Search

PURPOSE: Treatment of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs) has improved survival but is associated with significant financial burden. We measured the annual trend in TKI utilization, Medicare gross payment, and patient out-of-pocket (OOP) expenditure from 2007 to 2016. METHODS: We used SEER linked to Medicare part-D claims data to identify prevalent CML cases from 2007 to 2016. TKI utilization was measured as the proportion of cases with at least one TKI fill in each year. Average TKI gross payment and median per-member per-month OOP expenditure were calculated from claims data and plotted annually from 2007 to 2016. Year-to-year percent change in gross payment and OOP expenditure was compared with inflation indices. RESULTS: The cohort included 3,189 CML cases with at least one TKI claim. The proportion of prevalent patients with a TKI fill in a year increased from 17.9% in 2007 to 52.8% in 2015. The average annual gross payment per 30-day supply of a TKI increased by an average of 12.8% throughout the period from $9,000 to $10,000 US dollars in 2016. There was no increasing trend in median OOP expenditure per 30-day supply, which varied between $450 and $600 US dollars. CONCLUSION: Rising TKI use and TKI drug prices place considerable financial pressure on Medicare part-D insurers. Although there was no increasing trend in OOP expenditure, it may be burdensome for Medicare patients who are likely retired on a fixed income. Our findings support legislation that mitigates increasing drug prices to protect the Medicare system and its beneficiaries.

Heterocyclic compounds play tremendous roles and wide applications in the field of medicinal chemistry. Among them, quinazoline derivatives have been found to be exhibit various diverse broad pharmacological activities such as antibacterial, antifungal, anti-tuberculosis, anticancer, antivirus, anti-HIV, antimalarial, anti-convulsant, antileishmanial activity, anti-inflammatory, anti-hypertensive, and antidiabetic activity. Due to their vast biological activities, the research and development of Quinazolinone-containing compounds are increasingly active and alluring topics in the field of medicinal chemistry. Quinazolinone and their various derivatives possess wide spectrum of antimicrobial activity. In this work, we have summarized various derivatives of quinazolinone molecule and their substituents exhibits antimicrobial activity.

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) ( p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality ( p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival ( p = 0.017). In patients with a lower Hb, the median duration of hospitalization ( p = 0.02) and the mean duration of diarrhea ( p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization ( p = 0.06) and the mean duration of diarrhea ( p = 0.0009) longer, and the rate of infection was higher ( p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

AIMS: High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration–time curve, AUC) when using body surface area‐based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real‐time melphalan dose adjustments. METHODS: We performed a prospective PK study of melphalan 140 or 200 mg/m(2) in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days −2 and − 1, with PK sampling at 8–10 time points. PK testing was performed on day −2 in all patients, and on day −1 in 5 patients. RESULTS: Less than 20% interpatient variation in the day −2 and − 1 AUC was observed. The day −2 range in AUC (4.95–11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133–302 mg/m(2) to achieve the total median AUC. A 4‐time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8‐time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05). CONCLUSION: Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

Several commonly used immune-suppressing biologic drugs target proteins and cytokines involved in myeloma pathogenesis. Our objective was to determine whether targeted biologic disease-modifying antirheumatic drugs (DMARDs) are associated with risk of multiple myeloma (MM). We conducted a nested case-control study within a retrospective cohort of 56,886 commercially insured adults undergoing treatment for rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis between 2009 and 2015 using the Truven Health MarketScan Databases. MM cases (n = 287) were matched to up to 10 controls (n = 2,760) on age, sex and rheumatologic indication using incidence density sampling without replacement. Our exposures of interest were biologic DMARDs targeting tumor necrosis factor-alpha, interleukin 6, cytotoxic t-lymphocyte-associated protein-4 and depletion of B cells. Relative risks were estimated as adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. Cases and controls were similar with respect to use of prescription NSAIDs and concurrent conventional-synthetic DMARDs. Cases had slightly fewer etanercept users (4% vs. 7%) and slightly more tocilizumab users (1.4% vs. 0.4%). Compared to patients treated with only conventional-synthetic DMARDs, those receiving concomitant conventional-synthetic plus biologic DMARDs had lower risk of developing MM (OR = 0.48; 95% CI 0.30-0.88; p = 0.02). Risks differed by drug target with an inverse association observed with use of etanercept inhibiting tumor necrosis factor-alpha (OR = 0.55; 95% CI 0.30-1.02; p = 0.06) and a positive association with tocilizumab inhibiting interleukin-6 (OR = 4.33; 95% CI 1.33-14.19; p = 0.02) compared to biologic DMARD-naïve patients. Further investigation is warranted to understand the roles of drugs suppressing tumor necrosis factor-alpha and interleukin-6 in myeloma pathogenesis.

PURPOSE: To examine the impact of pre-diagnosis depressive symptoms and mental health-related quality of life (HRQOL) on survival among older patients with multiple myeloma (MM). METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey data resource. Patients aged 65 years and older diagnosed with first primary MM between 1998 and 2014 were identified and presence of depressive symptoms was determined based on responses to 3 depression screening questions prior to MM diagnosis. Veterans-RAND-12 mental component scores (MCS) were analyzed to evaluate mental HRQOL. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of all-cause and cancer-specific mortality. RESULTS: Of 522 patients, mean (SD) age at diagnosis was 76.9 (6.1) years and 158 (30%) reported depressive symptoms. Patients with depressive symptoms had a higher number of comorbid conditions and nearly all (84%) scored below the median MCS. Pre-diagnosis depressive symptoms were not associated with all-cause (HR=1.01, 95% CI: 0.79–1.29) or cancer-specific mortality (HR=0.94, 95% CI: 0.69–1.28). MM patients scoring in the second MCS tertile (versus the highest tertile) had a modestly increased risk of all-cause (HR=1.19, 95% CI 0.91–1.55) and cancer-specific mortality (HR=1.17, 95% CI 0.86–1.60), but these estimates were not statistically significant. CONCLUSION: Pre-diagnosis depressive symptoms and lower mental HRQoL did not impact survival among older MM patients. Highly prevalent depressive symptoms among older MM patients deserves clinical attention. Such efforts can inform clinicians in tailoring care for this vulnerable population.

Introduction/Background African American (AA) individuals have a twofold higher incidence of multiple myeloma (MM) compared with other racial groups. Outcomes are affected by factors such as disparate access to care as well as differences in disease biology. Patients and Methods We conducted a single-institution analysis to evaluate the effect of AA race on outcomes of MM patients who underwent autologous stem cell transplantation (ASCT) in the pre-novel and novel agent era. Results Sixty-one (47%) patients were AA and 69 (53%) were non-AA. Overall, 78 (60%) patients received any novel agent before transplantation and 52 (40%) received only chemotherapy. More non-AA patients received initial induction with a proteasome inhibitor (40 [60%] vs. 17 [28%]; P = .0007), and were treated with post-ASCT maintenance therapy (28 [41%] vs. 14 [23%]; P = .04). Time from diagnosis to ASCT in AA patients was 10 (range, 4-144) versus 8 (range, 3-54) months in non-AA patients (P = .01). Despite this, treatment-free survival (TFS) was equivalent between the 2 groups (x vs. y). Furthermore, AA patients had greater median overall survival (OS) compared with non-AA patients (not reached vs. 108 months; P = .03) and significantly improved OS in multivariable Cox proportional hazards models (adjusted hazard ratio, 0.30; 95% confidence interval, 0.11-0.81; P = .017). Median OS, landmarked at the time of relapse, was improved in AA patients (not reached vs. 68 months for P = .05). Conclusion Our study showed with long follow-up, equivalent TFS after ASCT in AA and non-AA patients yet improved OS. Post relapse survival is improved in AA patients suggesting a better response to salvage therapy.

Objective To compare polypharmacy and potentially inappropriate medication use in multiple myeloma patients receiving care under a traditional, physician-managed, or collaborative physician–pharmacist clinic. Design Retrospective chart review. Setting Urban academic cancer center. Data source Computerized electronic record. Patients Forty-four patients in the traditional physician-managed clinic and 57 patients in the collaborative physician-pharmacist clinic. Measurements and main results Patients in the collaborative clinic took fewer medications on average (9 vs. 7, p = 0.045). Although the median number of myeloma-related medications was higher (2 vs. 4, p Conclusions Multiple myeloma patients have a high rate of polypharmacy but comanagement with a pharmacist reduced the number of all medications, but in particular the number of non-myeloma-related medications.

Background Whether race/ethnicity plays a role in hematopoietic stem/progenitor cells (HSPC) mobilization in autologous donors has not been studied. We hypothesize that donor characteristic including race/ethnicity, age, sex, body mass index, and diagnostic groups influences HSPC mobilization. Diagnostic groups include healthy allogeneic donors, autologous multiple myeloma (MM) and non-MM donors. Study design and methods Here, we conducted a single-center retrospective study in 64 autologous patients and 48 allogeneic donors. Autologous donors were patients diagnosed with MM or non-MM. All donors were grouped as African American (AA), White (W), or "Other"(O). Results Multivariate analysis demonstrated diagnostic group differences for CD34+ cell yields between race/ethnicity. Specifically, non-MM patients had the lowest CD34+ cell yields in AA and O, but not in W. For pre-apheresis peripheral blood (PB) CD34+ cell numbers, race/ethnicity had a significant effect both in bivariate and multivariate analyses. Non-MM patients had the lowest, and AA patients had the highest PB CD34+ cells. The results support the view that past therapies used in MM are likely more conducive of recovery of HSPC. Conclusions Our study shows that race/ethnicity and diagnostic group differences influenced CD34+ cell mobilization response across donor types. Interestingly, autologous MM donors with the aid of plerixafor displayed comparable CD34 yields to allogeneic donors. Even though both MM and non-MM donors received plerixafor, non-MM donors had significantly lower CD34 yields among AA and O donors but not in W donors. Larger studies would be required to validate the role of diagnostic groups and race/ethnicity interactions.

Background: Multiple myeloma (MM) is associated with an increased incidence of venous thromboembolism (VTE) which results in greater morbidity and mortality in MM patients. Several MM treatments including receiving immunomodulatory drugs (IMiDs), cytotoxic chemotherapy, and high-dose dexamethasone also increase VTE risk. Clinical guidelines recommend thromboprophylactic regimens to mitigate the risk of VTE in MM patients. However, practices vary with respect to medications used for thromboprophylaxis, ranging from prescribing of aspirin to anticoagulant regimens with direct oral anticoagulants (DOAC) and warfarin. We aimed to describe patterns of warfarin- and DOAC-based thromboprophylaxis in newly diagnosed MM patients initiating IMiD-based treatment. Methods: We conducted a retrospective cohort study of MM patients using the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases. We included newly diagnosed MM patients initiating IMiD-based treatment between 2010 and 2017 with continuous health plan enrollment 12 months prior to and following diagnosis. We collected information on comorbidities, VTE risk factors and other MM therapies. The primary outcome of interest was initiating thromboprophylaxis with warfarin or DOAC within 90 days of treatment initiation. We evaluated prescribing trends over time and characteristics associated with DOAC- or warfarin-based thromboprophylaxis, we used univariate and multivariate multinomial logistic regression models comparing these two forms of thromboprophylaxis to those who did not receive thromboprophylaxis. Results: In a cohort of 6227 MM patients initiating IMiD-based regimens, the median age was 62 years and 43% were female. Over the entire study period, warfarin-based thromboprophylaxis was more prevalent relative to DOACs (10.5% vs. 6.9%). However, we observed a trend of increasing adoption of DOAC thromboprophylaxis from 2.4% of patients in 2010 to 12.7% in 2017; and the use of warfarin thromboprophylaxis consistently declined over time from 16.5% of patients in 2010 to 3.2% in 2017. In multivariable analyses, trends associated with increasing or decreasing odds of thromboprophylaxis with these agents were robust after adjustment for demographic and clinical characteristics including VTE risk factors and other MM treatment (DOAC: OR 1.35, 95% CI 1.28-1.44 and warfarin: OR 0.81, 95% CI 0.77-0.86). Conclusions: Over the study period, our findings indicate that DOAC-based thromobprophylaxis regimens were increasingly used over warfarin-based treatment in newly diagnosed commercially insured MM patients initiating IMiD therapy. Further research is needed to determine whether these patterns are associated with differences in clinical outcomes. Citation Format: Abdullah I. Abdelaziz, Karen Sweiss, Pritesh R. Patel, Brian C-H Chiu, Gregory S. Calip. Increasing uptake of direct oral anticoagulants for thromboprophylaxis among newly diagnosed multiple myeloma patients initiating immunomodulatory drug-based regimens, 2010 to 2017 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 738.

Introduction: There are racial/ethnic disparities in multiple myeloma (MM) treatment, including differences in the use of novel agents, stem cell transplantation, and supportive therapies such as bone-modifying agents (BMAs). BMAs reduce the frequency of fractures and skeletal-related pain, and some evidence suggests that more recently approved agents (i.e., denosumab) confer greater progression-free survival benefits than older agents (i.e., bisphosphonates). Here we describe disparities in the initiation of BMA use and uptake of denosumab among newly diagnosed MM patients by race/ethnicity. Methods: We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record-derived de-identified database. This analysis included adults (≥ 18 years) newly diagnosed with MM between January 2018 and September 2021 who initiated first-line therapy. Patient demographics and clinical characteristics were determined using structured and unstructured data, curated via technology-enabled abstraction. Cumulative incidence functions accounting for competing risks were used to estimate the initiation of BMA use within 90 days before the start of first-line MM therapy and 30 days post. We used multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for differences in the receipt of denosumab versus bisphosphonates alone (zoledronic acid or pamidronate) among patients who initiated BMA use. Results: Among 4460 newly diagnosed MM patients, 52% were White, 17% were Black, 7% were Latinx, and 2% were Asian. Overall, 2208 (50%) initiated BMA treatment, and utilization differed across racial/ethnic groups with higher rates observed among Asian (55%), White (51%), and Latinx (50%) patients compared to Black patients (44%) (P=0.023). Among patients that initiated BMAs, 53% received denosumab and 47% received bisphosphonates alone. Compared to White patients, Black (OR 1.06, 95% CI 0.83-1.36) and Asian (OR 0.82, 95% CI 0.44-1.53) patients had similar odds of receiving denosumab, whereas Latinx patients had significantly lower odds of receiving denosumab (OR 0.56, 95% CI 0.40-0.79). Conclusion: Among newly diagnosed MM patients, approximately half initiated BMAs. Substantial racial/ethnic disparities exist. For example, Black patients were less likely to receive any BMAs, and, even when treated, Latinx patients were less likely to receive denosumab. Future research should determine whether these treatment disparities impact progression-free and overall survival in real-world MM data. Citation Format: Jenny S. Guadamuz, Rebecca Rohrer, Ghulam Rehman Mohyuddin, Brian C.-H. Chiu, Pritesh R. Patel, Karen Sweiss, Erlene Seymour, Douglas Sborov, Gregory S. Calip. Racial/ethnic disparities in treatment with bone-modifying agents among newly diagnosed multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3669.

PURPOSE: Intravenous (IV) bisphosphonates reduce the risk of skeletal-related events in patients with multiple myeloma (MM). However, data describing racial differences in IV bisphosphonate utilization outside of clinical trial settings are limited. We evaluated population-level IV bisphosphonate initiation and discontinuation among patients of age ≥ 65 years with MM. METHODS: We conducted a retrospective cohort study of patients of age ≥ 65 years diagnosed with first primary MM between 2001 and 2011. Patients were identified using the SEER-Medicare linked database and followed through December 2013. Cumulative incidences of IV bisphosphonate initiation and time to discontinuation among users were compared between racial and ethnic groups. In Fine and Gray competing risk models, we estimated subdistribution hazard ratios (SHRs) and 95% CIs for initiation and discontinuation. RESULTS: We included 14,231 eligible patients with MM (median age, 76 years; 52% male). Over a median follow-up of 23.1 months, 54% of patients received at least one IV bisphosphonate dose. Our final analytical sample included 10,456 non-Hispanic (NH) Whites, 2,267 NH Blacks, 548 Asian and Pacific islanders, and 815 Hispanic and Latino patients. A higher proportion of White patients (56.1%) newly received IV bisphosphonates after MM diagnosis compared with NH Blacks (45.4%). Compared with White patients, NH Black patients were less likely to initiate IV bisphosphonates (SHR, 0.74; 95% CI, 0.70 to 0.79) and slightly more likely to discontinue treatment (SHR, 1.10; 95% CI, 1.01 to 1.19). CONCLUSION: Approximately half of the patients with MM of age ≥ 65 years did not receive IV bisphosphonates, with significant delay among racial minority groups. These findings highlight the need for improvement of IV bisphosphonate uptake in patients with MM of age ≥ 65 years.

Classic Hodgkin lymphoma (CHL) is a clonal lymphoid neoplasm derived from B cells. CHL usually involves the lymph nodes. Although cases with extranodal involvement by CHL have been reported, the involvement of the uterine cervix by CHL is an extremely uncommon phenomenon. Herein, we report an unusual case of a 51-year-old female with nodular sclerosis CHL, diagnosed initially via right inguinal lymph node biopsy. After two cycles of chemotherapy, she presented with vaginal spotting and CT scan demonstrated a uterine cervical lesion with hypermetabolic activity. Tissue biopsy sections of the uterine cervix showed cellular infiltrate consisting of large atypical cells including many lacunar cells and occasional Reed-Sternberg cells in the background of mixed reactive cells including small- to medium-sized lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. Immunohistochemical stains show that the large atypical cells are positive for CD30, CD15, MUM-1, and weakly positive for PAX-5. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) is negative. The morphological and immunohistochemical findings were consistent with involvement by nodular sclerosis CHL. This case demonstrates a rare presentation of CHL that may pose a diagnostic problem if its existence is not considered in the differential diagnosis. Furthermore, we reviewed the literature and only found two previous publications described uterine cervix involvement by CHL. Although it is very rare, CHL involvement should be included in the differential diagnosis and an appropriate work-up should be performed to evaluate CHL involvement of cervix when patients with CHL present with signs or symptoms suggesting a cervical lesion.

Purpose: We hypothesized that a multidisciplinary collaborative physician-pharmacist multiple myeloma clinic would improve adherence to treatment and supportive care guidelines as well as reduce delays in receiving oral antimyeloma therapy. Methods: From March 2014 to February 2015, an oncology pharmacist provided consultation for all patients in a specialist myeloma clinic. This included reviewing medications, ensuring physician adherence to supportive care guidelines, managing treatment-related adverse effects, and navigating issues involving access to oral specialty medications (collaborative clinic). Results: Outcome measures were retrospectively compared with those of patients being treated by the same physician during the previous year, in which ad hoc pharmacist consultation was available upon request (traditional clinic). The collaborative clinic led to significant improvements in adherence to supportive medications, such as bisphosphonates (96% v 68%; P < .001), calcium and vitamin D (100% v 41%; P < .001), acyclovir (100% v 58%; P < .001), and Pneumocystis jirovecii pneumonia prophylaxis (100% v 50%; P < .001). Appropriate venous thromboembolism prophylaxis in immunomodulatory drug–treated patients was prescribed in 100% versus 83% of cases ( P = .0035). The median time to initiation of bisphosphonate (5.5 v 97.5 days; P < .001) and P jirovecii pneumonia prophylaxis after autologous transplantation was shortened in the collaborative clinic (11 v 40.5 days; P < .001). Furthermore, the number (85% v 21%; P < .001) and duration (7 v 15 days; P = .002) of delays in obtaining immunomodulatory drug therapy were also significantly reduced. Conclusion: Our collaborative clinic model could potentially be applied to other practice sites to improve the management of patients with multiple myeloma. Prospective studies analyzing clinical outcomes, patient satisfaction, and cost effectiveness of this approach are warranted.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between 1/2014–3/2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor specific antibodies (DSA) and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells (PBSC). The initial two were conditioned with alemtuzumab/total body irradiation (TBI) 3Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University (Bolaños-Meade J, Blood 2012) with TBI 3Gy. G-CSF was administered from day+12 in those with HbS 0.5 x10(9)/L of 22 days (range, 18–23 days). One patient subsequently lost the graft and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute GVHD ≥ grade 2. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow up of 16 months (range, 11–29 months), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSA and patient declining HSCT, may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter prospective clinical trials.

Background: The incidence of multiple myeloma (MM) and enrichment of cytogenetic abnormalities differ significantly between racial/ethnic groups in the US, and their significance in determining myeloma progression and survival is not well understood. Whole genome sequencing has identified unique mutational signatures in MM, including an age-related process common in hyperdiploid myeloma. Our purpose was to describe racial and age-related differences in the impact of high-risk cytogenetic abnormalities (HRCAs) on survival in MM. Methods: We conducted a retrospective cohort study of adult MM patients starting first-line therapy between January 2011 and May 2021 using the nationwide Flatiron Health electronic health record-derived de-identified database. Patient-level demographic and clinical characteristics were ascertained using structured and unstructured data, curated via technology-enabled abstraction. Patients who had documented fluorescence in situ hybridization testing within 30 days prior to or 90 days following the start of first-line treatment were included. HRCAs, including gain or amplification 1q21, deletion 17p, t(4;14), t(14;16) and t(14;20), were identified and categorized as 0, 1, or 2+ HRCAs. Our outcomes of interest were real world progression free survival (rwPFS) and overall survival (rwOS). Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI), adjusted for demographic and clinical characteristics and treatment including time-dependent receipt of autologous stem cell transplantation. Results: From a cohort of 4889 MM patients, there were 790 (16%) Black and 2995 (61%) White patients with median ages at diagnosis of 68 and 70 years, respectively. Compared to White patients, a higher proportion of Black patients had IgG M-protein (61% vs 55%) and a lower proportion had 1+ HRCAs identified (31% vs 34%). Among all racial groups, compared to patients aged Multivariable models showed evidence of significant statistical interaction between age and prevalence of HRCA for rwPFS (P-int: 0.02). Among White patients, having 2+ HRCAs ("double-hit MM") compared to no HRCAs was associated with worse rwPFS in both younger and older patients ( Similarly, we also found evidence of statistical interaction between age and prevalence of HRCA for rwOS (P-int: 0.02). Among White patients, double-hit MM was significantly associated with worse rwOS but the magnitude of increased risk differed for younger (HR 3.39, 95% CI 2.24-5.14, P Conclusions: In this cohort of newly diagnosed MM patients treated in routine practice, having double-hit MM was differentially predictive of poor survival across age groups. Double-hit MM was associated with worse rwPFS and rwOS among White patients, but these trends were less consistent among Black patients. Our current understanding of cytogenetic risk stratification of MM requires further study and additional data for identifying low- and high-risk subsets of patients across different ages and racial groups. Figure. Kaplan-Meier survivor functions for rwPFS in White (Panel A) and Black (Panel B) patients by age group and number of HRCAs Figure 1 Figure 1. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Ascha: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Pierre: Flatiron Health, Inc: Current Employment; Roche: Current holder of stock options in a privately-held company. Maignan: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wadé: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Leng: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Seymour: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment. Patel: Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

Opioid analgesics are used to treat cancer-related pain and improve quality of life, however overuse of these high-risk drugs has been associated with significant public health implications as exhibited by the national attention received during the opioid pandemic. In addition, pain associated with hematologic malignancies is frequent yet not well understood. There is no data examining opioid use and outcomes in patients with hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we sought to describe chronic opioid use (COU) and its impact on long-term outcomes in patients undergoing allo-HSCT. We analyzed outcomes of adult patients ≥ 18 years (n=159) diagnosed with hematologic malignancies (n=151) or benign hematologic disorders (n=8) (excluding sickle cell disease) who received allo-HSCT between 2012 and 2019 at a single urban medical center. COU was defined as having a documented active prescription for 3 consecutive months. Daily opioid doses were converted to morphine milligram milliequivalents (MME) using standard conversion factors. Among the entire cohort, the median age was 55.4 (19.4-74.3) years, 94 (59.1%) were male, 70 (44%) were White, 42 (26.4%) were Hispanic, and 26 (16.4%) were Black. The majority of patients were diagnosed with acute leukemia, with 89 (56%) having AML and 16 (10%) having ALL patients. Of the remaining patients, 14 (8.8%) were CML-BP or CML-AP, 16 (10%) NHL/HD, and 15 (9.4%) MPDs. 33.5% of patients were found to have high or very high DRI prior to allo-HSCT. Most patients received either a myeloablative (n=102, 64.2%) or reduced-intensity (n=55, 34.6%) conditioning regimen. At baseline (immediately prior to allo-SCT), COU was observed in 38 (23.9%) patients, 20 (52.6%) of which were diagnosed with AML. Only 23 (60.5%) patients with COU had a documented indication for opioid analgesia. The baseline median MME per day was 23.5mg (range: 2-150). In logistic regression analysis including demographic and social factors such as insurance type (i.e. Medicare, Medicaid, private payer), education level, smoking, alcohol, illicit drug and/or benzodiazepine use, and employment status, only older age (RR 0.97, 95% CI 0.94-0.99; p=0.026) was associated with a lower likelihood of baseline COU. In total, 149 (93.7%) patients received opioids during the allo-HSCT admission, while 45 (28.3%) were discharged on opioids. The reason for being discharged on opioids was related to musculoskeletal pain (n=19), residual mucositis-related pain (n=7), and headache (n=3). This was found to persist over time, with 35 (92.1%) of the 45 patients discharged on opioids remaining on opioids at 180 days after allo-HSCT thus meeting the definition for COU. The only factor found to predict for COU at 6 months was discharge from initial transplant hospitalization with an opioid (RR 2.24, 95% CI 1.16-4.32, p=0.016). Not only did a significant number of post-transplant survivors meet the definition for COU, but the MME was found to be relatively high with a median of 50mg (range: 10-540) at discharge and 30mg (range: 4.5-202) on days +30, 90, 180 as well as at 1 and 5 years after allo-HSCT. In a multivariable modified Poisson regression with robust standard errors for binary outcomes, when adjusted for established prognostic characteristics (i.e., disease, DRI, HCT-CI), we found that COU prior to admission strongly predicted for worse overall survival (HR 2.99, 95% CI 1.59-5.64; p=0.001), progression free survival (HR 2.72, 95% CI 1.48-4.99), and GVHD free, relapse-free survival (HR 1.78, 95% CI 1.05-3.03; p=0.033). This study is the first to describe patterns of COU, an important public health problem, among patients undergoing allo-HSCT, and in particular in long term survivors. We demonstrate high rates of baseline COU in patients undergoing allo-HSCT as well as persistent long term COU, which is linked to prescribing patterns after the initial transplant hospitalization. In addition, we show the negative impact of baseline COU on overall survival, even when adjusted for disease- and transplant-related factors. These data highlight the need to improve understanding and management of pain in hematologic malignancies as well as to reinforce the need for continuous reassessment of the use of opioids prior to and after allo-HSCT. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Patel: Celgene: Consultancy.

Background Vaccine hesitancy, defined as the delay in acceptance or refusal of safe vaccines, remains a challenge in the general population. Given that patients with hematologic malignancies frequently encounter healthcare professionals and are at high risk of severe COVID-19 infection, their attitudes towards vaccines may differ from other patient groups. We therefore performed a survey-based study to investigate vaccine hesitancy within an ethnically diverse group of patients diagnosed with hematologic malignancies. Methods We administered a 122-item questionnaire from December 2020 to January 2021 (prior to commercial availability of the COVID-19 vaccines) to 60 patients with hematologic malignancies. Questions were separated into the following categories: demographic and socioeconomic data; personal impact of COVID-19 infection; COVID-19 pandemic experience; COVID-19 infection perceptions; COVID-19 vaccine perceptions; and baseline COVID-19 vaccine knowledge. Results The majority of patients were Black (n=33, 55%) or Hispanic (n=11, 18.3%) and were undergoing active treatment (n=43, 71.7%) or had received prior hematopoietic stem cell transplantation (n=9, 15%). Eight (13.3%) patients had prior COVID-19 infection. Sixteen (26.7%) patients reported infection in an immediate family member while 15 (25%) reported infection in a friend. 20 of these cases were moderate in severity requiring healthcare interaction, and 17 of these cases were reported to result in severe infection (n=7, 9.6%) or death (n=10, 13.7%). Only 16 (29.6%) patients perceived themselves to be at high or very high risk of COVID-19 infection. The COVID-19 pandemic was reported to moderately or severely affect employment/income in 10 (22.8%) patients and led to worse mental health in 10 (22.3%) patients. However, the majority of patients reported no negative impact on their cancer treatment (n=37, 88.1%) or prognosis (n=45, 93.8%). Of the 60 patients, 22 (40.7%) reported that if a COVID-19 vaccine was made publicly available in the next 30 days, they would not vaccinate themselves, either due to safety concerns (n=4, 20%) or indifference (n=6, 30%). Despite this, 43 (78.2%) patients stated that vaccination was an important tool in ending the pandemic. More patients agreed to accept the vaccine if it was made available in 6 months from the time of survey (n=40, 76.9%). Only 32 (59.3%) patients were extremely or very likely to accept a yearly vaccine. In terms of perception on cancer outcomes, 31 (62%) patients were uncertain if the vaccine would interact negatively with their current chemotherapy treatment, while 27 (52.9%) believed the vaccine would make their cancer worse. The biggest fear patients had about COVID-19 vaccines were side effects or death (n=15, 38.5%) and complications to cancer/cancer therapy (n=5, 12.8%). Only 6 (15.4%) patients stated they had no fears related to COVID-19 vaccination. In fact, only 21 (39.6%) patients agreed or strongly agreed that the side effects of most vaccines outweigh the benefits. In a modified (age- and sex-adjusted) Poisson regression model (Table 1) that included baseline demographics and answers to select survey questions, older age was associated with a stronger likelihood of vaccine acceptance (RR 1.73, 95% CI 1.11-2.71; p=0.016), while female gender was associated with less likelihood to accept the vaccine (RR 0.58, 95% CI 0.37-0.90; p=0.016). Patients reported as "other" race (e.g., Asian) were more inclined to accept the vaccine (RR. 2.21, 95% CI 1.16-4.20; p=0.016) compared to White patients. Finally, when compared to patients who receive information primarily from medical professionals, those patients who received their information from social media or friends were far less likely to accept the vaccine (RR 0.02, 95% CI 0.01-0.04; p Conclusion This is the first study to report that although patients with hematologic malignancies experienced significant medical and social burdens from the COVID-19 pandemic and have frequent interaction with healthcare professionals, a high rate of COVID-19 vaccine hesitancy still exists. We provide in depth information on the potential reasons for vaccine refusal in a diverse patient population and highlight potential areas for improvement in patient education. In particular, we show that vaccine disinformation received from friends and social media is a significant reason for vaccine refusal. Figure 1 Figure 1. Disclosures Calip: Pfizer: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Patel: Celgene: Consultancy.

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is recommended for patients undergoing hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy. Trimethoprim-sulfamethoxazole and inhaled pentamidine are used frequently, but are limited, by their tolerability and therefore compliance. Intravenous (IV) pentamidine is a potential alternative agent. Here we conducted the first prospective study of the safety and efficacy of IV pentamidine for PJP prophylaxis in adult patients undergoing HSCT or intensive chemotherapy (clinicaltrials.gov NCT02669706). Fifty patients requiring PJP prophylaxis were enrolled and received monthly IV pentamidine at 4 mg/kg (maximum 300 mg) while undergoing intensive chemotherapy or HSCT. Patients were followed for the occurrence of PJP pneumonia and for adverse events. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. There were no grade 3/4 events. The TSQM questionnaire indicated that the majority of patients were satisfied with the administration of IV pentamidine (n = 43, 86%, p = 0.01). There were no cases of PJP during the 24 month follow-up period. Our study illustrates the safety, feasibility, and high degree of patient satisfaction when using IV pentamidine for PJP prophylaxis.

A xenograft model of stem cell rejection was developed by co-transplantating human CD34+ and allogeneic CD3+ T cells into NOD-scid ɣ-chainnull mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34+ cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34+ cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day –1 to +27 (group A), from day –1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34+ cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34+ cells may be facilitated by treatment with abatacept and late stem cell boost.

In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m2 (Mel200) in the conditioning regimen prior to autologous stem cell transplant (ASCT) for multiple myeloma (NCT02043847). Twelve patients aged 18-75 with relapsed myeloma were enrolled in the study and received Mel200 and TMI 3 Gy (n = 3), 6 Gy (n = 3), or 9 Gy (n = 6) prior to transplant. There were no grade 4 extra-hematologic toxicities and a maximum tolerated dose was not reached. Median time to neutrophil and platelet engraftment was 11 and 13 d, respectively. At day 90, 73% of patients were in CR or VGPR. Median progression free survival (PFS) was 449 d and median overall survival (OS) was 966 d. We conclude that TMI at a dose of 9 Gy can be safely combined with Mel200 in therapeutic regimens for autologous transplant. Initial clinical results will prompt a phase 2 study.

Intensive cancer treatment followed by hematopoietic stem cell transplantation (HCT) results in moderate to severe fatigue and physical inactivity, leading to diminished functional ability. The purpose of this study was to determine the efficacy of an exercise intervention, strength training to enhance early recovery (STEER), on physical activity, fatigue, muscle strength, functional ability, and quality of life after HCT. This single-blind, randomized clinical trial compared strength training (n = 33) to usual care plus attention control with health education (UC + AC with HE) (n = 34). Subjects were stratified by type of transplantation and age. STEER consisted of a comprehensive program of progressive resistance introduced during hospitalization and continued for 6 weeks after hospital discharge. Fatigue, physical activity, muscle strength, functional ability, and quality of life were assessed before HCT hospital admission and after intervention completion. Data were analyzed using split-plot analysis of variance. Significant time × group interactions effects were noted for fatigue (P = .04). The STEER group reported improvement in fatigue from baseline to after intervention whereas the UC + AC with HE group reported worsened fatigue from baseline to after intervention. Time (P .001) and group effects (P = .05) were observed for physical activity. Physical activity declined from baseline to 6 weeks after hospitalization. The STEER group was more physically active. Functional ability tests (timed stair climb and timed up and go) resulted in a significant interaction effect (P = .03 and P = .05, respectively). Subjects in the UC + AC with HE group were significantly slower on both tests baseline to after intervention, whereas the STEER group's time remained stable. The STEER group completed both tests faster than the UC + AC with HE group after intervention. Study findings support the use of STEER after intensive cancer treatment and HCT. Strength training demonstrated positive effects on fatigue, physical activity, muscle strength, and functional ability. The exact recovery patterns between groups and over time varied; the STEER group either improved or maintained their status from baseline to after intervention (6 weeks after hospital discharge) whereas the health education group generally declined over time or did not change.

Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients >18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC > 1.0 x 109/L with ALC and AMC > 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

High dose melphalan and autologous stem cell transplantation is standard of care for the upfront treatment of multiple myeloma (MM). Several studies have shown upregulation of single DNA repair genes and whole DNA repair pathways as associated with melphalan resistance and poor outcomes after ASCT. Here we set out to identify the most important DNA repair enzymes and pathways to predict outcomes after ASCT using the MMRF CoMMpass dataset but instead found DNA repair gene expression to be a poor prognostic feature regardless of treatment. Of the 561 MM patients who received ASCT as part of frontline therapy, 378 (67%) patients had whole transcriptome sequencing data available for analysis in this study. The majority of patients in this cohort received a 3-drug novel agent-based regimen for first line treatment. We selected 81 genes of known function related to DNA damage repair across multiple pathways. Using the median mRNA expression as cutoff for each gene, we first compared PFS for high vs. low expressers and found 38 genes in non-homologous end joining (NHEJ), homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and Fanconi anemia (FA) pathway which predicted for inferior survival with higher expression (p≤0.05). We subsequently analyzed each gene individually in a multivariate Cox proportional hazards models adjusted for known prognostic and treatment-related factors (age, gender, race, ISS stage, LDH, normal/abnormal cytogenetics, high risk FISH/cytogenetics, cycles to first response, frontline treatment, and time to transplant) and found that 9 genes retained significance including 3 genes in NHEJ (POLL, PRKDC, NHEJ1), 3 in FA pathway (BRIP1, RMI1, FANCE) and 3 in MMR (MLH3, MSH2 and PMS1). In addition, increased pathway level gene overexpression for NHEJ (p=0.02) and MMR (0.009) pathways conferred worse PFS. Genes involved in NER did not retain significance despite this pathway being involved with repair of melphalan-induced bulky adducts formation. Additionally, high MMR pathway expression was significant despite this pathway not having a known role in repair of melphalan-induced DNA damage. To validate the specific importance of these genes in predicting response to ASCT, we tested whether high expression predicted outcomes in patients who did not undergo ASCT. In 387 non-ASCT patients with whole transcriptome sequencing available, NHEJ and MMR gene expression were significant predictors of PFS confirming that this finding was not specific to patients undergoing ASCT. We next correlated the expression of NHEJ and MMR genes and found significant co-expression of these genes (r=0.55-0.8), suggesting a common mediator leading to global upregulation of DNA repair. As increased MYC activity is a common finding in MM and is a master regulator of transcription, we hypothesized the DNA damage repair genes were upregulated by increased MYC activity. Gene Set Enrichment Analysis of hallmark gene sets confirmed that patients with increased DNA repair were also enriched for MYC targets (FDR=0.0063). Based on this, we hypothesized that oncogene-mediated constitutive DNA damage and replication stress (RS) are a hallmark of high risk and aggressive myeloma. Here we present novel findings to show that global DNA repair upregulation occurs in high risk disease as evidenced by the inferior PFS. We hypothesize that this could be attributed to MYC-related increased gene transcription resulting in DNA damage and RS which in turn recruits several DNA repair pathways. These specific DNA repair pathways and signal activation pathways involved with replication stress represent novel therapeutic targets in myeloma. Disclosures Calip: Flatiron Health: Current Employment. Hofmeister:Sanofi: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Nektar: Honoraria, Research Funding; Imbrium: Honoraria; Janssen: Honoraria, Research Funding; Oncopeptides: Honoraria; Karyopharm: Honoraria, Research Funding; Oncolytics Biotech: Research Funding. Patel:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy.

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) has been widely adopted in clinical practice. Pharmacokinetic (PK) studies report up to 10-fold interpatient variability in melphalan exposure. We previously identified low Hgb and/or creatinine clearance (CrCl), both determinants of melphalan PK, as strong predictors of survival and toxicity after high dose melphalan and autologous transplant. We thus hypothesized that these clinical variables could also predict for outcomes after Flu/Mel140 and hematopoietic stem cell transplantation (HSCT). Day -6 Hgb was grouped as low or high relative to the median ( The median overall survival (OS) was significantly shorter in patients with a lower Hgb compared to a higher Hgb (113 vs. 2536 days; p=0.004). This difference was due to an increased rate of transplant-related mortality (TRM) (26 (81.3%) versus 11 (36.7%) patients; p=0.0005). The median OS was also worse in patients with lower CrCl (75 vs. 317 days; p=0.003), with a significantly worse TRM (10 (90.1%) versus 27 (52.9%); p=0.0023). Multivariate Cox proportional hazards model adjusted for clinical and prognostic factors found that a higher Hgb predicted for better OS (HR 0.12, 95% CI 0.03-0.52; p=0.004) and TRM (HR 0.13, 95% CI 0.03-0.53); p=0.004). A higher Hgb and CrCl predicted for better OS (HR 0.08, 95% CI 0.01-0.63; p=0.017) and trended towards a decreased rate of TRM (HR 0.16, 95% CI 0.02-1.43; p=0.102). We then analyzed toxicity. In patients with a lower Hgb, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that lower Hgb and CrCl represent important determinants of toxicity and TRM after Flu/Mel140 and HSCT. These findings are consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. Our data suggest that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes after Flu/Mel140.

High dose melphalan (MEL) and autologous stem cell transplant (ASCT) is the standard of care in the treatment of multiple myeloma (MM). Resistance to MEL has been linked to increased DNA repair. Here we sought to identify which DNA repair pathways lead to MEL resistance. As inhibitors of the single strand DNA repair enzyme PARP1 are clinically available, we first examined whether PARP1 gene expression affected clinical outcomes. In a dataset of 414 patients treated with tandem ASCT, high PARP1 expression lead to reduced survival compared to patients with low expression (42.7 months vs. median not reached, p=0.003). We therefore tested in vitro the cytotoxicity of PARPi with veliparib (VEL), olaparib (OLA) or niraparib (NIRA) in RPMI8226 and U266 MM cell lines as well as their MEL resistance counterparts, RPMI8226-LR5 (LR5) and U266-LR6 (LR6). At physiologic doses PARPi alone was not cytotoxic. However, the MEL IC50 in RPMI8226 cells decreased from 27.8 to 23.1, 22.5 and 18.0 µM with the addition of VEL, OLA and NIRA respectively. Similarly, MEL IC50 decreased in U266 cells from 6.2 to 3.2, 3.3 and 3.0 µM. However, in LR5 and LR6 cells, PARPi did not completely reverse MEL resistance. We confirmed this in a NOD/SCID/gamma null xenograft mouse model with either MEL sensitive (RPMI8226) or resistant (LR5) MM. Treatment with a MEL-VEL combination prolonged survival in RPMI8226 mice compared to MEL alone (107 vs. 67.5 days, p=0.0009), but not in LR5 mice (41 vs. 39 days, p=0.09). Next we tested whether the double strand DNA repair mechanisms, homologous recombination (HR) and non-homologous end joining (NHEJ), cause MEL resistance which is not overcome by PARPi. Using an HR assay, LR6 cells had 4.5 fold higher HR ability than parent U226 cells (p = 0.05) showing this to be a possible mechanism of resistance. However, LR5 cells had equivalent HR ability to parent RPMI8226 cells. We therefore hypothesized that NHEJ may be a mediator of MEL resistance in LR5 cells. As DNA-PK is integral to NHEJ and may be a therapeutic target, we treated LR5 cells with the DNA-PK inhibitor NU7026 in combination with MEL. Although NU7026 alone at 2.5 µM had no cytotoxicity, in combination it completely reversed resistance to MEL resulting in a lower IC50 than even parent RPMI8226 cells (46.4 vs. 14.4 µM). Based on our findings, we hypothesized that combined expression of the HR gene BRCA1, the NHEJ gene DNA-PK, and PARP1 may predict survival in patients undergoing ASCT. Using the same clinical dataset, we found that overexpression of 0 (n=101), 1-2 (n=287), or all 3 genes (n=26) strongly predicted median survival (undefined vs. 57.8 vs. 14.8 months, p Here we demonstrated that MEL resistance is not completely reversed by PARPi, while it may be overcome by targeting HR and NHEJ pathways. In addition, we observed that a 3 gene analysis pre-ASCT may help predict patients that are inherently resistant or sensitive to high dose MEL.

High dose melphalan (HDM) and autologous stem cell transplantation (ASCT) is standard of care for multiple myeloma (MM). However, ∼40% of patients fail to achieve complete remission, in part due to variability in melphalan exposure (AUC) when using body-surface-area (BSA)-based dosing, which results in suboptimal exposure and response. HDM, 100mg/m2 on day -2 and -1, allows for potential day -1 dose modification if day -2 pharmacokinetic (PK) testing with rapid turnaround is performed. Here we describe a clinically reproducible method of PK testing that allows for real-time HDM dose adjustments. We developed an in-house melphalan assay and performed PK analysis using LC-MS/MS. Adult MM patients were administered HDM on days -2 and -1 prior to ASCT. Blood for PK sampling were drawn at 10 time points post-infusion on day -2 and day -1 in the first 5 patients and day -2 in the remainder. PK parameters were determined from plasma concentration versus time data by a noncompartmental analysis using WinNonlin 8.1. Toxicities up to 30 days after ASCT and day 90 disease response were analyzed. Eighteen patients received 200mg/m2 and 2 received 140mg/m2. Day -2 and -1 AUC correlated well (r=0.8), allowing for a method of dose adjustment using linear, dose-proportional calculations for future PK-directed studies. We observed a 2.3-fold variation in melphalan exposure within our patient cohort, with a median day -2 AUC of 7.49 (range: 4.95-11.28) mg*h/L, confirming significant interpatient variability. We then calculated the theoretical absolute day -1 dose required to target the total median melphalan AUC and compared it to the BSA-based dose. The change in day -1 dose ranged from -124 mg to +206 mg (Figure 1A). When expressed as BSA-based mg/m2/dose, we found that doses ranging from 133-308 mg/m2 were required to target the total median AUC (Figure 1B). Using D-optimality, we determined that reducing blood sampling (4 time points) did not affect AUC prediction, confirmed by comparing mean AUCs between both sampling schedules (7.76 vs. 7.80 mg*h/L; p=0.8193). We examined associations between AUC and clinical outcomes. In modified Poisson regression, higher AUC correlated with increased risk of febrile neutropenia (p=0.05) and a trend towards increased use of antiemetics (p=0.07). Collection of disease response data is ongoing. We report minimal intrapatient variability in melphalan day -2 and -1 AUC allowing a linear, dose-proportional method of dose-adjustment without need for a pre-transplant test dose. Dose adjustment simulations based on patients' PK data demonstrate that large, bi-directional dose adjustments are required to target a median AUC, emphasizing the importance of PK-directed HDM dosing. This novel dosing approach using rapid melphalan PK testing in MM patients undergoing ASCT will decrease interpatient variability and improve myeloma outcomes.

Patients with sickle cell disease (SCD) have access to fewer health care resources and therapies compared to other diseases, which contributes to increased morbidity and health care utilization. We compared health care utilization (inpatient hospital days, emergency care visits) and health care-related costs between SCD adults that underwent hematopoietic stem cell transplantation (HSCT) using a nonmyeloblative conditioning regimen versus those referred for HSCT but did not proceed due to lack of an HLA-matched sibling donor, denial by insurance, red blood cell antibodies to the potential donor, or declining further evaluation. Between 8/2011 and 4/2016, 83 SCD patients were referred for allogeneic HSCT and 16 underwent the procedure. The HSCT and non-HSCT groups were similar by age, sex, prior SCD-related therapy and complications. Compared to pre HSCT, significantly fewer inpatient hospital days (median of 1 versus 22 days, P = 0.003) and emergency care visits (median of 1 versus 4 visits, P = 0.04) were observed by the 2nd year post-HSCT. Similar results were observed in comparison to the standard-of-care group (median of 1 versus 12 hospital days, P = 0.002; median of 1 versus 3 emergency visits, P = 0.03). Lower health care costs were observed by the 2nd year post-HSCT (median of $16,281 versus $64,634 pre-HSCT (P = 0.01) and versus $54,082 in the standard-of-care group (P = 0.05). A median reduction of -$20,833/patient/year (IQR, -$67,078-+$4,442/patient/year) in health care costs compared to pre-HSCT was observed in the 2nd year post-HSCT. In conclusion, allogeneic HSCT leads to improvements in health care utilization and costs compared to standard-of-care therapy in high-risk SCD adults.

High-dose melphalan (MEL) and autologous stem cell transplantation (ASCT) is the standard of care in the treatment of multiple myeloma (MM). Resistance to MEL has been linked to increased DNA repair. Here we sought to identify whether inhibition of poly(ADP-ribose) polymerase (PARP) synergizes with MEL and can overcome resistance. We tested the synergistic cytotoxicity of 3 inhibitors of PARP (PARPi)—veliparib (VEL), olaparib (OLA), and niraparib (NIRA)—combined with MEL in RPMI8226 and U266 MM cell lines, as well as in their MEL resistance counterparts, RPMI8226-LR5 (LR5) and U266-LR6 (LR6). The addition of VEL, OLA, and NIRA to MEL reduced the half maximal inhibitory concentration (IC50) in RPMI8226 cells from 27.8 µM to 23.1 µM, 22.5 µM, and 18.0 µM, respectively. Similarly, the IC50 of MEL in U266 cells was decreased from 6.2 µM to 3.2 µM, 3.3 µM, and 3.0 µM, respectively. In LR5 and LR6 cells, PARPi did not reverse MEL resistance. We confirmed this in a NOD/SCID/gamma null xenograft mouse model with either MEL-sensitive (RPMI8226) or MEL-resistant (LR5) MM. Treatment with a MEL-VEL combination prolonged survival compared with MEL alone in RPMI8226 mice (107 days versus 67.5 days; P = .0009), but not in LR5 mice (41 versus 39 days; P = .09). We next tested whether 2 double-stranded DNA repair mechanisms, homologous recombination (HR) and nonhomologous end-joining (NHEJ), cause MEL resistance in LR5 and LR6 cells. In an HR assay, LR6 cells had a 4.5-fold greater HR capability than parent U226 cells (P = .05); however, LR5 cells had an equivalent HR ability as parent RPMI8226 cells. We hypothesized that NHEJ may be a mediator of MEL resistance in LR5 cells. Given that DNA-PK is integral to NHEJ and may be a therapeutic target, we treated LR5 cells with the DNA-PK inhibitor NU7026 in combination with MEL. Although NU7026 alone at 2.5 µM had no cytotoxicity, in combination it completely reversed resistance to MEL (MEL IC50, 46.4 µM versus 14.4 µM). We examined the clinical implications of our findings in a dataset of 414 patients treated with tandem ASCT. High PARP1 expressers had lower survival compared with patients with low expression (median 42.7 months versus median not reached; P = .003). We hypothesized that combined expression of the HR gene BRCA1, the NHEJ gene PRKDC (DNA-PK), and PARP1 may predict survival and found that overexpression of 0 (n = 101), 1 or 2 (n = 287), or all 3 (n = 26) genes had a negative impact on median survival (undefined versus 57.8 months versus 14.8 months; P

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.

PURPOSE: Patient-reported outcomes such as self-reported health (SRH) are important in understanding quality cancer care, yet little is known about links between SRH and outcomes in older patients with multiple myeloma (MM). We evaluated associations between SRH and mortality among older patients with MM. METHODS: We analyzed a retrospective cohort of patients ages ≥65 years diagnosed with first primary MM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) data resource. Pre-diagnosis SRH was grouped as high (excellent/very good/good) or low (fair/poor). We used Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between SRH and all-cause and MM-specific mortality. RESULTS: Of 521 MM patients with mean (SD) age at diagnosis of 76.8 (6.1) years, 32% reported low SRH. In multivariable analyses, low SRH was suggestive of modest increased risks of all-cause mortality (HR=1.32, 95% CI 1.02–1.71) and MM-specific mortality (HR=1.22, 95% CI 0.87–1.70) compared to high SRH. CONCLUSION: Findings suggest that low pre-diagnosis SRH is highly prevalent among older patients with MM and is associated with modestly increased all-cause mortality. Additional research is needed to address quality of life and modifiable factors that may accompany poor SRH in older patients with MM.

STUDY OBJECTIVE Bevacizumab is used in the treatment of recurrent glioblastoma, but evidence is limited on the incidence of thromboembolic complications regarding the use of this drug in real-world settings. We evaluated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) associated with the use of bevacizumab among adults diagnosed with high-grade gliomas in a commercially insured U.S. POPULATION DESIGN Nested case-control study. DATA SOURCE Truven Health MarketScan Commercial and Medicare Supplemental health claims databases (2009-2015). PATIENTS A total of 2157 patients with high-grade gliomas who underwent incident (first-time) craniotomy, radiation, and concurrent temozolomide treatment between 2009 and 2015 were identified. Overall, 25 cases of ATE and 99 cases of VTE were each identified in this cohort, and each case was matched to up to 10 controls (170 for ATE and 819 for VTE) based on sex, age, quarter year of index time, and follow-up duration by using incidence density sampling without replacement from the overall cohort. Controls were at risk for the outcome of interest (ATE or VTE) at the time of case occurrence and survived at least as long as their referent case. MEASUREMENTS AND MAIN RESULTS Exposure to bevacizumab was determined during inpatient or outpatient encounters between the index date (date of the incident craniotomy) and the ATE or VTE event or corresponding matched control date. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of ATE and VTE separately. A higher proportion of patients with ATE received bevacizumab compared with controls (28% vs 17%; adjusted OR 1.51, 95% CI 0.54-4.24), but this excess in odds was not statistically significant. Similarly, bevacizumab was not significantly associated with VTE (13% vs 9%; adjusted OR 1.40, 95% CI 0.71-2.75). CONCLUSION We found no significant association between the use of bevacizumab and the occurrence of thromboembolic events in patients with high-grade gliomas, although our study was limited by the small number of ATE events. Because the potential for complications from arterial thrombosis cannot be completely ruled out, further research is needed to confirm the thromboembolic safety of bevacizumab in a larger sample of patients with high-grade gliomas.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Background & Aim Both chemokine receptor CXCR4 antagonist plerixafor (P) as well as high volume (HV) leukapheresis have been shown to reduce mobilization failure rates. However, no direct comparisons of such collection methods currently exist. In this single center retrospective study, we compared the collection efficiency in adult patients diagnosed with multiple myeloma (MM) or non-Hodgkins Lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT) comparing yields based on pre apheresis peripheral blood (PB) CD34+ cell number ( 50 cells/µL, Fig 1). Methods, Results & Conclusion The collection methods used included HV vs. regular volume (RV) with or without P. There was a total of 116 patients (78 MM & 38 NHL) in the study group with a total of 191 collections. RV without P was used for patients whose pre-apheresis CD34 count was >50/µL. RV (+P) or HV (+P) or HV without P groups were used to investigate whether HV can substitute RV (+P) for poor mobilizers (

This cohort study examines the risk of skeletal-related events associated with the frequency of bisphosphonate treatment in patients with multiple myeloma.

Background: Multiple myeloma (MM) incidence and outcomes differ across racial/ethnic groups in the United States. Interactions between socioeconomic status (SES) with ethnicity in MM incidence and survival outcomes are not well understood. Our objective was to evaluate disparities in cancer-specific survival of patients diagnosed with MM by race/ethnicity. Methods: We conducted a population-based retrospective cohort study of patients ages 20+ years diagnosed with MM between 2000 and 2015 using Surveillance, Epidemiology and End Results, Census Tract-level SES and Rurality Database. SES was defined using the National Cancer Institute's time-dependent composite score developed by Yost et al. (2001). Yost index quintiles were where the 1st and 5th quintiles representing the lowest and highest SES categories respectively. Cumulative incidence functions were used to analyze cancer-specific survival across strata racial/ethnic and SES and equality of functions was determined using Gray's test. Subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) were calculated using the Fine and Gray regression models adjusted for age, sex, year of diagnosis, marital status, insurance status, and treatment with chemotherapy. Race-specific risk estimates were stratified by age ( Results: Overall, 58,095 MM patients were included in our analysis among whom 63.0% were non-Hispanic White, 19.5% were Black, 0.3% were American Indian/Alaskan Native, 5.8% were Asian/Pacific Islander and 11.4% were Hispanic. Compared to White MM patients (median age 69 years), Black (64 years), American Indian/Alaskan Native (64 years), Asian/Pacific Islander (67 years) and Hispanic (64 years) patients were younger on average. A higher proportion of Black (42.8%) and Hispanic (27.9%) MM patients were in the lowest SES quintile compared to White (10.6%), American Indian/Alaskan Native (15.2%), and Asian/Pacific Islander (8.9%) MM patients. Cumulative incidence functions for cancer-specific survival were significantly different across SES quintiles (P < 0.0001) and racial/ethnic groups (P < 0.0001). Overall, MM patients in the lowest SES quintile had a significantly increased risk of MM-specific mortality (SHR: 1.28, 95% CI 1.21-1.36) compared to patients in the highest quintile. Risk estimates comparing the lowest to the highest quintile of SES were higher among Black (SHR 1.39, 95% CI 1.08-1.77), Hispanic (SHR: 1.78, 95% CI 1.21-2.63), and White (SHR 1.44, 95% CI 1.23-1.69) MM patients ages Conclusion: Low SES level is independently associated with poor MM-specific survival. However, the impacts of SES on MM-specific survival differ by race/ethnicity and age with the greatest increased risk observed in younger Black, Hispanic, and White patients. Citation Format: Huiwen Deng, Ashwini Zolekar, Hsiao-Ching Huang, Mary H. Smart, Colin C. Hubbard, Brian C. Chiu, Pritesh R. Patel, Karen Sweiss, Gregory S. Calip. Racial differences in the impact of socioeconomic status on cancer-specific survival in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2628.

Background:AML is predominantly a disease of the elderly, yet outcomes remain dismal, particularly for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33–commonly expressed on AML blasts, and, critically, AML stem cells (LSC)–linked to the cytotoxin calicheamicin. GO resistance mechanisms include (i) decreased/aberrant blast CD33 expression, (ii) p-glycoprotein export of calicheamicin, and (iii) apoptosis resistance due to deficient activation of mitochondrial outer membrane permeabilization, a process highly dependent on BCL-2 expression. GO-induced apoptosis depends on the pro-apoptotic proteins Bax and Bak and is inhibited by overexpression of the anti-apoptotic proteins BCL-2 or BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, and thus facilitating apoptosis. LSC overexpress BCL-2, however VEN monotherapy is not effective in AML, as resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling, CD33 expression (including sequencing for isoforms), and BCL-2, BCL-XL, and MCL-1 protein levels; MRD measurement at post-therapy time points using digital drop PCR technology; and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue) Methods:This is a single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤ 3 lines of prior therapy, and no prior use of GO or VEN, previous VOD, BMT within 2 months, CNS disease, or history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused days 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts > 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and pt remaining in CR/CRi or PR (as above), then proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, anti-leukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. Progress: This study is currently open to its second dosing cohort and has enrolled 5 pts to date. No dose-limiting toxicities have been encountered. However, the COVID-19 pandemic has had a negative impact on enrollment, which is expected to improve as vaccinations expand. ClinicalTrials.gov NCT04070768. Citation Format: Saad Arain, Pritesh Patel, Karen Sweiss, Brian Parkin, Heiko Konig, Gregory Calip, Betul Gok Yavuz, John Quigley. Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: Big Ten Cancer Research Consortium BTCRC-AML17-113 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT224.