bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving the molecular risk classification for younger (<60 years) de novo cytogenetically normal acute myeloid leukemia (CN AML) patients (pts)
Authors: Marcucci G. , Maharry K. , Whitman S. P. , Paschka P. , Baldus C. D. , Langer C. , Mrózek K. , Kolitz J. E. , Larson R. A. , Bloomfield C. D. 
Published: August 2020

7002 Background: CN AML pts are currently stratified into Low-risk [FLT3-ITD negative (neg)/NPM1 mutated (mut)] and High-risk [FLT3-ITD positive (pos) or NPM1 wild type (wt)] groups (FLT3-ITD/NPM1-only classification). We recently showed that low ERG expression and CEBPAmut identify pts with better outcome within, respectively, the Low- and High-risk groups, and that WT1mut confers poor outcome regardless of FLT3-ITD/NPM1 status. Here, we assess if adding CEBPA and WT1 mutation and ERG expression testing improves the currently used CN AML molecular risk classification. Methods: FLT3, NPM1, CEBPA and WT1 mutations and ERG and BAALC expression were tested at diagnosis in 143 CN AML adults enrolled on CALGB treatment protocols 9621 and 19808. Pts were divided into two molecular risk groups: i) CALGB Group I that included Low-risk pts with low ERG & High-risk pts with CEBPAmut and ii) CALGB Group II that included WT1mut pts & Low-risk pts with high ERG & High- risk pts with CEBPAwt. Results: CALGB Group I (n=56) v Group II (n=87) had more complete remissions (CRs) (P=.005; 96% v 79%), and longer disease-free (DFS; P<.0001; 5 year (y) 69% v 21%) and overall (OS; P<.0001; 5 y 70% v 31%) survival [median follow-up for pts alive 6 y]. In multivariable (MV) analyses, Group I predicted higher rate of CR (P=.02), and longer DFS (P<.0001) and OS (P=.0002), after correcting for other variables (Table). In contrast, for the same cohort of pts grouped by the FLT3-ITD/NPM1-only classification, CRs were 94% v 82% and 5 y DFS 59% v 32% and OS 67% v 36% in the Low- v High-risk groups. Based on the Akaike Information Criterion, MV models for DFS and OS using the CALGB risk Groups were better than those using the FLT3-ITD/NPM1-only risk groups. Conclusions: Prognostic classification of younger de novo CN AML pts is improved by adding CEBPA and WT1 mutation and ERG expression testing. While mutational analyses are ready for use in clinical trials, quantification of ERG expression is yet to be standardized. [Table: see text] No significant financial relationships to disclose.
Phase Ib/II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in relapsed or refractory AML patients
Authors: Lancet J. E. , Karp J. , Cripe L. , Roboz G. , Wollman M. , Berman C. , Conroy A. , Hawtin R. , Fox J. , Michelson G. 
Published: August 2020

7005 Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Clinical activity is observed in ovarian cancer and AML. Voreloxin combined with cytarabine (Ara-C) show supra-additive activity preclinically. Interim results from a phase Ib/II study in relapsed or refractory AML are reported. Methods: Dose-escalation in relapsed/refractory AML patients (pts) with ≤ 3 prior induction regimens; phase II expansion in first-relapse pts (CR1 ≥ 3 months) at MTD. Voreloxin given d1 and d4, combined with: A) continuous infusion 400 mg/m2/d x 5d Ara-C (CIV), or B) bolus 1 g/m2/d IV x 5d Ara-C. Voreloxin starting dose: A) 10 mg/m2/dose; B) 70 mg/m2/dose. Treatment: induction, reinduction if needed, and up to 2 courses for consolidation. DLT, PK, and PD were assessed in cycle 1. Pts’ PBMC were evaluated for induction of DNA damage response markers. Ex vivo sensitivity of pt BMA to voreloxin and Ara-C were evaluated by CellTiter-Glo proliferation assay. Results: 52 pts treated to date (A: 41 pts, dose-escalation; 5 pts Phase 2; B: 6 pts dose-escalation). A) MTD is 80 mg/m2/dose voreloxin. Infections are the most common G3 or higher toxicity. Voreloxin PK were dose proportional to 50 mg/m2, then plateaued. Evaluation of PBMC pre- and posttreatment suggests modulation of pDNA-PKcs and pChk2 may reflect response. Ex vivo BMA assay results suggest that voreloxin is the primary contributor to the majority of CRs observed. Phase Ib: 9 CRs + CRp were observed in multiply relapsed or 1° refractory pts. B) 70 mg/m2/dose voreloxin, no DLT; too early to evaluate activity. Conclusions: Voreloxin in combination with CIV Ara-C is generally well-tolerated, with CR in relapsed/refractory pts. Enrollment continues: A) phase II; B) phase Ib. Ex vivo activity assay results suggest that voreloxin is the primary contributor to the majority of CR. Induction of pDNA-PKcs and pChk2 in PBMCs from treated pts may reflect response. [Table: see text]
Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)
Authors: Steensma D. , Kantarjian H. , Wijermans P. 
Published: August 2020

7011 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients using two dosing regimens: 15 mg/m2 intravenous (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days q 6 weeks (wks) and 20 mg/m2 IV over 1 hr once daily for 5 consecutive days q 4 wks. Methods: Results were reviewed from two randomized phase 3 studies comparing the 3-day dosing schedule of decitabine with supportive care, D-0007 and EORTC-06011, and two phase 2 studies with the 5-day dosing schedule, DACO-020 and ID03–0180. Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed. Results: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03–0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03–0180, 70%; DACO-020, 89%). Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table). The duration of improvement ranged between 9.2 and 11.3 months. A trend was observed for improved outcomes with an increased number of decitabine treatment cycles. Conclusions: Overall improvement rates by IWG criteria exceeded 30% in all 4 studies. Higher overall improvement rates corresponded to increased median number of treatment cycles. Increasing the number of decitabine treatment cycles administered may provide additional benefit to MDS patients. [Table: see text] [Table: see text]
Age-specific differences in oncogenic pathway deregulation and chemosensitivity in patients with acute myeloid leukemia: Strategies to maximize response to induction chemotherapy
Authors: Rao A. V. , Valk P. , Metzeler K. H. , Acharya C. , Rizzieri D. A. , Delwel R. , Bohlander S. H. , Buske C. , Potti A. , Lowenberg B. 
Published: August 2020

7013 Background: Despite all the advances made in understanding the poor prognosis of acute myeloid leukemia (AML) in the elderly, the underlying biology at a molecular signaling pathway level has yet to be defined. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets GSE1159 and GSE12417 were analyzed. Age-specific cohorts (young ≤45 years; n = 175 and elderly ≥55 years; n = 144) were prospectively identified. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity. Standard Kaplan-Meier survival curves were generated using the two-sided log-rank test and individual differences in the probability of oncogenic pathway deregulation between young vs. elderly were analyzed via the non-parametric Mann-Whitney U test and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: Elderly AML patients had worse OS (median 8.8 months vs. 24.1 months in younger patients; p = 0.001) and EFS (median 7.1 months vs. 15.3 months in younger patients; p < 0.0001). Analysis of oncogenic pathways revealed that older patients had higher probability of Ras, Src, and TNF pathway activation, p < 0.0001. Older patients were also less sensitive to anthracycline compared to younger AML patients, p < 0.0001. Unsupervised hierarchical clustering of younger AML patients revealed two clusters and clinically better survival for cluster 1 compared to cluster 2 (high Ras, Src, TNF pathway activation) and the latter were in turn less sensitive to adriamycin. However, in elderly patients those in cluster 2 also had high Ras, Src, TNF but this did not translate into differences in survival or chemotherapy sensitivity. Conclusions: AML arising in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to poor survival and resistance to adriamycin. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the older patient population. No significant financial relationships to disclose.
Use of SNP-array-based karyotyping for cytogenetic prognostication in unclassified cases of myelodysplasia and associated overlap disorders
Authors: Bhatnagar B. , Tiu R. V. , Gondek L. P. , O'Keefe C. , Huh J. , Advani A. S. , Sekeres M. A. , Maciejewski J. P. 
Published: August 2020

7016 Background: Myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) often have overlapping features resulting in unclassifiable cases (MDS-U and MDS/MPD-U). Chromosomal abnormalities impact prognosis, but 50% of cases show normal karyotype by metaphase cytogenetics (MC). Single nucleotide polymorphism arrays (SNP-A) are novel karyotyping tools with superior resolution and ability to detect copy neutral loss of heterozygosity, a defect not detected by MC. Methods: MDS-U (N = 17) and MDS/MPD-U (N = 61) patients were selected from an MDS database (N = 720, median age = 76, median follow-up = 42 mos). SNP-A was performed on 67 patients and 751 controls. An algorithm for identification of somatic lesions was designed: 1) Lesions detected by MC and SNP-A required no further analysis; 2) Micro-duplications/ deletions overlapping with copy number variants (CNV) were excluded. Lesions not in CNV databases were confirmed by CD3 lymphocytes; 3) UPD <25 Mb were unlikely somatic and excluded. Telomeric and interstitial (≥ 25 Mb) UPD were considered somatic. International Prognostic Scoring System (IPSS) was used to assess routine risk. Fisher's exact test was used for categorical variables. Overall (OS) and event-free (EFS) survival defined by the MDS working group criteria were analyzed by Kaplan Meier analysis (log-rank or Wilcoxon and 2-sided significance). Results: SNP-A yielded superior detection rate for chromosomal defects compared to MC (71% vs 47%, p = 0.008). UPD was seen in 17 patients and frequently involved chromosomes 1, 3, 6, 8, 11, 17. MDS/MPD-U and MDS-U patients had similar OS and EFS (OS = 42 vs. 45 mos, p = 0.13; EFS = 42 vs. 45 mos p = 0.63). SNP-A revealed a more complex karyotype in patients with advanced MDS. Furthermore, SNP-A karyotyping resulted in prognostic refinement of previously assigned IPSS: Unclassified cases = 6% versus 0%, int-1 = 45% versus 53%, int-2 = 6% versus 19%, high = 5% versus 8%. Overall, patients with new SNP-A lesions had worse OS and EFS (OS = 41 mos vs NR, p = 0.07; EFS = 32 vs 112 mos, p = 0.07). Conclusions: SNP-A karyotyping complements MC in detecting chromosomal defects in MDS-U and MDS/MPD-U. This technology will be helpful in refining diagnosis based on characteristic recurrent chromosomal lesions including UPD. No significant financial relationships to disclose.
Combined tumor necrosis factor-α (TNF–α) and interleukin-2 (IL-2) blockade in acute steroid refractory graft-versus-host disease (SR-GVHD) following allogeneic hematopoietic stem cell transplantation (HCT)
Authors: Ramanathan M. , Srinivasan R. , Geller N. , Donohue T. , Goodwin R. , Cook L. , Ramos C. , Barrett J. , Childs R. 
Published: August 2020

7023 Background: SR-GVHD is a frequent and often fatal complication of HCT. A variety of inflammatory cytokines have been implicated in the pathogenesis of GVHD; single agent therapy against targets such as the IL-2 receptor α chain (daclizumab) or TNF-α (infliximab) has modest activity in SR-GVHD. We hypothesized that concomitant blockade of both TNF-α and IL-2 pathways would be more effective in controlling SR-GVHD than inhibition of either cytokine alone. Methods: The incidence of and outcome following SR-GVHD in 141 pts undergoing nonmyeloablative HCT from an HLA-matched family donor at our institution between February 2001 and November 2008 were analyzed. All SR-GVHD pts were treated with a combination of daclizumab (1 mg/kg, days1, 4, 8, 15, 22) and infliximab (10 mg/kg, days1, 8, 15, 22); in addition, aspergillus prophylaxis, empiric broad-spectrum antibiotics, and a rapid reduction in the dose of corticosteroids was initiated in order to minimize the risk of opportunistic infections associated with immunosuppression. Results: Twenty-three pts (23/141, 16%) developed SR-GVHD (median age 35 y, range 17–65 y); involved organs included the GI tract (n = 23), liver (n = 3), and skin (n = 8). We observed a remarkably high response rate following therapy, with 20/23 (87%) pts experiencing complete resolution of GVHD. Responses were usually delayed (median onset 2 weeks) but durable. The most notable complication associated with therapy was the development of opportunistic infections (invasive fungal infections in 3 pts); in 2/3 of these cases, prophylactic antifungal therapy had been discontinued prematurely due to drug toxicity. The median survival for the SR-GVHD cohort was 255 days (range 67–2,148 days), with 10/23 pts surviving at the time of this analysis. Causes of death included underlying cancer (5 pts), CMV disease (2 pts), and infectious complications (5 pts). Conclusions: These data suggest combined TNF-α /IL-2 blockade is a highly effective therapeutic option for pts with SR-GVHD and highlight the need for aggressive antimicrobial prophylaxis in the management of this condition. No significant financial relationships to disclose.
Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study
Authors: Kantarjian H. , Giles F. , Bhalla K. , Pinilla J. , Larson R. A. , Gattermann N. , Ottmann O. G. , Gallagher N. J. , Baccarani M. , leCoutre P. 
Published: August 2020

7029 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM. Methods: Primary endpoint was major cytogenetic response (MCyR). Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), MCyR duration, overall survival (OS), and safety. Results: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of 19 months (mos) were evaluated; 72% were treated with ≥600 mg/day IM prior to enrollment. Median duration of prior IM treatment was 32 (<1–94) mos. Median dose intensity of nilotinib (790 mg/day; range 151–1,110 mg/day) closely approximated the planned dose. Nilotinib led to rapid and durable CHR and MCyR. CHR was observed in 94% of pts. 59% achieved an MCyR (2.8 mos median time to MCyR; 56% in IM-resistant, and 65% in IM-intolerant pts), including 73% of pts with a baseline CHR and 44% achieved a CCyR (41% in IM-resistant; 51% in IM-intolerant pts). Responses were durable, with 78% pts maintaining MCyR at 24 mos. Estimated OS rate was 88% at 24 mos. Safety profile did not change with longer follow-up. Most frequent grade (gr) 3/4 biochemical laboratory abnormalities were elevated lipase (17%), hypophosphataemia (16%), hyperglycemia (12%), and total bilirubin (8%) which were transient and clinically asymptomatic. Gr 3/4 non-hematologic AEs were infrequent: rash, headache, and diarrhea occurred in 2% of pts. Most common gr 3/4 hematological laboratory abnormalities were neutropenia (31%), thrombocytopenia (31%), and anemia (10%). Brief dose interruptions were successful in management of most AEs. Pleural or pericardial effusions (gr 3/4) were uncommon (< 1%). Conclusions: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in CML-CP pts failing prior therapy due to resistance or intolerance. Nilotinib was well tolerated with favorable risk/benefit. [Table: see text]
Long-term outcomes of high-dose therapy using busulfan, etoposide, and cyclophosphamide followed by allogeneic hematopoietic cell transplantation for patients with high-risk or advanced stages of myeloid malignancies
Authors: Naik S. G. , Negrin R. , Laport G. , Miklos D. , Shizuru J. , Arai S. , Blume K. , Wong R. , Lowsky R. , Johnston L. 
Published: August 2020

7033 Patients (pts) with high risk (HR) or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single institution long-term follow-up of 96 pts, median age 50 (20–60) yrs, who received HLA matched related HCT between 1992 and 2007. All pts were treated with a uniform preparatory regimen: busulfan 16.0 mg/kg (d-8 to-5), etoposide 60mg/kg (d-4), cyclophosphamide 60mg/kg (d-2), and graft-versus-host-disease (GVHD) prophylaxis of cyclosporine and prednisone. Disease status at transplantation was induction failure (IF) acute myeloid leukemia (AML) (n = 10), HR AML in 1st complete remission (CR1) n = 11, in CR2 (n = 5), in CR3 (n = 2), relapsed refractory (RR) AML (n = 14), chronic myeloid leukemia (CML) in second chronic phase (n = 6), blast crisis (n = 2), myelofibrosis (n = 6), myeloproliferative disorders (n = 2), and MDS (n = 38). Thirty-six % (n = 35) of pts received bone marrow while 64 % (n = 61) received G-CSF mobilized peripheral blood mononuclear cells (PBMC). With a median follow up of 5.6 yrs (1.6–14.6 yrs) actuarial 5-year overall survival (OS) was 32% (95% CI 22–42%) and 5-year probability for freedom from progression (FFP) was 64% (95% CI 52%-76%). Relapse rate was 32% at 1 year and remained at 36% (95%CI 24%-48%) at 2 and 5 years with no further increase in relapse beyond two years. Non-relapse mortality (NRM) was 29 % (95% CI 20%5–38%) at day 100 and 39% (95% CI 29%-49%) at one yr. Cumulative incidence of acute (grade 3–4) and chronic GVHD was 28% (95% CI 19%-37%) and 38% (95% CI 24%-52%), respectively. There was no statistically significant difference in OS; 31% versus 32% (p = 0.89) or FFP 71% versus 60% (p = 0.29) for recipients of BM versus PBMC with similar results in IF and RR AML. These results confirm that pts with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning. Relapse and acute GVHD remain significant causes of mortality. Strategies to augment graft-versus-tumor reactions and reduce GVHD remain essential for improving long-term outcomes. No significant financial relationships to disclose.
Clinical improvement with a novel CD20 mAb, ofatumumab, in fludarabine-refractory chronic lymphocytic leukemia (CLL) also refractory to alemtuzumab or with bulky lymphadenopathy
Authors: Kipps T. J. , Österborg A. , Mayer J. , Stilgenbauer S. , Hellmann A. , Williams C. D. , Furman R. , Chan G. , Russell C. , Wierda W. G. 
Published: August 2020

7043 Background: Patients (pts) with CLL refractory tofludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR) have a poor prognosis. Ofatumumab is a human mAb specific for a distinctive small-loop epitope of CD20 that appears more potent than rituximab in eliciting complement-dependent lysis of B cells in vitro. We report, for the first time, results from the planned interim analysis of the clinical benefit observed in pts with DR or BFR CLL treated with ofatumumab in an international pivotal clinical study. Methods: Pts with DR or BFR CLL received 8 weekly then 4 monthly ofatumumab infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was overall response rate (ORR; 1996 NCI-WG criteria), as assessed by an Independent Review Committee, over 24 wks. Results: Of 138 treated pts (DR: N = 59; BFR: N = 79; median age 64 and 62 yrs, respectively), 63% had Rai stage III/IV disease at screening. Pts had a median of 5 prior therapies. ORR (99% CI) was 58% (40, 74%) in the DR and 47% (32, 62%) in the BFR groups, and median overall survival (95% CI) was 13.7 mo (9.4, NR) and 15.4 mo (10.2, 20.2), respectively. Resolution of disease symptoms (maintained for ≥2 mo) were observed in a large proportion of pts (Table), including in pts considered nonresponders by NCI-WG criteria. Improvements in hematologic values were also observed in some pts with abnormal baseline values, particularly for platelet counts. Pts with thrombocytopenia at baseline (n = 73) experienced sustained increases in median platelet counts from 65 × 109/L to over 100 × 109/L by Wk 8; a similar pattern of rapid improvement was observed in Hgb values. Conclusions: Ofatumumab as single-agent achieves high ORR, and improves disease symptoms and hematologic parameters in heavily pretreated pts with DR and BFR disease who lack standard treatment options. [Table: see text] [Table: see text]
Comorbidity description using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in elderly de novo poor-risk AML patients (pts) treated with laromustine
Authors: Schiller G. J. , O'Brien S. M. , Vey N. , Pigneux A. , DeAngelo D. J. , Karp J. E. , Hudak D. , Kell J. , Stuart R. K. , Giles F. J. 
Published: August 2020

7050 Background: Treatment of older pts with AML is often complicated by comorbidities and pts with comorbidities are often underrepresented in clinical trials. The HCT-CI, which was developed in pts receiving allogeneic SCT, has been applied to pts receiving induction therapy for AML in an effort to assist in therapeutic and investigational decisions (Kantarjian 2006; Etienne 2007; Giles 2007). HCT-CI scores have been shown to be predictive of early death and survival in pts ≥ 60 years receiving induction therapy for AML, with early death rates of 3%, 11%, and 29% for pts with HCT-CI scores of 0, 1–2, and ≥ 3, respectively (Giles 2007). Methods: 140 pts age ≥ 60 with poor risk de novo AML from two phase II studies were scored for comorbidity by HCT-CI. In these studies, poor risk was defined by the presence of at least one risk factor: age ≥ 70, ECOG PS = 2, unfavorable cytogenetics, or cardiac, pulmonary, or hepatic dysfunction. All pts received induction therapy with 600 mg/m2 laromustine as a single 30–60 min infusion. A second induction cycle could be administered to pts with PR or hematologic improvement. Pts with CR or CRp were able to receive consolidation with laromustine 400 mg/m2 (Study CLI-033) or araC 400 mg/m2/day CIV for 5 days (Study CLI-043). Results: HCT-CI score was 0 in 7 (5%) pts, 1–2 in 19 (14%), and ≥ 3 in 114 (81%). The median HCT-CI score was 5 (range 0–13). The most common comorbidities were cardiac (42%), severe pulmonary (39%), infection (35%), and arrhythmia (31%). 52 (37%) of all pts achieved a CR/CRp; 39/114 (34%) of pts with HCT-CI score ≥ 3 achieved a CR/CRp. Deaths within 30 days of first induction were observed in 0/7 pts with HCT-CI score 0, 4/19 (21%) with score 1–2, and 16/114 (14%) with score ≥ 3. Overall survival at 12 months was 43%, 14%, and 21% for pts with HCT-CI scores of 0, 1–2, and ≥ 3, respectively. Conclusions: The majority (81%) of these older poor risk AML pts treated with laromustine had a HCT-CI score ≥ 3, confirming the poor risk nature of this patient group. The induction death rate for pts treated with laromustine and with HCT-CI score ≥ 3 was lower than that reported for a group of pts with HCT-CI score ≥ 3 treated with standard induction chemotherapy (14% vs 29%; Giles 2007). [Table: see text]