bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of smoking with poor risk ELN 2017, cytogenetics/molecular profile, and survival outcomes in acute myeloid leukemia.
Authors: Alfayez Mansour , Abou Dalle Iman , Richard-Carpentier Guillaume Abou , Pak Daewoo , Ning Jing , Pierce Sherry A. , Sasaki Koji , Naqvi Kiran , Daver Naval Guastad , Cortes Jorge E. , Ravandi Farhad , Pemmaraju Naveen , Ferrajoli Alessandra , Garcia-Manero Guillermo , Konopleva Marina , Borthakur Gautam , Kantarjian Hagop M. , Kadia Tapan , Dinardo Courtney Denton 
Published: March 2020

7002 Background: Smoking increases the relative risk of AML by 40% and 25% in active and former smokers, respectively, compared with non-smokers (Fircanis et al., 2014). While the relationship of smoking with AML development is recognized, whether smoking impacts underling AML biology and clinical outcome remains ill-defined. Methods: Newly diagnosed, treatment naïve AML pts seen at MDACC between 2012 and 2017 with available smoking history were evaluated, along with baseline parameters, co-occurring mutations, cytogenetics and clinical outcome. Results: We identified 858 pts [486 (57%) male; median age 67 yrs (14-97)], representing 535 (62%) treatment naïve and 323 (38%) salvage pts. Smoking status was recorded as smokers (active = 39 pt, former = 380 pt), versus never smoker (439 pt). In tx naïve group, smoking is associated with lower remission rates (OR 0.63, 95% CI 0.43-0.94, p = 0.02) and inferior OS (HR = 1.6, 95% CI 1.27-2.02, p < 0.001). Smoking status was not significant in multivariate analysis including AML biologic characteristics and ELN 2017 risk stratification. Therefore we postulated that worse OS may be driven by smoking associated AML biology rather than smoking associated comorbidities. Indeed, in univariate analysis smoking was associated with poor ELN risk (p = 0.015), complex karyotype (p = 0.0002), and TP53 mutation (p = 0.0235) while negatively associated with NPM1 (p = 0.018), FLT3-ITD (p = 0.032) and GATA2 (p = 0.0497). Age was a significant cofounder between smokers vs non-smoker ( < 0.0001). After controlling for age, significance was retained for ELN risk, complex karyotype and GATA2 at p = 0.0454, p = 0.0006, p = 0.048 respectively, while significance was lost for NPM1 (p = 0.079), FLT3-ITD (p = 0.1) and TP53 (p = 0.084). In analysis of young pts ( < 60 yr), smoking is positively associated with complex karyotype (p = 0.0042) and TP53 (p = 0.0289), and negatively associated with RUNX1 (p = 0.0143) and IDH2 (p = 0.0357). Conclusions: We report the largest analysis of smoking status and impact on molecular, cytogenetics, and AML clinical outcomes. Smoking history is associated with poorer risk molecular and cytogenetics, lower response rate and shorter survival in treatment naïve patients.
Clinical validation of long-range PCR assay for MLL partial tandem duplications for acute myeloid leukemia.
Authors: Rosenthal Sun Hee , Li Hai-Rong , Qu Kevin , Liu Yan , Owen Renius , Racke Frederick KARL , Lacbawan Felicitas L. 
Published: March 2020

7033 Background: Partial tandem duplication of the mixed lineage leukemia gene ( MLL-PTD) occurs in about 3% to 5% of adult acute myeloid leukemia (AML), mostly in patients with normal karyotypes, and is associated with poor prognosis. Real-time PCR on cDNA or RT-PCR followed by gel electrophoresis are the most commonly used methods for the detection of the mutation. However, those methods require RNA extraction, which is not often performed for molecular cytogenetic testing or next generation sequencing (NGS) for AML. In this study, we developed an MLL-PTD detection assay that uses long-range PCR on extracted DNA, a commonly processed sample type for AML molecular testing, to reduce sample processing requirements. Methods: DNA was extracted from de-identified 72 whole blood and 30 bone marrow aspirate specimens. Two PCR reactions were performed for each DNA sample: one to detect MLL-PTD and another to detect CHEK2 to monitor DNA integrity. The 3 most frequent forms of MLL-PTD (exons 2~8, 2~9, and 2~10) were detected using a forward DNA primer on exon 8 and a reverse primer on exon 2. MLL-PTD positivity was determined by the intensity of amplified DNA fragment at or above the lower detection limit control of this assay. Intra-assay precision, inter-assay precision, and limit of detection (LOD) were performed according to standard laboratory protocols. Results of this method were compared to those of NGS. Results: Intra-assay precision studies on 5 specimens yielded 100% genotype concordance. Inter-assay precision studies on 20 specimens yielded 100% concordance between replicates. LOD studies using a human eosinophilic leukemia cell line (EoL-1) with 12.5-kb PTD in size showed assay sensitivity of 5%; for smaller MLL-PTD positives (PTD ~3 kb and ~5 kb), LOD was 1%. For method comparison studies, 71 specimens (52 whole blood and 19 bone marrow) were also analyzed by NGS; concordance between the methods was 97.2% (69/71). Conclusions: We developed and validated long-range MLL-PTD detection assay for AML. The developed method uses DNA, which is commonly used for molecular testing for AML, and thus may reduce sample processing time by consolidating sample type across tests.
Phase II results of mitoxantrone in combination with clofarabine in children with relapsed/refractory acute leukemia.
Authors: Hochberg Jessica , Oesterheld Javier E. , Flower Allyson , Klejmont Liana , Basso Jaclyn , Harrison Lauren , Shi Qiuhu , Borowitz Michael J. , Loken Michael , Cairo Mitchell S. 
Published: March 2020

7036 Background: Despite improved outcomes in pediatric acute leukemia, those who relapse or are refractory do poorly. Mitoxantrone and clofarabine as single agents have proven efficacy in pediatric leukemia. Our previously reported phase I results demonstrated the MTD of this combination to be clofarabine 35 mg/m2 x 5 days and mitoxantrone 12 mg/m2 x 4 days. Here, we present our phase II data utilizing the RP2D. Methods: Prospective, open label safety and efficacy study (NCT01842672). Patients 0-30.99 yr old with ALL or AML with relapse OR induction failure were given 1 to 3 cycles of clofarabine (RP2D 35 mg/m2/day) Day 1-5, in combination with mitoxantrone 12 mg/m2/day on Day 3-6. Dexrazoxane was given prior to mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total 21 patients have enrolled at the RP2D clofarabine. Median age 8 yrs (0.5-22 yrs). Patient characteristics include 13 ALL (8=Induction Failure, 4=Relapse 1, 1=Relapse 2) and 8 AML (4=Induction Failure, 4=Relapse 1). Overall regimen was well tolerated. One patient with grade IV prolonged myelosuppression. Median time to neutrophil recovery was 24 days. Eighteen of 21 (85.7%) patients achieved an MRD negative CR. Three patients died of progressive disease. All 18 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. One patient developed MRD (2.6%) at Day +270 post HSCT and underwent subsequent therapy. The remaining 17 patients continue to demonstrate MRD negativity. Two patients died of transplant associated complications. The overall and event free survival for patients who responded to therapy are 89% (CI95 0.64-0.98) and 83% (CI95 0.58-0.96), respectively at a median follow up time of 24 months (range 2-58). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35 mg/m2 clofarabine in children with poor risk acute leukemias. Phase II data is encouraging with 85.7% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT with a 2 year survival rate of 89%. Longer follow up and a larger cohort is planned and ongoing. Clinical trial information: NCT01842672.
Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia.
Authors: Aboudalle Iman , Paranal Ronald , Paul Shilpa , Li Wen , Ning Jing , Cortes Jorge E. , Jabbour Elias , Kantarjian Hagop M. , Issa Ghayas C. 
Published: March 2020

7039 Background: Treatment of acute leukemia with intensive chemotherapy (IC) leads to increased risk of infection and bleeding because of myelosuppression. Luteinizing hormone (LH) blockade was found to improve hematopoietic recovery in mice after radiation or chemotherapy through protection of the hematopoietic stem cells (HSCs) which express the LH receptor (Velardi et al, Nat Med 2018). We hypothesized that LH blockade improves hematopoietic recovery following IC in patients (pts) with leukemia. Methods: We assessed gene expression of the LH receptor (LHR) in lineage-specific normal and AML hematopoietic cells from a reference dataset (Corces et al, Nat Gen 2016). We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received IC and Lupron, given for prevention or treatment of abnormal uterine bleeding. Results: LHR was greatest in HSCs, with little or no expression in mature subtypes within the hematopoietic hierarchy. Surprisingly, LHR was expressed on blasts. Since Lupron was more commonly given in younger pts, we performed propensity matching between the Lupron groups (AML N = 64; ALL N = 49) and control (Ctrl) groups (AML N = 128; ALL N = 98 pts). Baseline characteristics including blood counts were well balanced. Pts with AML who had received Lupron had a significantly higher increase in their platelet count following IC (13.8x109/L/year vs Ctrl; p = 0.02). Pts with ALL who had received Lupron had significantly higher increase in their absolute neutrophil count (0.37x109/L/year vs Ctrl; p = 0.02). AML pts in the Lupron group received significantly less blood transfusions vs Ctrl (mean: 23.9 vs 34.7 units; P = 0.002) and less platelet transfusions (mean: 24.4 vs 32.8 units; P = 0.06). There was no difference in event-free and overall survival between the groups in each leukemia cohort. Conclusions: Lupron use in leukemia pts receiving IC was associated with improved long-term blood count recovery. It was also associated with decreased transfusion requirements in AML. Despite expression of the LHR in blasts in addition to normal HSCs, there was no effect of LH blockade on rates of leukemia relapse or death.
IL2-STAT5 immune signatures to predict responses to PD-1 inhibition and azacitidine treatment in acute myeloid leukemia (AML): A subset analysis of a phase 2 study.
Authors: Abbas Hussein , Alfayez Mansour , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. , Dinardo Courtney Denton , Mathews Jairo , Flores Wilmer , Andreeff Michael , Kornblau Steven Mitchell , Konopleva Marina , Cortes Jorge E. , Neelapu Sattva Swarup , Kantarjian Hagop M. , Davis Richard Eric , Daver Naval Guastad 
Published: March 2020

7041 Background: Combining PD-1/PD-L1 blockade with hypomethylating agents (HMA) shows encouraging preliminary efficacy in AML, but immune features predictive of response are lacking. Methods: We treated 11 relapsed/refractory (R/R) AML patients with azacitidine (AZA) and nivolumab (Nivo) in a phase 2 clinical trial ( Daver N et al Cancer Discovery 2018). Patient characteristics: median (med) age 65 years (47-73), 63% adverse cytogenetics, 27% TP53 mutated. Pretreatment bone marrow aspirates had immune-phenotypic 17-color flow analysis and NanoString RNA quantification of 1469 immune-relevant genes. Results were correlated with clinical, pathological and molecular data. Results: The median courses of AZA+Nivo administered was 3 (range 1-17). The CR/CRi rate was 45% (including 2 CR, 1 CRi, 1 CRN and 1 CRP), with a median time to response of 1.8 months (range 0.8-4.9 months). The median overall survival was 13 months with 27% patients alive at 1 year. We found significant positive correlations between proportions of T-effector cells at baseline, and CD3+, CD8+, and T-regulatory cells at end of cycle (EOC) 1 (r > 0.75, p < 0.01 for all). At EOC2, these correlations were no longer significant. However, there was a significant positive correlation between T-effector cells at baseline and T-regulatory cells (r = 1, p < 0.001) at EOC4. Using NanoString analysis, we found 105 differentially expressed genes (fold change = 1.5, p < 0.05) between responders (5/11) and non-responders (6/11) at pretreatment. IL2-STAT5, TP53 and TNF Hallmark pathways and immune response from GO gene sets were highly enriched (q < 5x10-4) in responders. We then utilized z-score distribution analysis to quantify the degree of activation of known immunologic pathways. We found that signatures highly specific to neutrophils, NK cells, T-cells and eosinophils were significantly (p < 0.05) upregulated in patients with CR compared to non-responders at pretreatment. Conclusions: Our data demonstrates that a signature suggestive of lymphocyte activation in the pretreatment BM may be associated with augmented clinical response to PD-1 based therapies. Similar underlying pathways that have consistently predicted for responses to PD-1 inhibition in solid cancers, primarily IL2-STAT5 genes, may have predictive relevance in AML. Such pretreatment flow and NanoString signatures may help select AML patients most likely to benefit from PD-1 blockade plus HMA, further enhancing the benefit-risk ratio with such therapies.
Mast cells as mediators of fibrosis and effector cell recruitment in dermal chronic graft-versus-host disease.
Authors: Strattan Ethan , Palaniyandi Senthilnathan , Kumari Reena , Du Jing , Huang Timothy , Kesler Melissa , Sturgill Jamie , Hildebrandt Gerhard 
Published: March 2020

7050 Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with malignant neoplasms or inborn defects of hematopoiesis. Benefits of allo-HSCT are hampered by graft-versus-host-disease (GVHD), which can be debilitating and potentially lethal. In chronic GVHD (cGVHD), inflammation and aberrant wound healing lead to pathological fibrosis across multiple organs, most frequently in the skin, yet the exact pathophysiology is not well-understood. Mast cells (MCs) are primarily known for their role in atopic disease. However, recent studies have demonstrated new roles for MCs, showing that they can be involved in wound healing and in the pathogenesis of fibrotic disease. Given these new paradigms and the MC tropism to skin, alongside their reported role in other fibrotic diseases, we investigated whether MCs may play a role in the pathogenesis of dermal cGVHD. Methods: Cells: MCs were grown ex vivo from murine bone marrow. Transplant: 8 Gy radiation, followed by injection of LP/J marrow and splenocytes into C57BL/6J (WT) or B6.Cg-KitW-sh MC-deficient recipients. Results: Ex vivo, we show that MCs survive and are functional after lethal radiation, such as that used in conditioning prior to HCT. In a murine model of cGVHD WT mice had significantly more cGVHD symptoms than MC-deficient mice as measured by clinical scoring. This scoring correlated with a significant increase in skin pathology, collagen deposition, and expression of pro-fibrotic genes in WT as compared to B6.Cg-KitW-sh mice. Dermal MC numbers were increased in WT mice, but were nearly undetectable in B6.Cg-KitW-sh mice, implying that the MCs that are present were recipient-derived and had survived conditioning. Skin from WT but not B6.Cg-KitW-sh mice was enriched in cGVHD effector cells and in inflammatory cytokines and chemokines. Murine MCs, upon stimulation were sources of many of these factors, production of which was blocked when treated with ibrutinib and ruxolitinib, drugs used in cGVHD treatment. Conclusions: In summary, we show here a previously unknown role for MCs in the pathogenesis of dermal cGVHD, suggesting that MCs may be targetable to prevent and treat this devastating complication of allo HCT.
Smart start: Final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma.
Authors: Westin Jason , Nastoupil Loretta J. , Fayad Luis , Hagemeister Fredrick B. , Oki Yasuhiro , Turturro Francesco , Ahmed Sairah , Rodriguez Maria Alma , Lee Hun Ju , Steiner Raphael , Nair Ranjit , Parmar Simrit , Young Ken H , McDonnell Timothy , Chuang Hubert , Green Michael Richard , Neelapu Sattva Swarup , Davis Richard Eric 
Published: March 2020

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.
Second cancer incidence in CLL patients receiving BTK inhibitors.
Authors: Bond David Alan , Huang Ying , Fisher James L , Ruppert Amy S. , Owen Dwight Hall , Bertino Erin Marie , Rogers Kerry Anne , Bhat Seema Ali , Jaglowski Samantha Mary , Grever Michael R. , Byrd John C. , Maddocks Kami J. , Woyach Jennifer Ann 
Published: March 2020

7511 Background: Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment (tx) of CLL and are associated with partial restoration of immune function with ongoing tx. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized. Methods: CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline (bl) and outcome data were collected including incidence (inc) of Richter’s transformation (RT), non-melanoma skin cancer (NMSC), and SPN. Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model. Results: 691 pts were included; median age was 64 years (y), median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At median f/u of 44 months, 68 pts (10%) were diagnosed (dx) with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6) cancers. CIR of SPN at 3 y was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p < .01) and low bl CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p < .01) were associated with higher inc of SPN. RT was dx in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 y overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%). Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi. [Table: see text]
Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial.
Authors: Flinn Ian , Montillo Marco , Illés Árpád , Etienne Gabriel , Delgado Julio , Kuss Bryone J. , Tam Constantine Si Lun , Offner Fritz , Bosch Francesc , Davids Matthew Steven , Jäger Ulrich , Ghia Paolo , Cymbalista Florence , Weaver David T. , Lustgarten Stephanie , Youssoufian Hagop , Stilgenbauer Stephan , Lamanna Nicole 
Published: March 2020

7523 Background: Duvelisib (DUV), a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment (tx) of R/R CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [ P < .0001]; ORR, 74% vs 45% [ P < .0001]) in pts with R/R CLL/SLL. Tx-emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. We examined dose-modification patterns and their impact on response to DUV in the DUO trial. Methods: Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by IRC. Results: Among 158 DUV-treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1-133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for > 1 wk (84% [42/50]) or > 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for > 1 wk (17.8 vs 16.3 mo) or > 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3-6 mo: 0-3 mo, 64% (101/158); > 3-6 mo, 63% (86/137); > 6-9 mo, 47% (54/114); > 9-12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%). Conclusions: DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1-2 weeks or more do not appear to significantly impact response to DUV or PFS. Clinical trial information: NCT02004522.