bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of response to venetoclax combination treatment in older patients with acute myeloid leukemia.
Authors: Jonas Brian Andrew , Dinardo Courtney Denton , Pratz Keith , Wei Andrew , Hong Wan-Jen , Chyla Brenda , Duan Yinghui , Potluri Jalaja , Werner Michael , Pollyea Daniel Aaron
Published: May 2020

7531

Background: Venetoclax (Ven) has synergistic activity with hypomethylating agents (eg, azacitidine [Aza] or decitabine [Dec]) or low-dose cytarabine (LDAC). These Ven-based combinations have demonstrated rapid median response times. This analysis describes the rapidity and likelihood of response to Ven treatments, and its associated characteristics, in older patients with newly diagnosed acute myeloid leukemia (AML). Methods: Included are data from two open-label trials of Ven, at label recommended doses, in combination with Aza, Dec (NCT02203773; phase 1b), or low-dose cytarabine (NCT02287233; phase 1/2) in newly diagnosed patients with AML. Patients were classified based on CR/CRi timing: within 2 cycles of therapy, after 2 cycles, or never achieving CR/CRi. Within each group, baseline and post-baseline characteristics were evaluated to determine impact on response timing. The percentage of patients in each category and duration of response (DOR) in each category were also evaluated. Results: Data cutoff was August 2018. Of 197 patients, 42% (n = 83) had CR/CRi in ≤2 cycles, 22% (n = 44) had CR/CRi in > 2 cycles, and 36% (n = 70) did not achieve CR/CRi. Median DOR was 21.2 mos. (95% CI 14.1-NR) for ≤2 cycle responders and 8.1 mos. (95% CI 5.3-14.9) for > 2 cycle responders. Baseline characteristics are shown in the Table. Patients with baseline IDH1/2 mutation were more likely to have CR/CRi in ≤2 cycles, while those with secondary AML and no response by the end of cycle 2 were more likely to never achieve CR/CRi. Of the patients who achieved CR/CRi after 2 cycles of therapy, 43% (19/44) achieved MLFS within the first two cycles. Of those who never achieved CR/CRi, 17% (12/70) of patients achieved MLFS within 2 cycles. In depth regression analyses of factors predictive of response, including analysis of biomarkers, will be available upon presentation. Conclusions: Over 1/3rd of patients that achieved CR/CRi on Ven combination therapy within these two studies required more than 2 cycles of treatment. Therefore, prior to discontinuing therapy for nonresponders, it is critical to assess key predictive patient characteristics. Clinical trial information: NCT02203773 and NCT02287233 . [Table: see text]
Outcomes in older patients with high-risk/secondary AML who achieved remission with CPX-351 versus 7+3 but did not undergo transplant: Phase 3 exploratory analysis.
Authors: Lin Tara L. , Ryan Robert J , Faderl Stefan , Ritchie Ellen K.
Published: May 2020

7537

Background: CPX-351 (Vyxeos; daunorubicin [D] and cytarabine [C] liposome for injection) is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study (NCT01696084) in patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML, CPX-351 demonstrated significantly longer overall survival (OS) and higher rates of remission and hematopoietic cell transplant (HCT) vs conventional 7+3, with a comparable safety profile. To better understand the impact of treatment on outcomes in pts who did not undergo HCT, this exploratory analysis evaluated outcomes in the subgroup who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 vs 7+3 but did not undergo HCT. Methods: Pts were randomized 1:1 to receive ≤2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1-3 [2nd induction: 5+2]). Pts achieving CR or CRi could receive up to 2 consolidation cycles. Pts could receive HCT at the physician’s discretion. Results: CR+CRi was achieved by 73/153 (48%) pts with CPX-351 vs 52/156 (33%) with 7+3; of these pts, 33/73 (45%) vs 28/52 (54%) did not subsequently undergo HCT. The baseline characteristics of these pts were generally balanced between arms; however, the CPX-351 arm had more male pts vs 7+3 (64% vs 43%) and pts with ECOG PS of 1 (82% vs 54%), and fewer pts with antecedent MDS and HMA exposure (21% vs 39%). Median OS was longer with CPX-351 vs 7+3 (14.72 vs 7.59 mo; HR = 0.57 [95% CI: 0.31-1.03]; Table). There was no early mortality by Day 60 in either arm (see Table for additional data). Conclusions: CPX-351 improved median OS vs 7+3 in pts who achieved CR+CRi but did not undergo HCT, suggesting a treatment benefit with CPX-351 even among pts who do not undergo HCT. The CPX-351 safety profile in this subgroup was consistent with the overall study population and known profile of 7+3. Clinical trial information: NCT01696084 . [Table: see text]
Etanercept with extracorporeal photopheresis (ECP) for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.
Authors: Singh Sunny R K , Malapati Sindhu Janarthanam , Neme Klodiana , Michael Angela , Mikulandric Nancy , Vulaj Vera , Emole Josephine
Published: May 2020

7543

Background: Acute graft versus host disease (aGVHD) is a well-described complication of allogeneic stem cell transplantation (allo-SCT). Complete response to steroids is achieved in 40-50% of cases, with steroid refractory GVHD requiring second line therapy. Currently, there is no accepted standard of care in this setting. In our study, we assessed the safety and efficacy of etanercept with ECP for steroid refractory aGVHD in a single center tertiary care hospital. Methods: Thirty adult patients who underwent peripheral blood allo-SCT and developed steroid-refractory aGVHD between January 2010 - July 2019 were retrospectively analyzed. Patients were planned to receive etanercept 25 mg subcutaneously twice weekly for at least 4 weeks. Safety was assessed by estimating infection related mortality. For efficacy, we analyzed the change in grade of aGVHD using the Wilcoxon signed-rank test. Results: Median age at the time of allo-SCT was 57.6 years and the most common indication for transplant was Myelodysplastic syndrome. Median time from allo-SCT to steroid initiation was 39.5 days (range 14-183 days). Median time from steroid initiation to etanercept was 6 days, with 7.5 median number of etanercept doses received. A total of 25 patients (83.3%) received ECP. As depicted in the table, there was a significant improvement in severity of aGVHD after etanercept therapy compared to that before its initiation. Overall response rate was 83.3%, while overall mortality was 86.7%. Median overall survival for responders was 306 days (range 59-2005 days) and for non-responders was 181 days (range 89-261 days). Death attributed to infection alone occurred in 28% (n=7), infection along with GVHD in 28% (n=7) and infection with relapsed disease in 1 patient. Active infection within 6 months of transplant occurred in 93.3% patients. Conclusions: The use of Etanercept with ECP resulted in improvement of steroid refractory aGVHD following allo-SCT, with responses noted in the majority of patients. High rates of infection related mortality were also noted and remain a cause of concern. [Table: see text]
Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study.
Authors: Brümmendorf Tim H. , Cortes Jorge E. , Goh Yeow Tee , Yilmaz Musa , Klisovic Rebecca B. , Purcell Simon , Viqueira Andrea , Leip Eric , Gambacorti-Passerini Carlo
Published: May 2020

7549

Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (<1–155) mo and dose intensity 438 (87–599) mg/d; responses were durable (Table) and overall survival (OS) at 9 y was 74% vs 84% at 5 y. OS at 8 y was 69% in CP3L, 54% in AP CML and 23% in BP CML pts vs 78%, 59% and 23% at 4 y. 55 CP2L, 29 CP3L and 98 ADV pts died on study (10, 3 and 2 since the 4/5-y reports); 15, 5 and 3 had on-treatment transformations to AP/BP. Most common new treatment-emergent adverse events since y 5 in CP2L pts were pleural effusion (n=13), arthralgia (n=12) and increased blood creatinine (n=11). Conclusions: After ≥8 y, BOS continued to show durable efficacy and no new safety signals in pts with CP CML on long-term treatment, providing further support for BOS use after prior TKIs. Clinical trial information: NCT00261846 and NCT01903733 . [Table: see text]
A multicenter phase II study of venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome.
Authors: Davids Matthew Steven , Rogers Kerry Anne , Tyekucheva Svitlana , Pazienza Samantha , Renner Sarah K , Montegaard Josie , Rocchio Michael , Ihuoma Udochukwu , Jacobson Caron A. , Fisher David Christopher , Brown Jennifer R. , Thompson Philip A.
Published: May 2020

8004

Background: While therapeutic options for CLL have improved, patients (pts) who develop Richter’s Syndrome (RS) still have a poor prognosis. Chemoimmunotherapy regimens such as R-EPOCH lead to CR in about 20% of RS pts, but PFS/OS is typically < 6 mo. The oral Bcl-2 inhibitor venetoclax (ven) had a 43% single agent response rate in RS. Here, we report the results of a phase 2 study of VR-EPOCH in RS. Methods: This is a single-arm, phase 2, IST of VR-EPOCH for RS (NCT03054896) at 3 US sites. CLL pts with biopsy-confirmed DLBCL were treated with R-EPOCH for 1 cycle, then after count recovery underwent accelerated inpatient ven daily ramp-up (20/50/100/200/400 mg), then ven + R-EPOCH for up to 5 more 21d cycles (ven 400 mg qd, d1-10 each cycle). Responders went to alloHCT or to continuous daily ven 400 mg maintenance. Response evaluation by Lugano criteria with PET/CT. Results: As of the data cut on 2/3/2020, the study is fully enrolled with 27 pts. Median age: 63 yrs (range 49-77). CLL features: 26% del(17p); 44% complex karyotype; 48% IGHV unmutated; 41% TP53 and 15% NOTCH1 mutation. Median prior CLL treatments: 2 (range 0-5, prior ibrutinib [n = 8], ven [n = 2], and PI3Ki [n = 2]) with 6 untreated CLL pts. Median # ven + R-EPOCH cycles: 4 (range 0-6). 5 pts had dose de-escalation of R-EPOCH, 1 pt had dose escalation. ≥Gr 3 heme tox: neutropenia (58%), anemia (50%), thrombocytopenia (50%). ≥Gr 3 non-heme tox in > 15% of pts: febrile neutropenia (38%) and hypophosphatemia (23% each). No pts had TLS with daily ven ramp-up. Infections: pneumonia (n = 4), sepsis during C1 of R-EPOCH prior to starting ven (n = 3), enterocolitis (n = 3), sinusitis (n = 2), and 1 pt each with influenza A and norovirus. 10 pts have died, including 7 due to disease progression (2 during C1 before ven), and 1 each due to sepsis, sudden death, and GVHD post-alloHCT. In ITT analysis, 16 responded (ORR 59%); 13/27 (48%) had CR as best response, all with undetectable bone marrow MRD for CLL. Six pts were not evaluable for efficacy of the combo (5 had toxicity in C1 and never started ven, 1 withdrew after C1). In the 21 pts who started combo therapy, the ORR was 76%, CR rate 62%. Only 1 pt with CR has progressed. The pt on longest ven maintenance is in CR 2 years post chemo. 8 pts went to alloHCT, with pts still in CR now up to 2.5 yrs post-alloHCT. With a median follow-up of 9.3 mo (range 0.6-30), median PFS and OS are both 16.3 mo. Conclusions: VR-EPOCH is active for RS. Expected toxicities from intensive chemoimmunotherapy and ven were seen, but daily ven ramp-up was feasible. The 48% CR rate and median PFS of 16.3 mo are favorable in the context of historical results. Clinical trial information: NCT03054896 .
Retreatment (reTx) of patients (pts) with refractory large B-cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1.
Authors: Locke Frederick Lundry , Bartlett Nancy L. , Jacobson Caron A. , Oluwole Olalekan O. , Munoz Javier , Lekakis Lazaros J. , Topp Max S. , Avivi Irit , Kim Jenny J. , Chu Rong , Zheng Lianqing , Rossi John M. , Bot Adrian , Neelapu Sattva Swarup
Published: May 2020

8012

Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved in the US and EU for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In the ZUMA-1 pivotal study (NCT02348216), the objective response rate (ORR) was 83% (58% complete response [CR] rate; Locke et al. Lancet Oncol. 2019). While axi-cel has demonstrated durable responses in a subset of pts, approximately half of all responders relapsed, and little is known on the viability of reTx with CAR T cell therapy. Here we report outcomes of pts retreated with axi-cel in ZUMA-1. Methods: Pts with progressive disease (PD) were eligible for reTx if there was no evidence of CD19 loss by local review, and if during 1st Tx they did not experience any dose-limiting toxicities, as defined in Phase 1, or comparable toxicities in Phase 2. Pts received the same regimen at reTx as at 1st Tx: 2 × 106 CAR T cells/kg after conditioning chemotherapy. Results: Thirteen pts in Cohorts 1 – 4 received axi-cel reTx. Prior to 1st Tx, most pts (69%) had an IPI score 3-4, 85% had disease stage 3-4, and the median number of prior regimens was 3 (range, 2 – 6). At first Tx, 6 pts achieved a CR, 6 achieved partial response (PR), and 1 pt had stable disease (SD) prior to PD. Median duration of first response was 96 days (range, 56 – 274). There was no Grade ≥ 3 cytokine release syndrome (CRS; 6 pts each had Grade 1 and 2). There were no Grade 4 or 5 neurologic events (NEs; 2 pts had Grade 1, 1 had Grade 2, and 7 had Grade 3). Upon reTx, 54% of pts achieved response (4 CR, 3 PR). Response to reTx was more common among pts who achieved CR at 1st Tx (83%; 4/6 CR, 1 PR, 1 SD) than in pts who achieved PR at 1st Tx (33%; 2/6 PR, 1 SD, 3 PD), and no response was observed in the pt with SD at 1st Tx. Median duration of response at reTx was 81 days (range, 1 – 225+). Response with reTx was longer than that with 1st Tx for 2 pts. One pt remains in response 255 days post-reTx. Comparable rates of CRS were observed with reTx as with 1st Tx. Compared with 1st Tx, fewer pts experienced NEs with reTx, and those that did occur were of lower grade: 23% (3 of 13 pts) had Grade 3; 23% (3 of 13 pts) had Grade 1, and 8% (1 of 13 pts) had Grade 2. Peak CAR T cell expansion was lower upon reTx vs 1st Tx (median, 4.3 vs 66.1 CAR gene-marked cells/µL blood). Conclusions: Based on this limited sample size, reTx with axi-cel may have clinical efficacy, although transient, in some pts, especially those who achieve CR with 1st Tx. CAR T cell expansion and severe CRS and NEs may be attenuated at reTx. Further studies with additional pts are needed to confirm these results. Clinical trial information: NCT02348216 .
Outcomes of GDPT (gemcitabine, cisplatin, prednisone,thalidomide) versus CHOP in newly diagnosed peripheral T-cell lymphoma patients.
Authors: Li Ling , Sun Yuanyuan , Li Xin , Zhang Lei , Wang Xinhua , Fu Xiaorui , Sun Zhenchang , Zhang Xudong , Li Zhaoming , Wu Jingjing , Yu Hui , Chang Yu , Yan Jiaqin , Wu Xiaolong , Zhou Zhiyuan , Nan Feifei , Lin Tongyu , Zhang Mingzhi , Li Tian
Published: May 2020

8018

Background: Peripheral T-cell lymphoma(PTCL) is highly heterogeneous invasive NHL.There is no consensus standard treatment for it now. So outcomes of GDPT versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in treating newly diagnosed PTCL were compared. Methods: An open-label prospective clinical trial with 153 newly diagnosed PTCL patients conducted between January 2010 and December 2018 was designed. Patients were randomly assigned to the GDPT group (77 cases) and CHOP group (76 cases). Patients in each group were further divided into four subgroups: PTCL-NOS, ALCL, AITL, and an other types, in accordance with pathological patterns. Based on expression of RRM1, TOP2A, TUBB3 and ERCC1, patients were divided into groups with high and low gene expression levels. Clinical characteristics, side effects, efficacy, PFS and OS were compared. Results: There were no significant differences in the basic clinical features or side effects between the GDPT and CHOP groups. The ORR of the GDPT group was better than that of the CHOP group (66.3%vs. 50.0%, P= 0.042), as was the CR rate (42.9% vs. 27.6%, P= 0.049). Patients in the GDPT group had a longer PFS and OS than the CHOP group. The 4-year PFS and OS rates in the GDPT group were both superior to those in the CHOP group (63.6% vs. 53.0% for PFS, P= 0.035; 66.8% vs. 53.6% for OS, P= 0.039).In the GDPT group, the difference in CR between the four subgroups was statistically significant (P = 0.046).In the CHOP group, differences in both CR and ORR among the four subgroups were statistically significant ( P= < 0.001 and P= 0.005, respectively).There were also statistically significant differences in CR between patients treated with CHOP and GDPT in the PTCL-NOS subgroup, AITL subgroup, and the other types subgroup( P= 0.015; P= 0.003; P= 0.005, respectively).The data also showed a significant difference in OS among the four subgroups within the GDPT group ( P= 0.001).The OS of AITL was shorter than that of the other three subgroups. Four subgroups of CHOP showed a significant difference in PFS ( P= 0.019). There was no statistical association between responses and the gene expression levels of RRM1, ERCC1, TUBB3 and TOP2A. Conclusions: The GDPT group had better response rates and prolonged the patients’ PFS and OS. As a promising new regimen, GDPT is expected to become the first-line therapy for PTCL. New agents should be applied to patients who do not achieve good responses with previous treatment, such as those diagnosed with angioimmunoblastic T cell lymphoma. Clinical trial information: NCT01664975 .
Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index (CLL-IPI).
Authors: Wang Yucai , Achenbach Sara J , Rabe Kari G. , Shanafelt Tait D. , Call Timothy , Ding Wei , Kenderian Saad , Muchtar Eli , Leis Jose Francisco , Koehler Amber , Schwager Susan M. , Cerhan James Robert , Slager Susan L. , Kay Neil E. , Parikh Sameer Ashok
Published: May 2020

8026

Background: CLL progression and CLL-related complications (infections and second malignancies) were the leading cause of death (COD) in a prospective cohort of CLL patients (Strati, BJH 2017). The CLL-IPI integrates major clinical and molecular prognostic factors and stratifies patients into 4 risk groups with distinct prognosis. It is unknown if COD differs according to CLL-IPI risk group in patients with newly diagnosed CLL. Methods: Patients diagnosed with CLL between 1/2000-12/2019 and seen within 1 year of diagnosis were identified from the Mayo Clinic CLL database. Cumulative incidences of cause-specific death were analyzed using Gray’s test, with deaths from different causes treated as competing events and deaths from unknown causes excluded. Results: 1276 patients were included in this study. The median age at diagnosis was 63 years (range 24-92), and 880 (69%) were male. Based on CLL-IPI score, 449 (35%) had low risk disease, 443 (35%) had intermediate risk disease, and 384 (30%) had high/very high risk disease. Median follow-up time for the study was 6 years; 286 deaths occurred. The COD was CLL progression in 99 (35%), infection in 16 (6%), second malignancy in 47 (16%), CLL-unrelated in 59 (21%), and unknown in 65 (23%) patients. The rates of death due to CLL progression were higher (17.3% at 5 years; 30.3% at 10 years) than the rates due to CLL-related complications (5.7% at 5 years; 12.9% at 10 years) or due to CLL-unrelated causes (8.6% at 5 years; 16.9% at 10 years) in the CLL-IPI high/very high risk group, but not the CLL-IPI low or intermediate risk group (Table). A higher CLL-IPI risk group was associated with a higher rate of death due to CLL progression ( P < 0.001), as well as a higher rate of death due to CLL-related complications ( P = 0.013), and CLL-unrelated causes ( P < 0.001). Conclusions: Causes of death in newly diagnosed CLL patients differ according to their CLL-IPI risk group. In patients with high/very high risk CLL, improving CLL disease control with novel agents seems justified. In patients with low/intermediate risk CLL, there should be increased efforts to reverse immune dysfunction to reduce infections and second malignancies. [Table: see text]
Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.
Authors: Cheng Phoebe Tsz Man , Villa Diego , Gerrie Alina S. , Freeman Ciara L , Slack Graham W , Scott David W. , Connors Joseph M. , Sehn Laurie Helen , Savage Kerry J.
Published: May 2020

8031

Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (>60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged >60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (<10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p<.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and >80 y (59%/27%/31%) (DSS p=.011; PFS p<.0001; OS p<.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]
Relevance of bone marrow biopsies for response assessment in NCTN follicular lymphoma clinical trials.
Authors: Rutherford Sarah C. , Yin Jun , Pederson Levi , LaPlant Betsy , Shadman Mazyar , Li Hongli , LeBlanc Michael Leo , Blum Kristie A. , Dockter Travis , Martin Peter , Jung Sin-Ho , Grant Barbara W. , Rosenbaum Cara Ann , Ujjani Chaitra Shankar , Barr Paul M. , Unger Joseph M. , Cheson Bruce D. , Bartlett Nancy L. , Friedberg Jonathan W. , Leonard John Paul
Published: May 2020

8038

Background: Bone marrow biopsies (BMB) are performed pre/post therapy to confirm complete response (CR) in patients (pts) with lymphoma on clinical trials. We evaluated 2 prior data sets and concluded that BMB impact response assessment in a minority of pts with follicular lymphoma (FL) (Rutherford BJH 2017; Rutherford ASH abstract 1605, 2018). We sought to establish if BMB add value in assessing response or identify distinct progression free (PFS) or overall survival (OS) outcomes in a large, multicenter, multi-trial cohort. Methods: Data were pooled from 7 trials of 580 pts with untreated FL conducted through the Alliance for Clinical Trials in Oncology and SWOG from 2002-2016. The proportion of pts with positive (+) baseline BMB, CR on imaging after treatment, and (+) repeat BMB was calculated using total pts enrolled as the denominator. We tested against the null hypothesis that the proportion was = 10%, the threshold below which BMB would be considered irrelevant for response assessment, versus (vs) the alternative hypothesis that this proportion was < 10%, using 1-sided exact binomial test. Response criteria were CT-based. Imaging was not used to assess BM involvement. Because confirmatory BMB were not completed in all indicated pts, landmark survival analyses compared PFS/OS of pts with CR on imaging and negative (-) BMB vs pts with CR on imaging without repeat BMB. Pts with CR on imaging were categorized as having (-) repeat BMB or no repeat BMB within 60 days of first CR on imaging. PFS and OS were calculated from time of first CR and estimated using Kaplan-Meier and Cox models adjusting for age, sex, stage, Follicular Lymphoma International Prognostic Index (FLIPI) score, and treatment type (targeted vs chemotherapy plus targeted therapy), and stratified by treatment arm. Results: Median age was 55 with 51% male, 96% stage III-IV, and 88% grade I-II. FLIPI scores were 113 low, 265 intermediate, and 199 high risk. 67% received chemotherapy-based regimens. Baseline BMB was (+) in 321 (55%). Only 5/580 (0.8%) had (+) baseline BMB, CR on imaging, and subsequent (+) BMB (p < 0.0001). Of pts with CR on imaging, PFS and OS were not different among pts with (-) BMB vs pts without repeat BMB (PFS: HR = 1.08, 95%CI 0.61-1.93, p = 0.783; OS: HR = 0.52, 95%CI 0.20-1.40, p = 0.199). Conclusions: BMB requirements may discourage pt participation in trials and add pain, expense and time without providing necessary information. We recommend eliminating BMB for response assessment from FL clinical trials. Clinical trial information: NCT00553501, NCT01145495, NCT01190449, NCT01286272, NCT01829568, NCT00822120, and NCT00770224 .
Efficacy and safety of ABP 798 compared with rituximab: Results from the comparative clinical study in patients with non-Hodgkin’s.
Authors: Niederwieser Dietger , Hamm Caroline M. , Cobb Patrick , Mo Mindy , Forsyth Cecily , Tucci Alessandra , Hanes Vladimir , Delwail Vincent , Hajek Roman , Chien David
Published: May 2020

8044

Background: ABP 798* is being developed as a biosimilar to rituximab, a CD20-directed cytolytic antibody. A randomized, double-blind, active-controlled study compared the efficacy, safety, and immunogenicity of ABP 798 with rituximab reference product (RP) in subjects with CD20-positive NHL; results of the final analysis are presented here. Methods: Adult subjects with grade 1, 2, or 3a follicular B-cell NHL and low tumor burden were randomized to receive intravenous ABP 798 or RP (375 mg/m2) once weekly for 4 weeks, then at weeks 12 and 20. The primary endpoint was risk difference (RD) of overall response rate (ORR) by week 28. Secondary endpoints included RD of ORR at week 12, pharmacokinetics, pharmacodynamics, safety, and immunogenicity. Results: 254/256 randomized subjects were treated with at least one infusion of ABP 798 (n = 128) or RP (n = 126); ORR by week 28, based on independent central blinded assessment of the modified full analysis set, was comparable between the ABP 798 and RP groups (78% vs. 70%, respectively). The 2-sided 90% confidence interval of RD of ORR (-1.4%; 16.8%) was within the pre-specified margin (-15%; 35.5%) thereby establishing clinical equivalence between ABP 798 and RP. This result was supported by analyses of the secondary efficacy endpoint of RD of ORR at week 12. In the two groups, the geometric least squares means for serum concentrations over time (e.g., week 12, pre-dose: ABP 798, 21.89 vs. RP, 20.57; week 12 post-dose: ABP 798, 201.30 vs. RP, 203.52) and the extent of B-cell depletion from day 1 to day 8 (ABP 798, 98.3% vs. RP, 98.3%) were similar. Frequency, type, and severity of adverse events (AEs) were comparable between ABP 798 and RP groups; grade ≥3 AEs were reported in 10.9% and 10.3% of subjects and serious AEs in 3.9% and 4.0%, respectively. Most common AEs were headache, fatigue, and nausea; the most common AE of interest was infusion reactions. No new or unexpected safety signals were observed. Binding and neutralizing anti-drug antibodies were comparable between groups. Conclusions: Results of this study demonstrated clinical similarity between ABP 798 and rituximab RP in subjects with CD20-positive NHL. *At the time of this submission, ABP 798 had not been approved by the FDA or any relevant regulatory agency and the indications are yet undetermined. Please consult ABP 798’s later approved label in the relevant country for information regarding the approved uses for ABP 798.
The Integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).
Authors: Marchi Enrica , Ma Helen , Montanari Francesca , Sawas Ahmed , Lue Jennifer K , Deng Changchun , Whitfield Kareema T , Klein Sandra , Scotto Luigi , Jain Salvia Sanjay , Lister John , Benanni Nora N , Francescone Mark A , Kim Wonseog S , Zinzani Pier Luigi , O'Connor Owen A.
Published: May 2020

8049

Background: Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL and induce the expression of cancer testis antigen, suggesting a role in the addition of the immune-checkpoint inhibitor, pembrolizumab. Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with relapsed and refractory PTCL and CTCL. A standard 3+3 dose-escalation is applied in the triplet Arm (Arm B) while in the doublet Arms (A and C) de-escalation is applied in case of toxicity. Pharmacokinetic and pharmacodynamic studies are ongoing. Results: We treated a total of 12 patients with 4 patients in each Arm. All patients that received at least one dose of drug were evaluable for toxicity. There was a dose limiting toxicity (DLT) in each arm including prolonged grade 3 thrombocytopenia (Arm A), febrile neutropenia (Arm B), grade 3 hyponatremia, and rash (Arm C). There were no treatment-related deaths. Six patients out of 12 were evaluable for response at the time of this analysis. One patient achieved a complete remission, 2 had partial remission, 1 had stable disease, and 2 experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, and pembrolizumab. Table summarizes the patient characteristics, toxicities, and response rates. Conclusions: These preliminary clinical data suggest that the integration of pembrolizumab on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. Clinical trial information: 03240211 . [Table: see text]
Three-year follow-up of treatment-naïve and previously treated patients with Waldenström macroglobulinemia (WM) receiving single-agent zanubrutinib.
Authors: Tam Constantine Si Lun , Opat Stephen , Marlton Paula , Gottlieb David , Simpson David , Cull Gavin , Ritchie David , Verner Emma , Munoz Javier , Tedeschi Alessandra , Huang Jane , Novotny William , Tan Ziwen , Holmgren Eric , Atwal Siminder K. , Seymour John Francis , Roberts Andrew Warwick , Trotman Judith
Published: May 2020

8051

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naïve (TN) and relapsed/refractory (R/R) patients with WM. Methods: Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Results: Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusions: Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients was tolerable. Clinical trial information: NCT02343120 . [Table: see text]
Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: Comparison between the standard and IMWG MRD criteria and QIP-MS including FLC (QIP-FLC-MS).
Authors: Puíg Noemí , Contreras Teresa , Paiva Bruno , Cedena M Teresa , Martinez-Lopez Joaquin , Oriol Albert , Gutiérrez Norma , Ríos-Tamayo Rafael , Rosiñol Laura , Calasanz María José , Bargay Joan , de La Rubia Javier , Palomera Luis , Miguel Teodoro Hernández-Garcia , Garcia-Sanz Ramón , Blade Joan , Lahuerta Juan José , San Miguel Jesus , Mateos Maria-Victoria
Published: May 2020

8512

Background: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of sustained minimal residual disease (MRD) negativity in the bone marrow (BM) by next generation flow (NGF). The value of BM MRD assessment in MM is proven, but alternative, non-invasive methods, accurately reflecting disease burden are needed. Methods: Pts received six 4-week cycles of KRd as induction (K:36mg/m2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d:dexamethasone 40mg po weekly) followed by melphalan 200mg/m2, two further cycles of KRd as consolidation and up to 2 years of Rd (R:10mg/d, d:20mg/week). Efficacy was analyzed in parallel in BM samples by NGF and in serum by SPEP/IFE and QIP-MS/QIP-FLC-MS in 52 out of the 90 pts enrolled in the trial. Standard and MRD responses were carried out as per the IMWG guidelines. For QIP-MS serum immunoglobulins were purified using polyclonal antibodies (anti-IgG, -IgA, -IgM, -total κ and -total λ light chain, -free κ and -free λ light chain). Mass spectra were generated on a MALDI-TOF-MS system. Results: Overall response rate (ORR) was 98% post-induction, 98% post-ASCT, and 100% post-consolidation; 38.4%, 61.5% and 68.6% of pts reached ≥ complete response at each time-point and, among them, 23%, 44% and 55% achieved flow MRD-negativity. Using the combination of QIP-MS/QIP-FLC-MS, the percentage of pts without detectable disease at each timepoint lowered to 12%, 27% and 38% reflecting the higher sensitivity of the method. Against NGF, QIP-MS/QIP-FLC-MS provided negative predictive values of 67%, 92% and 89% (p = 0,0206; p < 0,001; p = 0,003) and identified disease in 95%, 97% and 92% of pts that were positive by NGF-MRD at each respective timepoint. Three pts from this cohort have progressed so far: two were NGF+/MS+ at the three timepoints whilst 1 remained NGF- but QIP-MS/FLC-MS+ throughout. Conclusions: The GEM-CESAR treatment strategy induces a high ORR in HRsMM pts, and the % of cases achieving flow-MRD negativity post-ASCT meets the primary endpoint of the trial. The combined use of QIP-MS and FLC-MS offers higher sensitivity relative to standard methods and may provide relevant information about the right timing for performing a BM aspirate/biopsy. Clinical trial information: NCT02415413 .
Impact of lenalidomide-bortezomib-dexamethasone (RVd) induction on patients with newly diagnosed multiple myeloma and renal impairment: Results from the Connect MM Registry.
Authors: Ailawadhi Sikander , Lee Hans Chulhee , Omel Jim , Toomey Kathleen , Hardin James W. , Gasparetto Cristina , Jagannath Sundar , Rifkin Robert M. , Durie Brian G. , Narang Mohit , Terebelo Howard R. , Wagner Lynne I. , Dhalla Mazaher , He Mia , Srinivasan Shankar , Joshi Prashant Ramesh , Robinson Suzanne , Abonour Rafat
Published: May 2020

8518

Background: Patients (pts) with newly diagnosed multiple myeloma (NDMM) and renal impairment (RI) are often excluded from clinical trials. Data are limited on the effects of induction treatment in these pts, who may also be ineligible for autologous stem cell transplant (SCT) due to severity of RI. This analysis investigated the impact of RVd induction on renal function in transplant eligible (TE) and noneligible (TNE) pts from the Connect MM Registry, a US, multicenter, prospective, observational study. Methods: Eligible pts were ≥ 18 y and had symptomatic MM diagnosed ≤ 2 mos prior to enrollment, as defined by the International Myeloma Working Group criteria. For this analysis, pts that received front-line RVd for ≥ 3 cycles were grouped per transplant eligibility and renal function at baseline (BL; creatinine clearance [CrCl] < 30, 30-50, > 50-80, and > 80). Pts with progressive disease at BL were excluded. Renal function at 3 mos was measured. Median unadjusted progression-free survival (PFS) was calculated from start of regimen in TE and TNE populations, with pts grouped by CrCl (≤ 60 or > 60) at BL. Results: As of 7/23/19, 421 TE and 212 TNE pts received RVd for ≥ 3 cycles. TE and TNE pts were grouped by BL CrCl of < 30 (20 and 16 pts), 30-50 (36 and 50 pts), > 50-80 (117 and 63 pts), and > 80 (248 and 83 pts). Renal function improvement was observed in all pts receiving RVd, including those with moderate (30-50 CrCl) and severe (< 30 CrCl) RI at BL (Table). In pts with > 60 CrCl and ≤ 60 CrCl at BL, median PFS in TE pts was 48.6 mos and 43.2 mos, respectively. In TNE pts, median PFS was 36.4 mos and 30.6 mos, respectively. Conclusions: The results from the Connect MM Registry indicate that pts with NDMM and RI (including moderate and severe) who receive front-line RVd for ≥ 3 cycles may see improvement in renal function at 3 mos, regardless of transplant eligibility. RVd therefore can potentially be used in pts with RI. This analysis provides real-world data that support further investigation of RVd treatment in pts with moderate or severe RI. Clinical trial information: NCT01081028 . [Table: see text]
DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment.
Authors: Lee Hans Chulhee , Cohen Adam D. , Chari Ajai , Hultcrantz Malin , Nooka Ajay K. , Callander Natalie Scott , Suvannasankha Attaya , Badros Ashraf , Libby Edward N. , Trudel Suzanne , Richardson Paul G. , Sborov Douglas Weston , Rodríguez Otero Paula , Lonial Sagar , Zhi Eric , Lewis Eric , Gupta Ira , Opalinska Joanna
Published: May 2020

8519

Background: Renal impairment, a frequent complication and poor prognostic factor in RRMM, often leads to poor tolerability of standard regimens. We report outcomes in patients with renal impairment receiving single-agent belantamab mafodotin (2.5 or 3.4 mg/kg; B-cell maturation antigen targeting immunoconjugate not renally metabolized) from the DREAMM-2 post-hoc analysis (NCT03525678). Methods: Eligible patients with RRMM had no active renal conditions and adequate renal function (based on albumin/creatinine ratio [<500 mg/g] and eGFR [mL/min/1.73 m2]: normal [≥90], mild impairment [mild, ≥60≤90], moderate impairment [mod, ≥30≤60]). Results: Overall response rates (95% CI) in patients with mild/mod impairment (2.5 mg/kg: 32% [21.4–44.0]; 3.4 mg/kg: 36% [25.6–48.5]) were similar to those in the overall population ( Lancet Oncol.2020). The median duration of response (DoR) was not reached (NR) in 2.5 mg/kg mild/mod subgroup (95% CI estimate: 4.2 months–NR); median DoR was 7.5 months (4.9–NR) in 3.4 mg/kg mild/mod subgroup. Rates of keratopathy and albuminuria were similar regardless of renal function; rates of anemia, pyrexia, and thrombocytopenia were more frequent in patients with impaired renal function (Table). eGFR did not change or changed to normal in most patients. Conclusions: Following treatment with single-agent belantamab mafodotin, patients with mild/mod renal impairment achieved a similar efficacy and safety profile as patients with normal renal function. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]
A phase II, single-arm study of denosumab in multiple myeloma patients with renal insufficiency.
Authors: O'Donnell Elizabeth , Yee Andrew Jenho , Nadeem Omar , Lipe Brea , Laubach Jacob , Malek Ehsan , Branagan Andrew , Friedman Robb S. , Richardson Paul G. , Nooka Ajay K. , Raje Noopur S.
Published: May 2020

8520

Background: Bone destruction is a devastating consequence of multiple myeloma (MM). An unmet medical need exists for the management of skeletal complications in MM patients with renal insufficiency. Despite the effectiveness of intravenous bisphosphonates, their use is limited in situations where renal dysfunction is present. Denosumab is a fully human monoclonal IgG2 antibody to RANKL that has been shown to be non-inferior to zoledronic acid for SRE rates in MM (Raje, et al. Lancet Oncol). More importantly, it does not have the same renal toxicity as the bisphosphonates. We hypothesize that denosumab can be safely and effectively administered in MM patients with renal insufficiency to improve bone health. This may fill a gap in clinical care for bone-directed therapy in this patient population. Methods: This multi-center study will include forty adult patients with newly diagnosed or relapsed MM with a creatinine clearance of less than 30 mL/min (NCT02833610). All patients will receive a subcutaneous injection of denosumab 120 mg Q4W for a total of 12 cycles. In addition, it is required that all subjects receive daily vitamin D and calcium supplementation at standard doses (at least 2000 mg calcium citrate and1000 IU of vitamin D), unless documented hypercalcemia develops on study. The primary objective is to assess the effect of denosumab 120 mg Q4W on serum c-terminal telopeptide (sCTX). Secondary objectives include evaluation of safety and tolerability of denosumab in patients with renal insufficiency, incidence of hypocalcemia, effect on bone mineral density, effect on urinary n-terminal telopeptide, and proportion of patients who have a documented skeletal-related event. Results: At the time of this analysis, a total of 20 out of a planned 40 patients have been enrolled, including 9 women, 11 men. Of those treated, 8 patients have completed the planned 12 cycles of therapy. Hypocalcemia was observed in 7 (35%) patients. Four patients (20%) experienced grade 3 hypocalcemia, 3 (15%) grade 2 or less. Two patients developed osteonecrosis of the jaw, one (5%) grade 1 and one (5%) grade 4 event. Data for the analysis of the primary endpoint of sCTX levels will be presented. Conclusions: Investigation of denosumab in MM patients with renal insufficiency defined as a creatinine clearance less than 30 mL/min is ongoing. Early data support that denosumab can be safely administered in this population. However, incidence of hypocalcemia despite aggressive prophylactic calcium dosing underscores the importance of the trial to inform safe practice in this more fragile population. Clinical trial information: NCT02833610 .
Genetic polymorphisms associated with clostridium difficile infection in multiple myeloma patients undergoing autologous stem cell transplantation.
Authors: Hamadeh Issam , Shahid Zainab , Bhutani Manisha , Patel Jai Narendra , Steuerwald Nury , Hamilton Alicia , Atrash Shebli , Friend Reed N. , Paul Barry , Voorhees Peter Michael , Usmani Saad Zafar , He Jiaxian
Published: May 2020

8522

Background: CDI is the primary cause of infectious diarrhea in immunocompromised patients including those undergoing autologous stem cell transplant (SCT). Given the key role of gut microbiome and its interaction with host immune system, we investigated whether polymorphisms in innate immunity genes (identified through Ingenuity Pathway Analysis) were associated with CDI. Methods: We queried our database to identify MM patients who underwent an autologous SCT between April 2015-June 2019. Patients who had their buccal swabs collected through an IRB approved specimen collection protocol were included herein. Data were collected on age, conditioning regimen, CDI diagnosis, time from admission until CDI diagnosis, absolute neutrophil count (ANC) at time of CDI diagnosis, and antibiotic prophylaxis. Genomic DNA was extracted from buccal swabs and genotyped for 62 single nucleotide polymorphisms (SNPs) in ASPH , RLBP1L1, ATP7B, IL-8, FAK, TNFRSF14, CTH, TLR and IL-4. Univariate and multivariate logistic regression analyses were performed to assess association between CDI and presence of SNPs in these genes. Results: A total of 83 patients were identified (25 cases and 58 controls). Baseline characteristics were comparable between two groups. Median age was 67 years (range: 50-79). All patients received high dose melphalan as conditioning, and the same antibiotic prophylaxis during peri-transplant period. Median time from hospitalization until CDI diagnosis was 10 days (IQR:9 days), and median ANC was 0.7/mL (IQR:1.6/mL). Two SNPs (rs2227307 T > G in IL-8 and rs2234167 G > A in TNFRSF14) were significantly associated with CDI risk in both univariate and multivariate logistic regression analyses (Table). Conclusions: Our findings suggest that rs227307G (in IL-8) and rs2234167A (in TNFRSF14) alleles are potential risk factors for CDI after autologous SCT. Our findings, if validated in a larger cohort, would support genetic testing as a screening tool to identify patients who might benefit from prophylaxis against CDI. [Table: see text]