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Hepatic veno-occlusive disease (VOD/sinusoidal obstructive syndrome) represents a constellation of clinical findings including right upper quadrant pain, jaundice, hepatomegaly, and ascites. In the post-hematopoietic stem cell transplant (SCT) setting, the reported incidence has been 10-15%, with severe VOD historically resulting in high mortality rates. Novel agents including calicheamicin conjugated with CD33 (gemtuzumab ozogamicin; GO) and CD22 (inotuzumab ozogamicin; InO) are increasingly used for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Both GO and InO are highly active, but also have unique hepatotoxicity profiles, including a higher risk of VOD in recipients of SCT. Introduction of GO and InO into pre-SCT leukemia management adds additional complexity to SCT patient selection and toxicity monitoring. In this article, we describe and review the risks and management associated with VOD in SCT recipients exposed to GO and InO.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age

7043 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients aged ≥1 year in the US and in adults in Europe. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 significantly improved overall survival and remission rates versus conventional 7+3, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the FLT3 inhibitor midostaurin (MID). Herein, we report preliminary results for the cohort of adults treated with CPX-351 + MID in the V-FAST (Vyxeos – First Phase Assessment with Targeted Agents) trial. Methods: V-FAST is an open-label, multicenter, multiarm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (midostaurin, venetoclax, enasidenib). Eligible adults in the CPX-351 + MID cohort were aged 18 to 75 years, had newly diagnosed AML with a FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation, were fit for intensive chemotherapy, and had an ECOG performance status of 0 to 2. The dose-exploration phase (3+3 design) determined a recommended phase 2 dose of CPX-351 100 units/m2 (daunorubicin 44 mg/m2 + cytarabine 100 mg/m2) on Days 1, 3, and 5 + MID 50 mg BID on Days 8 to 21. There were no dose-limiting toxicities, and additional patients were enrolled in the expansion phase at this dose. Results: A total of 23 patients received CPX-351 + MID and had sufficient data to be included in the analysis (cutoff date: 1/20/2022). Patient baseline characteristics are shown in the Table. Treatment-emergent adverse events (TEAEs) in ≥40% of patients included febrile neutropenia (78%), nausea (65%), increased alanine aminotransferase (57%), leukopenia (57%), thrombocytopenia (57%), headache (43%), and hyponatremia (43%). All patients experienced a grade 3/4 TEAE, primarily hematologic events. Nonhematologic grade 3/4 TEAEs in ≥2 patients included pneumonia (17%), lung infection (13%), and hyperglycemia (9%). There were no grade 5 TEAEs and no deaths on or before Day 60. Complete remission was achieved by 18/22 (82%) evaluable patients after the first induction cycle. Conclusions: Preliminary results from the V-FAST trial suggest CPX-351 + MID is feasible, with a manageable safety profile and promising remission rates in adults with newly diagnosed AML who have a FLT3 mutation. Clinical trial information: NCT04075747. [Table: see text]

7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh], 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]

12117 Background: Patients with hematologic malignancies are less likely to receive outpatient palliative care (OPC) compared to patients with other cancer types. Little is known about the characteristics or health care utilization of patients with hematologic malignancies who are co-managed by OPC. In this study, we evaluated referral patterns and health care utilization of patients with hematologic malignancies who were seen in an embedded OPC clinic. Methods: We conducted a retrospective cohort study of patients who established care with an embedded OPC nurse practitioner from 3/2016 – 5/2020 at a quaternary academic medical center. We obtained information about patients’ demographics, clinical characteristics, and reasons for referral to OPC from the electronic health record. Information about costs and health care utilization were provided by our finance team. For patients who were followed by OPC for at least 6 months, we used two-tailed t-tests to compare the number of hospitalizations and emergency department (ED) visits, as well as total costs, for the 6 months before and the 6 months after initiating OPC. This was approved by the UCSF IRB. Results: A total of 120 patients received OPC. Median age was 59 years (range 24-89), 48% were female, and 64% were Non-Hispanic White. Myeloma was the most common cancer (n = 50/120, 41.7%), followed by aggressive lymphoma (n = 21/120, 17.5%), and acute myeloid leukemia (n = 18/120, 15%). The primary reason for referral was for symptom management, such as pain (60%, n = 72/120), mood symptoms (12.5%, n = 15/120), and fatigue (7.5%, n = 9/120). Ten percent (n = 12/120) were referred for goals of care conversations prior to stem cell transplant (SCT). An advance directive was on file for 29% (n = 35/120) of patients, of which 34% (n = 12/35) were completed after OPC enrollment. Of the 38 patients who died, the median time from PC enrollment to death was 15.3 months, and 39% died on hospice. For the 65 patients who were followed by OPC for at least 6 months, the total number of inpatient hospitalizations, excluding SCT, went from 0.82 to 0.54 (p = 0.11) per person in the 6 months before compared to the 6 months after initiating OPC. ED visits went from 0.28 to 0.18 (p = 0.33). The total direct cost of inpatient hospitalizations, excluding SCT, decreased from $43,428 to $13,226 (p = 0.01), and the cost of ED visits went from $640 to $297 (p = 0.32) per person. Conclusions: There is an important role for embedded OPC for patients with hematologic malignancies, long before the end-of-life period, to manage symptoms and support decision-making. OPC is associated with a trend towards lower health care utilization and decreased hospitalization costs. Prospective studies are warranted to further explore the impact of OPC on symptoms and patient/caregiver experience, as well as to clarify how OPC impacts health care utilization.

Context: In 2019, our transplant program initiated prospective FLT3-ITD measurable residual disease (MRD) monitoring by next-generation sequencing (NGS) of the peripheral blood or bone marrow throughout the first three months following HCT for all patients with FLT3-ITD-mutated AML undergoing HCT. We encouraged FLT3 inhibitor use as post-HCT maintenance. Objective: To evaluate the impact of post-HCT FLT3 MRD testing and FLT3 inhibitor use in a non-clinical trial setting. Design: Observational study of adults with FLT3-ITD-mutated AML who underwent allogeneic HCT at Stanford University between April 2019 and August 2020. Setting: Tertiary referral center. Patients or Other Participants: Thirty-six adults with FLT3-ITD-mutated AML are included in this study. Two patients were excluded from analyses due to early graft failure and receipt of azacitidine/enasidenib maintenance therapy. Interventions: Twenty-four patients (71%) received an FLT3 inhibitor after HCT, initiated a median of 2.8 months after transplant (range: 0.7–17.1). The median duration was 6.8 months (range: 1.1–18.8). Main Outcome Measures: Progression-free survival (PFS) and overall survival (OS). Results: Ten patients (29%) had detectable MRD within the first three months following HCT, while 24 (71%) patients remained MRD-negative. Although there was a trend toward inferior PFS for patients with early post-HCT MRD (p = 0.12), OS was not significantly impacted by MRD (p = 0.66). FLT3 inhibitor therapy improved PFS and OS, particularly in MRD-negative patients (maintenance vs no maintenance: PFS not reached vs 5.52 months, p = 0.002; OS not reached vs 5.85 months, p = 0.006). Conclusions: Clinical relapse can be prevented, even in patients with post-HCT MRD, by using early FLT3 inhibitor maintenance therapy, in keeping with the results from the SORMAIN trial. Real-time sensitive MRD testing allows clinicians to begin early initiation of FLT3 inhibitor therapy. This work was partially supported by the National Institutes of Health Grant UL1-TR003142 and Grant P30-CA124435.

Context: Despite recent lower-intensity therapies that have improved outcomes for older AML patients, AML remains associated with poor prognosis as well as high symptom burden. While the benefits of early palliative care and electronic PROs have been well-described in oncology patients, neither have been well-studied in AML, and they have never been studied in combination. Objective: To evaluate the feasibility of a virtually mediated supportive care model utilizing both electronic PROs and palliative care for patients with AML being treated with lower-intensity therapy (NCT04885127). Design: This will be a prospective, single-arm, non-blinded trial with a year of enrollment and six months of follow-up. Setting: All patients will be enrolled at Stanford Comprehensive Cancer Center. Patients or Other Participants: We plan on enrolling 40 patients who are on first-line lower-intensity therapy for AML, defined as therapy that allows patients to receive care exclusively in the outpatient setting. Interventions: Patients who are enrolled will be referred to the subspecialty palliative care clinic for virtual consultation and monthly follow-up visits for 6 months. Patients will also be instructed on the use of Noona, a digital application that allows real-time, remote monitoring of PROs. Patients will be requested to fill out a Noona symptom questionnaire prior to each palliative care visit and will be prompted to maintain a weekly symptom diary, which will be available to both their primary leukemia and palliative care providers. They will also fill out health-related quality of life surveys, including Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9), and Satisfaction with Decision-Making Scale, at baseline, three, and six months. Main Outcome Measures: The primary outcome to be measured at completion of the study will be the feasibility of palliative care referral, defined as completion of the initial virtual consultation and at least 50% of the six scheduled monthly follow-up visits. Secondary outcomes will include the proportion of patients who complete the digital symptom questionnaires and the proportion of patients who complete their health-related quality of life surveys. Scores obtained from surveys will be used to generate hypotheses for future work.

Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

Context: Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. Objective: To report Phase 1b data of magrolimab + AZA in untreated AML. Design: This is an open-label, nonrandomized, Phase 1b, interventional study. Interventions: Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Patients or Other Participants: Treatment-naive AML patients unfit for intensive chemotherapy. Main Outcomes Measures: Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Results: Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Conclusions: Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397).

In acute myeloid leukemia (AML), a translocation between chromosomes 8q22 and 21q22 leads to the RUNX1-RUNXT1 fusion gene which, in the absence of a concomitant KIT mutation, generally portends a more favorable prognosis. Translocations at 21q22, other than those involving 8q22, are uncommon, and the specific prognostic and therapeutic implications are accordingly limited by the small number of reported cases. In this report, we describe the case of a 67-year-old gentleman who presented with AML harboring t(14;21)(q23;q22). Subsequent molecular analysis revealed mutations in RUNX1, ASXL1, and SF3B1, with translocation breakpoints identified within SYNE2 on chromosome 14 and RUNX1 on chromosome 21. The functional consequence of the DNA fusion between SYNE2 and RUNX1 is unclear. Nonetheless, despite several adverse risk factors associated with this patient's AML, he achieved a long-lasting remission with standard chemotherapy alone, potentially suggestive of a novel favorable-risk translocation in AML involving 21q22.

A 33-year-old woman with a 2-year history of documented human immunodeficiency virus (HIV) infection presented to the emergency room at San Francisco General Hospital with a new-onset seizure disor...

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

e19005 Background: CALGB 10403 is a pediatric-inspired ALL regimen that has recently been shown to have improved survival rates in adolescents and young adults with ALL when compared to historical outcomes with traditional adult ALL regimens (Stock et. al, 2019). Methods: This is a retrospective cohort study of ALL patients who received induction CALGB 10403 at Stanford University (both on and off trial), achieved CR1, and subsequently relapsed. Primary outcome of interest was event free survival from time of diagnosis. Events were defined as relapse or death. Secondary outcomes were overall survival and event free survival from first relapse. Patients were censored at time of last clinical follow up. Results: 25 patients met inclusion criteria and received front-line CALGB 10403 from April 2010 to September 2018. At the time of initial diagnosis median age was 30 years (range 18 – 39 years). 68% of patients were male. 48% of patients were overweight and 40% were obese. 76% of patients had precursor B cell ALL while 24% had T cell ALL. 12% had CNS disease at diagnosis. 36% of patients had WBC greater than 30k. 12% of patients had CRLF2 rearrangement. 12% of patients were MRD positive after first induction. 20% of patients received rituximab. Median event free survival time from diagnosis was 20 months (range 3 – 79 months) and median overall survival time was 53 months. Blinatumomab was the most common salvage therapy after 1st relapse, followed by inotuzumab. 15 patients (60%) achieved CR2, of which 4 (27%) were MRD positive after 2nd induction. 15 patients (60%) went to HSCT. Of the patients who achieved CR2, 8 relapsed for a second time. Median event free survival time after first relapse was 23 months. Survival 1 year after relapse was 60%. 11 of the 25 patients were alive at last follow up. Median follow up time of survivors was 6 years. Conclusions: This is a descriptive retrospective cohort study of adult patients in a real world setting who received CALGB 10403 induction and subsequently relapsed. Compared to other studies of relapsed ALL patients who were induced with traditional chemotherapy (Fielding et. al, 2007), survival 1 year after relapse was much higher (60% vs. 22%). As CALGB 10403 becomes an increasingly common induction regimen for AYA and adults with ALL, further outcomes study is required.[Table: see text]

7026 Background: CPX-351 (US: Vyxeos; EU: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, is approved by the US FDA and EMA for adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. Preclinical data suggest CPX-351 may exert synergistic activity when combined with agents such as the BCL-2 inhibitor venetoclax (VEN) or FLT3 inhibitor midostaurin (MIDO). Methods: V-FAST (Vyxeos – First Phase Assessment With Targeted Agents) is an open-label, multicenter, phase 1b master trial (NCT04075747) to evaluate safety and establish the recommended phase 2 dose (RP2D) of CPX-351 combined with targeted agents in patients (pts) aged 18-75 y with untreated AML who are fit for intensive chemotherapy. The study includes a dose-exploration phase (3+3 design) and subsequent expansion phase. Pts received CPX-351 (dose level 1 for first induction [DL1]: 100 units/m2 on Days 1, 3, and 5) plus VEN (Arm A; DL1: 400 mg on Days 1-14), MIDO (Arm B; DL1: 50 mg BID on Days 8-21), or the IDH2 inhibitor enasidenib ([ENA] Arm C; DL1: 100 mg on Days 8-28) based on mutation testing. Results: Among 21 pts with available data enrolled by 11/06/20 (24 pts enrolled total; data cut-off: 01/19/21), the median age was 54 y (range: 35, 69). In Arm A (n = 17), 11 (65%) pts had de novo AML, 5 (29%) had an antecedent hematologic disorder (2 [12%] had myelofibrosis), and 2 (12%) had t-AML; 12 (71%) had adverse-risk AML; and 6 (35%) had mutated TP53. In Arms B (n = 3) and C (n = 1), all pts had intermediate-risk de novo AML. DL1 was the RP2D in Arms A and B; the RP2D in Arm C is still under investigation. In Arm A, 1/6 pts in the dose-exploration phase had 2 dose-limiting toxicities (DLTs) of grade 4 neutropenia and thrombocytopenia that extended beyond 49 days; no DLTs have occurred for Arms B and C. The combinations exhibited manageable safety profiles (Table). Of pts with available response data, complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) pts in Arm A, including 4 (29%) with CR. All pts in Arms B and C achieved CR. Conclusions: These preliminary results suggest CPX-351 can be combined with VEN and MIDO with manageable toxicities in newly diagnosed AML pts, with DL1 determined to be the RP2D. The study is ongoing and actively enrolling pts; updated results will be presented at the meeting. Clinical trial information: NCT04075747. [Table: see text]

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

7000Background: IVO is an oral, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is being evaluated in a phase 1 dose escalation and expansion study of mIDH1 advanced hematologi...

10030Background: The optimal means of assessing fitness for AutoHCT in older adults with hematologic malignancies is unknown. Few studies have evaluated the impact of patient reported function on A...

BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Background Despite recent advances, treatment of relapsed refractory multiple myeloma (RRMM) remains a challenge. Venetoclax, a BH3 mimetic, is an oral, specific, and potent small molecule inhibitor of BCL-2 that has been approved for treatment of 17p-deleted CLL and in combination with azacitidine or decitabine in AML patients >/= 75 years of age.Pre-clinical and clinical studies suggest that bcl-2 inhibition can induce MM cell death and may synergize with bortezomib and dexamethasone. Based on this, several prospective clinical trials of venetoclax in RRMM have been performed. However, clinical use of this targeted therapeutic for salvage therapy in RRMM has not been well described. Methods We performed a single-center, retrospective chart review of all patients with RRMM diagnosed after January 1, 2009 who were treated with off-label use of venetoclax. The goal of this study was to describe the clinical characteristics of these patients, assess the response to salvage treatment with venetoclax as determined by the International Myeloma Working Group (IMWG) criteria, and assess the toxicities during salvage treatment with venetoclax in an academic practice setting. Results 43 patients were identified. Median number of lines of prior therapy was 7 (range 2-13). 12 patients had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), t(14;20), t(4,14), gain (1q), or nonhyperdiploidy. Of the 36 patients with cytogenetics/FISH available, 8 had t(11;14). 34 patients were refractory to bortezomib. 40 patients had progressed after carfilzomib, 36 after pomalidomide, and 41 after anti-CD38 antibody therapy. 39 patients were treated with venetoclax in combination with a proteasome inhibitor (bortezomib (n=36); carfilzomib (n=3)). 23 patients were treated with venetoclax, proteasome inhibitor, and dexamethasone. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily (11 received 800 mg/daily as final dose). Overall patients were on treatment for a median of 67 days (range 2-855). 2 patients received intermittent venetoclax therapy, defined as being off venetoclax for at least 3 months before restarting. Best response by IMWG criteria include; CR 5%( 2/43), VGPR 12% (5/43) and PR 16% (7/43) for an overall response rate of 33% (14/43). In addition, MR was seen in 5% (2/43) and stable disease in 9% (4/43). Fifty-one percent (22/43) had progressive disease (PD). Out of the 8 patients who had t(11;14), best responses were: 2 VGPR, 2 PR, 1 SD, and 3 PD for a response rate of 50% (4/8) in this subgroup. Median time to best response for all responding patients was 90 days (range 15-305) and median duration of response was 206 days (range 28-820). At time of data collection, median follow-up time from venetoclax treatment initiation was 192 days (range 8-1058). Four patients have not progressed and remain on therapy, 23 patients remain alive, and 4 patients have been lost to follow-up for over 6 months. The most common treatment related AEs were cytopenias including leukopenia in 26 /43 (60%) patients, neutropenia in 19/43 (44%) patients, and thrombocytopenia in 22/43 (51%) patients. Non-hematologic toxicities included diarrhea in 12/43 (30%) patients, nausea/vomiting in 15/43 (35%) patients, infections in 11/43 (26%) patients, and fatigue in 23/43 (53%) patients. 8/43 (19%) patients required dose reduction, 7/43 (16%) patients required temporary discontinuation of treatment, and 4/43 (9%) patients required permanent discontinuation due to treatment related AEs. 38/43 (88%) patients had any grade treatment related AEs, 27/43 (63%) patients had grade >/= 3 AEs and 2/43 (5%) patients had treatment related SAEs. One patient had a treatment related death from an infectious complication (CMV pneumonitis). Conclusions Venetoclax is an active and well-tolerated agent in relapsed multiple myeloma. Furthermore, it is easily administered in the outpatient setting. Additional areas of research with this therapy include understanding the importance of t(11:14) for response and selecting the best anti-MM partner for combination therapy. Disclosures Ledergor: Venetoclax: Other: off-label use; Immunai: Consultancy. Martin: Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wolf: Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Wong: Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This study is looking at the safety and efficacy of venetoclax in relapsed refractory myeloma patients who are treated off-label since venetoclax is not currently approved for multiple myeloma

7040 Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2nddose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.

e19514 Background: Despite recent advances, treatment of relapsed multiple myeloma (MM) remains a challenge. Pre-clinical studies suggest that bcl-2 inhibition can lead to MM cell death and may synergize with bortezomib. Methods: We performed a single-center, retrospective chart review of patients with relapsed MM following autologous stem cell transplantation (auto-HCT) who were treated with venetoclax, a bcl-2 inhibitor, with bortezomib. Results: 11 patients were identified. Median number of lines of prior therapy was 9 (range 5-13). 1 patient had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), or t(14;20). In the 8 patients with cytogenetics/FISH available, no patients had t(11,14). 9/11 patients were refractory to bortezomib. 11/11 patients had progressed after carfilzomib, 9/11 after pomalidomide, and 11/11 after anti-CD38 antibody therapy. In all cases, patients were treated with venetoclax in combination with bortezomib. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily. Overall patients received a median of 14.24 weeks of treatment (range 3-25.5). IMWG criteria were utilized to assess responses, including: 0/11 CR, 1/11 VGPR and 3/11 PR for an overall response rate of 36% (4/11). 1/11 had a minor response (light chain decrease by greater than 25% but less than 50%), 1/11 achieved stable disease, 5/11 had progressive disease. Median time to best response was 35 days (range 21-37) and median duration of response was 45 days (with several patients remaining on drug). All patients who responded had bortezomib-refractory disease. With median follow-up of 57 days, 4/11 patients have not progressed and 9/11 remain alive. The most common adverse effect was GI upset (bloating, nausea, vomiting, diarrhea) in 4/11 patients with no patients discontinuing due to side effects. There was no evidence of tumor lysis and there were no treatment-related deaths. Conclusions: Venetoclax is an active agent in relapsed multiple myeloma. Further efforts to study this therapy include prospective phase II trials and combination therapy with proteasome inhibitors and steroids.

Background Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. Patients and Methods In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) μmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. Results Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 ( P = .08). Conclusion Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 μmol/min.

18 Background: Unlike most metastatic solid tumors, many advanced hematologic malignancies are treated with curative intent. Accordingly, aggressive interventions often continue until late in the disease course because it can be difficult to discern when cure is no longer possible. This is particularly true for recipients of allogeneic hematopoietic cell transplant (alloHCT). We hypothesized that alloHCT recipients and their providers would be less likely to utilize specialty Palliative Care (PC) services or to engage in early communication regarding advance care planning. Methods: This was a single-center, retrospective chart review of all alloHCT recipients at the University of California, San Francisco who died between 2012-2016. Patients were excluded if there was insufficient data available for analysis. Results: Of the 122 alloHCT deaths identified, 75 met inclusion criteria. The median age at alloHCT was 55, and most patients were Caucasian (69%), were transplanted for acute leukemia or MDS (77%), and received a well-matched allograft (81%). 57% died from disease relapse and 20% died from treatment-related causes. 61% of alloHCT recipients died in the hospital, with 37% dying in an ICU. 52% of patients received chemotherapy within 2 months of death, and 17% within 2 weeks. While 79% of patients were DNR/DNI at the time of death, the median time from change of code status to death was 4.5 days. 80% of patients had no prior code status documented in an outpatient note, and a specific goals-of-care conversation was documented in < 25% of outpatient charts. The PC service was consulted for the majority of patients (57%), although the median time from consultation to death was 13 days, with 23% of all consultations occurring within 3 days of death. Only 16% of patients accessed specialty PC services more than 30 days prior to their death. Conclusions: Despite high rates of both disease- and treatment-related mortality, as well as significant morbidity associated with alloHCT, recipients of alloHCT at our institution infrequently engaged in early conversations about end-of-life care and rarely utilized specialty PC services more than 1 month prior to dying.