bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC or decitabine exerts anti-leukaemic activity in AML patients unfit for intensive chemotherapy: Phase II open-label study.
Authors: Loges Sonja , Heuser Michael , Chromik Jörg , Vigil Carlos Enrique , Paschka Peter , RE Francesca , Di Renzo Nicola , Lemoli Roberto , Mattei Daniele , Ben Batalla Isabel , Hellesøy Monica , Micklem David , Holt Robert J , Lorens Katherine , Lorens James B. , Shoaib Muhammad , Aly Hassan , Fiedler Walter M. , Cortes Jorge E. , Gjertsen Bjorn T.
Published: March 2020

7043

Background: The RTK AXL represents a therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti-tumour immunity. Bemcentinib is a first-in-class, highly selective, oral AXL inhibitor that has previously shown encouraging anti-leukaemic activity as a monotherapy in r/r AML and hr-MDS. Methods: A monotherapy dose-escalation and expansion part of this trial is complete. In this second, phase II part of the study, 11 and 15 AML pts unfit for intensive chemotherapy received bemcentinib at RP2D (200 mg po/d) in combination with low-dose cytarabine (LDAC) and decitabine, respectively. Median age was 77 yr (range: 50-83), median screen myeloblast count 39% (3-95%) and 2/19 (11%) of pts evaluable for FLT3 were FLT3+. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment. Results: The most common TRAEs (≥ 15% of pts) were ECG QT prolongation (35%) and diarrhoea (15%). Among these, 3 were Grade 3, and none 4 or 5. All TRAEs were manageable and/or reversible. As of Feb ‘19, 9 pts (2 de novo, 1 secondary, 6 r/r) in the bemcentinib + LDAC group were evaluable for response and 4 (44%; 2 de novo + 2 relapsed) achieved rapid CRi at C2D1. Responses were durable (range: 7 – 11 cycles) in 3 of the 4 responders. A further 2 pts (22%, 1 secondary + 1 relapsed) achieved durable SD (5 and 6 cycles). mPFS among the 5 pts with durable CRi or SD was 5 months (range: 3.5-7.7). Further, at the time of writing, 11 pts (8 de novo, 3 r/r) in the bemcentinib + decitabine group were evaluable for response of which 4 (36%, all de novo) achieved CRi after ≥ 4 cycles. One additional de novo pt achieved durable SD lasting for 5 cycles. Conclusions: Bemcentinib in combination with LDAC exerted early durable responses in patients with both de novo and relapsed AML whilst the combination of bemcentinib + decitabine exerted comparably fewer and later responses in de novo AML. Soluble biomarker correlations will be presented at the meeting. Both combinations were generally well-tolerated and further exploration is warranted. Clinical trial information: NCT02488408.
Late infectious complications in hematopoietic cell transplantation survivors.
Authors: Chow Eric Jessen , Cushing-Haugen Kara , Boeckh Michael , Carpenter Paul , Flowers Mary , Lee Stephanie , Leisenring Wendy M. , Mueller Beth , Hill Joshua A. , Foord Aimee
Published: March 2020

7046

Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p < 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p < 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p < 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.
Role of killer cell immunoglobulin-like receptor (KIR)-ligand interactions to prevent relapse in patients (pts) receiving matched unrelated stem cell transplant (SCT) for acute myeloid leukemia (AML).
Authors: Rafei Hind , Fernández-Viña Marcelo , Carmazzi Yudith , Moore Brandt , Willis Dana , Basar Rafet , Banerjee Pinaki Prosad , Daher May , Hosing Chitra , Kebriaei Partow , Khouri Issa F. , Mehta Rohtesh , Nieto Yago , Qazilbash Muzaffar H. , Shpall Elizabeth J. , Champlin Richard E. , Marin David , Rezvani Katayoun , Cao Kai
Published: March 2020

7049

Background: NK cells play a pivotal role in cancer immune vigilance. NK cell function is regulated by a balance between activating and inhibitory signals derived from various receptor-ligand interactions. Methods: 390 AML pts received 10/10 unrelated donor SCT. KIR genotype was performed by PCR with sequence specific primers. Hazard ratio (HR) for 2-year relapse was calculated using Fine-Gray regression and adjusted for disease risk index, remission status, pre-SCT MRD, conditioning regimen and presence of HLA-DP mismatch. KIR-ligand (K-L) match was defined as the presence a given KIR in the donor and the presence of its reported ligand in the patient (ex. 2DL1 and HLA-C2). KIRs that have no known ligands were not included in this analysis. The Table shows pt characteristics and K-L matches. Results: There was no correlation between the number of inhibitory or activating KIRs or KIR haplotype (A or B) and the probability of relapse after SCT. However, donor KIRs had a dramatic effect on relapse when they were considered together with the presence of the corresponding ligand in the pt. The 210 pts who had ≥3 inhibitory K-L matches had a significantly higher probability of relapse (HR=1.748, CI=1.147-2.667, p=0.009) than the remaining 180 pts. Similarly, the 96 pts who had at least one known activating K-L match had a lower probability of relapse (HR=0.581, CI=0.345-0.978, p=0.04). When we considered inhibitory and activating K-L matches together, we found that the 168 pts who had ≥3 inhibitory and no activating K-L matches had a significantly higher probability of relapse (HR 2.001, CI=1.376-2.908, p<0.001) than the 222 remaining pts. Conclusions: Donor-pt KIR-ligand matching should be taken into account when choosing unrelated donors for AML pts. [Table: see text]
Predictive accuracy of the low erythropoietin level for the diagnosis of polycythemia vera.
Authors: Lupak Oleksandra , Han Xiaoxia , Xie Peter , Mahmood Sharmeen , Mohammed Hadi , Donthireddy Vijayalakshmi
Published: March 2020

7060

Background: A low erythropoietin (EPO) level is a minor diagnostic criterion for Polycythemia Vera (PV) based on the updated 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms. The diagnostic value of EPO has been debated due to the increasing availability of advanced molecular testing. We hypothesized that EPO level below the normal range may not provide additional diagnostic information if JAK2 mutation status is positive. Methods: In this retrospective review we used Logistic regression to build a predictive model for the diagnosis of PV based on EPO value and JAK2V617F mutation status. 415 patient records were reviewed. 162 were used in the final statistical analysis. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the predictive accuracy. All statistical analysis was performed with R version 3.5.1. A p-value less than 0.05 was considered statistically significant. Results: EPO level below the normal range as a standalone diagnostic modality is significantly associated with PV (odds ratio (OR) 0.857; p-value < 0.001). When JAK2V617F mutation status is included in the prediction model, the association of the low erythropoietin level is not statistically significant (OR 0.962 and p-value 0.269). Positive JAK2V617F demonstrates a strong predictive value for PV (OR 670.5, p-value 0.006) either alone or in combination with other variables. Moreover, 34.2% of patients with the diagnosis of PV had EPO level within the normal range, which reflects it’s physiological variability. Conclusions: Results show that erythropoietin level below the normal range does not bring additional diagnostic value when JAK2V617F mutation status is positive. Additionally, erythropoietin level has a negative correlation with increased BMI and smoking status, making it not a reliable diagnostic marker.
Sintilimab for relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL): A multicenter, single-arm, phase 2 trial (ORIENT-4).
Authors: Tao Rong , Fan Lei , Song Yongping , Hu Yu , Zhang Wei , Wang Yafei , Xu Linxinyu , Zhou Hui , Li Jianyong
Published: March 2020

7504

Background: ENKTL account for more than 20% of the peripheral T-cell lymphoma in Asia. Patients with r/r ENKTL have a poor prognosis after failing an L-asparaginase based regimen, and the median overall survival is less than 6 months. The overexpression of PD-L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance, and recent studies of PD-1 antibodies in pts with r/r ENKTL have demonstrated potential efficacy. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has a safety profile consistent with other approved PD-1 antibodies and was approved for r/r classical Hodgkin lymphoma in China in 2018. This multicenter, single-arm, phase 2 study aims to validate the efficacy and safety of sintilimab monotherapy in patients with r/r ENKTL in China. Methods: Patients with pathologically confirmed r/r ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET-CT and CT/MRI with contrast. The primary endpoint was objective response rate based on LUGANO 2014 criteria. Data cut-off date for this analysis was Feb 2, 2019. Results: From Aug 31, 2017 to Feb 7, 2018, a total of 28 patients were enrolled: 60.7% male and the median age was 37 (range: 19–65) yr. Sixty-eight percent of patients were stage IV and 89.3% were ECOG PS ≥ 1. All patients had failed an L-asparaginase based regimen, the median lines of previous therapy were 3 (range: 1–13), 78.6% patients received prior radiotherapy and 7.1% had failed HSCT. Median duration of therapy was 14.04 (range: 1.4–17.3) months and 19 patients are still receiving sintilimab. Sixty-eight percent (19/28, 95%CI: 47.6%–84.1%) of patients achieved response (CR+PR), including 4 pts who experienced PD prior to having a response. DCR was 85.7%, including 5 pts who experienced PD before SD or response. The 1-year OS rate was 82.1% and the median OS has not been reached. Most TRAEs were G1–2 (67.9%) and no patients discontinued treatment due to AEs. The most common TRAE was decreased lymphocyte count (46.4%) and 84.6% were grade 1–2. SAEs occurred in 21.4% of patients and none were related to sintilimab. No patients died from AEs. Conclusions: Sintilimab is effective and well tolerated in r/r ENKTL and could be a promising treatment option for these patients. Early disease progression observed by PET scan in this study could be pseudoprogression as it did not correlate with poor outcome, which warrants further investigation. Clinical trial information: NCT03228836.
Serum B-cell maturation antigen as a prognostic marker for untreated chronic lymphocytic leukemia.
Authors: Soof Camilia M , Parikh Sameer Ashok , Slager Susan L. , Rabe Kari G. , Ghermezi Matthew , Spektor Tanya M. , Kay Neil E. , Berenson James R.
Published: March 2020

7525

Background: New prognostic markers in chronic lymphocytic leukemia (CLL) are in demand. Different groups have developed models which combine multiple prognostic markers into a single index to classify CLL patients (pts). The CLL-International Prognostic Index (CLL-IPI) combines five parameters: age, clinical stage, TP53 status, IGHV mutational status, and serum β2 microglobulin levels. B-cell maturation antigen (BCMA) is a cell membrane receptor expressed exclusively on late stage B-cells and plasma cells with elevated serum (s) levels found in B-cell malignancies, such as multiple myeloma (MM). In MM, sBCMA levels can be used to monitor disease status and predict overall survival (OS). To further evaluate this biomarker in other hematologic malignancies, we studied it in CLL. Methods: Untreated (UNTX) CLL pts seen and consented at Mayo Clinic were identified. sBCMA levels were measured on stored sera of 331 UNTX CLL pts using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&D Systems (Minneapolis, MN). The Mann-Whitney analysis was used to assess differences between CLL pts and healthy controls. The relationships between sBCMA and both time to first treatment (TFT) and OS were also assessed using Cox Regression models with an optimal sBCMA cutoff of 40.9 ng/mL. Results: The median age of pts was 61 years, and 71% were male. The distribution of CLL-IPI risk groups was as follows: 135 (41%) Low; 114 (34%) Intermediate; 67 (20%) High; 15 (5%) Very High. The median level of sBCMA in CLL pts (48.6 ng/mL) was higher (P <0.0001) than those of healthy controls (n = 104; 36.03 ng/mL). In CLL pts, sBCMA is significant in univariable analyses of TFT (HR 2.9 (95%CI, 2.0-4.2); P < 0.0001) and OS (HR 2.5 (95%CI, 1.5-4.0); P < 0.0003), and remains significant when adjusting for sex and CLL-IPI factors (HR 2.3 (95%CI, 1.6-3.3), P < 0.0001; HR 1.9 (95%CI 1.1-3.1), P = 0.01, respectively). Conclusions: sBCMA is elevated in CLL pts compared to healthy controls. After adjusting for CLL-IPI and sex, sBCMA levels provided independent prognostic value in predicting TFT and OS in this cohort. Measuring sBCMA with a readily accessible ELISA-based test, provides incremental value over the current CLL-IPI model in predicting prognosis of CLL.
Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Rogers Kerry Anne , Thompson Philip A. , Allan John Nathan , Coleman Morton , Sharman Jeff Porter , Cheson Bruce D. , Izumi Raquel , Frigault Melanie M. , Quah Cheng Seok , Raman Rakesh K. , Wang Min Hui , Kipps Thomas J.
Published: March 2020

7530

Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range <1-55); common AEs that led to IBR discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%) and rash (12%). At a median follow-up of 19 mo (range 1-31), 67% of pts remain on acalabrutinib; discontinuations were mostly due to PD (13%) and AEs (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common AEs (any grade) were diarrhea (48%), headache (40%), contusion (35%) and dizziness (32%). Serious AEs (≥2 pts) were pneumonia (10%), anemia (3%) and syncope (3%). Atrial fibrillation occurred in 3 pts (5%; all Gr 1/2) and major hemorrhage in 2 (3%; Gr 3 hematuria and Gr 2 subdural hematoma). Gr 5 AEs were pneumonia (n=2), bronchopulmonary aspergillosis (n=1) and ventricular fibrillation (n=1), all considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in IBR-intolerant pts, providing a viable strategy for continuing BTK inhibitor therapy. Clinical trial information: NCT02717611. [Table: see text]
Assessing the potential of immunotherapy in treating chronic lymphocytic leukemia through meta-analysis.
Authors: Aljabban Jihad , Allen David , McDermott Sean , Wanner Ross , Salhi Hussam , Syed Saad A , Chen David , Hadley Dexter , Khoulani Dania
Published: March 2020

7531

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and has a heterogenous presentation. CLL is known to shape the immune response to survive. Studying these processes will help gauge the potential success of immunotherapy and point to therapeutic targets. Methods: We used our Search, Tag, Analyze, Resource platform to meta-analyze patient samples from Gene Expression Omnibus. We tagged peripheral B cells from 741 CLL patients and peripheral B cell samples from 150 healthy donors as a control. We also tagged and compared B cell samples from 84 CLL progressors to 91 patients with stable CLL. Lastly, we tagged peripheral T cells from 70 CLL patients and T cells from 35 healthy donors as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Analysis of CLL cell samples identified T cell exhaustion signaling as our top canonical pathway. IL2, IL5, and TGFB1 were top upstream regulators. We found upregulation of PDL1, CTLA4, and Lag3, known markers for immunosuppressive B cells. FMOD, which sequesters TGFB, was also upregulated along with molecules that modulate BCR signaling such as MIR155HG. EBF1, required for B cell differentiation, and the co-stimulatory molecule CD80 were downregulated. Analysis of progressing CLL versus stable CLL highlighted metabolic changes. S-adenosyl-L-methionine biosynthesis, methionine degradation to homocysteine, cysteine biosynthesis, and acetate conversion to acetyl-CoA were top canonical pathways. No difference was seen in PDL1, CTLA4, and Lag3 expression but EBF1 was upregulated. Lastly, our T cell analysis demonstrated NFAT in regulation of the immune response as the top canonical pathway. Conclusions: Our results reinforce the promise immunotherapy can have in treatment of CLL and suggests more aggressive cases of CLL are a function of metabolic changes as opposed to differences in immune escape. We also suggest a role of NFAT in T cell exhaustion in the context of CLL.
PET/CT alone versus PET/CT and MRI-guided therapy in patients with upper aerodigestive tract natural killer/T-cell lymphoma, nasal type: A prospective study.
Authors: Lin Tongyu , Ren Quanguang , Huang He , Li Xue Ying , Hong Huangming , Wang Zhao , Fang Xiaojie , Guo Cheng-cheng , Li Fangfang , Zhang Limei , Huang Ying , Li Zhi-Ming , Cai Qingqing , Tian Ying , Wang Hanyu , Lin Xiaoping , Fan Wei , Zheng Lie , Lin Suxia , Liu Qing
Published: March 2020

7537

Background: Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL). Methods: We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthracycline-based chemotherapy with intensity-modulated radiation therapy (IMRT). Results: We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions ( P=0.011 and P=0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and 64.3% in the PET/CT group ( P<0.001). Similarly, the 5-year OS and PFS were longer in the PET/CT-MRI group than in the PET/CT group (84.5% vs. 67.8% and 78.3% vs. 65.6%; P=0.04 and P=0.03, respectively). Conclusions: HN-MRI and PET/CT-guided therapy could assist in decreasing local recurrence, which improved prognosis in UADT-ENKTL patients. Therefore, HN-MRI and PET/CT should be incorporated into routine pretreatment imaging examinations in patients with UADT-ENKTL. Clinical trial information: NCT01788137.
Ibrutinib maintenance following induction for untreated mantle cell lymphoma (MCL): Initial safety report.
Authors: Karmali Reem , Abramson Jeremy S. , Stephens Deborah Marie , Barnes Jeffrey A. , Kaplan Jason B. , Winter Jane N. , Ma Shuo , Petrich Adam Matthew , Hochberg Ephraim P. , Takvorian Tak , Nelson Valerie , Gordon Leo I. , Pro Barbara
Published: March 2020

7542

Background: Maintenance rituximab in MCL has improved survival, though the optimal approach is not yet defined. Ibrutinib, a selective BTK inhibitor, has profound activity in R/R MCL. Ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction. Methods: Patients with MCL with CR/PR to frontline chemo-immunotherapy (+/- autoSCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3 year PFS rate. Secondary objectives were PR to CR conversions, median OS at 4 years and toxicity with MRD assessments planned. Results: Accrual is complete with 36 patients, median age of 60 (range 46-90), 28 males, 28 with advanced stage and 9 with extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. 8/24 patients had a Ki-67 > / = 30%. For induction, 17 (47%) received BR, 18 (50%) a cytarabine-based regimen, 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. At median follow-up of 19 mos, 24/36 (67%) patients remain on I-M (median 15 cycles, range 1-49) with 1 PD and 1 death. TRAEs led to dose reductions/interruptions in 25 (69%) patients, including permanent dose reductions in 7 (19%) and treatment discontinuation in 9 (25%; Table). 3 additional patients discontinued I-M, 1 for endometrial adenocarcinoma, 1 PD, 1 death, cause unknown. Conclusions: Ibrutinib maintenance is feasible in MCL patients who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with prior reports of ibrutinib. Additional follow-up and MRD status correlations with PFS and OS will provide insight on clinical relevance for this approach. Clinical trial information: NCT02242097. [Table: see text]
Changes in circulating tumor DNA levels are associated with treatment response and progression-free survival in relapse/refractory DLBCL subjects.
Authors: Lovejoy Alexander F. , Lin Hai , Tabari Ehsan , Saelee Seng Lor , Kurtz David Matthew , Vitazka Patrik , Morschhauser Franck , Chu Yu-Waye , Szafer-Glusman Edith , Venstrom Jeffrey Michael , Luong Khai , Klass Daniel M.
Published: March 2020

7546

Background: Detection of an initial molecular response to therapy in DLBCL could help differentiate patients who will relapse (30-40% of frontline subjects) from those who will not. Recent studies in DLBCL showed ability to detect residual disease and molecular response to therapy from analysis of circulating tumor DNA (ctDNA). Here we performed targeted next generation sequencing (NGS) of baseline ctDNA vs. tumor tissue, and on-treatment ctDNA samples in 32 relapse/refractory DLBCL subjects from the ROMULUS study to assess correlation of outcome with molecular response. Methods: We sequenced plasma, plasma depleted whole blood (PDWB), and tumor DNA from 32 subjects (range 2-6 samples / subject). Library preparation and NGS were performed using hybrid capture-based workflows, with a panel of ~300 kb targeting regions relevant for disease detection in DLBCL. Variants were called from tissue and plasma data, and PDWB data were used to filter out non-tumor specific variants. Results: 83% of variants detected in tissue (1441/1745) were found in the corresponding plasma samples, and 78% of variants detected in plasma (1441/1846) were found in corresponding tissue samples, in line with previous reports. To follow ctDNA changes with treatment, tumor-specific variants were determined from tissue or cycle 1 day 1 (C1D1) plasma samples. These variants were then monitored in C1D1 and later timepoints, with similar ctDNA levels based on variants determined from C1D1 plasma or tissue (R2=0.99). Change in ctDNA levels from C1D1 to C2D1 separated subjects that responded from subjects that progressed (Wilcoxon p-value: 9.39×10-4). Subjects that showed a 10-fold or higher drop in ctDNA levels between C1D1 and C2D1 had significantly longer PFS than those with a smaller ctDNA fold change (HR: 8.06; p=0.0008). Conclusions: This study showed that tumor-specific variants can be identified in baseline plasma with similar performance as from tumor tissue, and that monitoring molecular response as an early change in ctDNA levels after one cycle of treatment correlated with outcomes in this DLBCL study. Clinical trial information: NCT01691898.
Allogeneic stem cell transplantation (AlloSCT) for patients (pts) with lymphoma and chronic lymphocytic leukemia (CLL) following targeted small molecules inhibitors (SMIs).
Authors: Mukherjee Akash , Milton Denai R. , Jabbour Elias , Gulbis Alison , Kadia Tapan M. , Thompson Philip A. , Keating Michael J. , Jain Nitin , Ledesma Celina , Fayad Luis , Nastoupil Loretta J. , Burger Jan Andreas , Ferrajoli Alessandra , Estrov Zeev , Kantarjian Hagop M. , Champlin Richard E. , Khouri Issa F.
Published: March 2020

7550

Background: SMIs have improved outcomes in lymphoma/CLL. There is paucity of information about the safety and efficacy of alloSCT following SMIs. Methods: Data from 49 pts who received alloSCT between 2013-2018 at MDA and who have been previously treated with SMIs were retrospectively analyzed. Results: Histologies included CLL (n=31, 63%), mantle cell lymphoma (MCL) (n= 13, 27%), and follicular lymphoma (n= 5, 10%). Prior SMIs included ibrutinib [(n=46; 94%); 57% as ≥ 3rd line of therapy], venetoclax [(n=19, 39%); 68% as ≥ 3rd line of therapy], idelalisib (n=6, 12%). Ibrutinib was discontinued prior alloSCT in 31(67%) pts. due to refractoriness (n=25), or intolerance (n=6). Seven of 19 (37%) pts had venetoclax discontinued to due refractoriness (n=6) or intolerance (n=1). Risk factors for CLL pts at alloSCT included a prior Richter’s (n=14, 45%), unmutated IGHV (15/23, 65%), presence of del17p (n=23; 74%), and complex cytogenetics (n=15; 48%). In addition, 18/20 (90%) CLL pts had abnormal mutations: most frequent were TP53 (n=14; 78%), BTK (n=6; 33%), SF3B1 (n=4; 22%) and 8/18 (44%) pts had > 2 mutations. Risk factors for MCL pts included: Ki67≥ 30 % (n=10/12, 83%), blastoid histology (n=6, 46%). Median age was 51 years, and 9 (18%) pts had a HCT-CI >4. Median prior lines of therapies was 4. Median duration of SMI therapy was 4.6 months. At transplant 40 (82%) pts had sensitive and 9 (18%) had refractory disease. Conditioning was nonmyeloablative (BFR or FCR) in 62%, RIC in 20% and myeloablative in 18%. Most pts (61%) received matched unrelated or matched sibling donors (22%); 8 (16%) had an alternative donor. The median follow-up for survivors was 12.4 months (range, 1-41.6). OS and PFS at 1 year were 77% and 68%, respectively. The CI of acute grade 2-4 and 3-4 GVHD were 33% and 7%, respectively. CI of 1-year chronic GVHD was 19%. Disease refractoriness and acute 3-4 GVHD were predicators for inferior OS and PFS by MV analysis. Similar survival results were observed in pts with or without mutations. Fourteen pts died due to progression (n=9), infection (n=2), acute (n=2) or chronic GVHD (n=1). Conclusions: AlloSCT is an effective therapy in pts with lymphoma/CLL pretreated with SMI. Our results suggest that alloSCT can overcome high-risk mutations associated with exposure to SMIs. Prospective confirmation in a larger # of pts is needed.
Monitoring ctDNA in r/r DLBCL patients following the CAR T-cell therapy axicabtagene ciloleucel: Day 28 landmark analysis.
Authors: Frank Matthew Joshua , Hossain Nasheed M. , Bukhari Ali Abbas , Dean Erin , Spiegel Jay Y. , Claire Gursharan K. , Kirsch Ilan , Jacob Allison , Mullins Chelsea D. , Lee Lik Wee , Kong Katherine A. , Craig Juliana K. , Mackall Crystal , Rapoport Aaron , Dahiya Saurabh , Locke Frederick Lundry , Miklos David Bernard
Published: March 2020

7552

Background: Axicabtagene Ciloleucel (Axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long‐term analysis of the Zuma‐1 clinical trial showed ~40% of patients remained progression-free at 2 years (Locke, Lancet Oncology 2018). Early identification of patients who will later progress after CAR T cell therapy may improve clinical care and patient outcomes. Methods: As of 2/1/2019, we enrolled 50 patients on a multi-institutional, prospective study measuring circulating tumor DNA(ctDNA) minimal residual disease (MRD) in r/r DLBCL patients undergoing treatment with Axi-cel. Using an next generation sequencing-MRD assay (Adaptive Biotechnologies; Seattle WA), ctDNA levels were measured pre, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. A pre-planned comparison between EDTA, Streck, and CFD tubes for the initial 10 enrolled patients determined the CFD tube provided optimal analyte stability over 144 hours following sample collection. CFD tubes are being used to collect all study samples. Results: 24 subjects have 3 or more months clinical follow up and their treatment ctDNA MRD significantly associated with clinical outcomes. A day 28 landmark analysis shows 12 patients were MRD negative and 12 patients were MRD positive as defined by detection of none or any tumor-associated ctDNA, respectively. 10 of 12 MRD+ patients subsequently developed progressive disease. In contrast, only 2 MRD- patients subsequently progressed and the 10 other patients remain in a CR. (p = 0.0033, Fisher's exact test). With a median follow up of 237 days, median PFS after Axi-cel infusion for day 28 MRD+ vs. MRD- patients is 93 days vs. not reach, p = 0.0010 by Log-rank test. Median OS for day 28 MRD+ vs. MRD- patients is 281 days after Axi-cel infusion vs. not reach, p = 0.0399 by Log-rank test. Conclusions: After Axi-cel infusion, day 28 ctDNA-based MRD significantly associates with PFS and OS and identified early at-risk patients prior to progression. These results provide a rationale for designing MRD-based risk-adaptive CAR T-cell clinical trials.
Long-term follow-up of patients (pts) with relapsed or refractory (r/r) follicular lymphoma (FL) treated with copanlisib.
Authors: Leppä Sirpa , Santoro Armando , Demeter Judit , Follows George , Lenz Georg , Kim Won Seog , Mollica Luigina , Nagler Arnon , Diong Colin Phipps , Provencio Mariano , Stevens Don A. , Trevarthen David R. , Wang MingLu , Wirtz Oliver , Miriyala Ashok , Garcia Vargas Jose , Childs Barrett H. , Zinzani Pier Luigi , Dreyling Martin H.
Published: March 2020

7553

Background: The pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib was approved by the FDA in September 2017 for treatment of relapsed FL based on results from the CHRONOS-1 study in pts with indolent non-Hodgkin lymphoma. We report efficacy and safety results of a 2-year (yr) follow-up of FL pts. Methods: Pts with indolent FL (grade [G] 1-3a) r/r to ≥2 prior lines of treatment received copanlisib (60 mg i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Adverse events were reported using MedDRA (v20.1). Data cut-off: February 20, 2018. Results: 104 FL pts were enrolled. Median age was 62 yr (39% >65 yr), the median number of prior lines of anti-cancer therapy was 3 (range 2-8), and 27 pts (26%) were classified as having G3a disease. The ORR was 59%, with complete responses (CR) in 20% ( n=21); 14 pts had a CR at the primary analysis in June 2016. The median duration of response (mDoR) was 12.2 months (mo) (range 0.03-43 mo). Stable disease (SD) was observed in 33% of pts; median duration of SD was 7.8 mo (range 1.3-23 mo). Median progression-free survival (mPFS) was 11.2 mo (range 0.03-44 mo) with 33% alive and progression-free at 2 yrs. Median overall survival (mOS) was 3.2 yr (range 0.06-4.2 yr) with 67% alive at 2 yrs. Median duration of treatment was 26 weeks (wk) (range 1-192 wk); median duration of safety follow-up was 29 wk. In the G3a subset, the ORR was 67% (26% CR), mDoR was 10.9 mo, mPFS was 12.5 mo, and mOS was 2.5 yr. The most common treatment-emergent adverse events occurring in >25% of pts included (all grade/G3+): diarrhea (37%/9%), neutropenia (26%/23%), and pyrexia (28%/5%). Hyperglycemia (49%/40%) and hypertension (29%/23%) were transient. Incidences of pneumonitis (6.7%/1.9%) and colitis (1.0% G4) were low. Conclusions: Long-term follow-up of r/r FL pts treated with copanlisib revealed robust and durable responses with CRs exceeding 20%, including in pts with higher grade disease. The safety profile continues to be both manageable and favorable, with no evidence of late-onset severe toxicities. Clinical trial information: NCT01660451.
Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.
Authors: Mateos Maria-Victoria , Nahi Hareth , Legiec Wojciech , Grosicki Sebastian , Vorobyev Vladimir , Spicka Ivan , Hungria Vania TM , Korenkova Sibirina , Bahlis Nizar J. , Flogegard Max , Blade Joan , Moreau Philippe , Kaiser Martin , Iida Shinsuke , Laubach Jacob , Ahmadi Tahamtan , Parasrampuria Dolly A. , Peng Lixian , Qi Ming , Usmani Saad Zafar
Published: March 2020

8005

Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P<0.0001). Median duration of injection was 5 mins for DARA SC and median duration of infusion was 421/255/205 mins for the first/second/subsequent DARA IV infusions. Median PFS was 5.6 mos DARA SC vs 6.1 mos DARA IV (HR, 0.99; 95% CI, 0.78-1.26). Most common TEAEs (≥15%) were anemia, neutropenia, thrombocytopenia, and diarrhea. Primary reasons for treatment discontinuation included progressive disease (43% SC vs 44% IV) and AEs (7% SC vs 8% IV). Conclusions: Efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to IV. DARA SC significantly decreased IRR rate and administration time, with a comparable safety profile to DARA IV. Clinical trial information: NCT03277105.
Combined use of two monoclonal antibodies in patients with systemic AL amyloidosis and cardiac involvement.
Authors: Godara Amandeep , Siddiqui Nauman Saleem , Lee Lisa , Toskic Denis , Fogaren Teresa , Varga Cindy , Comenzo Ray
Published: March 2020

8009

Background: Systemic AL amyloidosis (AL) is a rare disease in which circulating immunoglobulin light chains misfold, are directly toxic to key organs and also cause organ failure by mass effect. Patients with cardiac involvement have a poor prognosis; 25% of them die within 6 months of diagnosis. Depth of hematologic and organ response has prognostic significance and as new therapies become available, combining targeted therapies might hold the key to improve survival and deepen responses. Methods: We report the outcomes of 9 patients with AL amyloidosis who simultaneously received dual monoclonal antibody therapy with daratumumab and the investigational anti-fibril antibody NEOD001 at our institution. We also provide a descriptive comparison of 10 other AL amyloidosis patients who received treatment with daratumumab alone. Results: Of these 9 patients, there were 4 men/5 women with a median age of 68 years (range, 52-75) and a median of 261 days from diagnosis (range, 51-2037). Median NT-proBNP was 3807 pg/ml (range, 1326-13193). These 9 patients did not respond to initial therapy with a bortezomib-based regimen. Infusions of both monoclonals were separated by 2 days and were well tolerated without any unexpected toxicity. 88% of patients achieved ≥VGPR with daratumumab+NEOD001 in a median of 33 days and cardiac responses were achieved in < 90 days. In contrast, patients receiving daratumumab alone (n=10) achieved hematologic and cardiac responses at later times (Table). Conclusions: In conclusion, dual monoclonal antibodies targeting different epitopes can be safely combined in patients with systemic AL amyloidosis. Although this report features a small number of patients, high rates of hematologic and cardiac responses achieved suggest that this combination should be studied further, possibly in a prospective randomized trial. [Table: see text]
Overall survival (OS) with oral selinexor plus low dose dexamethasone (Sd) in patients with triple class refractory-multiple myeloma (TCR-MM).
Authors: Richardson Paul G. , Jagannath Sundar , Chari Ajai , Vogl Dan T. , Dimopoulos Meletios A. , Moreau Philippe , Dingli David , Wei L J , Li Lingling , Tang Shijie , Reichman William , Kauffman Michael G. , Shah Jatin J. , Shacham Sharon , Lonial Sagar
Published: March 2020

8014

Background: TCR-MM is defined as being refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs, representing an urgent unmet medical need with a median OS of 3-5 months( Pick M et al, Eur J Haem 2018; Gandhi U et al, ASH 2018). Sd has shown a 26.2% overall response rate (ORR) in 122 patients (pts) with TCR-MM in the Phase 2b STORM study ( Chari A et al, ASH 2018). Here, we evaluate the OS of pts in the STORM study with Sd and in pts with bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (“penta”)-exposed, TCR-MM from an observational cohort not receiving Sd. Methods: Data were drawn from STORM and a retrospective cohort from the nationally representative Flatiron Health Analytic Database (FHAD). All pts from both sources had penta-exposed TCR-MM. In order to align study populations, OS was evaluated in pts in STORM whose first therapy after their MM reached TCR status was Sd and in pts in the FHAD who received ≥1 therapy after their MM reached TCR status. The index date for this evaluation was the start date of treatment after their MM reached TCR status. A Cox proportional hazards regression model was performed to assess the survival impact of Sd. In STORM, ORR was assessed by an Independent Review Committee based on IMWG criteria. Results: In the FHAD, 69 pts with TCR-MM were identified. Characteristics of the two groups of pts were similar, except that pts in STORM were more heavily pretreated, had a higher frequency of high-risk MM, a longer time since initial diagnosis of MM, and higher baseline hemoglobin and platelet values. Among the 122 pts in STORM, 64 received Sd as their first therapy after their MM became TCR, and ORR was 32.8%. Among the 69 pts from FHAD, 37 received ≥1 therapy after their MM became TCR. Median OS (N = 64) was 10.4 months for pts receiving Sd in STORM and 5.2 months (N = 37) for pts not receiving Sd in FHAD (HR = 0.49, p = 0.0241). Conclusions: The prognosis of TCR-MM in the real-world population appears very poor. Within the limits of this analysis, median OS of pts receiving Sd as their first therapy after their MM becomes TCR is significantly better than those not receiving Sd, suggesting that Sd may be associated with an OS benefit in pts with TCR-MM. Clinical trial information: NCT02336815.
Faster and sustained improvement in health-related quality of life (HRQoL) for newly diagnosed multiple myeloma (NDMM) patients ineligible for transplant treated with daratumumab, lenalidomide, and dexamethasone (D-Rd) versus Rd alone: MAIA.
Authors: Perrot Aurore , Facon Thierry , Plesner Torben , Usmani Saad Zafar , Kumar Shaji , Bahlis Nizar J. , Ramasamy Karthik , Roussel Murielle , Araujo Carla , Jaccard Arnaud , Delforge Michel , McKay Caroline , Gries Katharine , Trudeau Jeremiah , Hulin Cyrille , Weisel Katja
Published: March 2020

8016

Background: MAIA, an ongoing phase 3 trial of transplant-ineligible patients (pts) with NDMM, demonstrated significant improvement in progression-free survival with D-Rd vs Rd alone. Assessment of pt-reported outcomes alongside efficacy endpoints provides pt perspective on their quality of survival and overall value of HRQoL while on treatments (tx). Methods: The EORTC QLQ-C30 and EQ-5D-5L questionnaires were completed by pts using an electronic device at baseline and every 3 mo during tx; interim results are presented for first 12 mo. Tx effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature. Results: Compliance rates were high and comparable at baseline ( > 90%) and through month 12 ( > 80%) for both groups (D-Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D-Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D-Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: -0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D-Rd was also observed in EQ-5D-5L Visual Analog Scale (VAS) scores (LS mean change; D-Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D-Rd. Of note, meaningful differences were observed between the tx groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D-Rd (LS mean change at cycle 3; D-Rd: -17.9 [95% CI: -20.7, -15.0], Rd: -11.0 [95% CI: -14.0, -8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D-Rd. There was a decline in cognitive functioning at cycle 12 in both tx arms, with no statistically significant differences between groups. Conclusions: Faster and sustained improvement in HRQoL was observed in pts treated with D-Rd vs Rd with similar findings reflected across pain subscale. Clinical trial information: NCT02252172.
Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM).
Authors: Dispenzieri Angela , Soof Camilia M , Rajkumar S. Vincent , Gertz Morie A. , Kumar Shaji , Bujarski Sean , Kyle Robert A. , Berenson James R.
Published: March 2020

8020

Background: BCMA (B-cell maturation antigen) is a TNF receptor family member found on normal and malignant B-cells, including multiple myeloma (MM). It plays a role in proliferation and antiapoptotic pathways. Levels of serum (s)BMCA are elevated in patients (pts) with plasma cell disorders (PCD) and increase with each stage of disease: healthy donor< MGUS<SMM< active untreated MM. The purpose of this study was to test whether sBCMA levels predict progression of MGUS or SMM to MM. Methods: There were 3 cohorts in this retrospective study: MGUS progressing to MM (n=42); MGUS not progressing to MM (n=49); SMM progressing to MM (n=32). sBCMA levels were measured using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&D Systems (Minneapolis, MN). The Kruskal-Wallis analysis was used to assess differences. The relationships between sBCMA and both time to progression and overall survival were also assessed using Cox proportional hazard models. Results: The highest values of sBCMA were seen among pts with more advanced PCD (Table). The lowest baseline levels were seen in pts with MGUS who did not progress; the change of sBCMA over time was lowest in the MGUS non-progressors. ROC analysis identified a cutoff of 74.4 ng/mL to be predictive of progression at 5 years. This cut-point was associated with a risk ratio of progression of 5.8 (95%CI 3.2, 11.3) for all comers, a risk ratio of death for all comers of 2.5 (95%CI 1.5, 4.2), and a risk ratio of death for MGUS pts of 3.3 (95%CI 1.9, 5.7). Conclusions: Serum BCMA levels were predictive of diagnosis, progression and death among pts with MGUS or SMM. Limitations of the current study are that only a minority of pts had baseline bone marrow exams or serum FLCs to place sBCMA risk in the context of other previously described risk factors. Serum FLC is now being determined on all patients. [Table: see text]