City Of Hope Research Articles

Abstract C098: CYR61 expression in prostate cancer patients at City of Hope

Abstract In the US, African-American (AA) and Hispanic/Latino (H/L) men have higher rates of advanced prostate cancer (PCa), increased PCa-specific mortality, and are more likely to undergo metastasis than non-Hispanic White (NHW) men attributed to a lack of access to early screening, and a higher prevalence of risk factors such as obesity, diet, and genetic differences. Consequently, effective treatment of advanced PCa and elimination of racial and ethnic disparities for this malignancy require the identification of mechanisms of disease progression. In PCa, the cysteine-rich angiogenic inducer 61 (CYR61) contributes to malignant cell growth through interactions with extracellular ligands, such as integrins avb3 and a6b4. In previous studies, we have found that CYR61 is upregulated in metastatic PCa cell lines and knockdown of this protein significantly reduced metastatic cell proliferation, viability, prostasphere formation, and activation of the PI3/AKT pathway, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Interestingly, we have observed that in metastatic PCa cell models, IGF1 induction increased CYR61 protein expression. However, the correlation between PCa aggressiveness and levels of CYR61 in tumor-derived tissues from patients is poorly studied. Our goal with this study is to identify possible correlations in CYR61 expression that may reflect health disparities in PCa outcomes. We used in silico analyses from whole exome paired tumor/normal DNA sequencing and tumor RNA sequencing data available on 542 PCa cases in the City of Hope POSEIDON database to determine whether gene expression of CYR61 and IGF1 was correlated with genetic ancestry, Gleason score, and tumor purity. In univariate analyses, we found that H/L PCa cases had significantly higher levels of expression of CYR61 than NHW PCa cases (p = 0.043) and that both H/L and AA PCa cases had higher IGF1 expression levels, although only significant in AA (p=0.031). We also found that PCa patients with Gleason scores of 8 and higher had significantly lower expression of IGF1 than those with Gleason scores of 7 or less (p=0.006). Both CYR61 and IGF1 expression levels were significantly lower in those with luminal B (p=0.00000000053, p=0.000009, respectively) and with basal subtypes (p=0.00035, p=0.000069, respectively compared to luminal A subtype. Tumor purity was estimated by RNA-seq based on 141 genes specific to stroma and 141 genes specific to immune cells. CYR61 expression was significantly correlated with stromal and immune infiltration. These results suggest that reduced CYR61 expression is associated with more aggressive PCa. Additional analyses are ongoing to understand the interplay of variables of race and ethnicity, age, Gleason score, and tumor purity and to investigate outcomes of biochemical recurrence and death from PCa. Citation Format: Greisha L. Ortiz-Hernandez, Yuan Chun Ding, Susan L. Neuhausen. CYR61 expression in prostate cancer patients at City of Hope [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C098.

Abstract C085: Somatic mutational profiles of breast tumors from Hispanic/Latino women

Abstract Background: Breast cancer is the leading cause of cancer mortality among Hispanic/Latina (H/L) women. Precision medicine holds promise for more effective treatments by targeting therapies based on somatic mutations, copy number changes, mutational signatures, and/or germline risk variants. However, there is a paucity of genomics data for H/L women with breast cancer leading to a disparity in the application of precision medicine. We have previously characterized mutational profiles of 146 breast tumors from 140 H/L women. Here, we analyze data from whole exome tumor/normal sequencing and tumor RNA sequencing from 430 self-reported H/L breast cancer cases and compare their profiles to 385 tumors from self-reported White breast cancer cases. Methods: All participants were treated at City of Hope and all sequencing data were generated using Ashion GEM ExTra (Exact Sciences). Tumor/germline sequence data were aligned to the human genome (Build37) and variants were called using the FreeBayes workflow. To determine significantly mutated genes, we used MutSigCV and dNdS. We used Fisher’s exact test to determine if the frequency of somatic mutations was significantly different among H/L women and White women and corrected for multiple hypothesis testing using Benjamini-Hochberg false discovery rate (FDR). Results: Seventeen genes and 19 genes had q-values < 0.05 in H/L and White samples, respectively. Of those, AKT1, CBFB, FOXA1, MAP2K4, MAP3K1, MLL3, PIK3CA, PTEN, RB1, RUNX1, TBX3, TP53, and ZFPM1 were significantly mutated in both. CTCF and HS6ST1 were significantly mutated only in tumors from H/L. ARID1A, CDKN1B, NCOR1, and PRRT2 were significantly mutated only in tumors from White women. There was a significantly higher frequency of TP53 mutations (FDR q-value = 0.007) and CTCF mutations (FDR q-value = 0.057) in tumors from H/L compared to tumors from Whites. Conclusions: We found TP53 and CTCF to be more commonly mutated in tumors from H/L women. CTCF mutations are seen in other tumor types, but our study is the first to demonstrate that this gene is significantly mutated in breast cancer in any population. Since CTCF is a broadly active transcriptional regulator, tumors with these mutations may be associated with broad dysregulation of gene expression. Citation Format: Yuan Chun Ding, Shu Tao, Allen Mao, Elad Ziv, Susan L. Neuhausen. Somatic mutational profiles of breast tumors from Hispanic/Latino women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C085.

Abstract B115: Intensive Course in genetic cancer risk assessment: Empowering clinicians, expanding clinical knowledge, and elevating care in underserved populations

Abstract Background: Despite efforts to integrate genetic cancer risk assessment (GCRA) services into mainstream medicine, the dearth of healthcare providers adequately trained in clinical cancer genetics remains a significant barrier to care, particularly in underserved communities. Since 2001, City of Hope has helped address this need through a distance mediated lntensive Course (IC) and Clinical Cancer Genomics Community of Practice (CCGCoP), with a focus on training and supporting clinicians who deliver care to underserved patient populations. Here we report on the reach, education, and practice outcomes from the past five annual cohorts of the IC in its pursuit to expand GCRA care to underserved areas and minority populations. Methods: Practice catchment area and patient population data were collected on the course application. Cancer genetics knowledge was assessed at baseline and immediate post-course; professional self-efficacy and practice changes were measured at baseline, immediate, and 12 months post-course. Results: Of 762 participants from five IC cohorts (2020-2024), 566 (74%) indicated they provide all or part of their care in an underserved area and/or to minority populations; 55 (10%) practice outside the U.S. Of these 566 clinicians, mean pre-to-post course knowledge scores increased 59%, and mean pre-to-post self-efficacy scores increased by 38%. Of 195 participants who completed a one-year post-course practice survey, 68 (35%) did not practice GCRA at baseline, of whom 61 (88%) reported implementing GCRA into their practice one-year post-course. Of 126 participants who were practicing GCRA at baseline, 55 (44%) reported an increase in their GCRA patient volume at one-year post-course. Open-ended feedback revealed that participants highly valued IC training and ongoing CCGCoP support for building and sustaining their GCRA skills, resources, and practices. Conclusions:Results demonstrate the efficacy of distance-mediated training and ongoing practice support in enhancing clinician competencies and knowledge of practicing GCRA therefore increasing access to GCRA services for underserved and minority patient populations. Efforts are underway to leverage the resources of the IC and CCGCoP to develop a more flexible, cost-effective course model and collaborate with champions to increase access to best practices in GCRA in diverse underserved settings across the US and internationally. Citation Format: Dev Tanna, John Luna, Alex Capasso, Kathleen Blazer. Intensive Course in genetic cancer risk assessment: Empowering clinicians, expanding clinical knowledge, and elevating care in underserved populations [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B115.

Abstract C044: Social vulnerability is an important predictor of cardiovascular disease risk after allogeneic hematopoietic cell transplantation

Abstract Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for malignant and non-malignant hematologic diseases. However, long-term HCT survivors have a >4-fold risk of developing cardiovascular disease (CVD) compared to the general population, and CVD is a leading cause of excess mortality after HCT. Comorbidities that emerge after HCT such as hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are important modifiers of CVD risk, but the impact of social determinants of health (SDOH) on the development of these risk factors and resultant CVD has not been well-characterized. Methods: This retrospective cohort study included 889 patients who underwent an allogenic HCT between 2013 and 2019 at City of Hope and survived ≥1y after HCT. Demographic, disease, treatment, comorbidity, and health outcomes data were abstracted from medical records. The social vulnerability index (SVI), obtained from the Center for Disease Control, represented overall social vulnerability and included 4 themes: socioeconomic status, household composition & disability, minority status & language, and housing & transportation. SVI scores were derived using patients’ addresses at time of HCT. SVI scores ranged from 0 (least vulnerable) to 100 (most vulnerable). Fine-Gray regression analysis evaluated the association between SVI and risk of HTN, DM, and DL, adjusted for age at HCT and treating death as competing risk. We also evaluated the association between having 0, 1, ≥2 cardiovascular risk factors on incidence of clinically significant CVD (heart failure, coronary artery disease, pericarditis, stroke, intracranial hemorrhage, arrhythmia, and/or valvular disease) after HCT. Results: Mean age at HCT was 44.2y (standard deviation 19.8y); 56.7% were male, 43.8% were non-Hispanic White, 35.4% were Hispanic, and 12.9% were Asian. The most common diagnosis was acute myeloid leukemia (39.6%); 48.6% received reduced intensity conditioning. Higher overall SVI was associated with increased risk of HTN (adjusted Hazard Ratio per 10 unit increase in SVI [aHR] 1.10, 95%CI 1.02-1.19) and DM (aHR 1.13, 95%CI 1.03-1.25). There was also an increased risk for DL for the highest SVI tertile for the housing & transportation theme (aHR 1.61, 95%CI 1.10-2.37). Accumulation of de novo risk factors after HCT was associated with an incremental 5y incidence of CVD (None: 6.1%, 95% CI 3.4%-9.9%; 1 risk factor: 15.7%, 95% CI 7.1%-27.3%; >2 risk factors: 31.6%, 95%CI 12.8%-52.4%; p<0.001). In the adjusted multivariable model, survivors with >2 risk factors had 7.0-fold (aHR 6.99, 95%CI 2.86-17.05) risk of CVD compared to those without (ref). Conclusion: Among allogeneic HCT recipients, higher SVI was associated with increased risk of HTN, DM, and DL after HCT, which in turn were associated with incrementally higher 5y incidence of CVD. These findings underscore the importance of SDOH on clinically important outcomes after allogeneic HCT, and may ultimately inform tailored approaches for risk-based screening and resource allocation in long-term survivors. Citation Format: Osariemen V Ogiamien, Sitong Chen, Lizel Atencio, Alysia Bosworth, Meagan Echevarria, Caitlyn Estrada, Mareen Kassabian, Lanie Lindenfeld, F. Lennie Wong, Saro H Armenian, Rusha Bhandari. Social vulnerability is an important predictor of cardiovascular disease risk after allogeneic hematopoietic cell transplantation [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C044.

Impact of spliceosome mutation on outcomes of myelodysplastic syndrome and chronic myelomonocytic leukemia patients undergoing allogeneic hematopoietic cell transplantation

IntroductionAllogeneic Hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The impact of spliceosome mutations on allo-HCT outcome is unclear and further understanding is needed to assess the implications of this class of mutations on risk of relapse, overall survival (OS) and non-relapse mortality (NRM) in order to make decision regarding timing of allo-HCT. We examined the allo-HCT outcomes of MDS/CMML patients based on their spliceosome mutation profile to understand the impact of these mutations on transplant outcomes. ObjectiveTo compare outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT. MethodsThis is a single institution, retrospective study of MDS/CMML patients who underwent allo-HCT with myeloablative or reduced intensity conditioning (RIC) regimen at City of Hope from January 2016 to December 2021. Among them, patients who underwent molecular mutation profiling by NGS (Next Generation Sequencing) for a set of genes known to be mutated in myeloid neoplasms are included in this analysis. We compared OS, relapse free survival, NRM and acute/chronic graft versus host disease (GVHD) incidence between the spliceosome-mutated and unmutated groups. ResultsWe identified 258 consecutive MDS/CMML patients who underwent allo-HCT. Of these, 126 (48.8 %) patients had molecular profiling done among whom 57 (45.2 %) patients carried a spliceosome mutation. 84.9 % of patients had MDS and 55.6 % underwent a matched unrelated donor transplant. The median age for the whole cohort was 66 years (range 12–77).78.6 % and 73.7 % received RIC in the spliceosome and non-spliceosome groups, respectively. The 2-year OS for the whole cohort was 66.5 % (95 %CI 0.55–0.75) with a day 100 NRM of 7.1 % and 2-year cumulative incidence of relapse of 20 %. Grade II-IV acute GVHD at day 100 was 36.3 % (95 % CI 0.27–0.44) and any chronic GVHD at 2-years was 48.4 % (95 % CI 0.37–0.58). Patients who carried a spliceosome mutation had a significantly better 2-year survival of 83.8 % vs 55.9 % in the non-spliceosome group (P=0.002) and a better PFS of 73.7 % vs 50.0 % (P=0.007). There was no difference in the cumulative incidence of relapse at 2-years 15.9 % vs 18.5 % (P=0.59) between two groups but the spliceosome group had a significantly lower NRM at 2-years 10.4 % vs 31.5 % (P=0.009). There was no difference in incidence of acute or chronic GVHD between the two groups. ConclusionsAmong patients with MDS or CMML who underwent allo-HCT, our study shows better OS for patients who have spliceosome mutations due to lower NRM compared to those carrying non- spliceosome mutations. This favorable outcome of the spliceosome-mutated patients could have implications for timing of allo-HCT, particularly for patients in the intermediate MDS prognostic risk groups.

Total Body Irradiation and Fludarabine with Post-Transplantation Cyclophosphamide for Mismatched Related or Unrelated Donor Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative treatment for most patients with hematologic malignancies. A well-matched donor (related or unrelated) remains the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we investigated outcomes of patients who underwent mismatched donor (related or unrelated) HCT with a radiation-based myeloablative conditioning MAC regimen in combination with fludarabine, and post-transplantation cyclophosphamide (PTCy) as higher-intensity graft-versus-host disease (GVHD) prophylaxis. We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT (related/haploidentical versus unrelated [MMUD]) with fractionated-total body irradiation (fTBI) plus fludarabine and PTCy as GVHD prophylaxis at City of Hope from 2015 to 2021. Diagnoses included acute lymphoblastic leukemia (46.5%), acute myelogenous leukemia (36.1%), and myelodysplastic syndrome (6.5%). The median age at HCT was 38 years, and 126 patients (81.3%) were an ethnic minority. The Hematopoietic Stem Cell Transplantation Comorbidity Index was ≥3 in 36.1% of the patients, and 29% had a Disease Risk Index (DRI) of high/very high. The donor type was haploidentical in 67.1% of cases and MMUD in 32.9%. At 2 years post-HCT, disease-free survival (DFS) was 75.4% and overall survival (OS) was 80.6% for all subjects. Donor type did not impact OS (hazard ratio [HR], .72; 95% confidence interval [CI], .35 to 1.49; P = .37) and DFS (HR, .78; 95% CI, .41 to 1.48; P = .44), but younger donors was associated with less grade III-IV acute GVHD (HR, 6.60; 95% CI, 1.80 to 24.19; P = .004) and less moderate or severe chronic GVHD (HR, 3.53; 95% CI, 1.70 to 7.34; P < .001), with a trend toward better survival (P = .099). The use of an MMUD was associated with significantly faster neutrophil recovery (median, 15 days versus 16 days; P = .014) and platelet recovery (median, 18 days versus 24 days; P = .029); however, there was no difference in GVHD outcomes between the haploidentical donor and MMUD groups. Nonrelapse mortality (HR, .86; 95% CI, .34 to 2.20; P = .76) and relapse risk (HR, .78; 95% CI, .33 to 1.85; P = .57) were comparable in the 2 groups. Patient age <40 years and low-intermediate DRI showed a DFS benefit (P = .004 and .029, respectively). High or very high DRI was the only predictor of increased relapse (HR, 2.89; 95% CI, 1.32 to 6.34; P = .008). In conclusion, fludarabine/fTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of donor relationship to the patient, provided promising results, and increased access to HCT for patients without a matched donor, especially patients from ethnic minorities and patients of mixed race.

Lower Weight-Based Mycophenolate Mofetil Dosing is Associated with Superior Outcomes after Haploidentical Hematopoietic Cell Transplant with Post-transplant Cyclophosphamide

Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR = 0.45, 95% CI: 0.21 to 0.94, P = .03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR = 0.58, 95% CI: 0.34 to 0.99, P = .045). MMF relative dose exposure was not associated with engraftment, GVHD, nonrelapse mortality, or OS. In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen.

Keeping health care professionals healthy: Systematic strategies for mitigation, wellness, and burnout prevention.

9013 Background: Health care professionals are deeply committed to the compassionate care of their patients. However, the same level of caring and compassion is not typically extended to colleagues, much less toward themselves. Escalating issues include: burnout, demoralization, personal conflicts, early retirement, and high turnover. Literature and training offer few suggestions to proactively address these complexities. There is a lack of attention to creating truly healthy work environments, with strategic infrastructure to enhance leadership, communication, and relationship among team members that directly impact wellness, engagement, and productivity. We will present the Staff Leadership Model (SLM) that integrates courageous and compassionate communication to foster healthier work environments, including how to implement and sustain the necessary infrastructure. Methods: In 4 large academic cancer settings, evolving iterations of the SLM were developed since 1995, focusing on maximizing inherent human capacities. In 2007, the Department of Supportive Care Medicine (DSCM), an interdisciplinary department at City of Hope (COH), systematically integrated the SLM. Specific processes, such as onboarding and skills training, regularly scheduled, open and honest communication, ways of working agreements, and performance evaluations that actively support value-driven behaviors, were implemented. Tailored interpersonal strategies were implemented, such as small group democratic meeting structure that equalizes all members, and problem-solving skills to deal with conflict. Clinicians received annual Press Ganey-administered surveys that measured clinician engagementas well as clinician resilience, measuring the ability to disconnect from work and ability to find meaning in their work, providing early warning indicators of burnout. Results: Sustained success has been demonstrated: 1) 5 years top tier clinician/staff engagement scores, with increase from 4.24 in 2022 to 4.32 in 2023 (+0.14 vs. overall COH) ; 2) 3.96 resilience index score vs. 3.80 overall COH in 2023 (3.23 decompression score vs. COH 2.94 and 4.69 activation score vs. COH 4.65); 3) Growth of the department from 25 professionals in 2007 to 170+ in 2024; 4) A clearly-defined clinical triage created through the expertise of the professionals; and 5) Staff creativity and leadership resulting in the creation and consistent growth of innovative, market-differentiating programs. Conclusions: Results support the relationship between the SLM and healthier work environments that increase engagement and decrease burnout, as reflected by the consistently high scores. The resilience index is a new survey measure with one year data. Cause-effect relation will continue to be evaluated. Overall, SLM creates a culture of health, wellness, support, and optimized individuals and teams.

Geriatric assessment-directed supportive care intervention (GAIN-S)-implementation via telehealth in a lower-resourced community.

1510 Background: Based on randomized controlled trials,ASCO guidelines recommend use of geriatric assessment (GA)-directed interventions for older adults with cancer. The translation of these models to lower resourced settings has been limited. We assessed the feasibility of implementing GA-directed supportive care (GAIN-S) via telehealth in a lower resourced community setting. Methods: A quality improvement study was conducted in a high poverty, limited access, and low resourced community oncology practice (City of Hope - Antelope Valley [COH-AV]). Eligible participants were 65+ years with a new diagnosis of a malignant neoplasm under evaluation for cancer therapy. Before starting therapy, patients completed: baseline GA, SupportScreen, and the Fulmer SPICES assessment. A geriatric nurse practitioner (GNP) reviewed GA results and implemented multidisciplinary supportive care interventions (GAIN-S) via telehealth between April 2020 and January 2023. Key evaluation measures included: number of patients who completed GAIN-S; number of referrals to multidisciplinary supportive care services and completion rate; advance directives (ADs); and patient satisfaction with telehealth visits. Participants’ demographics, including distance traveled for care, type of cancer, stage, treatment, and telehealth satisfaction items, were summarized using descriptive statistics. To analyze and visualize the implementation process, run charts were utilized. Results: 251 patients (mean age 74, 62% Non-Hispanic White, 22% live 60+ miles from COH-AV, 56% stage II or less, 30% received chemotherapy) completed baseline assessments. 242 had initial visits with GNP, 197 via televideo and 45 via telephone. GNP reviewed vulnerabilities with 209 patients and generated 460 referrals for supportive care services, with 85% of services implemented. Highest numbers of referrals were to pharmacy (177), social work (142), occupational therapy (76), and physical therapy (48). GNP discussed GA-guided care plans with all patients and 43 patients completed AD after discussion with GNP. Over 92% of patients were satisfied with telehealth-based GAIN-S in terms of both ease of visit and access to care with their provider and with telehealth. Conclusions: Telehealth-based GAIN-S has proven to be feasible in providing accessible healthcare to older patients with cancer in a lower resourced community setting. This approach, well-received by most patients, highlights the potential of telehealth in delivering GAIN-S effectively in such settings.

Improving goal concordant care clinician workshops: Do patients benefit?

9035 Background: From 2020-2023, the Alliance of Dedicated Cancer Centers (ADCC) undertook a national initiative to improve goal concordant care (IGCC) where all cancer patients and their families receive care that aligns with their values and priorities. One of the core components of the program was to implement a formal communications skills training program supporting the delivery of goal concordant care. As an ADCC member, City of Hope’s (COH) Department of Supportive Care Medicine created the Improving Goal Concordant Care Virtual Workshop Series to address this need. Methods: The 2-part workshop series covered: Goal concordant care, having difficult conversations, advanced care planning (ACP), advance directives, Physician Orders for Life Sustaining Treatment forms, and code status. Physicians and nurse practitioners (NPs) were independently evaluated regarding their quality of care pre-/post workshop #1 by their outpatients through the “Heard and Understood (HAU)” survey, a patient-reported quality measure with 4 items: I felt heard and understood (HU), Provider understood what was important my life (UL), Provider saw me as a person (SP), Provider put my best interests first (BI). Response categories ranged from 1, not at all trueto 5, completely true. Top-box rates and percentage of patients responding completely true for a given item were calculated for each clinician. Pre-/post changes in top-box rates were examined with paired t-tests. Differences in rates over time, by clinician type, were evaluated using mixed effect modeling. Survey items were initially analyzed individually, then combined. A p-value &lt; 0.05 was considered statistically significant. Results: A total of 37 clinicians (26 Physicians and 11 NPs) were evaluated. Patients’ experience with physicians (NPs excluded) improved between pre/post training: The rates increased for the overall HAU scale (4.31, p=0.002), as well as for several individual items such as HU, UL and BI (5.24, 6.33 and 2.52 respectively, p-values&lt;0.05). Notably, the rates for HU increased for physicians but not for NPs (5.24 vs -3.22, difference= 8.46, p=0.012), though NPs had a higher top-box rate at baseline compared to physicians (90.74 vs 78.04, p&lt;0.001). Between group rate differences were not significant for the overall HAU scale over time. Conclusions: Patients’ experience with hematology and oncology physicians improved after physicians received IGCC communication skills training. Moreover, the patients’ experience with NPs was rated higher than physicians before training, but there were no significant differences after training. To further improve physician-patient communication regarding ACP and goal concordant care, the program will adapt and expand to additional departments throughout the COH clinical network.

Trends in pharmaceutical industry payments to US cancer centers, 2014-2021.

11065 Background: US National Cancer Institute-designated comprehensive cancer centers (NCICCCs) receive federal funding to support their public missions. However, these institutions also receive substantial funds (both research and non-research) from the pharmaceutical companies, which have private, for-profit goals. The amount of industry money received by NCICCCs, with respect to their federal funding, is poorly understood. The goal of this study was to examine trends in industry payments to US cancer centers. Methods: NCICCCs were identified (N=51). Industry payments to each NCICCC from 2014-2021 were obtained from Open Payments, and NIH grant funding from NIH RePORT. Given our interest in NCICCCs, we focused on the subset of industry payments (those designated as being related to a cancer drug, both research and non-research) and NIH grant funding (grants awarded by the NCI specifically, as opposed to other institutes) that were likely to be cancer-related (we also measured overall industry payments and overall NIH funding). In order to capture both industry payments and grant funding broadly, we manually identified teaching hospitals and research universities affiliated with each NCICCC and included payments and grants to these as well. All amounts were inflation-adjusted to 2021 dollars. Results: Oncology-related industry payments increased from $320 million in 2014 to $896 million in 2021. NCI funding increased slightly during the same period, from $2,481 million to $2,691 million. Overall industry payments increased from $1,811 million in 2014 to $3,015 million in 2019 (exceeding NCI funding in that year), though overall industry payments subsequently declined to $1,977 million in 2021. Non-research (as opposed to research) payments were the minority of industry payments; the year with the greatest proportion of non-research payments was 2019, at 39%. NCI funding exceeded oncology-related industry payments at all NCICCCs except for two: City of Hope ($1,137 million oncology-related industry payments vs. $311 million in NCI funding) and MD Anderson ($1,040 million vs. $1,001 million). Conclusions: Oncology-related industry payments to NCICCCs has increased substantially more than NCI funding in recent years. Although most industry payments are research-related, a substantial portion are not. A small number of NCICCCs receive comparable or greater amounts of money from industry than they receive in grant funding from the NCI. These trends raise concerns regarding the influence of industry payments and the ability of these institutions to maintain their public missions.

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Abstract 1831: Reduction of PMN-MDSC level/activity following the consumption of white button mushroom in prostate cancer murine models and patients: A translational study to mitigate cancer progression

Abstract Frequent consumption of edible mushrooms, such as white button mushrooms (WBM), has been associated with a lower risk of prostate cancer [1]. Our laboratory at City of Hope has over 20 years of collective experience in defining the anticancer mechanisms of WBM [2, 3]. Previous studies have indicated that WBM consumption has anti-androgenic activities in prostate cancers in both preclinical models [4] and clinical trials [5]. In our first-in-human phase 1 trial on prostate cancer patients, we ensured the safety of consuming WBM in humans. In addition to observing a therapeutic-responsive decline in prostate-specific antigen (PSA), the levels of myeloid-derived suppressor cells (MDSCs) reduced in responders to WBM treatments [5]. These observations led us to hypothesize that WBM may mitigate the progression of prostate cancer in part by modulating the immune response. In the current study, we conducted translational research in syngeneic murine models and in prostate cancer patients from an ongoing phase 2 trial, aiming to define the immunomodulatory activity and mechanisms of WBM. We confirmed that WBM consumption in mouse models altered the number and function of immunosuppressive cells (MDSCs) and anti-tumor immune cells (T &amp; NK cells), ultimately enhancing the intratumor and systemic immune responses. At a bulk-transcriptional level, we observed the elevated expression of programmed cell death protein 1 (PD-1) in xenograft tumors. In our single immune cell profiling of patients’ blood specimens following 3 months of WBM consumption in freeze-dried tablets form, we investigated the transcriptional landscape of circulating immune cells in response to WBM interventions. The level of circulating neutrophil-associated PMN-MDSCs decreased, and the remaining cells showed transcriptional profiles associated with "neutrophil chemotaxis", "leukocyte aggregation", and "regulation of inflammatory response", as functions associated with enhanced anti-tumor activity. Lastly, we also showed in a mouse model that WBM consumption synergistically enhances the anticancer activity of anti-PD1 drugs, indicating that WBM may be used as adjuvant therapy with immune checkpoint inhibitors. In summary, our results from prostate cancer patients and murine models show the immunomodulatory effects of WBM consumption and provide a scientific foundation for the application of WBM in alleviating prostate cancer progression. References 1, Zhang S., et al. Int. J. Cancer. 2019; 146:2712-2720. 2, Chen S., et al. Cancer Res. 2006; 66:12026-12034. 3, Adams L.S., et al. Nutr. Cancer. 2008; 60:744-756. 4, Wang X., et al. J. Nutr. Biochem. 2021; 89:108580.5, Twardowski P., et al. Cancer. 2015; 121:2942-2950. Citation Format: Xiaoqiang Wang, Shoubao Ma, Przemyslaw Twardowski, Clayton Lau, Yin Chan, Kelly Wong, Jinhui Wang, Xiwei Wu, Paul Frankel, Timothy G. Wilson, Timothy W. Synold, Cary Presant, Jianhua Yu, Shiuan Chen. Reduction of PMN-MDSC level/activity following the consumption of white button mushroom in prostate cancer murine models and patients: A translational study to mitigate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1831.

Abstract 2112: Identification of biomarkers associated with sensitivity to a novel PCNA inhibitor (AOH1996) by CRISPRi screening

Abstract Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is essential for cancer cell growth and survival. We discovered a cancer-associated isoform of PCNA (caPCNA), which is ubiquitously and highly expressed in a broad range of cancer cells and tumor tissues but is not significantly expressed in non-malignant cells. Further studies of this novel caPCNA isoform as an anti-cancer drug target led to the identification of a cancer distinct region of PCNA which is partly delineated by the L126-Y133 peptide sequence and the discovery of a small molecule (AOH1996), which binds to this cancer distinct region as shown by crystallization studies. By targeting caPCNA, AOH1996 selectively kills cancer cells by interfering with the resolution of transcription-replication conflicts (TRC). Importantly, it causes no discernable toxicity at 6 times of its effective dose in mice. AOH1996 is currently in a phase 1 clinical trial for adult solid tumors at City of Hope (IND 138273). To identify genes that may be used as biomarkers for patient selection or potential targets for combination therapies, we screened a CRISPR interference (CRISPRi) library, which targets genes that are involved in cell signaling and cell cycle regulation. After culturing transduced cells in the presence of DMSO or 250 nM AOH1996 (corresponding to IC20) in triplicates for 14 generations, we measured the relative abundance of each guide RNA (gRNA) construct. Significant changes in the abundance of the gRNA constructs in AOH1996-treated cells relative to that in DMSO-treated cells were determined by the MAGeCK method. The target genes of the depleted or enriched gRNAs are predominantly involved in DNA repair, cell cycle regulation, and transcription regulation, which is consistent with the action mechanism of AOH1996. We validated the effect of these genes on sensitivity to AOH1996 and identified a panel of target proteins whose up or down-regulation is associated with sensitivity to AOH1996. Some of these proteins are targets of known chemotherapeutic drugs, which may be used in combination with AOH1996 in the clinic. Citation Format: Long Gu, Ming li, Chun-Wei Chen, Robert J. Hickey, Linda H. Malkas. Identification of biomarkers associated with sensitivity to a novel PCNA inhibitor (AOH1996) by CRISPRi screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2112.

Orofacial complications from immune checkpoint inhibitors: A retrospective analysis from two academic medical centers.

Immune checkpoint inhibitors (ICIs) are FDA-approved for various cancers, yet their orofacial immune-related adverse events (irAEs) remain poorly understood. Our two-center retrospective study aims to better understand the prevalence and nature of these orofacial irAEs. We retrospectively collected demographics, ICI details, and onset of orofacial irAEs in ICI-treated patients at University of California San Francisco and City of Hope (2013-2021). Orofacial irAEs were identified by ICD-10 codes and data categorized as dry mouth/xerostomia, oral mucosal lesions, and orofacial neuropathies. Patients with pre-existing orofacial conditions resembling the reported irAEs were excluded. Among 3768 ICI-treated patients, 408 (10.8%) developed 467 orofacial irAEs: oral mucosal diseases (41.4%), dry mouth/xerostomia (41.0%), and orofacial neuropathies (17.6%). Notably, head and neck cancers had the highest incidence of orofacial irAEs. Orofacial irAEs are relatively common in patients receiving ICIs, necessitating careful monitoring and management of these complications during and after the treatment.

Favorable Survival Outcomes in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant with Fludarabine/Melphalan-Conditioning with Tacrolimus/Sirolimus-Based Gvhd Prophylaxis

Introduction: Fludarabine/melphalan (F/M) conditioning is associated with superior disease-free survival (DFS) compared to busulfan-based reduced-intensity conditioning (RIC) regimens in patients with AML/MDS undergoing allogeneic hematopoietic cell transplantation (alloHCT). A recent CIBMTR analysis in AML patients reported 5-year OS, cumulative incidence of Relapse (CIR) and NRM of 29%, 36% and 36% respectively after F/M conditioning when Tac/MTX was used for graft-vs-host disease (GVHD) prophylaxis (Blood Adv 2020). At City of Hope (COH), tacrolimus and sirolimus (T/S)-based GVHD prophylaxis has been used in patients undergoing HLA-matched sibling and unrelated donor alloHCT, based on the results of a phase 2 study by Rodriguez et al (Blood 2010). Here, we retrospectively reviewed clinical outcomes of 409 consecutive AML patients who underwent RIC alloHCT at COH from 2008-2019 with F/M conditioning and T/S-based GVHD prophylaxis. The primary objective was to assess long term survival outcomes and associated risk factors adjusted for secular trends in patient demographics undergoing alloHCT over time. Methods: Descriptive statistics were used to summarize patient demographics, and disease characteristics. Kaplan-Meier curves and log-rank test were used to evaluate OS and LFS. Cumulative incidence curves and Gray test were used to examine differences in relapse and NRM. The assumptions of proportionality for Cox regression and Fine-Gray models were checked by corresponding tests and plots of the scaled Schoenfeld residuals. To study changes in patient demographics, we divided patients into early era of 2008-2012 (n=140; 34%) and late era of 2013-2019 (n=269; 66%). Results: Patient and HCT characteristics are shown in Table 1. Briefly, the median age was 63 years (range: 19-78) and 70% of patients underwent alloHCT in CR-1. Cytogenetics (ELN 2017) were classified as adverse risk in 25% (n=104) and intermediate risk in 65% (n=265) patients. By disease risk index (DRI), patients were categorized as low (32%; n=131), intermediate (47%; n=193), or high/very high risk (20%; n=84). KPS of 80-100 was recorded in 93% of patients and HCT comorbidity index score of ≥3 was seen in 41%. AML-from prior hematologic disorder (secondary AML) or therapy related was documented in 32% (n=133) and data on somatic mutations and measurable residual disease (MRD) were available only in the recent era. Compared to the early era, HCT recipients of the recent era were significantly older(64 vs 60 years; p=0.0001), had higher HCT-CI (median score of 3 vs 1; p&amp;lt;0.0001), and more patients with KPS &amp;lt; 80 (9% vs 2 %; p=0.0024). With the median follow-up duration of 4 years (range: 0.3-12.5) for the whole cohort, the 5-year OS and DFS were 53% (95% CI: 0.48-0.58) and 51% (95% CI: 0.46-0.56), respectively. The cumulative incidence of relapse (CIR) at 5 years was 23% (95% CI: 0.19-0.28). The non-relapse mortality (NRM) at day+100 and 5 years were 5% (95% CI: 0.03-0.08) and 25% (95% CI:0.20-0.29), respectively. Day +100 grade 2-4 acute GVHD was 37% (95% CI: 0.32-0.42) and 2-year chronic GVHD was 70% (95% CI: 0.65-0.74). Overall survival (OS) and disease-free survival (DFS) were not significantly different in the two eras (Figure 1). Despite high incidence of cGVHD, only 21% (n=86) required prednisone at one year with median dose of 10 mg/day (range: 2-60mg/day). In key subgroups of interest, the 5-year OS were: 70% for FLT3-ITD mutation (n=50), 70% for NPM1 mutation (n=47), 83% for IDH 1/2 mutation (n=30), 65% for patients older than ≥70 (n=55), and 55% (95%CI :43-63) for secondary AML (n=102). MRD by multi-color flow cytometry was available in 58 patients in CR of whom 18 were MRD-positive; this was associated with worse 5-year OS (26%: 95% CI: 5.5-53%). Multivariate analyses (MVA) identified DRI high/very high-risk as the only independent variable associated with worse OS (HR=1.62, [95%CI: 1.16-2.27]) and DFS (HR=1.76, [95%CI: 1.28-2.41]), primarily due to increased NRM (HR 1.86, 95%CI [1.21-2.87]), while its impact on relapse was insignificant. Conclusion: Fludarabine-melphalan with T/S associated with favorable long-term OS with good disease control without excessive NRM, even in high-risk patient subgroups and changing demographics of older adults with higher comorbidity. However, cGVHD rates remain high and novel strategies are being explored to realize the OS benefits of the FM backbone while attenuating chronic GVHD and NRM.

Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy

Introduction:CD19-targeted chimeric antigen receptor (CD19CAR) T cell therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR T cell therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). However, available data for post CAR T alloHCT in r/r B-ALL are limited, especially for the role of the second alloHCT post CAR T response among patients (pts) who relapsed following their first alloHCT. Methods: We performed a retrospective analysis of adult pts with r/r B-ALL who responded to CD19CAR T cell therapy and underwent consolidation with alloHCT while in CR without interim therapy at City of Hope (COH) between 2016 and 2023. The decision to consolidate with alloHCT was based on the discretion of the treating physician and pt eligibility. We assessed overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) using Kaplan-Meier method on total pts and stratified by transplant time points (first vs. second). Results: We identified 39 pts, of whom 24 (62%) and 15 (38%) received their firstand second alloHCT as consolidation post CAR T cells, respectively. The median age was 29 years (range: 19-67), 25 (64%) were male, 28 (72%) were Hispanic, and 25 (64%) had Ph-like ALL. Twenty-five (64%) pts received investigational CD19CAR T cell products. Disease status pre-lymphodepletion was isolated r/r (≥5% blasts) in the bone marrow (BM) in 21 (54%) pts, extramedullary disease +/- BM in 12 (31%) pts, and minimal residual disease (MRD)+ only in 6 (15%) pts. Blinatumomab and inotuzumab were administered previously to 67% and 18% of pts, respectively. At the time of alloHCT, the median number of prior lines of therapy was 5 (range: 2-7). Disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 6, 19 and 14 pts, respectively. All pts were MRD- prior to alloHCT except for 2 pts who converted to MRD+ just before alloHCT and 1 pt with unknown MRD status; all 3 pts received their first alloHCT. The median time from CAR T cell therapy until alloHCT was 91 days (range: 42-262). Conditioning regimen was myeloablative in 21 (54%) pts and specifically radiation-based in 20 (51%). Donors were unrelated in 22 (56%) and haploidentical in 9 (23%). Table 1 shows pts characteristics for those who underwent first and second alloHCT. Overall, with a median follow up of 19.7 months, the 18-month OS, RFS, CIR and NRM were 65% (95%CI: 0.499-0.0843), 56% (95%CI: 0.407-0.765), 19% (95%CI: 0.092-0.405) and 25% (95%CI: 0.134-0.463), respectively. NRM at day 100 was 3% (95%CI: 0.004-0.192). Thirteen pts died post alloHCT; causes of death were relapsed ALL (n=4), sepsis (n=3), respiratory failure (n=2), graft-versus-host disease (n=1), HHV6 encephalitis (n=1), veno-occlusive disease (n=1) and toxoplasma encephalopathy (n=1). At 18 months, OS (59% vs. 75%, p=0.41), RFS (50% vs. 65%, p=0.49), CIR (25% vs. 1%, p=0.26), and NRM (25% vs. 25%, p=0.83) were comparable for those who underwent their first or second alloHCT post CD19CAR T cell therapy, respectively. Figure 1 shows the Kaplan-Meier analysis of OS. Conclusions: We report low early NRM and favorable survival outcomes for alloHCT consolidation post response to CD19CAR T cell therapy in heavily pre-treated adult pts with r/r B-ALL, despite 5 median prior lines of therapy and Ph-like disease in over half of pts. Outcomes for second alloHCT were promising in this setting and comparable to first alloHCT.

Fractionated Total Body Irradiation and Fludarabine Based Conditioning Regimen with Post-Transplant Cyclophosphamide (PTCy) for Mismatched Related and Unrelated Donors HCT for Acute Leukemia and MDS

Background: Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curable treatment option for several hematological malignancies. Preparative and graft-versus-host disease (GVHD) prophylactic regimens combined with graft-versus-leukemia effect (GVL) are important in preventing graft rejection, disease relapse and GVHD; and subsequently impact the success of this life saving procedure. Choice of regimen depends on patient, donor/graft source and disease characteristics. Objectives: Assess the outcomes of patients who underwent haploidentical (haplo) or mismatched unrelated donor (MMUD) HCT with myeloablative conditioning (MAC) regimen using radiation in combination with fludarabine (FLU) with PTCy as higher intensity GVHD prophylaxis and evaluate the feasibility of a fludarabine and fractionated total body irradiation (FLU/FTBI)-based regimen in both donors. Study Design: Retrospective analysis to study the outcomes of patients receiving FLU/FTBI as myeloablative conditioning for mismatched (related or unrelated) donor HCT combined with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis. Results: One hundred and fifty-five consecutive patients undergoing HCT at City of Hope (COH) from January 2015 to December 2021 were included. Median age was 38 years (range 9-60) and 56.8% of patients were male and 97.5% had a Karnofsky performance status (KPS) ≥ 80. HCT comorbidity index was ≥ 3 in 36.1% cases and 29% with a disease risk index (DRI) of high/very high. Disease diagnosis included acute lymphoblastic leukemia (ALL) (46.5% of cases) and acute myeloid leukemia (AML) (36.1% of cases). The median donor age was 31-years with 67.1% haplo donors and 32.9% mismatched unrelated donors (MMUD). MMUD HCT led to faster neutrophil recovery (15 vs 16 days, p= 0.01) and platelet count recovery (18 vs 23 days, p= 0.029). Day 100 cumulative incidence of grade II-IV and III-IV acute GVHD had no statistical difference between the two cohorts. With a median follow-up of 24 months (range 3 to 81), 100-day and 1-year NRM was 1.9% and 8.5%, respectively. There was no difference in the NRM between MMUD and haplo (HR 0.92, CI (0.35,2.39), p=0.86). Two-year relapse rate and DFS were 11.8% and 76.9%, respectively. In this study, 7 out of 51 patients in the MMUD group and 17 out of 104 patients in the haplo group relapsed with no statistically significant difference between the groups (HR 0.82, CI: (0.35,1.97), p=0.67). At a median follow-up of 2 years, GRFS was 60% (95% CI 0.51- 0.67). There was no statistically significant difference in GRFS between the MMUD and haplo groups (HR 0.76, CI (0.44,1.32), p=0.33). Two-year OS was 80.1%. There were no DFS or OS differences between the MMUD and haplo groups. On multivariate analysis, age less than 40 and low to intermediate DRI showed a DFS benefit (p = 0.004 and 0.029 respectively). None of the demographic factors affected OS or GRFS. Disease risk index was the only factor on multivariate analysis affecting relapse rates with higher risk of relapse with higher DRI (p= 0.017) and extensive chronic GVHD risk (p= 0.014) with no impact on acute GVHD. Conclusions: FLU/FTBI followed by PTCy for GVHD prophylaxis is a well-tolerated myeloablative regimen in mismatched donors with acute leukemia or myelodysplastic syndrome (MDS) with low transplant related morbidity and mortality and has produced promising HCT outcomes.

Outcomes of Patients Undergoing Fludarabine and Melphalan-Based Conditioning with Post-Transplant Cyclophosphamide for Peripheral Blood Stem Cell Allogeneic Hematopoietic Cell Transplant: Donor Type Effect

Background Reduced intensity conditioning (RIC) has expanded eligibility of older patients (pts) with hematological disorders for allogeneic hematopoietic cell transplant (HCT). Fludarabine and melphalan (FM) has been shown to improve disease control with an acceptable toxicity profile when combined with CNI-based GVHD prophylaxis regimens. The emergence of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis has improved outcomes of HCT across different HLA disparities and improved accessibility of HCT, especially in patient with no available matched donor. With recent data showing improved outcomes with RIC (Bolaños-Meade et al. NEJM 2023 and Shaw et al, JCO 2021), PTCy has been proposed as the standard of care for GVHD prophylaxis regardless of donor type. Herein, we report the largest experience with FM and PTCy as GVHD prophylaxis. Methods We retrospectively reviewed pts who underwent FM-based PBSC HCT with PTCy as GVHD prophylaxis at City of Hope from January 2015 to December 2021. Descriptive statistics were used to describe baseline characteristics. Kaplan-Meier Curves and log-rank tests were used to calculate and compare overall survival (OS) and disease-free survival (DFS), respectively. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and GVHD were calculated and compared via a competing-risk analysis and Gray's test, respectively. Multivariate analyses (MVA) were performed using the multivariable Cox regression model for OS and DFS, and multivariable Fine and Gray regression model for the other variables. The primary aim was to evaluate the effect of donor types on HCT outcomes. Results Baseline characteristics of 248 pts are summarized in Table 1. The median age was 63 (range, 20-82). 63.9% were male. The most common diagnoses were AML (n=90), MDS/MPN (n=58), lymphoma (n=40), and ALL (n=39). Of 248 pts, 89 (35.9%) received HCT from a matched related/unrelated donor (MRD/MUD), 118 (47.6%) from a haplo-identical (haplo) donor and 49 (19.8%) from a mismatched unrelated donor (MMUD). The median times to neutrophil and platelet engraftment were 18 days (range, 18-19) and 32 days (range, 30-34), respectively. On MVA, MRD/MUD was associated with faster engraftment over haplo donors for neutrophils (hazard ratio [HR] 0.64, 95% CI, 0.47,0.87, P=0.015) and for platelets (0.49, 95% CI, 0.34-0.70, p&amp;lt;0.001), compared to MRD/MUD but there was no difference in engraftment between haplo and MMUD. With a median follow-up for surviving pts of 24.4 months (range, 3.3-81.2), the 2-year OS and DFS for the all pts were 60.4% (95% CI, 53.7-66.5) and 55.5% (95% CI, 48.9-61.6), respectively. The 2-year OS and DFS for pts receiving haplo donors, MMUD, and MRD/MUD were 56.1%, 52.6%, and 72.5%, and 50.7%, 46.7%, and 68.4%, respectively (Figure 1). On MVA, compared with MRD/MUD, the 2-year OS was lower with haplo (HR 2.02, 95% CI, 1.19-3.42) and with MMUD (HR 2.03, 95% CI, 1.11-3.72 (p=0.023), while there was no difference between haplo and MMUD. Additionally, donor age &amp;gt;=35 years was associated with lower OS (HR 1.57, 95% CI, 1.04-2.35, p=0.031). There was a trend toward lower DFS with haplo (HR 1.61 (95% CI, 1.00-2.60)) and with MMUD, HR 1.73 (95% CI, 0.99-3.02, (p=0.093) when compared with MRD/MUD. 2-year NRM and CIR for all pts were 27.7% (95% CI, 22.1-33.5) and 16.8% (95% CI, 12.3-21.9), respectively. There were no differences in CIR based on donor type on MVA (p=0.87). NRM was higher in haplo and MMUD compared to MRD/MUD but this lost significance (p=0.13) in MVA after adjusting for KPS (HR 1.79, 95% CI, 0.98-3.26, p=0.019) and donor age &amp;gt;=35 years (HR: 1.87, 95% CI, 0.93-3.74, p=0.049). Day 100 CI of grade 2-4 and grade 3-4 acute GVHD for all pts were 39.5% (95% CI, 33.4-45.6) and 14.5% (95% CI, 10.5-19.2) and the 1-year CI of extensive chronic GVHD was 31.0% (95% CI, 25.2-37.0) There were no differences in grade 3-4 acute GVHD at day 100 or 1-year CI of extensive chronic GVHD based on donor type (p=0.46 and 0.13, respectively), although MVA revealed a strong trend towards a higher CI of grade 2-4 aGVHD at day 100 with MMUD group, HR 1.73 (95% CI, 1.02,2.95), p=0.079) Conclusions FM with PTCy was associated with promising disease control and acceptable NRM. Outcomes of pts undergoing MRD/MUD appears to be superior in this setting due to decreased NRM, while outcomes of pts undergoing HCT with haplo or MMUD are comparable. Donors &amp;lt;35 years was the strongest predictor of improved outcomes.