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Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Background/Objective: To provide updated results from a Phase 1b trial (NCT03625505) of BCL-2 inhibitor venetoclax and FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Ven+Gilt) in patients with relapsed/refractory (R/R) FLT3-mutated (FLT3Mut+) acute myeloid leukemia (AML). Methods: Patients with R/R AML FLT3Mut+ received up to Ven 400mg daily with Gilt (80 or 120 mg) daily in 28-day cycles, following Ven ramp-up. Primary endpoint was modified composite complete remission (mCRc) to align with Phase 3 ADMIRAL trial CRc responses. Secondary endpoint was mCRc duration of response (DOR); overall survival (OS), and changes in FLT3 allelic burden were exploratory. Adverse events (AEs) were monitored. Results: At data cutoff (November 30, 2020), 43 patients (median age 63 yrs) with FLT3Mut+ were enrolled. FLT3 internal tandem duplications (ITD) were identified in 86% patients, and 14% had only tyrosine kinase domain (TKD) mutations. Baseline cytogenetic risk was favorable in 5%, 55% intermediate, 31% poor, and 12% had no mitoses/missing data. Median (range) prior lines of therapy were 2 (1–5), and 77% patients had 2 or more prior lines of therapy: 65% received at least one prior FLT3 inhibitor, and 7% received prior Ven; 33% had prior transplant. Grade 3/4 AEs were reported in 98% of patients; grade ≥3 cytopenias occurred in 79% and were predominantly managed by Ven/Gilt dose interruptions. The only grade 3/4 nonhematologic AEs reported in >20% of patients was pneumonia (n=9; 21%) and 1 instance of clinical tumor lysis syndrome. Serious AEs were reported in 74% of patients. Overall, 30- and 60-day mortality rates were 0% and 12%, respectively. AEs led to either Ven or Gilt interruptions in 56% patients, reductions in 7%, and discontinuations in 14%. mCRc was achieved by 86% of FLT3Mut+ efficacy population (36/42) with median time to first response of 1.0 mo (range: 0.7–4.6) and 86% with prior FLT3 tyrosine kinase inhibitor (TKI) exposure (24/28). FLT3 molecular clearance ( Conclusions: Updated analyses show Ven+Gilt achieved high rates of mCRc in patients with heavily pre-treated and prior TKI-exposed R/R FLT3Mut+AML with encouraging molecular clearance rates. Using similar criteria to previous FLT3Mut+ studies, high mCRc rate with Ven+Gilt suggests strong anti-leukemic activity. Cytopenias were prominent but manageable.

Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

New drug approvals now afford AML physicians a wider choice of initial treatment options than ever before. Although chemotherapy for AML is by no means ready to be replaced entirely by novel agents, the role of traditional cytotoxics in in AML therapy is rapidly changing. In particular, biologically targeted agents such as the BCL2 inhibitor venetoclax and inhibitors of FLT3 and IDH mutations stand out as drugs likely to take AML therapy in important new directions. Maximum response and survival benefits likely require combinations of novel agents and chemotherapy or multiple novel agents together. The recently-published phase 3 VIALE-A study demonstrates a very successful example of a new combination approach, which led to venetoclax plus azacitidine establishing itself as the new standard of care for patients unfit for intensive chemotherapy. One could reasonably expect other subsets of AML to benefit from this regimen or other applications of venetoclax combinations. Building on this experience, venetoclax-based regimens also have the potential to replace standard intensive cytarabine/anthracycline “7&3” induction approach for some if not many patients who are fit for induction. This review will describe novel agents with the greatest potential for impactful frontline applications that will change the AML treatment paradigm.

Introduction In QuANTUM-R, the once-daily, oral, highly potent and selective FLT3 inhibitor Q improved clinical benefit vs SC (median overall survival [mOS], 6.2 vs 4.7 mo [HR, 0.76 (95% CI, 0.58-0.98); P = .02]) in R/R FLT3-ITD AML (NCT02039726). Before randomization, 25% (Q) and 23% (SC) of pts had 1 prior HSCT. Objective To describe post hoc analyses in pts who underwent subsequent HSCT during QuANTUM-R. Methods Pts with FLT3-ITD R/R AML received Q (60 mg [30-mg lead-in]) or SC. Pts in the Q arm could resume Q 30-100 d after HSCT. Decisions to proceed to HSCT and resume Q after HSCT were made per investigator discretion/institutional policy. Results Of 367 randomized pts, 85 in the Q arm underwent any subsequent HSCT (allogeneic HSCT [allo-HSCT], 84 [6 with and 78 w/o additional AML therapy]; autologous HSCT, 1), and 19 in the SC arm underwent any HSCT (5 with and 14 w/o additional AML therapy]). Q + SC pooled data showed a longer mOS (95% CI) in 104 pts with any HSCT vs 263 w/o (12.2 [10.0-24.1] vs 4.4 [4.1-4.9] mo; P Regardless of treatment, mOS was longer with any HSCT vs w/o (Q, 11.9 [10.2-25.1] vs 4.5 [4.1-5.4] mo; SC, 12.7 [6.1-NA] vs 4.0 [2.7-5.0] mo); respective 1-year OS rates were 50% vs 13% and 51% vs 12%. In the Q arm, mOS (95% CI) was longer in pts with a best response of CRc who resumed Q after allo-HSCT (27.1 [18.2-NA] mo) vs pts not resuming Q (5.4 [4.7-11.4] mo; Fig 2). In 48 pts (62%) in the Q arm resuming Q after allo-HSCT, median time from allo-HSCT to Q resumption was 65 d (range, 30-106 d). Four pts (5%) in the Q arm died Conclusion Independent of HSCT, Q improved survival vs SC in pts with FLT3-ITD R/R AML in QuANTUM-R. Q + SC pooled analyses showed longer survival in pts with HSCT vs pts w/o and in pts with CRc before allo-HSCT. Survival in transplanted pts was similar in both arms, indicating that HSCT-eligible pts received transplants appropriately, and the higher HSCT rate in the Q arm was beneficial. In pts preselected for low-intensity SC at study entry, 13 were able to undergo HSCT after Q treatment. Q resumption after HSCT was associated with better survival outcomes and was tolerable. These data illustrate the value of using Q to target the FLT3-ITD mutation as a part of the overall treatment sequence in pts with FLT3-ITD R/R AML.

High-dose melphalan with autologous stem cell support improves survival for patients with myeloma. For selected patients, we have been using a protocol of short hospitalization, discharging patients to home with careful outpatient monitoring in the office, which we hypothesized would reduce complications and utilization of inpatient beds.We reviewed 301 initial autologous transplants for myeloma, categorized as brief stay (≤ 4 days, 82 patients) or prolonged stay (≥ 5 days, 219 patients). Selection for a brief stay was determined by clinical characteristics, availability of caregivers at home, distance from our medical center, and patient preference.Within the brief stay population, 67% required readmission before day + 100, but this group still had fewer cumulative hospital days (9 vs. 18, P.0001). There were fewer documented infections among brief stay patients (22% vs. 46% P.001) and fewer admissions to intensive care units (0% vs. 5.9%, P = .02). The groups had similar rates of bleeding (1.2% vs. 1.4% P = 1.0) and thrombosis (3.7% vs. 4.6% P = 1.0). No patients in the brief stay group died within 100 days, compared with mortality of 1.8% (P = .6) in the prolonged stay group.Carefully selected patients receiving an autologous stem cell transplant for treatment of myeloma can be managed with a brief initial hospitalization and outpatient follow-up, with low morbidity and mortality.

Background: The initial treatment of FLT3 wild type acute myeloid leukemia (AML) has not significantly changed since induction therapy with Ara-C and anthracyclines was first developed. Preclinical data suggests constitutive activation of the AKT3/mammalian target of rapamycin (mTOR) pathway may play a role in pathogenesis of this disease in a subset of AML patients. Previous data from our group has shown that the presence of phosphorylated ribosomal S6 (pS6) in AML blasts as detected by flow cytometry may predict response to the combination of sirolimus and induction chemotherapy. Here we report the clinical and pharmacodynamics results of a phase II study of the combination of these drugs. Methods: Subjects had newly diagnosed AML based on WHO criteria. Subjects received oral sirolimus starting on day 1 (12 mg loading dose) then 4 mg daily on days 2-10 with idarubicin 12mg/m2 days 4-7 and cytarabine 100mg/m2 days 4-10. Clinical response was assessed at hematologic recovery or by day 42 using IWG for response. Samples for pharmacodynamic studies of blasts were drawn prior to treatment with sirolimus on day 1, and then again prior to dosing of idarubicin and cytarabine on day 4. Assessment of pS6 on gated blasts, a biomarker of mTORC1 activation, was assessed by flow cytometry using previously described methods. Results: 55 patients enrolled on this trial received sirolimus with an average age of 58 years. Toxicity was similar to published 7+3 data and prolonged aplasia without recovery was not observed. Twenty-nine patients (53%) had high risk cytogenetic or molecular mutations, 15 (27%) had intermediate risk disease, and 11 (20%) patients had lower risk disease. As a whole, 35 patients (64%) entered into CR or CRp, 1 had a PR, 17 (27%) were non-responders. Two (4%) patients (ages 64 and 71) died during induction. Thirteen (45%) patients with high risk disease had a CR or CRp, 14 (48%) were non-responders, and 2 died in induction. Of the 15 subjects with intermediate risk disease, 11 (79%) patients had a CR or CRp, 1 had a partial response, and 3 were non-responders. All low risk patients had a CR, and 9 of 11 are alive and in remission at the time of censoring of data with a median time on study of 674 days. One patient with low risk disease subsequently relapsed, went to stem cell transplant, and is currently in CR. Two patients with low risk disease refused to proceed with standard of care consolidation; of these, 1 is alive and in remission 946 days from study entry, and 1 died in relapse. Fifteen patients (27%) subsequently underwent allogeneic stem cell transplantation in CR, and 8 (53%) are still alive an average of 358 days after transplant. Thirty-seven of 55 patients had adequate samples for pharmacodynamic analysis. Surprisingly, all patients demonstrated activation of ribosomal S6 prior to therapy in contrast to 67% positivity seen in previous studies that focused on patients with relapsed AML. mTORC1 was inhibited greater than 40% in 28/37 (76%) of patients. Inhibition did not correlate with either overall survival or age of patients. Conclusions: Sirolimus and 7+3 is a well-tolerated regimen. mTORC1 appears to be activated in almost all patients at the time of diagnosis of AML as assessed by flow cytometric assessment of ribosomal S6. Inhibition of mTORC1 did not correlate with response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity when mTORC1 is inhibited. Given the large percentage of samples with mTORC1 activation in this upfront AML study, future research into dual mTORC inhibitors may prove valuable. Disclosures Carroll: Astellas Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Research Funding. Porcu: Innate Pharma: Research Funding; Kura: Research Funding; Miragen: Research Funding; Kiowa: Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Cell Medica: Research Funding; Celgene: Research Funding. Perl: Arog Pharmaceuticals: Consultancy; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Seattle Genetics: Other: Advisory board; Asana Biosciences: Other: Scientific advisory board; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Other: Scientific Advisory Board.

Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options.

Introduction Grade (gr) 2-4 mucositis complicates myeloablative (MAC) allogeneic hematopoietic transplantation (HCT) in 90% of patients. Methotrexate (MTX) GVHD prophylaxis (ppx) contributes to mucositis and delays engraftment. Severe mucositis increases patient-controlled analgesia (PCA) and TPN (total parenteral nutrition) use, length of stay (LOS) and precludes completion of post HCT MTX. Leucovorin (LCV) following MTX is controversial. Objectives To address exacerbation of mucositis by MTX, we implemented routine LCV post MAC alloHCT and compared outcomes with historical controls. The primary endpoint was the duration of gr 2-4 mucositis. Secondary endpoints were the incidence of gr 3-4 mucositis, time to engraftment, TPN and PCA use, LOS, incidence of GVHD and relapse. Methods Thirty-two consecutive adults received MAC alloHCT and MTX ppx with LCV 15 mg PO q6h x 4 doses, 12 h post d+3, +6, and +11 MTX and were compared to 33 consecutive historical controls. Controls did not receive routine LCV, but may have received ≥ 1 dose post d+6 or +11 MTX at physician discretion. Results Baseline characteristics were similar between the groups. All patients received tacrolimus and MTX GVHD ppx, most with Cy/TBI conditioning. Forty percent received peripheral blood stem cells and 60% had a matched unrelated donor. The median age was 46 y and 50% had AML. Thirty percent of controls received ≥ 1 LCV dose (most post d+11 MTX). The mean duration of gr 2-4 mucositis was shorter with LCV vs. control (7.4 vs. 11 d, p = 0.02). A trend towards lower incidence of gr 3-4 mucositis was observed with LCV (34% vs. 58%, p = 0.08). TPN use was similar between groups (25% vs. 36%, p = 0.4), however duration was shorter with LCV (8.6 vs. 21 d, p = 0.02). A trend towards less frequent PCA use was observed with LCV (34% vs. 58%, p = 0.08). Neutrophil engraftment was faster with LCV (17.6 vs. 20 d, p = 0.04) and a trend towards faster platelet engraftment was observed (15 vs. 20 d, p = 0.06). LOS was shorter with LCV (27 vs. 33 d, p = 0.01). LCV did not impact the incidence of GVHD. Relapse was less common in the LCV group (3% vs. 27%, p = 0.01) albeit with a shorter follow up (mean 202 d vs. 560 d). Conclusion Routine LCV addition to MAC alloHCT with MTX ppx shortened the duration of gr 2-4 mucositis, expedited neutrophil engraftment, shortened TPN and LOS and showed trends towards reduction in clinically important endpoints related to mucositis incidence, severity and associated supportive care. Our small sample size and non-randomized design may limit the strength of these conclusions. Differences between the groups may have been biased towards the null as 30% of controls received ≥ 1 LCV dose. LCV ppx warrants prospective evaluation to assess effects on mucositis, engraftment, GVHD, resource utilization and LOS.

Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder.To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy.We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015.We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P .001), anemia (P = .002), thrombocytopenia (P .001), absence of arthralgia (P .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (χThis was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings.When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy.

Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia 2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations ([Figure 1][1]), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days ([Figure 2][2], median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. ![Figure 1:][3] Figure 1: ASXL1 and co-mutations ![Figure 2:][3] Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare. [1]: #F1 [2]: #F2 [3]: pending:yes