Kantarjian, Hagop M.

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.

AbstractTrabectedin is an FDA‐approved DNA minor groove binder that has activity against translocation‐associated sarcomas. Lurbinectedin is a next‐generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose‐finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty‐two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1‐hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose‐limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia‐free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease‐related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21‐23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single‐agent lurbinectedin was transiently leukemia suppressive for some patients.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life‐threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy‐associated HLH (M‐HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M‐HLH may occur in up to 1% of patients with hematologic malignancies. M‐HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M‐HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M‐HLH with optimal combinations of T‐lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M‐HLH. Cancer 2017;123:3229‐40. © 2017 American Cancer Society.

BACKGROUNDRAS/RAF/mitogen‐activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen‐activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.METHODSThis phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild‐type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).RESULTSThe most commonly reported treatment‐related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS‐mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.CONCLUSIONSThe selective, single‐agent activity of trametinib against RAS‐mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871–9. © 2016 American Cancer Society.

Abstract Background: SGI-110 (guadecitabine) is a novel HMA that prolongs in vivo exposure of the active moiety decitabine following subcutaneous (SC) administration. We previously reported guadecitabine clinical activity in previously untreated elderly AML with Overall Complete Response (CR+CRi+CRp) of 55% using a standard 5-day regimen (Yee et al, 2014). Here we report the first results of a more intensive 10-day regimen in the same patient population. Methods: Elderly AML patients (≥ 65y) with at least one of the following characteristics were enrolled: age ≥ 75y; poor Performance Status (PS) ≥ 2; significant comorbidities particularly cardiopulmonary dysfunction; poor risk cytogenetics; or secondary AML. Guadecitabine 60 mg/m2/d SC was administered for 10 days (Days 1-5; and 8-12) for the first 1-2 cycles followed by the 5-day regimen (Days 1-5) for subsequent cycles. Cycles were scheduled every 28 days. Primary endpoint was Overall Complete Response (Overall CR). Secondary endpoints included Overall Survival, Safety including all-cause 30-day and 60-day early mortality, and global maximum DNA demethylation from baseline by LINE-1 assay. Results: Fifty two patients were treated with median age 77 (range 66-92) including 40 (77%) ≥75y; 34 (65%) male; 21 (40%) PS ≥ 2; 19 (36%) poor risk cytogenetics; and 13 (25%) secondary AML. The median bone marrow blasts percentage was 49% (range 16-98%). All patients had a minimum follow up of 3 months; 26 (50%) patients remain on treatment at the time of the analysis. Overall CR was observed in 24 patients (46%):14 CR (27%), 8 CRi (15%), and 2 CRp (4%). There was no significant difference between median DNA demethylation in responders (- 27%) and non-responders (-28%). Early all-cause 30-day and 60-day mortality occurred in 2 (4%) and 10 (19%) patients respectively. The most common Grade ≥3 Adverse Events considered by investigators to be drug-related were febrile neutropenia (33%), thrombocytopenia (27%), neutropenia (21%), anemia (15%), bacteremia (10%), and pneumonia (6%). Conclusions: Administration of guadecitabine as a more intense 10-day regimen for the first 1-2 cycles was active with acceptable toxicity. However, and although it was not a randomized comparison, the 10-day regimen did not result in higher rate of Overall CR in previously untreated AML than what was previously reported for the 5-day regimen. A Phase III randomized clinical trial in previously untreated AML patients not considered candidates for intensive chemotherapy has been initiated with the 5-day regimen of guadecitabine. Reference: Yee K, Daver N, Kropf P, et al: European Hematology Association Meeting, June 12-15, 2104; Milan, Italy. Abstract S647. Citation Format: Gail Roboz, Hagop Kantarjian, Patricia Kropf, Ellen Richie, Nitin Jain, Elizabeth Griffiths, Nikola A. Podoltsev, Katherine Walsh, Casey O'Connell, Wendy Stock, David Rizzieri, Raoul Tibes, Todd Rosenblat, Woonbok Chung, Pietro Taverna, Xiang Yao Su, Sue Naim, Mohammad Azab, Jean-Pierre Issa. First results of a 10-day regimen of SGI-110 (guadecitabine), a second generation hypomethylating agent (HMA) in previously untreated elderly AML who are not candidates for intensive chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT321. doi:10.1158/1538-7445.AM2015-CT321

SummaryMyelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT‐I,) a double‐blind trial, where patients with intermediate‐2 or high‐risk MF were randomized to twice‐daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post‐polycythaemia vera, post‐essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib‐treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT‐I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT‐I.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10–15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild‐type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome. Am. J. Hematol. 88:365–369, 2013. © 2013 Wiley Periodicals, Inc.

Abstract SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE's were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214