorities are based on 1 or 2 outcome measures such as spleen volume reduction and/or improved quality-of-life. This 1–2 dimensional approach fails to capture the clinical complexity of MF. A European LeukemiaNet (ELN) taskforce developed a composite endpoint which allows multiple outcomes to be simultaneously measured. The panel used the Desirability-Of-Outcome-Ranking (DOOR) method to assign 25 outcomes into 4 quartiles based on a multi-dimensional desirability score and build a 5-layer composite outcome named Desirability-of-Myelofibrosis-Outcomes (DEMYO). Outcome operational definitions were tested by Delphi consensus and correlations with survival validated by a literature review. The outcomes assigned to the first two quartiles were negatively correlated with leukemia-free survival and survival. DEMYO comprehensively captures relevant MF clinical features and meaningful endpoints. Despite DEMYO requires validation based on available trial data, it is expected to improve the quality of Health Authority approvals for new drugs for MF.

Introduction TP53 alterations (TP53+) are seen in <5% of patients (pts) with chronic myeloproliferative neoplasms (MPNs) but are more common in accelerated/blast phase (MPN-AP/BP) [Luque Paz D, et al 2020]. While pts with low-burden TP53+ (Variant allele frequency (VAF) <5%) may remain stable for years [Kubesova et al, 2018]; biallelic loss of TP53 is thought to confer higher risk for progression [Li et al, 2022] and worse overall survival (OS) than non-TP53+ pts [Rolles et al, 2023]. However, TP53 abnormalities have not been incorporated into currently utilized molecular based prediction models (MIPSS or MIPSS70) or compared with currently validated high molecular-risk (HMR) mutations (mut). We report the outcomes of the largest cohort of TP53+ MPN pts to date in comparison with HMR mut, and identify a VAF cut-off associated with highest risk of progression to MPN-AP/BP. Methods We retrospectively reviewed 2583 MPN pts from Mount Sinai Hospital (MSH) and Memorial Sloan Kettering Cancer Center (MSK) with at least one next generation sequencing (NGS) performed. Deidentified data from an additional cohort of 8 TP53+ MPN pts was received from University of Miami Sylvester Cancer Center (UMiami). Patient characteristics such as MPN subtype, gender, age at MPN diagnosis, driver mutation, thrombosis history were recorded. We also recorded date of transformation to MPN-AP/BP, dates of NGS testing, mutational and cytogenetic data, and survival status. We defined multi-hit TP53 as presence of =/>2 TP53mut, VAF > 50% or TP53 mutation + 17p deletion. Additional cohorts of pts with HMR mut (ASXL1, EZH2, IDH1/2, U2AF1, SRSF2 as per MIPSS70v.2) from MSH and non-TP53+ pts from the MPN-Research Consortium Tissue Bank were used as comparator arms. Patient characteristics were compared between TP53 single-hit and multi-hit using Chi-Sq test for categorical variables and Kruskal-Wallis test for continuous variables. Cumulative incidence function and Kaplan-Meier method were used to compare leukemic transformation and OS, respectively, between groups. Successive VAF levels with minimum groups of 25% of the total cohort were used to identify an optimal VAF cut-off. Results Of the 2583 MPN pts from MSH and MSK, 66 pts (2.6%) were found to have a TP53 mutation. Including 8 additional pts from UMiami, we analyzed a total of 74 TP53+ MPN pts; 40 single-hit and 34 multi-hit. Median age at MPN diagnosis was 61 years with a male predominance (60%). Distribution of driver mut was similar in single-hit vs multi-hit cohort with JAK2V617F being the most common (58%), whereas 11% of pts had triple negative disease . Thrombotic history was available for 45 TP53+ pts, with a high frequency of venous/arterial thrombosis (21/45 or 46.7%) in the TP53+ group as compared to 18.5% in the non-TP53+ MPN cohort (p= 0.0001). A significantly higher number of multi-hit TP53+ pts had a concurrent complex karyotype (79% vs 24% in single-hit; p<.001). MPN diagnosis at the time of detection of TP53+ was ET/PV (25.7%), MF (44.6%), MDS/MPN overlap syndrome (6.8%), MPN-U (2.7%) and MPN-AP/BP (20.3%), respectively. One or more genetic samples with TP53+ was available prior to transformation to MPN-AP/BP in 77% of pts (21/34 multi-hit; 36/40 single-hit) while a TP53+ was detected at the time of MPN-AP/BP diagnosis in the rest. Multi-hit TP53+ was associated with a significantly higher incidence of transformation to MPN-AP/BP as compared to single-hit; [65% vs 17.5%; HR=4.08 (1.71-9.71), p=0.0015]. Compared with HMR mut, multi-hit (HR=2.41; p=0.004) but not single-hit (HR=0.53; p=.277) TP53+ MPN pts were found to have a significantly increased risk of MPN-AP/BP transformation. One-year OS from the time of mutation detection was significantly inferior for both multi-hit (53.3%) and single-hit (75%) TP53+ pts as compared to HMR mut (98.8%, p=<.001). Cut-point analysis identified VAF >36% to be associated with the highest risk of transformation (HR=3.08) with lowest p-value (0.002). Conclusions Multi-hit TP53 alterations are associated with a significantly increased risk of leukemic evolution as compared to previously validated HMR mut, whereas both multi and single-hit TP53 mut are associated with worse OS highlighting the importance of TP53 in MPN disease progression.

Background New therapies for myelofibrosis (MF) are being developed but how these compare with current therapies is limited to analyzing single outcome measures such as spleen volume reduction or quality-of-life (QoL). However, these outcome trajectories might diverge and some endpoints may not be clinically relevant. To remedy this an ELN (European LeukemiaNet) taskforce developed a composite endpoint using the Desirability-Of-Outcome-Ranking (DOOR) method which allows multiple outcomes to be simultaneously considered and therapies achieving diverging endpoints compared. Methods An Expert Panel used DOOR to divide outcome relevancy into 8 dimensions: clinical meaningfulness, modifiability, reliability, feasibility, decisional value, acceptability, frequency, and cost. Next, a weight was assigned to each dimension using the mean Likert score assigned by the panelists. Next, the panel validated which dimensions were met by each of 30 outcomes most frequently listed by clinical trials. A weighted score (WS) for each outcome was calculated based on weights assigned to a dimension and accomplishment rates assigned to outcomes. Outcomes were then distributed into quartiles. Next, operational definitions of outcomes were tested in Delphi consensus method requiring > 75% agreement. Last, a literature review indicated correlations of the outcomes ranked in the 1st 2 quartiles with survival. Results Three composite endpoints were developed and named DEMYOs (DEsirability-of-MYelofibrosis-Outcomes). DEMYO-1, the proportion of people alive and free of severe vascular events, blast transformation, severe anaemia and thrombocytopenia and very-severe symptom burden, encompassed outcomes in the 1st quartile (WS > 29.5) and is the proposed composite endpoint for trials of people with advanced JAK-inhibitor refractory MF. DEMYO-2, defined as the proportion of people alive and free of accelerated or blast phase, severe or worsening anaemia, severe and major vascular events, severe or symptomatic splenomegaly, severe or worsening symptoms and any emergent adverse genetic abnormality, included the outcomes ranked in the 1st 2 quartiles (WS > 26.5) and is proposed for trials of people with a sub-optimal response to JAK-inhibitors. DEMYO-3, defined as the proportion of people alive and free of blast transformation, vascular events, severe, symptomatic or worsening clinical features and of worsening prognostic co-variates, included outcomes in the 1st 3 quartiles (WS > 23.5) and is proposed for trials of people not yet receiving JAK-inhibitors. Interpretation DEMYO composite endpoints capture relevant clinical features of MF and represent endpoints important to patients, physicians and other stakeholders. DEMYO validation is feasible by available trial data and, once validated, the composite endpoints can be endorsed by medicines regulatory agencies. DOOR proved feasible and robust in this 1st-in-haematology application and we encourage further use. No funding

ABSTRACTSpleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST‐2 study. Patients on study at the start of the 12‐week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non‐responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non‐responders (HR, 0.00; 95% CI, 0.00–0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781

Abstract Background The US Food and Drug Administration (FDA) released a draft guidance document detailing core patient-reported outcomes in cancer clinical trials, including physical function (PF). This study aimed to develop analytic methods and visualizations of patient-reported PF in patients with cancer. Methods We applied an estimand framework to a patient-reported tolerability endpoint to develop data summaries cross-sectionally and over time, along with visualizations. We accomplished this through iterative feedback with clinicians, statisticians, and FDA stakeholders using three clinical trial datasets in hematologic malignancies. Graphical approaches were applied to three datasets in hematologic malignancies: (1) patients with myeloproliferative neoplasms enrolled in MPN-RC 111/112 trials completed EORTC QLQ-C30 over 12 months; (2) patients with hematologic malignancies undergoing CAR-T cell therapy or autologous transplant who completed FACT questionnaires over 6 months; and (3) patients with multiple myeloma or amyloidosis who completed the PROMIS-29 questionnaire over 6 months. Zoom polls were administered to two stakeholder groups (clinicians/clinical investigators and patient advocates) to elicit feedback. Results Visualizations included stacked bar charts, line plots of arithmetic mean changes from baseline, pie charts, waffle plots, and waterfall plots of PF data. Graphics considered scaled scores and individual items and included delineation of PRO completion rate at each time point. Confidence intervals and reference lines were included as applicable, and colorblind accessible colors were implemented to ensure inclusivity of all visualizations. Data summaries over time reporting “worst” change were difficult to interpret. In terms of stakeholders’ preference, patients preferred stacked bar charts while clinicians equally favored stacked bar charts and line plots; both patients and clinicians preferred waterfall plots to pie charts. Patient feedback highlighted the need for various graphics to convey group level trends and granular individual-patient level information. Conclusion Patient-reported PF informs the evaluation of treatment tolerability in cancer trials. Data summaries and visualizations of physical function developed through an iterative process were reviewed favorably by patients, clinicians and FDA stakeholders in this study. Future work to systematically assess accuracy of interpretation of the various analytic and visualization methods is a necessary next step across clinical, regulatory, payer and patient stakeholders. Trial registration NCT01259817, NCT01259856