ALBERT

Description: Introduction Pegaspargase (PEG) is a critical component of therapy for pediatric acute lymphoblastic leukemia (ALL); however, complete asparaginase treatment may be hampered by the development of hypersensitivity reactions. Inadequate exposure to asparaginase has been shown to result in inferior outcomes (Gupta 2020). Although Erwinia asparaginase can be utilized as a replacement in patients with PEG allergy, recent shortages of Erwinia leave some patients who develop allergy to PEG without an alternative. Premedication with antihistamines and corticosteroids, as well as decreasing the pegaspargase infusion rate have been proposed as approaches to reduce hypersensitivity reactions (Cooper 2019, Bade 2019, Stock 2019). We evaluated the episodes of hypersensitivity reactions to PEG during three time periods with differing premedication and infusion practices at a single institution. Methods We utilized pharmacy records to conduct a retrospective chart review on PEG administration at Children's Healthcare of Atlanta from June 2017 to May 2020. Abstraction captured data on clinical hypersensitivity reactions to PEG over 3 time periods. PEG 2500 units/m2 was delivered as an intravenous infusion according to the schedules used in Children's Oncology Group ALL protocols. In the first time period (P1, June 22, 2017 to June 21, 2018) PEG was infused over 1 hour without premedication. In the second period (P2, June 22, 2018 to May 19, 2019) PEG was infused over 1 hour following premedication with ranitidine and diphenhydramine. In the final period (P3, May 20, 2019 to May 19, 2020) PEG was infused over 2 hours with normal saline piggyback intravenous fluids following premedication with ranitidine (or famotidine), diphenhydramine and hydrocortisone. Asparaginase activity was measured 7-10 days after PEG doses in consolidation and subsequent phases in P1 and P2, and also after induction in P3. Silent inactivation was defined as asparaginase activity

Description: With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximise sustained TFR by improving our understanding of its key determinants. Chronic phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of 21.85 days (last quartile) (P

Description: Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study. Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS 〉0.1% at screening (19 pts with BCR-ABL1IS 10% or Ph+ 〉65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100). MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in 〉10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock). Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs. Disclosures Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani:Novartis: Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami:Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia:Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo:Novartis: Honoraria; Takeda: Honoraria. Kim:Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee:Novartis: Other: Travel support for attendance at investigator meeting. García Gutiérrez:Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone:Novartis: Current Employment. Allepuz:Novartis: Current Employment. Quenet:Novartis: Current Employment. Bédoucha:Novartis: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.

Description: Venetoclax (VEN), a highly selective BCL-2 inhibitor with limited single-agent activity in AML, has shown encouraging efficacy in combination with hypomethylating agents (HMA). Nevertheless, patients relapse and have limited treatment options. Like BCL-2, MCL-1 plays critical roles in the survival of AML cells and AML stem/progenitor cells. MCL-1 is also a known resistance factor to VEN. Preclinical studies have demonstrated that combined inhibition of BCL-2 and MCL-1 is highly effective in VEN-resistant AML cells. Diverse mechanisms contribute to the resistance to VEN, and likely also to BH3 mimetics targeting MCL-1 that are currently under clinical development in AML. The effectiveness of co-targeting BCL-2 and MCL-1 in the setting of various resistance mechanisms has not been fully explored. We investigated combined inhibition of BCL-2 and MCL-1 in AML cells resistant to apoptotic stimuli through various mechanisms and demonstrate that co-inhibition of BCL-2 with VEN and MCL-1 with AMG176 synergistically targets AML cells that exhibit intrinsic or acquired resistance to BH3 mimetics in vitro and in vivo. We generated AML cells with acquired resistance to VEN (VEN-R) or AMG176 (AMG-R) by exposing the cells to increased doses of the drug and we also generated the cells genetically overexpressing BCL-2, MCL-1, or BCL-2A1. We found that both VEN-R and AMG-R MV4-11 cells expressed increased levels of MCL-1, BCL-2, and BCL2A1, but decreased BAX. Although BCL-XL levels decreased in AMG-R MV4-11 cells, BAK, PUMA, and BID levels were also markedly lower in these resistant cells compared to the parental controls. VEN or AMG176 as single agents had diminished activity against AML cells with acquired resistance not only to VEN, but also to AMG176 and AML cells genetically overexpressing MCL-1, BCL-2, or BCL2-A1. In addition, we found that TP53 mutated primary AML cells expressed low levels of BAX and that Molm13 cells acquired a TP53 mutation (R248W) expressed lower levels of BAX and were more resistant to VEN, consistent with clinical observations, and they were also more resistant to AMG176. However, when VEN and AMG176 were combined, synergy was observed (combination index 〈 1). We next treated AML patient samples and found that combined inhibition of BCL-2 and MCL-1 was synergistic in primary AML cells and stem/progenitor cells obtained from patients with various cytogenetics/mutations, including TP53 mutations, and from patients resistant to/relapsed from VEN- or VEN/HMA-based therapy, even when AML cells were co-cultured with bone marrow-derived mesenchymal stromal cells that mimic the bone marrow microenvironment. To demonstrate potential clinical relevance, we developed a PDX model from a clinically-acquired VEN/HMA resistant AML patient and treated the PDX-bearing mice with VEN, AMG176, and the combination. Remarkably, the combination of VEN and AMG176 demonstrated strong antileukemia activities, markedly diminished not only AML blasts but also AML stem/progenitor cells, as determined by CyTOF analysis, and significantly extended survival (median 336 vs 126 d for controls, P 〈 0001), while VEN (129 d) alone and even AMG176 (131 d) alone had minimal efficacy. Several mice in the combination group survived over 400 d and died probably from old age with only minimal residual leukemia. In conclusion, we demonstrate the alteration of multiple BCL-2 family proteins contributes to BH3 mimetic resistance that can be overcome by combined inhibition of MCL-1 and BCL-2. The striking effectiveness of co-targeting BCL-2 and MCL-1 in AML resistance to a BH3 mimetic via various mechanisms or to VEN/HMA suggests broad clinical applications of this strategy, and warrants clinical evaluations. Disclosures Carter: Amgen: Research Funding; Ascentage: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding. Hughes:Amgen: Current Employment. Chen:Amgen: Current Employment. Morrow:Amgen: Current Employment. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding.

Description: Leukemia stem cells (LSCs) are the subset of leukemic cells that drive leukemia progression, resist therapy, and remain latent to spark disease relapse. LSCs are quantified by efficiency of xenografting immunodeficient mice, a measurement that is predictive of leukemia outcome. Although LSCs have been previously thought to be rare and phenotypically primitive, recent data indicate that LSCs may actually be heterogeneous. Here, we use single-cell transcriptomics combined with limiting dilution xenotransplantation to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL), an aggressive form of childhood leukemia. Compared to acute myeloid leukemia (AML), LSCs are abundant in MLL-r B-ALL. Recapitulating the unique clinical behavior of this form of leukemia, MLL-r B-ALL cells undergo a B-lymphoid to myeloid lineage switch under chemotherapy pressure consistent with primitive, multipotent transcriptional programs present in LSCs. Although we identify rare, chemotherapy-resistant, primitive LSCs, we also observe LSCs emerging from more differentiated populations. These facultative LSCs self-renew and possess the capability to replenish the full cellular diversity of MLL-r B-ALL. Using CITE-seq, we find that stem cell programs can be fully uncoupled from immunophenotype in MLL-r B-ALL. In mechanistic studies, we find that the phenotypically differentiated LSCs that drive bottom-up reconstitution of the leukemic cellular ontogeny bear signatures of MYC activation and oxidative phosphorylation. We confirm recruitment of these pathways in actively reconstituting, phenotypically differentiated LSCs, and define a pathway by which MYC rewires metabolism in MLL-r B-ALL LSCs. We find that MYC is required for LSC plasticity in vitro and in vivo. Targeting oxidative metabolism impairs LSC engraftment, identifying a potential therapeutic intervention. We conclude that the high LSC content and dual lineage and LSC plasticities of MLL-r B-ALL contribute to its chemotherapy resistance and persistently poor outcomes. Disclosures Shalek: Honeycomb Biotechnologies: Consultancy, Current equity holder in publicly-traded company; Cellarity: Consultancy, Current equity holder in publicly-traded company; Repertoire Immune Medicines: Consultancy, Current equity holder in publicly-traded company; Merck: Consultancy; Orche Bio: Consultancy, Current equity holder in publicly-traded company; Dahlia Biosciences: Consultancy, Current equity holder in publicly-traded company.

Description: Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

Description: BACKGROUND: High-grade B-cell lymphomas (HGBLs) with rearrangement of MYC and BCL2 and/or BCL6, known as "double-hit" or "triple-hit" B-cell lymphomas (DHL/THL), are an aggressive sub-type of non-Hodgkin mature B-cell lymphoma with chromosomal rearrangements involving MYC with BCL2 and/or BCL6 genes. DHL/THLs typically have poor outcomes and early relapses with first-line R-CHOP, and intensive induction chemoimmunotherapy regimens are associated with improved outcomes. Infusional dose-adjusted (DA)-R-EPOCH is commonly used, yet there is a lack of clear evidence that dose-adjustment enhances survival, and variations in compliance with dose-adjustment exist. DA-R-EPOCH has been incorporated as the backbone of prospective clinical trials testing the addition of novel agents for frontline management of DHL/THL, and these combinations may lead to a greater degree of myelosuppression that may disrupt dose-adjustments and hinder dose-escalations relative to using DA-R-EPOCH alone. Therefore, we sought to determine if patients with DHL/THL treated with induction DA-R-EPOCH have differences in clinical outcomes (OS, PFS, treatment-related adverse events and others) based upon compliance with dose-adjustment and cumulative doses of R-EPOCH administered. METHODS: Adult (age ≥18 years) patients with DHL/THL treated with induction DA-R-EPOCH chemoimmunotherapy from 2014 to 2019 at six collaborating medical centers were included in this study. To be included, patients must be without CNS-involvement at diagnosis, have received ≥4 cycles of DA-R-EPOCH, have adequate clinicopathologic data regarding chemoimmunotherapy dosing, survival, treatment response/remission status, cell counts, CNS and antimicrobial prophylaxis, admissions for cytopenias or IV antibiotics, and demographic data including age, international prognostic index (IPI), CNS-IPI, ECOG performance status, and cumulative illness rating score (CIRS, if available). An initial cycle of R-CHOP was permitted. De-identified data from participating sites were combined, and chemotherapy doses were aggregated and divided into quartiles based on cumulative doses of doxorubicin, etoposide, and cyclophosphamide received. Correlation between CIRS and dose was assessed by Spearman's correlation. OS and PFS were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: 109 total patients were included in this study. The median age was 63 years (range 29-83), and approximately 60% of patients were male, 58% were age 60 or older, 60% had an IPI score of ≥3, and 66% were Ann Arbor Stage IV at induction. For all patients, 2-year and 5-year OS rates were 75% (95% CI: 67-84%) and 70% (59-82%), with 27 total deaths in the study period. 2-year and 5-year PFS rates were 65% (56-75%) and 60% (49-72%), respectively. 94 of 109 patients received CNS prophylaxis (86%). 26 patients had received an initial cycle of R-CHOP (24%). PFS and OS were significantly worse for patients with higher risk IPI score (P = 0.03, 0.04, respectively), but there was no difference in PFS or OS based on CIRS score (P = 0.70, 0.60, respectively). 75 patients (68.8%) were dose-escalated while 34 patients (31.2%) were not; there was no difference in PFS (Fig 1) or OS (Fig 2) between these groups. When stratified by cumulative dose-level in quartiles, those who received the lowest cumulative doses (1st quartile) had a significantly reduced OS (1st, 2nd, 3rd and 4th quartile 2-year OS of 55%, 75%, 85%, and 84%, P = 0.046). Cause of death was largely from disease progression (74%), with only one treatment-related death in each dosing quartile. Dose intensity was not correlated with baseline CIRS score (R = -0.06, P = 0.56), but did correlate negatively with IPI (R = 0.22, P = 0.04). CONCLUSIONS: OS and PFS did not differ for DHL/THL patients treated with R-EPOCH with dose-escalation in at least one cycle as compared to those with no dose-escalation. Although cumulative doses beyond the 1st quartile were associated with improved OS, there was no significant difference between 2nd, 3rd and 4th quartiles. Dose-escalation was negatively associated with IPI scores but not CIRS scores. Further investigation into factors affecting adherence to dose-adjustment is warranted. The effect of adding novel agents to the DA-R-EPOCH backbone on dose-adjustment and cumulative doses of chemotherapeutic agents received should be evaluated in prospective clinical trials. Disclosures Haverkos: Viracta THerapeutics: Consultancy. Hughes:Acerta Pharma and HOPA: Research Funding; AstraZeneca: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Grover:Genentech: Research Funding; Tessa: Consultancy. Portell:Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy. Voorhees:AstraZeneca: Research Funding. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Kahl:Genentech: Consultancy; Pharmacyclics LLC: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche Laboratories Inc: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

Description: INTRODUCTION: With the FDA approval of CPX-351 (Vyxeos; Jazz Pharmaceuticals, Inc.; Palo Alto, CA), the prospect of inducing select patients with acute myeloid leukemia (AML) with a regimen that does not require continuous intravenous in the outpatient (OP) setting became a reality. With the recognition that an OP-induction strategy has the potential benefits of reduced healthcare resource utilization (HRU),1,2 improved quality of life3 and decreased risk of nosocomial infections, some centers have opted to administer Vyxeos in the OP setting and to admit patients only if complications which necessitate inpatient (IP) management occur. The safety and decreased HRU of this approach during consolidation has been demonstrated4 in the study population treated on the pivotal phase III trial (NCT01696084).5 We present the first real-world experience of OP AML induction with Vyxeos without planned hospital admission. METHODS: We performed a retrospective analysis of all patients at our institution treated with OP-Vyxeos without planned admission (OP-Vyxeos) between August, 2017 and June, 2020. Patients were deemed safe for OP induction if they met the criteria outlined in Table 1 at diagnosis or could be stabilized in the hospital and discharged when these criteria were met. Primary and secondary objectives were to evaluate the safety and HRU, respectively, of this approach. The primary endpoint was 30-day mortality. Secondary endpoints included 60-day mortality, rate of adverse effects (AEs), number of hospitalizations, number of hospital days, number of intensive care (ICU) days, and number of days receiving intravenous (IV) antibiotics. When possible, primary and secondary endpoints were compared to patients who received Vyxeos induction in the inpatient setting (IP-Vyxeos) on the phase III trial.5,6 RESULTS: Twenty-five patients received OP-Vyxeos at our institution between August, 2017 and June, 2020 and all were evaluable for the primary endpoint. Baseline characteristics of the OP- and IP-Vyxeos populations are presented in Table 2. The mean age of OP-Vyxeos patients was less than IP-Vyxeos patients (65.4 years vs. 67.7 years) and a higher proportion of OP-Vyxeos patients were

Description: Introduction Immunomodulatory drugs (IMiDs), particularly lenalidomide, are associated with adverse skin reactions most commonly rash, xeroderma, and pruritus. While multiple myeloma disproportionately impacts black patients, the clinical trials used for registration of these medications predominantly enrolled white patients. The incidence and severity of skin pigment changes in black patients are therefore not known. Hyperpigmentation can be a highly visible and distressing side effect leading to noncompliance. Methods This retrospective study evaluated all patients treated with thalidomide, lenalidomide or pomalidomide from January 2013 to March 2020 across all indications at Boston Medical Center. An internally developed survey consisting of 14-questions was mailed to all patients identified through prescriptions written in the electronic medical record (Epic). The survey questions included ethnicity and race identification and whether skin changes, particularly hyperpigmentation, occurred during treatment. For those patients with skin changes, follow-up questions asked about the nature of the skin change, pattern, location and duration. Distress related to skin changes was reported on a scale of 1 to 10; 1 being minimal distress and 10 being maximal distress. Photographs were requested (if available) before, during and after IMiD therapy. Results A total of 214 patients were identified who were prescribed thalidomide (4, 1.9%), lenalidomide (204, 95.3%) or pomalidomide (81, 37.9%). Of the 214 surveys, 106 (49.5%) were completed and all of the responses were included in statistical analysis. Of the 106 patients, 49 (46.2%) identified as black/African American and 57 (53.8%) reported being non-black (Asian, Hispanic or Latino, American Indian/Alaskan Native, White, Native Hawaiian/Other Pacific Islander or other). Skin changes were reported by 27 (25.5%) of the patients who completed surveys. Consistency and description of the skin changes can be found in Table 1. Hyperpigmentation (skin darkening), specifically, was reported by 20 (40.8%) of the black/African American patients and 2 (3.5%) of the non-black patients. The most commonly reported location of hyperpigmentation was on the palms and soles (15, 68.2%), forearms (7, 31.8%) and face (6, 27.3%). Onset began within 3 months of starting therapy in 10 (45.5%) of these patients. Of the 11 patients who are no longer on IMiD therapy, 4 (36.6%) had full resolution of skin changes, 5 (45.5%) noted partial resolution, and 2 (18.2%) had no improvement. The reported distress score ranged from 1-9 (median 5). Photographs of typical skin hyperpigmentation will be included at conference presentation. Conclusion Skin hyperpigmentation due to IMiD therapy is commonly seen in black/African American patients. Specifically, hyperpigmentation is 11.6 times more likely to occur in black/African American patients as compared to all other races. In these patients, hyperpigmentation is most noticeable on the palms, face and soles of the feet. These changes typically occur early in the course of therapy and do not completely reverse, even long after drug cessation. It is important for providers to discuss the possibility of these skin changes when using IMiDs in this patient population. Disclosures Blevins: Epizyme: Other: Focus Group. Hughes:Karyopharm: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Speakers Bureau; Rigel: Other: advisory board. Sarosiek:Spectrum: Research Funding. Sanchorawala:UpToDate: Patents & Royalties; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Oncopeptide: Research Funding; Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Sloan:Abbvie: Consultancy; Stemline: Consultancy.