bluuebunny/crossref_metadata_2025 huggingface dataset:
Relation between measurable residual disease and morphologic relapse in AML.
Authors: Shih Lauren , Othus Megan , Gardner Kelda , Shaw Carole , Halpern Anna B. , Becker Pamela Sue , Walter Roland B. , Estey Elihu , Percival Mary-Elizabeth M.
Published: May 2020

7535

Background: Measurable residual disease (MRD) in AML portends a poor prognosis. The outcomes and treatments of MRD after an initial MRD negative complete remission (MRD- CR) are unclear. Methods: We retrospectively identified 432 patients ≥ 18 years of age treated for AML or high grade myeloid neoplasm (10-19% blasts in blood and/or marrow) at University of Washington/Seattle Cancer Care Alliance from 2008-2017 who achieved MRD- CR after initial treatment. Next disease recurrence was recorded, with patients either developing MRD ( < 5% blasts via multiparameter flow cytometry; n = 44) or developing morphologic relapse (≥5% blasts; n = 100). The remaining patients remained in MRD- CR (n = 288, median follow up time 3.7 years). A landmark analysis at one year was performed to compare overall survival (OS). Results: Patients who developed MRD tended to be older (p = 0.009), but baseline characteristics were otherwise similar. Therapies for MRD included allogeneic transplant, low intensity chemotherapy, and high intensity chemotherapy; no significant associations were found between type MRD directed therapy and survival. Landmark OS at 1 year after MRD- CR was significantly different for patients without relapse at 1 year compared to those with MRD or morphologic relapse (median OS was 8.5 years for no relapse, 2.2 years for MRD, and 1.0 years for morphologic relapse). A multivariable Cox regression model among patients alive at 1 year showed patients without relapse had significantly improved OS compared to those with morphologic relapse [HR 0.18 (95% CI 0.1-0.31)]. Although there was a trend towards improved OS, we did not identify a significant difference between patients with MRD relapse compared to morphologic relapse [HR 0.54 (95% CI 0.27-1.11)]. There were no significant differences in patient characteristics for patients with MRD vs morphologic relapse matched by time of relapse (days 30-90, 90-150, 150-210). Conclusions: Following MRD- CR, development of either MRD or morphologic relapse were both associated with decreased OS. Notably, no significant differences in terms of survival were seen between patients who presented with MRD as opposed to morphologic relapse. No clear predictors were identified for MRD vs morphologic relapse. In this cohort, development of MRD carried a poor OS prognosis, similar to the prognosis of developing morphologic relapse. Future clinical trials should focus on MRD directed therapies, as no consensus exists about optimal treatment of MRD.
Antibacterial antibiotic exposures and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.
Authors: Zhang Shijia , Shanley Ryan , Rashidi Armin
Published: May 2020

7541

Background: Cytomegalovirus seropositive (CMV+) recipients of CMV seronegative (CMV-) hematopoietic cell allografts are at the highest risk for CMV reactivation. Inspired by the recently described effect of antibiotic (abx)-induced dysbiosis on anti-viral immunity, we retrospectively evaluated whether antibacterial abx exposures influence the risk of CMV reactivation after CMV- to CMV+ cord blood (CB) or matched sibling donor (MSD) transplantation, the serologic setting with highest risk of CMV reactivation. Methods: We identified 213 eligible patients (pts; 146 CB, 67 MSD, mean age 50, range 18-73). Exposures to fluoroquinolones (FQN), 3rd or higher generation cephalosporins (CPN3+), intravenous vancomycin (Vanc), piperacillin-tazobactam (Pip-Tazo), carbapenems, and metronidazole/clindamycin (Metro/Clinda) from day (D) -7 to D +14 (binary variables) or until CMV reactivation (or D +100, whichever occurred first; time-varying variables) were included in multivariable Fine-Gray regression models with competing risk for non-CMV death to estimate the risk of CMV reactivation by D +100. Other pre-defined covariates were ATG use during conditioning, anti-CMV abx exposure for other viruses, and acute GVHD. Results: 91% of pts received FQN, 67% CPN3+, 56% Vanc, 21% Pip-Tazo, 22% carbapenems, and 28% Metro/Clinda until D +14. These numbers increased to 94%, 81%, 76%, 31%, 38%, and 39% by D +100 (or CMV reactivation), respectively. 83 pts (39%: 66 CB, 17 MSD) had CMV reactivation by D +100. Vanc exposure by D +14 almost doubled the risk of CMV reactivation (HR 1.96, 95%CI 1.11-3.46, P = 0.02). With abx exposures up to D +100 modeled as time-varying covariates, Vanc exposure predicted a higher risk for CMV reactivation (HR 1.86, 95%CI 0.99-3.52, P = 0.06). The table below summarizes the results, excluding non-abx covariates for brevity. Conclusions: Our results suggest that vancomycin-sensitive bacteria may protect against CMV reactivation. Identifying the specific taxa and their location (intestinal vs. extraintestinal) requires more research. Microbiota considerations and abx exposure patterns can help personalize CMV prophylaxis. [Table: see text]
Toxicities after high dose post-transplant cyclophosphamide in haploidentical donor transplants: Risk factors and impact on survival.
Authors: Modi Dipenkumar , Albanyan Omar , Kim Seongho , Deol Abhinav , Alavi Asif , Kin Andrew Daniel , Ayash Lois Jeanne , Ratanatharathorn Voravit , Uberti Joseph P.
Published: May 2020

7545

Background: Post-transplant cyclophosphamide (pCY) when given at 50mg/kg on day +3 and +4 in haploidentical donor transplants (HIDT) leads to considerable morbidity. Information on its toxicity and impact on outcomes is limited. Methods: We analyzed 91 patients (pt) undergoing HIDT with pCY to estimate incidence and risk factors of mucositis, hemorrhagic cystitis, renal and cardiac toxicities during the first 6 months after transplant and its impact on overall survival (OS). We compared these complications with 91 pt who were matched for age, disease, disease status at transplant, conditioning regimen and received 8/8 HLA-matched transplants without pCY (non-pCY cohort). Results: Fourteen pt (15%) in non-pCY and 28 (31%) in pCY experienced hypoxia requiring oxygen (p = 0.03). Ten pt (11%) in non-pCY and 21 (23%) in pCY developed clinically significant hypotension (p = 0.05). Day +100 cumulative incidence rate (CIR) of mucositis was 59.3% for non-pCY and 84.6% for pCY (p < 0.001). Seven pt (13%) in non-pCY cohort and 39 (51%) in pCY developed grade 3-4 mucositis (p < 0.001). Two pt (2%) in non-pCY and 22 (24%) in pCY developed gross hematuria (p = 0.05). Day +180 CIR of hemorrhagic cystitis was 13.2% for non-pCY and 29.7% for pCY (p = 0.005). Hemorrhagic cystitis did not have an adverse impact on non-relapse mortality (NRM) and OS. Day +180 CIR of renal toxicities was 17.6% for non-pCY and 28.6% for pCY (p = 0.10). The CIR of cardiac toxicities at day +180 was 9.9% for non-pCY and 14.3% for pCY (p = 0.34). Congestive heart failure (59%) and atrial fibrillation (36%) were the most common cardio-toxicities. One-year NRM was 38.5% in pt developing cardio-toxicity in the pCY cohort compared to no cardio-toxicity (15.3% in non-pCY and 18.3% in pCY, p = 0.004). OS was inferior in pt with cardio-toxicity in non-pCY (HR 5.49, p < 0.001) and pCY (HR 2.3, p = 0.03) compared to pt without cardio-toxicity. In multivariable analysis, pCY was associated with an increased risk of mucositis (HR 1.48, p = 0.03), and hemorrhagic cystitis (HR 2.67, p = 0.004). The number of infused CD34 cells was associated an increased risk of cardiac toxicity (HR 1.13, p = 0.005). pCY was not associated with higher cardiac complications, and no impact of the number of infused CD34 cells, conditioning regimen and prior transplant was observed on hemorrhagic cystitis and mucositis. Conclusions: pCY was associated with significant morbidity compared to HLA-matched non-pCY cohort. Although cardio-toxicities were similar between both groups, it was associated with worse survival.
Grade III-IV cytokine release syndrome is associated with inferior survival in patients undergoing haploidentical donor stem cell transplants.
Authors: Albanyan Omar , Kim Seongho , Deol Abhinav , Alavi Asif , Kin Andrew Daniel , Ayash Lois Jeanne , Ratanatharathorn Voravit , Uberti Joseph P. , Modi Dipenkumar
Published: May 2020

7546

Background: Haploidentical transplant (HIDT) with post-transplant cyclophosphamide (pCY) is being increasingly used because of the universal availability of donor and rapid graft acquisition time. Cytokine release syndrome (CRS) is one of the commonly occurring complications in this population. The information on the impact of CRS on the post-HIDT outcomes is limited. Methods: We retrospectively evaluated 91 patients who underwent HIDT between June 2012 and June 2019 for the onset and severity of CRS. CRS was graded per ASTCT guidelines. The primary objective was to compare RFS (relapse-free survival), NRM (non-relapse mortality), OS (overall survival) and GVHD in patients with no CRS, CRS grade 1-2 and 3-4. Results: All received peripheral blood stem cells and pCY/tacrolimus/mycophenolate as GVHD prophylaxis. Fifty-six (62%) received reduced intensity and 35 (38%) received full intensity conditioning regimen. Ten (10.9%) had no CRS, 74 (81.3%) developed grade 1-2 CRS and seven (7.7%) experienced grade 3-4 CRS. Median time to onset of CRS was one day post-transplant. The most common symptoms were fever (87%), fatigue (30%), nausea/vomiting (24%), rigors (24%), diarrhea (20%) and rash (11%). Fifteen (20%) with grade 1-2 and six (85%) with grade 3-4 CRS received tocilizumab. Day +100 cumulative incidence of grade III-IV acute GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 0%, 2.7%, and 14.3%, respectively (P = 0.36). One-year cumulative incidence of chronic GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 31.9% and 14.3%, respectively (P = 0.70). One-year NRM for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 16.5%, and 57.1%, respectively (P = 0.002). One-year RFS for no CRS, grade 1-2 and grade 3-4 CRS was 48%, 63.4% and 28.6%, respectively (p = 0.03). OS at 1-year for no CRS, grade 1-2 and grade 3-4 CRS was 60%, 73.9%, and 28.6%, respectively (P = 0.008). Multivariable analysis revealed that grade 3-4 CRS was associated with significantly higher NRM (HR 5.54, P = 0.002), worse RFS (HR 3.41, P = 0.011) and worse OS (HR 4.91, P = 0.001). Conditioning regimen, degree of HLA match and disease risk index did not affect post-transplant outcomes and were not predictors for developing CRS. Conclusions: Our study showed that grade 3-4 CRS was associated with inferior post-transplant outcomes. However, no impact on acute or chronic GVHD was noted. Therefore, early recognition and prompt management of CRS may help improve outcomes.
Myelodysplastic syndrome survival and secondary AML trends in the United States.
Authors: Swenson Wade T. , Swenson Abigail Paige
Published: May 2020

7552

Background: Myelodysplastic syndrome (MDS) is a rare heterogeneous group of hematologic stem cell disorders. The most recent FDA therapies approved for the treatment of MDS were decitabine (May 2006), lenalidomide (June 2005), and azacitidine (November 2004). This analysis utilized a population-based cancer registry to identify changes in survival rates and secondary AML rates among patients with MDS. Methods: SEER 18 regions database (November 2017 submission) was accessed to obtain data on survival and secondary malignancies using SEER*Stat 8.3.6. ICD-O-3 codes were used to identify patients with refractory anemia (RA), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, refractory cytopenia with multilineage dysplasia, MDS with 5q deletion, therapy-related MDS, and MDS, not otherwise specified. An observed survival analysis was conducted using a cohort diagnosed between 2001 and 2004 and another diagnosed between 2009 and 2012. Secondary AML risk was calculated using multiple primary - standardized incidence ratios (MP-SIR) to obtain observed/expected (O/E) ratio. Results: Three-year observed survival rates for patients diagnosed between 2001 and 2004 was 53.2% (50.4%, 55.9%) and was 61.2% (57.9%, 64.3%) for patients diagnosed between 2009 and 2012. There was no observed survival difference among other MDS subtypes. O/E ratio for development of AML among patients with RA was 2.77 (0.57, 8.11) for patients diagnosed between 2001 and 2004, and 49.49 (33.39, 70.65) for patients diagnosed between 2009 and 2012. Conclusions: Survival among patients diagnosed with RA has improved in recent years, whereas survival among other subtypes of MDS has not changed. Secondary AML rates have increased among RA patients identified in the population-based cancer registry.
Long-term outcome of 117 patients with Erdheim-Chester disease and mixed histiocytosis receiving targeted therapies (BRAF and MEK inhibitors): A monocentric experience.
Authors: Cohen-Aubart Fleur , Charlotte Frédéric , Idbaih Ahmed , Barete Stéphane , Benameur NeLa , Emile Jean-François , Amoura Zahir , Spano Jean-Philippe , Haroche Julien
Published: May 2020

7560

Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.
Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL.
Authors: Osborne Wendy , Marzolini Maria , Tholouli Eleni , Ramakrishnan Aravind , Bachier Carlos R. , McSweeney Peter A , Irvine David , Zhang Michael , Al-Hajj Muhammad Ali , Pule Martin , Thomas Simon , Jonnaert Maud , Peddareddigari Vijay Gopal Reddy , Khokhar Nushmia Z. , Chen Robert W. , Ardeshna Kirit
Published: May 2020

8001

Background: CD19 directed CAR T cells are effective in patients with r/r DLBCL, however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we evaluate the safety and efficacy of AUTO3, a CAR T targeting CD19/22 with limited duration of PD-1 blockade. Methods: We constructed a bicistronic retroviral vector encoding both an anti-CD19 (OX40 co-stim) and an anti-CD22 (41BB co-stim) CAR with humanized binders. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy. Patients (≥ 18 years) with r/r DLBCL (NOS) or transformed (tDLBCL); ECOG <2, adequate organ function are eligible. Lymphodepletion was Flu/Cy prior to AUTO3. Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 10^6 CAR T cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg q 3 wks starting on D14 (regimen A), or with a single dose of pem 200 mg on D-1 (regimen B). The primary endpoint is frequency of DLTs and grade (G) 3-5 adverse events (AE) and secondary endpoints included ORR, CRR, and biomarkers. Results: As of Jan 21, 2020, 28 patients underwent leukapheresis, 27 successfully manufactured, 1 being manufactured, and 19 patients treated with AUTO3. The median age was 57 (28 - 71) and median number of prior therapies was 3 (2 - 10). 89% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G > 3 treatment emergent AEs that occurred > 15% were neutropenia (89%), thrombocytopenia (58%), anemia (47%), febrile neutropenia (16%), and hypophosphataemia (16%). Across all dose levels, there were 0% sCRS with primary infusion and 5% severe neurotoxicity (sNT) (1/19), which resolved. There were no cases of sCRS and no neurotoxicity of any grade at > 50 x 106 cells. Eighteen patients were evaluable for efficacy. Among the 11 treated at dose > 50 x 106, the ORR and CRR were 64% and 55%, and all CRs are ongoing (1-12 mth). Two out of 3 patients achieved CR at 450 x 106 cells on pem regimen B. Additional patients and longer follow up, as well as biomarkers, will be presented. Conclusions: AUTO3 at > 50 x 106 CAR T cells with pembrolizumab induces CRs without severe CRS or neurotoxicities of any grade. Clinical trial information: NCT03287817 .
Prognostic impact of dose, duration, and timing of corticosteroid therapy in patients with large B-cell lymphoma treated with standard of care axicabtagene ciloleucel (Axi-cel).
Authors: Strati Paolo , furqan fateeha , Westin Jason , Fayad Luis , Ahmed Sairah , Lee Hun Ju , Iyer Swaminathan Padmanabhan , Nair Ranjit , Nastoupil Loretta J. , Parmar Simrit , Rodriguez Maria Alma , Samaniego Felipe , Steiner Raphael , Wang Michael , Pinnix Chelsea Camille , Flowers Christopher , Horowitz Sandra B. , Classen Catherine , Mistry Haleigh , Neelapu Sattva Swarup
Published: May 2020

8011

Background: Corticosteroids are commonly used for management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether the dose, duration, and timing of corticosteroid therapy may impact clinical efficacy of CAR T-cell therapy. Methods: This is a retrospective analysis of patients with relapsed or refractory LBCL treated with standard of care axi-cel at MD Anderson Cancer Center, Houston, Texas between 01/2018 and 05/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) was defined as time from axi-cel infusion to progression/death or last follow-up, and the Breslow test was used for comparisons between subgroups. Results: One hundred patients with relapsed or refractory LBCL were included in the study, and 60 (60%) received corticosteroids for management of toxicities after axi-cel infusion. There was no significant difference in baseline tumor burden, disease stage or international prognostic index between the 2 groups. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803 mg) and the median duration of corticosteroid treatment was 9 days (range 1-30); 45 (45%) patients started corticosteroid treatment between day 0 and 7, and 15 (15%) beyond day 7. After a median follow-up of 10 months (95% CI 8-10 months), median PFS was 8 months (95% CI, 3-13 months), and use of corticosteroids (any dose) showed a trend for association with shorter PFS (6 vs 9 months, p = 0.13). Use of high-dose corticosteroids (Quartiles (Q) 3-4, 195-1803 mg) significantly associated with shorter PFS (2 vs 9 months, p = 0.005). A trend for shorter PFS was observed among patients receiving corticosteroids for a prolonged time (Q3-Q4, 10-30 days) (5 vs 8 months, p = 0.12) and among patients starting corticosteroids within the first 7 days after axi-cel infusion (6 vs 11 months, p = 0.07). At most recent follow-up, 36 patients died, 28 of progression. Median overall survival has not been reached, and was significantly shorter among patients who received corticosteroids (13 vs not reached, p = 0.006). Conclusions: Early and prolonged use of high-dose corticosteroids is associated with early progression and death in patients with LBCL treated with axi-cel. Additional evaluation is needed to understand the mechanism underlying this association.
Acalabrutinib (Acala) versus idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results.
Authors: Ghia Paolo , Pluta Andrzej , Wach Malgorzata , Lysak Daniel , Kozak Tomas , Simkovic Martin , Kaplan Polina , Kraychok Iryna , Illes Arpad , De La Serna Javier , Dolan Sean , Campbell Philip , Musuraca Gerardo , Jacob Abraham , Avery Eric Joseph , Lee Jae Hoon , Wang Denise , Patel Priti , Quah Cheng Seok , Jurczak Wojciech
Published: May 2020

8015

Background: Acala is a next-generation, highly selective, covalent Bruton tyrosine kinase inhibitor approved for patients (pts) with CLL including those with R/R CLL. The efficacy and safety of acala alone vs IdR or BR were shown in R/R CLL pts in a preplanned interim analysis of ASCEND; final results are reported herein. Methods: In this randomized, multicenter, phase 3, open-label study (NCT02970318), R/R CLL pts were randomized 1:1 to receive oral (PO) acala 100 mg BID or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or toxicity; R: 375 x1 then 500 mg/m2 intravenously [IV] for 8 total infusions) or BR (B: 70 mg/m2 IV and R: 375 x1 then 500 mg/m2 IV for 6 total cycles) until progression or toxicity. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: 310 pts (acala, n=155; IdR, n=119; BR, n=36) were enrolled (median age: 67 y; del(17p) 16%, del(11q) 27%, Rai stage 3/4 42%). At a median follow-up of 22.0 m, acala significantly prolonged INV-assessed PFS vs IdR/BR (median: not reached vs 16.8 m; hazard ratio: 0.27, P<0.0001); 18-m PFS rates were 82% for acala and 48% for IdR/BR. 18-m OS rate was 88% for both treatment regimens. ORR was 80% with acala vs 84% with IdR/BR (ORR + partial response with lymphocytosis: 92% vs 88%, respectively). Common adverse events (AEs) are listed in the Table. AEs led to drug discontinuation in 16% of acala, 56% of IdR, and 17% of BR pts. AEs of interest included atrial fibrillation (acala 6%, IdR/BR 3%), major hemorrhage (all grade; acala 3%, IdR/BR 3%), grade ≥3 infections (acala 20%, IdR/BR 25%), and second primary malignancies excluding non-melanoma skin cancer (acala 5%, IdR/BR 2%). Conclusions: Final ASCEND results with additional follow-up confirm earlier findings and support the favorable efficacy and safety of acala compared with standard-of-care regimens in R/R CLL pts. Clinical trial information: NCT02970318 . [Table: see text]
Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.
Authors: Zelenetz Andrew David , Reddy Nishitha , Jagadeesh Deepa , Stathis Anastasios , Salman Huda S. , Soumerai Jacob D. , Kenkre Vaishalee Padgaonkar , Asch Adam Steven , Llorin-Sangalang Judith , Li Joanne , Gorbatchevsky Igor , Pagel John M.
Published: May 2020

8016

Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .
Comparison of efficacy and safety with obinutuzumab plus chemotherapy versus rituximab plus chemotherapy in patients with previously untreated follicular lymphoma: Updated results from the phase III Gallium Study.
Authors: Townsend William , Buske Christian , Cartron Guillaume , Cunningham David , Dyer Martin J.S. , Gribben John G. , Zhang Zilu , Rufibach Kaspar , Nielsen Tina , Herold Michael , Hiddemann Wolfgang , Marcus Robert
Published: May 2020

8023

Background: Immunochemotherapy is standard of care for patients (pts) with previously untreated advanced stage follicular lymphoma (FL). Four-year data from the Phase III GALLIUM study (NCT01332968) have previously demonstrated an improvement in the primary endpoint of investigator-assessed progression-free survival (PFS) for obinutuzumab (GA101, G) plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R-chemo) (Townsend et al. ASH 2018). Here, we report efficacy and safety results from an updated analysis. Methods: Eligibility criteria: ≥18 years; advanced stage, previously untreated grade 1–3a FL; requiring treatment according to Groupe d’Etude des Lymphomes Folliculaires criteria. Pts were randomized 1:1 to receive G 1000mg IV (day [D] 1, 8 and 15 of Cycle 1; D1 of each subsequent cycle) or R 375mg/m2 IV (D1 of each cycle) with CHOP, CVP, or bendamustine for 6 or 8 cycles. Responders received maintenance therapy with the same monoclonal antibody every 2 months for 2 years. Results: 1202 pts (median age 59 years) were enrolled (n = 601 per treatment arm). Median duration of follow-up was 76.5 months. Pts receiving G- vs R-chemo demonstrated improved PFS (5-year PFS: hazard ratio [HR] 0.76; 95% CI: 0.62–0.92; p = 0.0043; 70.5% [95% CI: 66.4–74.1] vs 63.2% [95% CI: 59.0–67.1]). There was no notable difference in 5-year overall survival (OS), with few events in either arm (HR 0.87; 95% CI: 0.62–1.22; p = 0.41; G-chemo: 90.2% [95% CI: 87.5–92.4]; R-chemo: 89.4% [95% CI: 86.6–91.6]). Time-to-next-treatment (TTNT) was greater in the G- vs R-chemo arm (5-year TTNT rate: HR 0.72; 95% CI: 0.57–0.90; p = 0.0039; 79.7% [95% CI: 76.1–82.7] vs 72.9% [95% CI: 69.1–76.4]). Incidence of grade 3–5 adverse events was 79.3% in the G-chemo arm and 71.2% in the R-chemo arm, and consistent with those reported in the primary analysis (Marcus et al. N Engl J Med 2017). Conclusions: These data further demonstrate the clinically meaningful and durable benefit of treatment with G-chemo relative to R-chemo in previously untreated FL pts. Acknowledgement: GALLIUM was sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of William Townsend, was provided by Louise Profit and Stephanie Lacey of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Clinical trial information: NCT01332968 .
Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial.
Authors: Al-Sawaf Othman , Zhang Can , Tandon Maneesh , Sinha Arijit , Fink Anna Maria , Robrecht Sandra , Tausch Eugen , Schary William L. , Ritgen Matthias , Wendtner Clemens Martin , Kreuzer Karl A , Eichhorst Barbara , Stilgenbauer Stephan , Hallek Michael J. , Fischer Kirsten ,   CLL14 Study Investigators
Published: May 2020

8027

Background: The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG) in patients with previously untreated CLL and coexisting conditions. Here, we report follow-up data on safety and efficacy. Methods: Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. Primary endpoint was investigator-assessed progression-free survival. Key secondary endpoints were response rates, rates of minimal residual disease (measured every 6 months up to 5 years after last patient enrolment) and overall survival. Follow-up is ongoing but all patients are off study treatment. This trial was registered with ClinicalTrials.gov, number NCT02242942. Results: Of the 432 enrolled patients, 216 were randomly assigned to receive VenG and 216 to receive ClbG. After a median follow-up of 39.6 months (interquartile range 36.75 - 43.04), progression-free survival continued to be superior for VenG as compared to ClbG (median not reached vs 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p < 0.001). At 3 years, the estimated progression-free survival rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status. Of note, PFS was also significantly longer for VenG treated patients with mutated IGHV status. Assessment of minimal residual disease 18 months after end of treatment showed that 47.2% of patients in the VenG arm had undetectable (u) uMRD ( < 10−4), 13% had low (L)-MRD (≥ 10−4 and < 10−2) and 7.9% high (H)-MRD (≥ 10−2), compared to 7.4% uMRD, 17.1% L-MRD, 26.9% H-MRD in the ClbG arm. No difference has been observed (HR 1.027, 95% CI 0.602-1.753, p = 0.921) for overall survival; median overall survival has not been reached in either group. Second primary malignancies were reported in 36 (17%) patients in the VenG arm and 22 (10.3%) in the ClbG arm. No new safety signals were observed. Conclusions: The results suggest that the superior efficacy and deep remissions after fixed-duration VenG are maintained during extended follow-up, and show the long-term benefits of 12 cycles of VenG across all known risk categories. Clinical trial information: NCT02242942 .
Effect of antibiotic use prior to or concurrent with immune checkpoint inhibitors on outcomes in patients with Hodgkin lymphoma.
Authors: Hwang Steven R , Higgins Alexandra , LaPlant Betsy , Maurer Matthew J. , Ansell Stephen M. , Thanarajasingam Gita , Bennani N. Nora
Published: May 2020

8030

Background: There is growing interest in the identification of modifiable patient-specific factors that may predict response to immune checkpoint inhibitors (ICIs) in classical Hodgkin lymphoma (cHL). Recently, it has been proposed that antibiotic use could decrease the efficacy of ICIs in the treatment of advanced solid malignancies. The objective of our study is to assess whether antibiotic use prior to or concurrent with ICIs is associated with changes in outcomes in patients with cHL. Methods: Patients who received a PD-1 or CTLA-4 blocker for the treatment of cHL at Mayo Clinic Rochester between January 1, 2011 and October 20, 2018 were identified. We conducted a longitudinal retrospective chart review to identify those who received antibiotics within 30 or 90 days prior to initiation or concurrent with ICI therapy. Univariate cox regression analysis was used to assess for an association between antibiotic use and overall survival (OS) and progression-free survival (PFS) within these groups; a time-dependent variable was used for concurrent antibiotic use. Results: A total of sixty-two patients were identified (61% male, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 38 months (range: 4-78). Twenty-one patients (34%) received antibiotics within 90 days of initiation of ICI, of which thirteen (21%) received antibiotics within 30 days. Thirty-five patients (57%) received antibiotics concurrently with ICI. Concurrent and prior antibiotic use within 90 days of ICI were both associated with inferior PFS (concurrent HR = 6.38 [95% CI 3.02-13.47]; 90-day HR = 2.21 [95% CI 1.10-4.47]) and OS (concurrent HR = 8.77 [95% CI 1.91-40.36]; 90-day HR = 2.96 [95% CI 1.09-8.04]). Conclusions: Antibiotic use is associated with inferior outcomes in patients with cHL treated with ICIs in this single institution cohort. This may reflect potential antibiotic effects on the gut microbiome (GMB) and immune system as has been suggested in prior studies. Further confirmatory studies and examination of potential confounding covariates are needed.
Mantle cell lymphoma: initial report from the North American Mantle Cell Lymphoma Consortium.
Authors: Fu Kai , Yu Guohua , Bi Chengfeng , Cheng Hongxia , Smith Lynette , Yuan Ji , Naushad Hina , Link Brian K. , Nichols Craig R. , Barr Paul M. , Kahl Brad S. , Stewart Douglas , Barta Stefan K , Beaven Anne , Advani Ranjana H. , Martin Peter , Greiner Timothy , Weisenburger Dennis , Armitage James O. , Vose Julie
Published: May 2020

8035

Background: The goal of the North American Mantle Cell Lymphoma (MCL) Project is to evaluate the clinical, biological, and genomic markers that affect the outcome of patients with MCL. Methods: We have retrospectively studied the clinical and pathological features of 307/421 patients diagnosed with MCL between January 2000 to December 2012 from 23 institutions across North American. Results: The male to female ratio of MCL patients was 3.5:1, with a median age of 66 years (range: 24-106 years). Approximately 29% of patients (78/269) presented with B symptoms and 257 (257/307, 83.7%) patients had extranodal involvement at diagnosis. Median follow-up was 7.1 years (range, 0.03 to 16.6 years) with the five-year PFS and OS at 27.8%, and 54.4%, respectively. Univariate analysis revealed that the following factors were significantly associated with both inferior OS and PFS ( p< 0.05): older age (≥60 years), presence of B symptoms, advanced Ann Arbor stage, elevated LDH, low platelets (≤100K/ml), blastoid/pleomorphic cytology, Ki67 proliferation ≥30%, circulating tumor cells, no transplantation (vs. transplantation), and allogeneic (vs. autologous) stem cell transplantation. In addition, large tumor size (maximal diameter > 3cm), high WBC ( > 10×103/ml), CD5 or CD23 positivity, and a complex karyotype were associated with inferior OS ( p< 0.05). Multivariate Cox regression analysis showed age (≥ 60y; p= 0.0028, HR = 2.44, 95% CI: 1.36-4.38) and high LDH ( p= 0.0062, HR = 2.19, 95% CI: 1.25-3.84) were the two factors predicting the clinical outcome. MIPI-c, a commonly used prognostic scoring system which includes Ki67, stratified the 100 MCL cases into four group with distinct clinical outcomes ( p< 0.001). Using readily-available clinical and pathological variables, we developed a simple and robust scoring system, MIPI-P (pathology), which consisted of age (≥60 years), LDH (high), Ki67 index (≥30%), Ann Arbor stage (III/IV), and cytological type (blastoid/pleomorphic), each contributing one point. The MIPI-P system stratified 104 MCL cases into three distinct groups ( p< 0.001). Median survival for the different groups were: low grade (0-1 points): 11.8 years; intermediate grade (2-3 points): 4.9 years; and high grade (4-5 points): 1.6 years. We further validated this system in an independent cohort of 33 MCL cases and confirmed that the modified MIPI-P provided robust prognostic predication ( p= 0.014). Conclusions: The clinical and biologic characteristics of MCL can provide information assisting with the prognosis of patients with MCL.
Real-world outcomes of elderly patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T) therapy.
Authors: Fitzgerald Lindsey , Kittai Adam , Nastoupil Loretta J. , Waller Alexandra , Jacobson Caron A. , Saucier Anna , Kamdar Manali K. , Spradley Janet , Denlinger Nathan , Chipman Jonathan , Hu Boyu
Published: May 2020

8039

Background: CAR-T has drastically improved outcomes for R/R DLBCL patients (pts). While CAR-T is now standard of care for the treatment of R/R DLBCL, little is known about its efficacy and toxicity in elderly pts. Methods: We conducted a multi-center retrospective analysis of pts age ≥ 70 years old with R/R DLBCL treated with either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Pt demographics, tumor characteristics, CAR-T data, survival and toxicity outcomes were collected at the time of T cell infusion and follow up. Comorbidities were measured using the cumulative illness rating score (CIRS) and hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Results: A total of 77 pts were analyzed with a median age of 73 (range, 70-88); 30 (39%) pts were age ≥75. Most pts received axi-cel (n = 61, 79%). Unfavorable tumor characteristics included 27 (35%) pts with activated B-cell subtype and 12 (16%) with double/triple hit lymphomas. Median CIRS was 8 (range 0-25) and median HCT-CI was 2 (range 0-9) with significantly higher median CIRS and HCT-CI in pts age ≥75. With a median time to follow up of 5.2 months (m), median progression free survival (PFS) was 12m and median overall survival (OS) was 15.5m. There was no difference in PFS when comparing younger pts (age 70-74) to older pts (age ≥ 75), but median OS was significantly shorter for older pts (7.8m vs. not reached; hazard ratio [HR] 0.46, CI 0.21-0.98; p = 0.04). In a multivariate analysis (MVA) of PFS adjusting for baseline characteristics, HCT-CI > 2 (HR 0.23, CI 0.07-0.77; p = 0.02) and use of axi-cel (HR 0.07, CI 0.02-0.32; p = < 0.001) were associated with worse PFS. Grade 3/4 (Lee criteria) cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) were assessed in MVA adjusting for baseline characteristics. CRS was associated with CIRS ≥6 (odds ratio [OR] 3.92, CI 1.07-14.3; p = 0.002) and use of axi-cel (OR 44.9, CI 8.20-245.6; p = 0.006). CRES was associated with older age (OR 6.10, CI 1.86-20.0; p = 0.003), CIRS ≥6 (OR 3.92, CI 1.07-14.3; p = 0.04) and use of axi-cel (OR 44.9, CI 8.2-245.6; p = < 0.0001). Conclusions: Pts age ≥75 treated with CAR-T had worse OS, but comparable PFS as compared to younger pts. Validated frailty measurements (CIRS) predicted for increased CRS and CRES. Use of axi-cel was associated with worse PFS and increased toxicities in the elderly, but propensity matched scoring analysis will need to confirm this. Additional pts and longer follow up are required to validate these results.
Clinicopathologic features and outcomes of de novo transformed indolent lymphoma.
Authors: Chin Collin K , Cheah Chan , Jain Preetesh , Fowler Nathan Hale , Fayad Luis , Westin Jason , Rodriguez Maria Alma , Noorani Mansoor , Neelapu Sattva Swarup , Hagemeister Fredrick B. , Medeiros L Jeffrey , Vega Francisco , Samaniego Felipe , Flowers Christopher , Nastoupil Loretta J.
Published: May 2020

8061

Background: Untreated transformed indolent lymphoma (unTIL) can present as a composite lymphoma (COM), 2 or more separate sites of disease with one site transformed (discordant; DIS) or following indolent lymphoma sequentially (SEQ). Current practices are guided by small retrospective studies or extrapolated from trials involving non-transformed lymphomas. Methods: 353 patients (pts) with biopsy-proven unTIL treated with curative chemoimmunotherapy between 01/2000 to 01/2019 were included (intention to treat). All indolent B-cell lymphomas (iNHL) were included except CLL/SLL. Patients with MCL and non-DLBCL transformation were excluded. Prior therapy for iNHL was not allowed except one line of non-chemotherapy-based therapy. Kaplan-Meier method was used for time-to-event analysis including progression-free (PFS) and overall survival (OS). Results: 252 (71%) pts presented with COM, 50 (14%) DIS and 51 (14%) SEQ lymphoma. The underlying iNHL was: 308 (87%) follicular lymphoma, 37 (10%) nodal MZL, 7 (2%) MALT lymphoma, and 1 (0.3%) WM. Frontline therapy (FLT) included: RCHOP for 271 (77%), DAEPOCHR for 60 (17%), clinical trial for 7 (2%), BR for 4 (1%), RHCVAD for 2 (1%), RCEOP for 2 (1%), radiation therapy for 2 (1%), RFND for (1%) 2, RCVP for 2 (1%), and rituximab only for 1 (0.3%). 9 (3%) pts had ASCT in first remission. 50 (15%) pts received maintenance rituximab (MR) with fewer cases of HGBL-DH compared to the non-MR cohort (0% v 10%). With a median follow-up of 3.4 years (range 0.1-19.1), 4-year PFS and OS rates were 59% and 88%. By univariate analysis (UVA) the underlying type of iNHL, cell-of-origin and choice of induction therapy (DAEPOCHR v RCHOP) were not associated with inferior outcomes. SEQ transformations were associated with inferior OS on UVA (P = 0.02) which was not significant on multivariable analysis (MVA) (P = 0.3). MVA identified ECOG PS > 1, B symptoms and HGBL-DH as independent prognostic factors for inferior PFS and OS. In patients who achieved PR or greater following FLT, MR was associated with improved PFS on MVA (HR 0.6, 95% CI 0.3-0.9, P = 0.04) without an OS benefit (P = 0.2). 39 (31%) pts relapsed with iNHL only (mPFS 2.4 yrs, 4-yr OS 94%) and 88 (69%) relapsed with transformed lymphoma (mPFS 1.1 yrs, 4-yr OS 69%) with no significant difference in pattern of relapse with MR (P = 0.2). Conclusions: The clinicopathologic features of unTIL are similar to those of de novo DLBCL. Escalation of therapy beyond R-CHOP may not be required in the absence of HGBL-DH. unTIL should be included in future clinical trials involving de novo DLBCL given the similar clinicopathologic features.
DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM).
Authors: Nooka Ajay K. , Stockerl-Goldstein Keith , Quach Hang , Forbes Adam , Mateos Maria-Victoria , Khot Amit , Tan Alan , Abonour Rafat , Chopra Bikramjit , Rogers Rachel , Ferron-Brady Geraldine , Davidge Jacqueline , Frey Steve , Yeakey Anne , Talekar Mala , Luptakova Katarina , Gupta Ira , Popat Rakesh
Published: May 2020

8502

Background: Belantamab mafodotin, a B-cell maturation antigen targeting immunoconjugate, demonstrated clinically meaningful, single-agent activity in patients with heavily pre-treated RRMM refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody (DREAMM-2, NCT03525678, Lancet Oncol.2020). The multimodal mechanism of action and manageable safety profile make belantamab mafodotin a promising candidate for use in different RRMM combination regimens. Methods: DREAMM-6 (NCT03544281) is an ongoing, two-part, two-arm, study evaluating the safety, tolerability, and clinical activity of belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) and lenalidomide/dexamethasone in patients previously treated with ≥1 prior therapy line. Here, we present data for belantamab mafodotin in combination with BorDex. Part 1 (dose escalation) and Part 2 (dose expansion) evaluated belantamab mafodotin (2.5 and 3.4 mg/kg) administered as SINGLE (Day 1) or SPLIT dose (divided equally on Days 1 and 8) in combination with BorDex. Results: As of February 6, 2020, 52 patients were enrolled: 6 patients were enrolled at 2.5 mg/kg single dose and 7 at 3.4 mg/kg single dosing in Part 1, and 45 patients in Part 2. No dose-limiting toxicities were observed. Corneal events (including keratopathy, blurred vision, and dry eye) and thrombocytopenia were the most frequently reported AEs and were clinically manageable. Conclusions: In DREAMM-6, preliminary data demonstrate that the combination of belantamab mafodotin and BorDex has an acceptable safety profile, with no new safety signals identified. Funding: GlaxoSmithKline (207497). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281 .