bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences among Asian/Asian American, and Caucasian breast and gynecologic cancer patient-reported survivorship needs, symptoms, and illness mindsets (N=220).
Authors: Schapira Lidia , Hofmeister Elisa , Kurian Allison W. , Zion Sean , Shen Hanyang , Torres Tara , Berek Jonathan S. , Palesh Oxana
Published: March 2020

11620

Background: Cancer experiences are mediated by host and disease factors and affected by social and cultural determinants of health. We sought to characterize perceived supportive care needs and domains of psychosocial functioning among a diverse group of women attending routine appointments for treatment or follow-up of breast and gynecologic cancers. Methods: From July 2018 until January 2019, all patients seen at the Stanford Women’s Cancers Program (serving women treated for breast and gynecologic cancers) were approached to participate. 220 cancer patients (78% breast and 22% gynecologic), mean age 54 (SD = 12) completed an online survey on their supportive care needs assessment (The Short-form Supportive Care Needs Survey Questionnaire) which contains physical, social, information, sexual and psychological scales, anxiety and depression (Patient Health Questionnaire-4) and mindsets about illness and the body mindset (Brief Illness Mindset Inventory). Only 14% of patients refused to take part in the survey. Results: T-test showed that Asian/Asian-American cancer patients (n = 57, 26%) reported fewer needs related to coping with physical symptoms, side effects of treatment and performing usual tasks and activities compared to Caucasian patients (n = 137, 62%), p = .038. Moreover, Asian/Asian-American cancer patients reported fewer depression symptoms (p = .049). Chi-square analyses showed that Asian/Asian-American patients reported less use of psychotherapy over their lifetimes (24.6% vs. 54.0%, p < .001), but significantly higher utilization of Chinese Medicine for cancer symptom management (24.6% vs. 5.8%; p < . 001) compared to the Caucasian patients. T-tests showed that Asian/Asian American patients reported significantly greater agreement with the mindsets that ‘cancer is a catastrophe’ (p = .006) and that their ‘body is an adversary’ (p = .047). Conclusions: In this population of breast and gynecologic patients and survivors we found differences in cancer mindsets, coping and use of mental health and complementary therapies between Asian and Asian-American and Caucasian women. Further analysis to understand the cultural differences are ongoing.
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.
Outcomes of stem cell transplant in patients with Richter transformation.
Authors: Wang Yucai , Tschautscher Marcella , Rabe Kari G. , Parikh Sameer Ashok , Call Timothy , Muchtar Eli , Kay Neil E. , Leis Jose Francisco , Koehler Amber , Johnston Patrick B. , Inwards David James , Porrata Luis F. , Hogan William J. , Kenderian Saad , Ding Wei
Published: March 2020

7526

Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.
Occurrence of other cancers in patients with chronic lymphocytic leukemia and mutations in protection of telomeres 1 (POT1) gene.
Authors: Molica Matteo , Dinardo Courtney Denton , Patel Keyur P. , Keating Michael J. , Wierda William G. , Thompson Philip A. , Jain Nitin , Takahashi Koichi , Kanagal-Shamanna Rashmi , Routbort Mark , Tang Guilin , Tang Zhenya , Ferrajoli Alessandra
Published: March 2020

7529

Background: Mutations in POT1 gene in CLL lead to uncapping of the telomeric ends, causing fusion events and chromosomal aberrations. POT1 is mutated in approximately 4% of pts with CLL. Recent studies reported germline variants in POT1 in pts with familial CLL and in familial melanoma, cardiac angiosarcoma and glioma. We evaluated pts characteristics and the presence of other cancers (OC) in pts with CLL with POT1 mutation seen at our institution. Methods: We performed next generation sequencing (NGS)-based analysis for the detection of mutations in 29 genes frequently mutated in pts with CLL using blood and/or bone marrow samples containing a minimum of 10% clonal B-cells from 1467 pts diagnosed with CLL. Clinical characteristics, prognostic factors (FISH and IGHV status), personal and familial history of OC were collected in pts with POT1 mutations. Results: Mutations in POT1 were found in 52 of the 1467 pts studied (3.5%). Pts with POT1 mutation were young (median age 59 years), commonly presented with early stage disease (Binet stage A 69% vs B/C 31%: p=0.0046 and Rai stage 0-I 65% vs II-IV 35%; p=0.043) and predominantly male (37 male vs 15 female). According to FISH, the more frequent abnormalities were del13q (33%), no abnormalities (25%) and del11q (21%). IGHV status was more commonly unmutated (69%). The most frequent DNA mutations associated with POT1 were NOTCH1 (44%), TP53 (27%) and SF3B1 (23%). Other cancers (excluding non-melanoma skin cancer) were reported in 19 of the 52 pts with POT1 mutation (37%). The most common types were prostate cancer (12%), malignant melanoma (10%) and kidney cancer (8%). Twelve (23%) pts were diagnosed with OC before and 7 pts (13%) after the diagnosis CLL (Table). Four (8%) pts had more than one other cancer diagnoses. Twenty-eight (54%) pts had one of more first degree relatives with history of cancer. Conclusions: POT1 mutations were observed in 3.5% of pts with CLL. These pts are young and often have unmutated IGHV. We observed a high occurrence of OC, particularly malignant melanoma and kidney cancer in these pts. Additional studies are ongoing to determine the proportion of pts with germline POT1 mutation, the distribution of variant allelic frequencies and additional chromosomal abnormalities in pts with OC. Other Cancers in 52 CLL pts with POT1. [Table: see text]
Circulating tumor DNA to predict response and resistance by anti-PD-1 therapy in Chinese relapsed/refractory classic Hodgkin lymphoma.
Authors: Su Hang , Song Yongping , Jiang Wenqi , Sun Xiuhua , Qian Wenbin , Zhang Wei , Gao Yuhuan , Jin Zhengmin , Zhou Jianfeng , Jin Chuan , Zou Liqun , Qiu Lugui , Li Wei , Yang Jianmin , Hou Ming , Xiong Yan , Zhou Hui , Du Xinhua , Wang Xiong , Shi Yuankai
Published: March 2020

7534

Background: A large fraction of patients with relapsed/refractory (r/r) Classic Hodgkin Lymphoma (cHL) enjoy a beneficial response induced by PD-1. However, no reliable predictive biomarkers for response or resistance are available. Sintilimab, an anti-PD1 agent, has recently demonstrated efficacy and safety in a multi-center, single-arm, phase II study of Chinese patients with r/r cHL (ORIENT-1). The predictive value of circulating tumor DNA (ctDNA) in longitudinal samples from patients in ORIENT-1 was investigated. Methods: A total of 192 plasma samples were collected from 75 patients prior to treatment and during therapy. After ctDNA extraction next-generation sequencing (NGS) was performed using the HiSeq Sequencing System to assess either a 619 or 659 gene panels at an average sequencing depth of 1260×. The panels include frequently mutated genes in cHL and other hematological malignancies. DNA from paired granulocytes was sequenced as presumptive germline control. Results: The genomic profiling of baseline ctDNA revealed a mean allele mutation frequency of 5.47%. Among the most frequently mutated genes in these cHL patients, PCLO and LRP1B are likely unique to Chinese r/r cHL patients. Truncating mutation of B2M, DNMT3, TNFRSF14 and KDM2B were found in patients with acquired resistance, of which TNFRSF14 and KDM2B have not been reported before and need to be confirmed in further study. The baseline ctDNA level was significantly different between objective response group (CR+PR, n = 41, median = 8.72) and non-responder group (SD+PD, n = 9, median = 2.9) ( p= 0.0070) Patients with ctDNA high achieved response earlier than others ( p< 0.05). A drop of 40% in ctDNA after three cycles of therapy confirmed as best cut-off to predict progression associated with clinical benefit, demonstrating 100% specificity. Patients with ctDNA drop ≥40% achieved response significantly earlier (median = 71 days) than others (median = 216 days, p= 0.0074). Conclusions: Our study demonstrated that ctDNA could serve as valuable biomarker for prediction of response or resistance to anti-PD1 immunotherapy.
Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).
Authors: Neelapu Sattva Swarup , Jacobson Caron A. , Oluwole Olalekan O. , Munoz Javier , Deol Abhinav , Miklos David Bernard , Bartlett Nancy L. , Braunschweig Ira , Jiang Yizhou , Kim Jenny J. , Zheng Lianqing , Rossi John M. , Locke Frederick Lundry
Published: March 2020

7555

Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.
Rituximab-based maintenance therapy in Waldenström macroglobulinemia: A case control study.
Authors: Zanwar Saurabh , Abeykoon Jithma P. , Gertz Morie A. , Kumar Shaji , Inwards David James , Porrata Luis F. , Thompson Carrie A. , Witzig Thomas E. , Habermann Thomas Matthew , Go Ronald S. , Lacy Martha , Rajkumar S. Vincent , Dispenzieri Angela , Buadi Francis , Gonsalves Wilson I. , Leung Nelson , Hayman Suzanne R. , Kyle Robert A. , Ansell Stephen M. , Kapoor Prashant
Published: March 2020

7559

Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 & 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]
Early imaging biomarker assessment to predict long-term responses for large B-cell lymphoma (LBCL) after CAR-T therapy.
Authors: Sirous Reza , Bukhari Ali Abbas , El Chaer Firas , Yared Jean , Hardy Nancy Maureen , Kocoglu Mehmet Hakan , Badros Ashraf Z. , Borogovac Azra , Hutnick Elizabeth , Gahres Natalie , Ruehle Kathleen , Rapoport Aaron , Saboury Babak , Dahiya Saurabh
Published: March 2020

7560

Background: Axicabtagene Ciloleucel (Axi-cel), an anti-CD19 CART cell therapy, achieved 58% complete response (CR) rate, in patients with relapsed refractory (r/r) LBCL on the ZUMA-1 study (Neelapu, NEJM 2017). Early response assessment (PET-CT) at day 30 is a common clinical practice. Patients with partial response (PR) at day 30 pose a therapeutic dilemma. ZUMA-1 analysis showed 1/3rd PR patients would convert to a CR. No biomarkers exist to predict eventual response. We report comprehensive PET-CT biomarker analysis on patients with PR at day 30 treated with Axi-cel for r/r LBCL. Methods: Ten patients with PR based on PET-CT imaging at day 30 were retrospectively assessed. Day 30 PET-CT was compared to baseline and a day 90 PET-CT. Global burden of disease of each patient at every time-point were quantified using Total Tumor Glycolysis (TTG) methodology as the imaging biomarker. Using adaptive-thresholding method, each lesion on FDG PET image was segmented and the following parameters were quantified: metabolic-volume (MV), SUVmax, SUVpeak, Partial-Volume-Corrected SUVmean and five other imaging biomarkers. To evaluate the effect of baseline and early imaging biomarkers to predict the subsequent burden of disease multiple regression analysis was performed (STATA 15). Results: Day 90 PET-CT assessment revealed, 4 patients had progressive disease (PD), 4 had CR, and 2 had PR. TTG of patients with PD at day 90 was 900 vs. 29 in patients with non-PD (CR, PR). The Global-SUVmean of the patients with PD at day 90 was 725 vs. 86 in patient with non-PD. Regression analysis showed early-TTG as a significant predictor of subsequent-TTG (beta-coefficient = 1.26 (0.39-2.13); P-value = 0.02; adjusted-R-squared = 0.97), while the baseline-TTG didn’t have any effect on subsequent-TTG (P-value = 0.3). Additionally, the regression analysis didn’t show any significant predictive value in SUVmean and SUVmax of baseline and day 30 scans to predict subsequent burden of disease (TTG or Global-SUVmean) with P-values > 0.8. Conclusions: Early post-axi-cel TTG, rather than baseline, can predict subsequent response to treatment. None of the SUV indices, commonly used in daily practice, were predictive of eventual response.
Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.
Authors: Topp Max S. , Duell Johannes , Zugmaier Gerhard , Attal Michel , Moreau Philippe , Langer Christian , Kroenke Jan , Facon Thierry , Salnikov Alexey , Lesley Robin , Beutner Karl , Kalabus James , Rasmussen Erik , Riemann Kathrin , Minella Alex C. , Munzert Gerd Michael , Einsele Hermann
Published: March 2020

8007

Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.
Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma.
Authors: Zhou Ping , Kugelmass Adin , Toskic Denis , Godara Amandeep , Fogaren Teresa , Varga Cindy , Comenzo Ray
Published: March 2020

8010

Background: In systemic AL amyloidosis (AL), caused by clonal Ig free light chains (LC) produced in 75% of cases by λ clones, patients often present with advanced organ damage, making earlier diagnosis a critical unmet need. Five λ IGLV germline genes account for 75% of AL λ-type ( IGLV 6-57, 1-44, 2-14, 1-51, 3-1) (Blood 2017;129:299), representing 56% of all AL patients. Relative risk of AL versus MM with these clonal genes can be high (7.3, 6-57; 2.5, 1-44), intermediate (1.7, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). Progression to AL from smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) occurs but is not well appreciated (JCO 2014; 32:2679). SAVE is a trial for λ SMM or λ MGUS patients with a κ:λ FLC ratio < 0.26 and difference between involved and uninvolved FLC > 23mg/L (JCO 2014;32:2699). Methods: Eligible patients ship peripheral blood (PB) or bone marrow (BM) samples to us for RT-PCR with cDNA from CD138+ cells, using primers for the Vλ families (Blood 2001;98:714). Amplicons are sequenced and the IGLV germline genes identified in IMGT (ImMunoGene-Tics, www.imgt.org). If the germline gene is AL-related, further evaluation is pursued. Results: Twenty asymptomatic λ patients from 18 states have been enrolled (3M, 17F) and 23 PB and 4 BM specimens obtained. Medians of months from diagnosis, involved FLC, κ:λ ratios, MNC and CD138-selected cells were 20.5 months, 113mg/L, κ:λ 0.06, 8.1x106 (0.8-24) and 3x105 (0-30), respectively. Seventeen patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 BM. Increased risk of AL was identified in 7 patients, 2 of whom had undiagnosed AL (both with IGLV2-14 germline genes). One patient with SMM diagnosed in 2016 had AL λ-type with GI involvement and is 9 months status post MEL 200 stem cell transplant (SCT), and the second with SMM diagnosed in 2009 had cardiac AL λ-type by heart biopsy with an NT-proBNP 171 (but with a suggestive MRI) and is en route to SCT. Conclusions: The SAVE trial enables early diagnosis of AL λ-type based on the λ IGLV gene used by the clonal plasma cells. By RT-PCR in this pilot study we identified the clonal λ gene 85% of the time. Earlier diagnosis will enable treatment with effective therapy such as MEL 200 SCT. Clinical trial information: NCT02741999.