bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX).
Authors: Harrison Claire N. , Vannucchi Alessandro M. , Platzbecker Uwe , Cervantes Francisco , Gupta Vikas , Lavie David , Passamonti Francesco , Winton Elliott F. , Dong Hua , Kawashima Jun , Maltzman Julia D. , Kiladjian Jean-Jacques , Verstovsek Srdan 
Published: September 2018

7001 Background: MMB, an oral JAK inhibitor, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion requirements in patients (pts) with MF. This study of previously RUX treated pts with MF tested the superiority of MMB vs BAT in splenic volume reduction, Sx amelioration, and transfusion requirement at 24 weeks. Methods: Eligibility included primary or post-ET/PV MF; DIPSS high risk, Int-2, or symptomatic Int-1; prior RUX ≥4 weeks who either required transfusions or dose reduction to <20 mg BID with at least one of Gr ≥3 thrombocytopenia, anemia, or bleed; palpable spleen ≥5cm; and no Gr ≥2 peripheral neuropathy. Stratification was by transfusion dependency and baseline TSS (modified MPN-SAF Total Sx Score) <18 or ≥18. Pts were randomized 2:1 to 24 weeks of open-label MMB 200 mg QD or BAT. Assessments included spleen volume by MRI, and patient-reported Sx using a daily eDiary for TSS. 1° endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline). 2°endpoints, evaluated sequentially, were rates of TSS response (TSS RR; ≥50% reduction from baseline), RBC transfusion, RBC transfusion independence (TI) and RBC transfusion dependence (TD). Results: 73 of 104 (70%) and 40 of 52 (77%) pts receiving MMB or BAT, respectively, completed the 24 week randomized treatment phase. BAT for 88% of pts included RUX, and 27% of pts were on RUX in combination with other drugs. Efficacy results are in Table. The most common Gr ≥3 adverse events in MMB pts were anemia (13%) and thrombocytopenia (7%), and in BAT pts, anemia (13%), thrombocytopenia (6%) and abdominal pain (6%); treatment emergent peripheral neuropathy occurred in 11 (11%) of MMB (1 Gr3) and in no BAT pts. Conclusions: In previously RUX-treated patients with MF, 24 weeks of MMB was not superior to BAT for SRR, but significantly better in improving disease related symptoms and transfusion independence. Clinical trial information: NCT02101268. [Table: see text]
Factors associated with allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO) versus (v) conventional chemotherapy (C).
Authors: Kebriaei Partow , DeAngelo Daniel J. , Stelljes Matthias , Gökbuget Nicola , Kantarjian Hagop M. , Advani Anjali S. , Merchant Akil , Wang Tao , Loberiza Fausto Rodriguez , Sleight Barbara , Vandendries Erik , Marks David I. 
Published: September 2018

7007 Background: InO therapy in R/R ALL resulted in superior complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates v C in the Phase 3 INO-VATE trial (NCT01564784; Kantarjian NEJM 2016). More InO v C pts proceeded to HSCT (41% [45/109] v 11% [12/109]; P<0.001). Factors associated with outcomes after HSCT are described. Methods: Full details have been published. Multivariate analyses (MVA) using Cox regression modeling were conducted to determine predictors of non-relapse mortality (NRM) and overall survival (OS). Results: As of 3/8/16, 108/326 pts underwent allogeneic HSCT (InO n=77; C n=31). Baseline characteristics were generally similar, except baseline platelet values were lower in InO v C pts. More InO v C pts achieved minimal residual disease negativity (MRDneg [best status]; 71% v 26%; P<0.0001). Less InO v C pts received additional therapy before HSCT (14% v 55%, P<0.0001). NRM rates were higher in InO v C pts at 1 year (yr; 36% [95% CI 26–47] v 20% [8–36]) and 2 yrs (39% [27–51] v 31% [13–51]), but relapse rates were lower (1 yr, 23% [15–33] v 29% [13–48]; 2 yrs, 33% [22–44] v 46% [24–65]). No significant difference in post-HSCT survival was detected in InO v C pts; however, visual inspection of the curve suggested the survival probability varied before and after 15 months post-HSCT (1 yr, 44% [95% CI 33–55] v 65% [44–79]; 2 yr, 39% [28–50] v 34% [15–54]). Fatal veno-occlusive disease (VOD) was observed in 5 InO pts (all during the first 100 days from the date of HSCT) and no C pts. MVA showed that conditioning regimens without dual alkylators and thiotepa were associated (2-sided; P<0.05) with lower risk of NRM and post-HSCT survival, respectively. Conclusions: Compared with C, InO permitted more pts with R/R ALL to proceed to HSCT in CR/CRi with MRDneg (best status). Despite increased NRM and fatal VOD, long-term survival was attainable in InO pts. In pts previously treated with InO, interventions to reduce NRM and improve OS after HSCT include avoiding dual alkylator conditioning regimens, especially those containing thiotepa. Funding: Pfizer Clinical trial information: NCT01564784.
A phase I trial of ipilimumab (ipi) in patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMAs) failure.
Authors: Zeidan Amer M , Knaus Hanna , Robinson Tara M. , Zeidner Joshua F. , Blackford Amanda L. , Rizzieri David , Frattini Mark G. , Levy Moshe Yair , Schroeder Mark A. , Ferguson Anna K. , Sheldon Katherine , Dezern Amy Elizabeth , Gojo Ivana , Gore Steven , Streicher Howard , Luznik Leo , Duffield Amy , Smith B. Douglas 
Published: September 2018

7010 Background: Pts with HR-MDS after HMA failure have a poor overall survival (OS) of < 6 months. Immune escape is associated with resistance to HMAs in MDS. We hypothesized that CTLA-4 blockade in these pts would be tolerable and lead to clinical responses. Methods: This investigator-initiated, CTEP-sponsored, multi-center phase 1b study enrolled pts after failure of HMAs. In dose-escalation, ipi monotherapy was given at 2 dose levels (DL): 3 and 10mg/kg. Four doses (every 3 weeks) were administered followed by a maintenance phase (4 doses every 3 months) for non-porgressors. Toxicities and responses were evaluated with CTCAE4 and IWG2006 criteria, respectively. OS was estimated using the Kaplan-Meier method. The impact on T-cells were studied by flow cytometry and TCR sequencing. Results: 29 pts from 7 centers were enrolled. Mean age (SD) was 67 (8) years. Most had IPSS high/int-2 (55%), 45% had int-1. Three of 6 pts in DL1 and 4 of 5 pts in DL2 experienced grade [G]2-4 immune-related adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. The DL1 (3mg/kg) was expanded with no G2-4 IRAEs reported in the 18 additional pts. A total of 15 deaths occurred due to disease progression or other complications but none attributed to ipilimumab. In total, 52% received all 4 induction doses, and 24% received ≥1 maintenance dose. Best objective responses were 2 marrow complete responses (mCR, 7%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 6 pts (21%) and for ≥54 weeks in 3 pts (10%). Five pts (17%) subsequently underwent allogeneic transplantation (alloSCT) without evidence of excessive toxicity. Median OS (censoring at alloSCT) was 294 days (95%CI, 240-671+) and 400 days (95%CI, 240-671+) for those who received maintenance (n = 7). Pts who achieved PSD and mCR had significantly increased expression of ICOS, a marker of T-cell activation. Conclusions: Immune checkpoint blockade with ipi is tolerable and can lead to PSD/mCR in a proportion of pts. However, ipi monotherapy efficacy is limited after HMA failure and combination-based approaches should be considered. Increased frequencies of ICOS expression might predict clinical benefit. Clinical trial information: NCT01757639.
Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).
Authors: Erba Harry Paul , Becker Pamela S. , Shami Paul J. , Grunwald Michael Richard , Flesher Donna L. , Zhang Yilong , Rasmussen Erik , Henary Haby A. , Wang Eunice S. 
Published: September 2018

7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.
Overall survival (OS) with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia (tAML): Subgroup analysis of a phase III study.
Authors: Lancet Jeffrey E. , Rizzieri David , Schiller Gary J. , Stuart Robert K. , Kolitz Jonathan E. , Solomon Scott R. , Newell Laura F. , Erba Harry Paul , Uy Geoffrey L. , Ryan Robert , Chiarella Michael , Louie Arthur Chin , Cortes Jorge E. 
Published: September 2018

7035 Background: tAML may occur as a late complication of cytotoxic therapy and is associated with a poor prognosis. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). In a randomized, open-label, controlled phase III trial in patients (pts) aged 60-75 years with newly diagnosed, secondary AML (tAML or after MDS), CPX-351 significantly improved OS versus 7+3. The current analysis of this phase III study evaluated outcomes in the subgroup of pts with tAML. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation therapy. The study was not powered for this subgroup analysis. Results: 304 pts were enrolled and received study treatment, including 62 (20%) pts with tAML; demographics of tAML pts were similar between study arms. Pts with tAML had typically received prior non-anthracycline chemotherapy alone (25%), radiation alone (25%), or non-anthracycline chemotherapy + radiation (32%). CPX-351 was associated with an OS benefit versus 7+3 in older tAML pts and numerically longer event-free survival (EFS) and remission duration (Table). A greater proportion of tAML pts achieved CR+CRi (47% vs 36%, respectively) and proceeded to stem cell transplantation (37% vs 27%) with CPX-351. The safety profile of CPX-351 was comparable to that of 7+3. Conclusions: CPX-351 is associated with improved outcomes in older pts with newly diagnosed tAML. Outcomes in the tAML subgroup mirrored the overall study population, indicating CPX-351 may represent a new therapeutic option for this difficult to treat population. Clinical trial information: NCT01696084. [Table: see text]
Idarubicin and cytarabine with clofarabine or fludarabine in adults with newly diagnosed acute myeloid leukemia: Updated results of a randomized phase II study.
Authors: Issa Ghayas C. , Kantarjian Hagop M. , Short Nicholas James , Ravandi Farhad , Huang Xuelin , Garcia-Manero Guillermo , Plunkett William , Gandhi Varsha , Pemmaraju Naveen , Daver Naval Guastad , Borthakur Gautam , Jain Nitin , Konopleva Marina , Estrov Zeev , Kadia Tapan M. , Dinardo Courtney Denton , Brandt Mark , O'Brien Susan Mary , Cortes Jorge E. , Jabbour Elias 
Published: September 2018

7037 Background: The purine nucleoside analogues fludarabine and clofarabine are effective agents in the treatment of acute myeloid leukemia (AML). This study evaluated the efficacy and safety of combining idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Methods: Using a Bayesian adaptive design, patients (pts) deemed suitable for intensive chemotherapy were randomized to receive CIA (n = 106) or FIA (n = 76). All pts received idarubicin 10 mg/m2 IV daily on Days 1-3 and cytarabine 1 g/m2 IV daily on Days 1-5. Clofarabine and fludarabine were given at 15 mg/m2 and 30 mg/m2, respectively, IV daily on Days 1-5. Pts with FLT3 mutations could receive sorafenib. Up to 6 cycles of consolidation were allowed for responding pts. Results: Baseline characteristics were similar comparing CIA to FIA with a median age of 53 years (range, 20-66) vs 49 years (range, 18-66) respectively and ELN risk intermediate-2/adverse of 57% and 58% respectively. With a median follow-up of 27 months (range, 1-58), the CIA and FIA arms had a similar CR/CRp rate (80% and 82%, respectively). MRD negativity rate by multiparameter flow cytometry at the time of CR/CRp was higher comparing CIA to FIA (80% vs. 65%, respectively, P = 0.07). The median EFS were 13 months and 12 months, respectively (P = 0.91), and the median OS were 24 months and not reached, respectively (P = 0.23). There were more adverse events (all grades) associated with CIA, particularly AST/ALT elevation (29% vs 4%), hyperbilirubinemia (26% vs 9%) and rash (31% vs 9%). Early mortality was similar in the 2 arms (60-day mortality: 4% for CIA vs 1% for FIA; P = 0.32). Comparing the 2 arms to a historical cohort of pts treated with IA showed similar response rates, EFS and OS excluding pts with FLT3 mutations from this analysis. However, in pts < 50 years of age, FIA was associated with improved survival compared with IA (2-year EFS rate: 58% vs 30%, P = 0.05; 2-year OS rate: 72% vs 36%; P = 0.009). Conclusions: CIA and FIA have similar efficacy in younger pts with newly diagnosed AML. FIA is associated with a better toxicity profile and may improve survival compared to IA in pts < 50 years of age. Clinical trial information: NCT01289457.
Allogeneic stem cell transplant (AHCT) in the eighth decade: Age is just a number.
Authors: Narra Ravi Kishore , Chhabra Saurabh , Narayana Swapna , Shah Nirav Niranjan , Hamadani Mehdi , Szabo Aniko , Pasquini Marcelo C. , Hari Parameswaran 
Published: September 2018

7045 Background: Allogeneic hematopoietic cell transplant (AHCT) is a curative treatment for hematological malignancies but older adults ( > 70 years) have been historically excluded due to age-related comorbidities and concern for increased non-relapse mortality (NRM). Reduced intensity conditioning (RIC) regimens, and improvements in supportive measures have broadened AHCT to older adults. Limited data exist regarding AHCT in their eighth decade ( > 70). Methods: We evaluated 24 consecutive pts aged > 70 years receiving AHCT for various hematological malignancies between 2012 and 2016 at the Medical College of Wisconsin. Results: Median age was 72 (range, 70-76), and 62% were male. Disease indications included 11 AML, 6 CMML, 1 MDS, 1 NHL, 1 MM with only 11 patients (46%) in CR at transplant. 15 patients (62%) had normal karyotype, while other 9 had complex karyotype (n = 4), trisomy 11 (n = 1), trisomy 8 (n = 1). 6 patients (26%) had low-risk DRI score, 9 (39%) intermediate and 8 (35%) had high-risk score. Median HCT-CI score was 1.5 (range, 0-5) and 79% patients had a score of ≤2. Donors were related in 50% cases (3 haploidentical, 7 matched siblings and 2 syngeneic). Conditioning was RIC in 23 pts and all peripheral blood grafts. Median follow up was 14.2 months (range, 1.5-42.3). At day 28, 92% had neutrophil engraftment and 87% platelet engraftment. 2 patients had primary graft failure. 4 patients had acute GVHD, 4 had chronic GVHD,1 had both. Median CD3 chimerism was 99% (range, 74-100), CD33 was 100% (range, 78-100). Median of hospital-free days in the first 100 days was 80 and 160 days in the first 6 months after AHCT. 4 pts (17%) underwent AHCT entirely in outpatient setting. 6 patients relapsed at a median of 145 days (range 40-195). Survival at 2 years was 67% with relapse-free survival of 56% and NRM of 14%. Causes of death included sepsis (n = 1), fungal pneumonia (n = 1), cardiac (1), IPS (1), relapse (3). Conclusions: This experience with septuagenarians undergoing AHCT demonstrated an excellent 2 yr survival of 67% and that they can receive AHCT in the outpatient setting with a median hospital-free period of 80 days within the first 100 days. In carefully selected patients NRM with AHCT is manageable. Age alone should not determine eligibility for AHCT.
Allogeneic transplant leads to markedly improved survival in older patients with AML.
Authors: Lachowiez Curtis Andrew , Cook Rachel J. , Meyers Gabrielle 
Published: September 2018

7048 Background: AML is a disease of the elderly, and outcomes with standard treatment are dismal. Allogeneic transplant is the only curative therapy for most patients with AML. Recent work has shown age is not a factor in transplant outcomes, and should not be a limiting factor for transplant. The treatment pathway for older patients with AML should take into account their disease risk, comorbidities, and treatments with a proven survival advantage. We investigated our institutional experience to help guide the establishment of optimal pathways for patients. Methods: We conducted a retrospective analysis of 118 patients over age 65 with AML treated at our institution between 2010-2015. Patients receiving therapy (n = 90) were categorized into two groups: intensive induction therapy (7+3 based) or induction therapy with a hypomethylating agent. The groups were well matched in regard to comorbidities. Results: In poor risk patients, complete remission (CR) was achieved in 42% (n = 30/71). Select patients up to age 75 proceeded to allogeneic transplant if they achieved CR. Survival in CR1 was higher in the transplant (n = 22, median 719 days, 95% CI: 366-1071 days), than in the non-transplant group (n = 8, median 257 days, 95% CI: 92-421 days, p-value < .001). In analyzing all risk groups, overall survival was superior in transplant (median 1188 days) versus non-transplant recipients (median 185 days) (see 1, 2, and 3 year survival in table). No difference in median survival occurred based on age at induction (older than 70: n = 9, younger than 70: n = 16, p-value = 0.316). There was no difference in median survival based on chemotherapy regimen without transplant: intensive induction (n = 24, survival 250 days, p-value 0.179) compared to hypomethylating agents (n = 22, survival 139 days). Conclusions: We confirm that transplant can be safely performed in patients over 70 years of age, and highlight the survival advantage of transplant to chemotherapy alone. Additionally, our data found no survival benefit of hypomethylating agents in elderly patients with poor risk AML.[Table: see text]
Clinical relevance of mutations in patients with myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with normal karyotype.
Authors: Montalban-Bravo Guillermo , Alfonso Pierola Ana , Takahashi Koichi , Konopleva Marina , Jabbour Elias , Borthakur Gautam , Daver Naval Guastad , Dinardo Courtney Denton , Estrov Zeev , Kadia Tapan M. , Pemmaraju Naveen , Ravandi Farhad , Bueso-Ramos Carlos E. , Kantarjian Hagop M. , Patel Keyur , Garcia-Manero Guillermo 
Published: September 2018

7053 Background: Clinical outcomes of patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous. Specific mutations and mutation patterns are known to define prognostic groups in normal karyotype acute myeloid leukemia. Whether this is the case in MDS and MDS/MPN remains unknown. Methods: We evaluated 325 previously untreated patients with MDS or MDS/MPN with normal karyotype evaluated from 2012 to 2016. Next generation sequencing (NGS) on whole bone marrow DNA analyzing a panel of 28 or 53 genes was performed at the time of diagnosis. Results: A total of 225 (69%) patients had MDS and 100 (31%) had MDS/MPN including 77 (24%) patients with chronic myelomonocytic leukemia (CMML). Median age was 69 years (31-92). Among patients with MDS, 189 (84%) had lower-risk and 36 (16%) had higher-risk based on IPSS. NGS data was obtained by 53-gene panel in 93 (29%) patients and by 28-gene panel in 232 (71%). A total of 202 (62%) patients had detectable mutations. Median number of mutations was 1 (range 0-6). Detected mutations are detailed in Table 1. A total of 111 (34%) patients, 70 with MDS and 41 with MDS/MPN, received therapy with hypomethylating agents. Median follow up was 12 months (0-167). By univariate analysis, NRAS (HR 3.28, CI 1.25-8.62, p=0.016) and TP53 (HR 4.9, CI 1.44-16.67, p=0.011) predicted for shorter overall survival (OS) among MDS patients. After multivariate analysis including IPSS-R, only TP53retained its impact in OS (HR 5.25, CI 1.44-19.13, p=0.012). Among MDS/MPN patients, no mutation was found to significantly impact OS. Conclusions: With the exception of TP53mutations, no other identified mutation seemed to independently define prognosis of patients with MDS or MDS/MPN with normal karyotype. In view of the high proportion of lower-risk patients, longer follow up is required to better define prognostic impact of mutations in this population. [Table: see text]