bluuebunny/crossref_metadata_2025 huggingface dataset:
Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory chronic myelomonocytic leukemia (CMML).
Authors: Patnaik Mrinal Mahesh , Ali Haris , Gupta Vikas , Schiller Gary J. , Lee Sangmin , Yacoub Abdulraheem , Talpaz Moshe , Wysowskyj Halyna , Shemesh Shay , Chen Janice , Brooks Christopher , Poradosu Enrique , Rupprecht Nicole , Pardanani Animesh Dev , Tefferi Ayalew , Wang Eunice S. , Taparia Minakshi , Verstovsek Srdan , Khoury Joseph , Pemmaraju Naveen
Published: March 2020

7059

Background: Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ~6-7 mos median OS in relapsed/refractory (r/r) setting. Splenomegaly is a poor prognostic factor and potential target in CMML. CD123 is detected on blasts, monocytes, and neoplastic microenvironmental plasmacytoid dendritic cell (pDC) infiltrates part of the CMML malignant clone (Solary, et al). Tagraxofusp, a novel CD123 targeted therapy, demonstrated high levels of activity in BPDCN, an aggressive hematologic malignancy derived from CD123-expressing pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel approach in CMML. Methods: Multicenter, 2-stage Ph1/2 enrolling patients (pts) with r/r CMML. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed on days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing), pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 20 pts (12 CMML-1; 8 CMML-2) enrolled. 18 pts 2nd-line (2 pts in 1L), HMAs most common prior therapy. Median age 69 (43-80); 81% male. 11 (52%) had baseline splenomegaly (spleen palpable below left costal margin by physical exam) of 2-27 cm. Most common TRAEs: hypoalbuminaemia (35%), thrombocytopenia (35%), nausea (30%), vomiting (30%), and fatigue (20%). Most common ≥Gr3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome in 3 pts (15%; all Gr1&2). 100% (10/10) of pts with splenomegaly had spleen response: 80% (8/10) had reductions ≥50% and 67% (4/6) with spleen size ≥5 cm had reductions ≥50%. 3 pts achieved bone marrow complete responses, including 1 pt bridged to SCT in remission. Conclusions: Tagraxofusp demonstrated single agent activity in CMML as 80% of pts showed ≥50% reduction in splenomegaly by palpation. Splenomegaly in CMML, as in myelofibrosis, is a major cause of morbidity and associated with poor prognosis and impaired QoL. Targeting splenomegaly in myeloid neoplasms with proliferative features may be an important therapeutic goal. Given CD123 expression on CMML blasts, monocytes, and malignant pDCs, tagraxofusp may offer a targeted approach, especially in pts with splenomegaly. Updated safety and efficacy data to be presented. Registrational trial planned. Clinical trial information: NCT02268253.
Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.
Authors: Fischer Kirsten , Al-Sawaf Othman , Bahlo Jasmin , Fink Anna-Maria , Tandon Maneesh , Dixon Mark , Robrecht Sandra , Humphrey Kathryn , Böttcher Sebastian , Tausch Eugen , Humerickhouse Rod , Eichhorst Barbara , Wendtner Clemens-Martin , Langerak Anton W. , Kreuzer Karl-Anton , Goede Valentin , Stilgenbauer Stephan , Mobasher Mehrdad , Ritgen Matthias , Hallek Michael J. ,   CLL14 Study Investigators
Published: March 2020

7502

Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles (C) of standard Clb or Ven 400 mg daily in combination with G for first 6 C. Primary endpoint was PFS. MRD− in peripheral blood (PB) or bone marrow (BM) 3 months (mo) after treatment completion was a key secondary endpoint. MRD was analyzed serially from C4 every 3 mo by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10-4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5,10-6). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P<0.0001). MRD− by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 mo after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD− was associated with longer PFS. Higher MRD− rates were achieved early and were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 mo after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off-treatment: 19 mo). MRD− rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD− at <10-4, 31% vs 4% at <10-6 and 35% vs 15% at ≥10-6–<10-5, respectively. Conclusions: Fixed-duration VenG induced deep (<10-6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.
Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open label, registration directed phase II study.
Authors: Fowler Nathan Hale , Samaniego Felipe , Jurczak Wojciech , Lech-Maranda Ewa , Ghosh Nilanjan , Patten Piers , Reeves James Andrew , Leslie Lori Ann , Chavez Julio C. , Ghia Paolo , Tarella Corrado , Burke John M. , Sharman Jeff Porter , Kolibaba Kathryn , O'Connor Owen A. , Cheah Chan , Miskin Hari P. , Sportelli Peter , Weiss Michael S. , Zinzani Pier Luigi
Published: March 2020

7506

Background: Rituximab (RTX) alone or with chemo has substantially improved outcomes for patients (pts) with marginal zone lymphoma (MZL), but relapse is common and not all pts are candidates for or respond to current salvage therapies. Umbralisib is a novel, next-gen PI3Kδ inhibitor with unique inhibition of casein kinase-1ε (CK1ε) and a differentiated tolerability profile compared to earlier PI3Kδ inhibitors (Burris et al, 2018). This registration-directed study evaluates the efficacy and safety of umbralisib in pts with rel/ref (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS ≤2, and ≥1 prior therapy including ≥1 anti-CD20 mAb-containing regimen. Pts received umbralisib 800 mg orally once daily until PD or unacceptable toxicity. The primary endpoint was overall response (ORR) as assessed by independent review (IRC) per 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: 69 pts were enrolled; we report on the first 38 who are eligible for at least 6 months (mos) of follow-up as of the data cutoff. Among the 38 pts: extranodal (n = 23), nodal (n = 8), and splenic (n = 7). Median age was 67 years (range, 34-81). Median # of prior systemic therapies was 2 (range, 1-5). Seven pts (18%) had monotherapy RTX only, and 26 (68%) had at least one anti-CD20 mAb-containing chemoimmunotherapy. Median follow-up was 9.6 mos. ORR was 55% (4 CRs and 17 PRs). Eleven pts (29%) had stable disease (SD) of which 6 of these SD pts remain on study ranging from 7-12+ mos. The clinical benefit rate (CR+PR+SD) was 84%, and 91% of pts with at least 1 post-baseline assessment experienced tumor reductions. Median time to initial response was 2.7 mos, while median DOR was not reached (95% CI: 8.4-NR). The 12-month PFS was 71%. The most common all causality (≥20%) adverse events (AE) of any grade included: diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). The most common Grade 3/4 events were neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). As of the cutoff date 58% continue treatment. Conclusions: PI3Kδ inhibition with single-agent umbralisib is active and well tolerated in pts with R/R MZL, achieving durable responses with chemotherapy-free therapy. Clinical trial information: NCT02793583.
Phase 1/2 trial of acalabrutinib plus pembrolizumab (Pem) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL).
Authors: Witzig Thomas E. , Maddocks Kami J. , De Vos Sven , Lyons Roger M. , Edenfield William Jeffery , Sharman Jeff Porter , Vose Julie , Yimer Habte Aragaw , Wei Helen , Chan Edward M , Patel Priti , Di Simone Christopher , Gandhi Mitul , Vaughn Jennifer , Kolibaba Kathryn , Cheson Bruce D. , Samaniego Felipe
Published: March 2020

7519

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor, has a 24% overall response rate (ORR) as a single agent in R/R DLBCL. Pem targets PD-1, an immune checkpoint that limits anticancer responses. Pem showed responses in patients (pts) with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib + Pem in R/R DLBCL. Methods: Pts with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received acalabrutinib 100 mg PO BID until progressive disease (PD) + Pem 200 mg/kg IV Q3W up to 2 y. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one pts (30 GCB; 31 non-GCB) were accrued, with a median age (range) of 67 y (30-85) and a median of 3 (1-8) prior therapies; 1 pt had prior autologous transplant. The most common Gr 3/4 adverse events (AEs) were neutropenia (15%) and anemia (11%). Gr 5 AEs were respiratory failure (n=3), sepsis, septic shock and abdominal abscess (n=1 each). All Gr atrial fibrillation was 5% (n=3), and major hemorrhage (≥ Gr 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Gr 3/4 immune-mediated events were elevated alanine aminotransferase (n=4), pneumonitis (n=2) and colitis (n=1). The ORR was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 mo (0.4-30.4+). Acalabrutinib/Pem discontinuations were due to PD (62%/56%) and AEs (15%/26%). As of June 2018, 10 pts remain on study; 6 on active therapy and 7 without PD. Conclusions: Acalabrutinib + Pem was well tolerated, with meaningful activity and some exceptional responders (>24 mo) in these R/R DLBCL pts. Randomized trials of the combination vs single agent are needed. Clinical trial information: NCT02362035. [Table: see text]
Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL.
Authors: Nowakowski Grzegorz S. , Willenbacher Wolfgang , Greil Richard , Larsen Thomas Stauffer , Patel Krish , Jäger Ulrich , Manges Robert F. , Trumper Lorenz H. , Haioun Corinne , Everaus Hele , Kalakonda Nagesh , Knoble Jeanna , Brown Peter , Joergensen Judit Meszaros , Cunningham David , Domper Neus , Casadebaig Marie-Laure , Manzke Oliver , Munoz Javier
Published: March 2020

7520

Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.
Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis.
Authors: Maddocks Kami J. , Duell Johannes , González Barca Eva , Jurczak Wojciech , Liberati Anna Marina , Nagy Zsolt , Obr Aleš , Gaidano Gianluca , André Marc , Kalakonda Nagesh , Dreyling Martin H. , Zinzani Pier Luigi , Dirnberger-Hertweck Maren , Weirather Johannes , Ambarkhane Sumeet Vijay , Salles Gilles A.
Published: March 2020

7521

Background: MOR208, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody has shown single agent activity in patients (pts) with R-R DLBCL and encouraging activity when combined with LEN in the phase II L-MIND study. Here we report an update with primary endpoint and subgroup analyses (cut off June 5, 2018). Methods: Key inclusion criteria were adequate organ function, ≤3 prior lines of therapy, including ≥1 anti-CD20 therapy, and ineligibility for stem cell transplantation. Treatment comprised up to 12, 28-day (d) cycles (C) of MOR208, 12 mg/kg IV, q1w C1–3 (loading dose on d4 of C1), and q2w C4–12 + LEN 25 mg PO d1–21, C1–12. Pts progression-free after 12 C received MOR208 q2w until progression. The primary endpoint was independent review committee (IRC)-assessed ORR as per Cheson 2007 criteria. Results: Recruitment is complete (N = 81): median age 72 years (range 41–87), median of 2 prior therapies, 19 (23%) of pts had early relapse (≤12 months [mo] from diagnosis), 32 (40%) were rituximab (RTX) refractory (no response to or progression during or within 6 mo of a prior RTX therapy), 34 (42%) were refractory to their last therapy, 21/40 (26%/49%) pts had non-germinal center B cell-like (GCB)- / GCB-DLBCL, and 42 (52%) had an International Prognostic Index (IPI) of 3–5. MOR208 + LEN therapy was well tolerated; 72% of pts stayed on a LEN dose of ≥20 mg/day. Treatment-related serious adverse events, mainly infections (10%) or neutropenic fever (5%), occurred in 17% of pts. Investigator (INV)-assessed complete response (CR) and partial response rates were 33% and 25%, respectively, giving an ORR of 58%, comparable to the IRC assessment (ORR 54%; CR 32%). ORR was 46% in pts with ≥2 prior therapies, 59%/56% in rituximab- / last treatment-refractory pts, 58% in early relapse pts, 57% in pts with a baseline IPI of 3–5, and 71% in pts with non-GCB- vs 53% with GCB-DLBCL. INV-assessed median PFS and OS (ITT analysis) were 16.2 mo (95% CI: 6.3–NR) and not reached (95% CI: 18.6–NR), respectively. Conclusions: MOR208 + LEN shows encouraging activity including a durable PFS in R-R DLBCL, and in pt subgroups with poor prognosis. Clinical trial information: NCT02399085.
Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): Final analysis of the phase 3 COMPLEMENT 1 trial.
Authors: Offner Fritz , Robak Tadeusz , Janssens Ann , Kanakasetty Govind Babu , Kloczko Janusz , Grosicki Sebastian , Mayer Jiri , Panagiotidis Panagiotis , Schuh Anna , Pettitt Andrew , Montillo Marco , Werner Olena , Vincent Ghislaine , Khanna Sadhvi , Hillmen Peter
Published: March 2020

7528

Background: Previously in the COMPLEMENT 1 study, treatment with OFA and CHL in pts with untreated CLL had shown a significant improvement in the progression-free survival (PFS) compared with CHL alone, and was well tolerated. Here, we report the final overall survival (OS) analysis of the 5-year (y) follow-up, updated investigator-assessed PFS and safety from the study. Methods: Untreated pts, not fit for fludarabine-based therapy (due to advanced age or co-morbidities) were randomized 1:1 to OFA+CHL or CHL alone. Pts in OFA+CHL arm received OFA (Cycle 1: 300 mg day (d) 1, 1000 mg d8; subsequent cycles: 1000 mg d1) in addition to CHL (10 mg/m2, d1-7) for 3 to 12 cycles of 28 d each. Pts in CHL arm received CHL only. Results: Overall, 447 pts were randomized to OFA+CHL (n = 221) or CHL (n = 226); 168 (76%) and 164 (73%) pts completed the scheduled treatments, respectively. Baseline characteristics were similar in both arms. The investigator-assessed median PFS was 23.4 months (mos) in the OFA+CHL arm and 14.7 mos in the CHL arm (HR: 0.61 [95% CI 0.49, 0.76], p < 0.001). Median OS could not be estimated for the OFA+CHL arm and was 84.7 mos for the CHL arm (HR: 0.88 [95% CI 0.65, 1.17], p = 0.363). Estimated OS rate (95% CI) at 5 y was 68.5% (61.5%, 74.5%) in the OFA+CHL arm, and 65.7% (58.6%, 71.9%) in the CHL arm. Post-treatment anti-cancer therapy after discontinuation was received by a greater proportion of pts in the CHL (66%) vs. OFA+CHL (56%), and started earlier in the CHL arm (486 d) vs. OFA+CHL (743 d) arm. Overall, 84 (39%) pts in the OFA+CHL, and 99 (44%) pts in the CHL arms died during the study with 5 on-treatment deaths in each group. Grade ≥3 adverse events were seen in 64% and 48% of pts in the OFA+CHL vs. CHL arms, respectively, most common being (≥5% in either arm) neutropenia (26% vs. 15%), thrombocytopenia (5% vs. 10%), pneumonia (9% vs. 5%), and anemia (5% vs. 5%). Conclusions: This 5-y survival follow-up analysis supported the results from primary analysis with an estimated 12% (not significant) and 39% risk reduction in OS and PFS, respectively, in the OFA+CHL arm compared with the CHL arm. No new safety concerns were observed in the OFA+CHL arm. Clinical trial information: NCT00748189.
Sintilimab for relapsed/refractory classical Hodgkin’s lymphoma: Extended follow-up on the multicenter, single-arm phase II ORIENT-1 study.
Authors: Su Hang , Song Yongping , Jiang Wenqi , Sun Xiuhua , Qian Wenbin , Zhang Wei , Gao Yuhuan , Jin Zhengming , Zhou Jianfeng , Jin Chuan , Zou Liqun , Qiu Lugui , Li Wei , Yang Jianmin , Hou Ming , Zeng Shan , Liu Peng , Shi Yuankai , Zhou Hui , Wang Shuyan
Published: March 2020

7533

Background: Classical Hodgkin’s lymphoma (cHL) is characterized by chromosome 9p24.1 alterations and PD-1 ligand overexpression. Sintilimab, a programmed death-1 checkpoint inhibitor, has demonstrated efficacy in relapsed/refractory cHL after the primary analysis of the ORIENT-1 study. Here, we report the updated safety and efficacy prolines after extended follow-up. Methods: ORIENT-1 is a multicenter, single-arm, phase II study in China. Classical Hodgkin’s lymphoma patients who had failed ≥2 lines of systemic therapy, including autologous hematopoietic stem cell transplantation (HSCT) were enrolled. Sintilimab, 200 mg IV was given every 3 weeks, until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) according to 2007 IWG criteria. Results: 96 patients were treated. As of the data cutoff on 16 October, 2018 72.9% of patients were continuing treatment with a median follow-up of 14 months. Median number of treatment cycles was 20 (range: 1 to 26). ORR was 85.4% (82/96, 95%CI: 76.7 to 91.8) based on IRRC review. Twenty-eight patients (29.2%) achieved complete response (CR) by PET scan. At the time of analysis, 59 out of 82 patients who had achieved complete or partial response continued to have an on-going response. The median duration of response (DoR) and progression free survival (PFS) have not been reached. The most common treatment-related adverse event (TRAE) was pyrexia (40.6%, 39/96), 92.3% of which was grade 1 or 2. The most common grade 3 or 4 TRAEs were pyrexia (3.1%) and anemia (3.1%). One death occurred which was not considered treatment related. Conclusions: ORIENT-1 study has the largest cohort of cHL patients in China treated with a PD-1. In addition to a high rate of response, sintilimab also demonstrated durable efficacy and favorable long-term safety profile after extended follow-up. Clinical trial information: NCT03114683.
Time to next treatment in patients with previously treated cutaneous T-cell lymphoma (CTCL) receiving mogamulizumab or vorinostat: A MAVORIC post-hoc analysis.
Authors: Pro Barbara , Kim Youn H. , Ortiz-Romero Pablo L. , Sokol Lubomir , Scarisbrick Julia , Musiek Amy , Vermeer Maarten , Dummer Reinhard , Halwani Ahmad Sami , Fierro Maria Teresa , Moriya Junji , Leoni Mollie , Bagot Martine
Published: March 2020

7539

Background: CTCLs are chronic skin malignancies, characterized by relapsing/remitting behavior and progressive resistance to treatments, with a reported median time to next treatment (TTNT; ie, systemic treatment excluding topical steroids) in mycosis fungoides (MF) and Sezary syndrome (SS) of 5.4 months (mo) (Hughes et al. Blood, 2015). The phase 3 MAVORIC study demonstrated mogamulizumab (MOGA) was superior to vorinostat (VORI) in progression-free survival (median 7.7 vs 3.1 mo, P<0.0001) and confirmed overall response rates (28% vs 4.8%, P<0.0001) in previously treated patients with MF/SS (Kim et al. Lancet Oncol 2018). This post-hoc analysis examines TTNT to further explore the patient clinical experience. Methods: Patients with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive MOGA (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral VORI (400 mg daily). Patients on VORI were permitted to crossover to MOGA upon approval. TTNT was defined as time to any therapy excluding topical steroids or focal radiation. The length of TTNT was assessed overall and by disease stage grouping (IB/II and III/IV) and disease type (MF and SS). Results: Median TTNT for the full ITT population was longer with MOGA at 11 mo (95% CI, 8.8-12.6) compared to VORI at 3.5 mo and consistently longer for MOGA vs VORI across disease stage grouping or by disease type (Table). Conclusions: TTNT in MF/SS represents an additional measure of clinical benefit and disease control in patients who may have progressed based on strict protocol definitions of progression. This post hoc analysis showing a prolonged TTNT across disease stages and types supports a clinical benefit for MF and SS patients who receive MOGA. Clinical trial information: NCT01728805. [Table: see text]
Prognostic value of baseline SUVmax in patients with advanced stage follicular lymphoma receiving frontline rituximab-based therapy.
Authors: Strati Paolo , Ahmed Mohamed Amin , Fowler Nathan Hale , Hagemeister Fredrick B. , Fayad Luis , Rodriguez Maria Alma , Samaniego Felipe , Wang Michael , Westin Jason , Romaguera Jorge Enrique , Noorani Mansoor , Phansalkar Karishma , Cheah Chan , Feng Lei , Davis Richard Eric , Nastoupil Loretta J. , Neelapu Sattva Swarup
Published: March 2020

7540

Background: Positron emission tomography (PET) is recommended in follicular lymphoma (FL) for initial staging, evaluation of potential transformation, and response assessment. The prognostic value of pre-treatment PET scan has not been adequately explored. Methods: We performed a single-institution retrospective analysis of patients with advanced stage FL, without histological evidence of transformation, treated with frontline rituximab-based therapy, and analyzed the prognostic significance of baseline maximum standardized uptake value (SUVmax). Results: The median follow-up for the cohort was 94 months. Of 346 patients, 151 (44%) received R-CHOP and 195 (56%) received non-R-CHOP regimens. Among multiple single unit increments of SUVmax, a value of >18 showed the strongest association with progression-free survival (PFS) (hazard ratio [HR] 1.5, 95% confidence interval (CI) 0.95-2.3, p=0.08), and was selected as cut-off for further analysis. Fifty-two (15%) patients had a SUVmax > 18. On univariate analysis, factors associated with SUVmax > 18 were male sex (67% vs 52%, p=0.05), elevated β2-microglobulin (65% vs 47%, p=0.02), elevated LDH (37% vs 13%, p<0.001), presence of B symptoms (35% vs 14%, p=0.01), and largest lymph node ≥ 6 cm (64% vs 30%, p<0.001). On multivariate analysis, largest lymph node ≥ 6 cm was the only factor maintaining its association with SUVmax > 18 (odds ratio [OR] 2.7, 95% CI 1.3-5.3, p=0.006). SUVmax > 18 significantly associated with a lower CR rate among patients treated with non-R-CHOP regimens (45% vs 92%) (p<0.001) but not among patients treated with R-CHOP (p=1). SUVmax > 18 associated with significantly shorter PFS among patients treated with non-R-CHOP regimens (77 months vs not reached, p=0.02), but not among patients treated with R-CHOP (p=0.73). SUVmax > 18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (15 year OS 70% vs 75%, p=0.02) and non-R-CHOP regimens (15 year OS 50% vs 75%, p=0.001). Conclusions: In conclusion, baseline SUVmax has prognostic value in patients with advanced stage FL receiving rituximab-based therapies. Evaluation in prospective studies is needed to further confirm these findings.
Survival disparities of diffuse large B-cell lymphoma in a community-based cancer center.
Authors: Jorge Vinicius Machado , Tiu Andrew Chua , Moussa Peter , Gupta Sorab , Djibo Djeneba Audrey , Dourado Claudia M.
Published: March 2020

7541

Background: Non-Hodgkin’s Lymphoma (NHL) is a heterogeneous group of hematologic malignancy from immature or mature lymphocytes or natural killer cells. It is the 9th leading cause of death for both sexes. Diffuse Large B Cell Lymphoma (DLBCL), a subset of NHL, comprises 30 – 40% of all NHL. The etiology for the racial disparities in survival among patients with DLBCL is still unknown. The Revised International Prognostic Index (R-IPI), a tool which predicts the outcome of DLBCL patients, has not yet been fully validated in African Americans (AA). Methods: We conducted a single cohort study of patients diagnosed with DLBCL from January 1, 2007 to December 31, 2017 from our tumor registry in a single community-based cancer center. We abstracted demographic, clinical, histopathologic, treatment, and R-IPI variables. Our primary endpoint was overall survival (OS). Our secondary endpoints were factors that determine mortality through Cox multivariate analysis. Results: Among 381 patients with NHL, 181 (47.5%) patients had biopsy-proven DLBCL. Median age was 65 years old, 47% were males, 41% were AA, 44% were Caucasians, 46% were stage IV by Ann-Arbor staging. African-Americans (AA) had a median OS of 15.7 months (95% CI, 10.31 to 23.90) compared to non-AA 93.6 months (95% CI, 61.48 to 142.57). Even after adjusting for race, R-IPI was correlated with mortality on all patients. Lactate dehydrogenase levels were significantly higher in AA (P<0.001) but there was no difference in the interval from diagnosis to initiation of treatment in all groups. The presence of B symptoms HR 1.80 (95% CI, 1.17 to 2.77), African-American race HR 2.19 (95% CI, 1.38 to 3.52), positive HIV HR 2.16 (95% CI, 1.15 to 4.05), chronic liver disease HR 1.87 (95% CI, 1.09 to 3.23), and malnutrition HR 2.46 (95% CI, 1.30 to 4.65) were all independently associated with increased mortality. Histopathologic features such as the cell of origin, BCL6, and BCL2 rearrangements were not independently associated with increased mortality. Conclusions: There is an overwhelming disparity in survival among AA with DLBCL. The R-IPI is a reliable tool for predicting mortality in AA with DLBCL.
Outcomes of lenalidomide in diffuse large B-cell (DLBCL) and high-grade NHL (HGBCL): A single-center retrospective analysis.
Authors: Rodgers Thomas David , Baran Andrea M , Reagan Patrick Michael , Casulo Carla , Evans Andrew , Burack Walter Richard , Friedberg Jonathan W. , Barr Paul M.
Published: March 2020

7547

Background: Outcomes remain poor for patients with relapsed refractory DLBCL and HGBCL, especially those ineligible for a stem cell transplant or CAR T-cell therapy. Lenalidomide has efficacy in these groups, most notably in the activated B-cell like (ABC) subtype when defined by gene expression profiling. We analyzed the outcomes of consecutive patients with DLBCL treated with lenalidomide, focusing on characteristics such as transformed histology and MYC translocation status. Methods: We performed a retrospective review of consecutive patients with transformed indolent NHL, DLBCL, and HGBCL treated with lenalidomide at the University of Rochester between 2011-2018. Cell of origin was determined by Hans algorithm and FISH was performed to detect MYC, BCL2, and BCL6 translocations. Kaplan Meier estimates and descriptive statistics were utilized for analysis. Results: 62 patients were identified with a median age of 76 years, the majority with > 2 prior therapies. ORR was 43.5%, including 14 patients with a CR. Median PFS was 4.6 months with 18 patients achieving a PFS > 1 year. Median OS was 14 months. No difference in PFS, OS, or ORR was observed between the de novo germinal center b-cell (GCB) and non-GCB populations (PFS 4 vs. 5 months, p = 0.87). 16 patients with transformed FL had a median PFS of 24 months and a median OS of 46.7 months (vs. de novo GCB OS of 7.8 months, p = 0.02). Notably, 6/7 MYC+ patients achieved an objective response, including 3 with a CR. All patients with double and triple hit disease had an objective response, including two PRs and one CR. Conclusions: Our experience confirms the clinical activity of lenalidomide in heavily pretreated older adults with DLBCL. Outcomes did not differ by cell of origin using the Hans immunohistochemistry algorithm and durable responses were observed, particularly in transformed FL. Nearly all of the MYC+ patients responded, including those with double/triple hit genetics, and almost half achieved a CR. Based on our data, lenalidomide may be an optimal bridge to consolidative cellular therapy in high-risk patients irrespective of genotype, particularly in transformed indolent histologies.
Extranodal (EN) and spleen disease by FDG-PET/CT is associated with early clinical failure in untreated follicular lymphoma (FL).
Authors: St-Pierre Frederique , Broski Stephen M , LaPlant Betsy , Ristow Kay , Maurer Matthew John , Macon William R , Habermann Thomas Matthew , Ansell Stephen M. , Thompson Carrie A. , Micallef Ivana N. M. , Nowakowski Grzegorz S. , Witzig Thomas E.
Published: March 2020

7554

Background: Predicting early clinical failure in patients with untreated FL is important but difficult. Lymphoma involvement of EN sites is better detected by FDG-PET/CT than CT alone, but PET parameters are not part of the usual predictive indices. We aimed to determine the incidence and patterns of spleen and EN disease using PET/CT, and learn if they are useful in predicting early clinical failure. Methods: PET/CT images from 613 cases of newly diagnosed FL between 2003 – 2016 were retrospectively reviewed. The location, pattern, and number of EN sites, as well as splenic involvement, were recorded. Associations with outcomes were assessed using event-free survival (EFS) and overall survival (OS). Results: 49% (301/613) of patients had PET/CT-detected EN involvement, and 28% (171/613) had spleen involvement. Presence of ≥2 EN sites, spleen, bone, or soft tissue involvement, as well as a multifocal on diffuse pattern of bone involvement by imaging, were univariate predictors of EFS; presence of ≥2 EN sites and bone involvement pattern were also predictive of OS. In a multivariate analysis with FLIPI-2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (Table). When the multivariate analysis was performed using PRIMA-PI factors, the presence of ≥2 EN sites was an adverse independent prognostic factor for OS (HR 2.28; 95% CI 1.01-5.18; p=0.05). Conclusions: Baseline PET/CT identifies EN and spleen sites of disease that can predict early clinical failure of FL. These results may be useful to better identify high-risk patients and guide appropriate therapy. [Table: see text]
A phase I trial using CD19 CAR-T expressing PD-1/CD28 chimeric switch-receptor for refractory or relapsed B-cell lymphoma.
Authors: Liu Hui , Lei Wen , Zhang Chaoting , Yang Chunmei , Wei Juying , Guo Qunyi , Guo Xiaojun , Chen Zhilu , Lu Ying , Lu Zheming , Qian Wenbin
Published: March 2020

7557

Background: The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has established efficacy in the treatment of refractory or relapsed (R/R) B-cell lymphoma. However, the existence of different immunosuppressive pathways such PD-1/PD-L1 pathway can restrict the full potential of CAR-T therapy. A recent study demonstrates that a novel PD-1/CD28 chimeric switch-receptor, comprising the extracellular domain of PD-1 and the transmembrane and cytoplasmic signaling domains of CD28, can be used a modality for augmenting antitumor activity of mesothelin- and prostate specific cancer antigen-specific CAR-T cells in either pleural mesothelioma or prostate cancer xenograft model. Here, we describe the first human trial of CD19-PD-1/CD28-CAR-T cells (a CD19-specific CAR-T expressing PD-1/CD28 chimeric switch-receptor) to evaluate safety and efficacy. Methods: This phase I, single-arm, open-label, multicenter trial enrolled patients (18-75 years) with R/R large B-cell lymphoma. PD-L1 expression was confirmed by immunohistochemistry using an anti-PD-L1 mAb (SP142), and confirmed by the review committee with a central evaluation. Seventeen patients received conditioning chemotherapy (cyclophosphamide [500 mg/m2] and fludarabine [30 mg/m2] on days -5, -4 and -3) and followed by CD19-PD-1/CD28-CART cells infusion at doses ranging 0.5 to 4 × 106 CAR+ T cells/kg on day 0. Response was assessed by F-FDG PET/CT at month 3 after CAR-T infusion, according to the International Working Group Response Criteria for Malignant Lymphoma, and duration of response was evaluated by ultrasonic and computed tomography every three months from month 3 to month 12. Results: At data cutoff, 17 patients had received CD19-PD-1/CD28-CART cells. Overall PD-L1 positivity was 15/17 (88.2%) and the mean percentage of PD-L1 positivity was 19.7% (range, 5-50%). Fourteen patients (82.35%) developed cytokine release syndrome (grade ≤ 2) and four (23.53%) developed neurotoxicity (grade = 1), which was reversible in all. The overall response rate was 58.8% (10/17) and complete remission rate was 41.2% (7/17). At a median follow-up 5 months, median overall survival for all patients was not reached. Conclusions: This trial showed the feasibility, controllable toxicities, and effective activity of CD19-PD-1/CD28-CART cells for treating patients with R/R B-cell lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the PD-1/PD-L1 pathway in lymphoma in the clinical setting. Clinical trial information: NCT03258047.
Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
Authors: Lin John , Muffly Lori S. , Spinner Michael Alexander , Barnes James I , Owens Douglas K. , Goldhaber-Fiebert Jeremy D
Published: March 2020

7561

Background: Two anti-CD19 chimeric antigen receptor T-cell therapies are approved for large B-cell lymphoma (DLBCL): axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. Each costs $373,000 (wholesale acquisition). We evaluated each therapy’s cost-effectiveness. Methods: A decision analytic Markov model evaluated axi-cel and tisagenlecleucel in multiply relapsed/refractory adult DLBCL from a US health-payer perspective over a lifetime horizon. The model was informed by recent multi-center, single-arm clinical trials. Under a range of plausible long-term effectiveness assumptions, axi-cel and tisagenlecleucel were each compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were un-discounted life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). Sensitivity analyses explored uncertainty. Results: In an optimistic scenario, assuming 40% five-year progression-free survival (PFS), axi-cel increased life-expectancy by 8.15 years at $129,000/QALY (95% UI: $90,000-215,000/QALY) gained. At 30% five-year PFS, improvements in life-expectancy were more modest (6.4 years) and expensive ($159,000/QALY [$107,000-281,000/QALY] gained). In an optimistic scenario, assuming 35% five-year PFS, tisagenlecleucel increased life-expectancy by 4.6 years at $168,000/QALY ($104,000-453,000/QALY) gained. At 25% five-year PFS, improvements in life-expectancies were more modest (3.4 years) and expensive ($224,000/QALY [$124,000-1,190,000/QALY] gained). Administering CAR-T to all indicated patients would increase US healthcare costs by $10 billion over 5 years. Price reductions to $250,000 or payment only for initial CR or 90-day CR/PR (at current prices) would allow both therapies to cost < $150,000/QALY down to 25% PFS. Conclusions: At current prices, it is possible that each CAR-T therapy may meet a < $150,000/QALY threshold; this is dependent on long-term benefit compared with chemoimmunotherapy and SCT, which is uncertain. Widespread adoption would increase non-Hodgkin lymphoma healthcare costs substantially. Price reductions or payment for initial CR or 90-day CR/PR would favorably influence cost-effectiveness even if long-term outcomes are modest.
Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria.
Authors: San Miguel Jesus , Mateos Maria-Victoria , Gonzalez Veronica , Dimopoulos Meletios A. , Kastritis Efstathios , Hajek Roman , Fernández de Larrea Rodríguez Carlos , Morgan Gareth John , Merlini Giampaolo , Mangiacavalli Silvia , Goldschmidt Hartmut , Cavo Michele , Kyriakou Charalampia , Qi Ming , Ukropec Jon , Weiss Brendan M. , Cameron Chris , Rajkumar S. Vincent , Durie Brian G. , Kumar Shaji
Published: March 2020

8000

Background: The diagnostic criteria for MM were revised in 2014, recategorizing ultra-high risk (i.e., 80% at two years) as active myeloma requiring therapy. The removal of patients at the highest risk of progression from the smoldering group requires reassessment of current risk stratification models. Methods: We designed a multicenter, retrospective study of SMM patients to develop a risk stratification model. Patients diagnosed with SMM on/after January 1, 2004 were included if they had no disease progression within 6 months, had baseline data from diagnosis (+/- 3 months), had a follow up of ≥1 year, and did not participate in a therapeutic trial of SMM. Various clinical and laboratory factors were explored to identify factors that predicted progression at 2 years. Univariate Cox regressions were run for each factor. For factors with p-values ≤ 0.25, optimal cut points were identified using Youden’s index. Binary factors were used in stepwise regression to fit multivariable Cox model and significant risk factors were determined (F-test). Results: Overall, 2004 patients were included (ages 26-93, 51% female). Factors independently associated with progression (optimal cutoffs) included: Serum M protein (2 g/dL), involved to uninvolved serum-free light chain ratio (20), and marrow plasma cell % (20%). Patients were stratified using the risk factors: Low- (0 factors), Intermediate- (1), and High-Risk (≥2). Previously used high risk markers such as Bence Jones proteinuria (≥500 mg/24 hours) and severe immunoparesis (50% decrease in uninvolved immunoglobulin levels) were both significant in univariate analysis, but were eliminated on step wise selection. Compared to the low risk group, intermediate- and high-risk groups had significantly higher rate of progression (Table). Within the high-risk group, having all 3 risk factors (n=61) versus 2 did not add to the model, with insufficient separation between 2 and 3 factors. Conclusions: We have developed a risk stratification model for SMM that incorporates revised cutoffs for previously used parameters (20/2/20) that can be universally applied. Additonal analysis are being conducted to develop models that utilize common cytogenetic abnormalities, as well as those without FLC given lack of availability of all tests across the world. [Table: see text]
Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.
Authors: Gay Francesca , Cerrato Chiara , Petrucci Maria Teresa , Zambello Renato , Gamberi Barbara , Ballanti Stelvio , Omedè Paola , Palmieri Salvatore , Troia Rossella , Spada Stefano , Gozzetti Alessandro , Caravita Tommaso , Spadano Antonio , Palumbo Antonio , Montefusco Vittorio , Musto Pellegrino , Cavo Michele , Boccadoro Mario
Published: March 2020

8002

Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (<18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]
First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Lonial Sagar , van de Donk Niels W.C.J. , Popat Rakesh , Zonder Jeffrey A. , Minnema Monique C. , Larsen Jeremy , Nguyen Tuong Vi , Chen Min S. , Bensmaine Amine , Cota Mariana , Sonneveld Pieter
Published: March 2020

8006

Background: IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and DEX. Methods: A phase 1b/2a multicenter, open-label, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER. Eligible pts had RRMM and must have received ≥ 2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All pts had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in pts age > 75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose escalation committee. Results: As of Jan 2019,58 pts received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) pts and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% pts, respectively. Three pts discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table); 20 of 51 pts remain on treatment (2–27+ cycles). Conclusions: IBER + DEX showed favorable efficacy and safety in heavily pretreated pts with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT. Clinical trial information: NCT02773030. [Table: see text]