Background Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Tinostamustine was well tolerated, ...with signals of efficacy, during the dose-escalation stage of a Phase I study in patients with relapsed/refractory (R/R) haematological malignancies (Zinzani et al. HemaSphere 2019;3(S1):102:PF300) and for patients with HL in the cohort-expansion stage (Ghesquières et al. Blood 2021;138(S1):2472; Sureda et al. Blood 2022;140(S1):3696). Aims We report safety and efficacy findings from patients with advanced haematological malignancies including HL, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), T-cell prolymphocytic leukaemia (T-PLL) and MM treated with tinostamustine in the expansion cohorts of a Phase I study. Methods Patients with advanced haematological malignancies, for whom no standard treatment with proven clinical benefit was available or recommended, were recruited to receive the recommended Phase II dose of tinostamustine. Patients with HL must have received ≥2 lines of prior therapy, CTCL 1-4 prior standard systemic therapies, PTCL >1 prior line of combination therapy, T-PLL ≥1 prior line of therapy and MM ≥1 prior systemic therapy. Adverse events (AEs) were assessed for severity using US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03, June 2010; for QTc prolongations CTCAE version 5.0 was used). Treatment-related AEs, fatal AEs, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Primary efficacy objectives were to estimate the overall response rate (ORR; complete response CR + partial response PR) and clinical benefit rate (CBR; CR + PR + stable disease ≥4 cycles SD) for each cohort and to evaluate the safety of tinostamustine. Secondary efficacy variables included progression-free survival (PFS) and overall survival (OS); all outcomes were evaluated from Cycle 3 until progression or toxicity. Results 48 patients with advanced haematological malignancies were enrolled to the study and received treatment with tinostamustine (HL, n=20; CTCL, n=13; PTCL, n=8; T-PLL, n=1; MM, n=6; Table). Patients with HL, CTCL, PTCL and T-PLL received 50 mg/m 2 (1 patient), 80 mg/m 2 (7 patients) and 100 mg/m 2 (34 patients) over 60 minutes on Day 1 of a 21-day cycle; patients with MM: 60 mg/m 2 over 60 minutes on Day 1 and Day 15 of a 28-day cycle. Patients received a median of 3.5 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed. Treatment-emergent AEs (TEAEs) occurred in 46/48 (95.8%) patients (500 events), with 28 patients experiencing 90 events ≥Grade 3. Gastrointestinal AEs were observed in 33/48 patients, the majority of which were nausea or vomiting. Haematological AEs, including thrombocytopenia, anaemia and neutropenia, occurred in 27/48 patients. Serious TEAEs considered related to tinostamustine occurred in 11 patients with HL or CTCL ( Table) and included thrombocytopenia (n=3) and infusion-related reaction (n=1); one patient with CTCL experienced a fatal TEAE of decreased appetite. Overall, 22/48 (45.8%) patients discontinued due to progressive disease and 13/48 (21.6%) discontinued due to AEs. In the 46 patients included in the efficacy analysis, ORR was 30.4% (95% confidence interval CI: 17.7%, 45.8%) and CBR 52.2% (95% CI: 36.9%, 67.1%). 4 patients achieved a CR (2 patients with HL, 2 CTCL), 10 a PR (5 HL, 4 CTCL, 1 PTCL) and 14 SD (4 HL, 4 CTCL, 3 PTCL, 3 MM). Median PFS was 4.3 months (95% CI: 2.7, 6.6 months; HL, 3.8 2.2, 9.4 months; CTCL, 7.3 3.2, not estimable (NE) months; PTCL, 2.6 1.4, NE months; T-PLL, 0.5 NE, NE months; MM, 2.4 1.4, NE months;). Median OS was 10.3 (95% CI: 2.2, NE) months for PTCL, 5.6 (95% CI: NE, NE) months for T-PLL and not estimable for HL, CTCL and MM. Conclusions Results from expansion cohorts further demonstrate that tinostamustine has manageable tolerability in patients with advanced haematological malignancies with no unexpected AEs. The principal TEAEs were haematological and gastrointestinal. An ORR of 30.4% and a median progression-free survival of 4.3 months were observed, revealing signals of efficacy in this heavily pre-treated patient population for whom no other standard therapy with proven clinical benefit was available or recommended. Funding: Mundipharma Research Limited and Purdue Pharma, LP
7013 Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. In prespecified interim and primary analyses of TRANSFORM (NCT03575351), liso-cel showed significant improvements ...in efficacy vs SOC in pts with R/R LBCL. Here we report results after ~3-y FU. Methods: TRANSFORM is a randomized phase 3 study comparing liso-cel vs SOC (CT R-DHAP, R-ICE, or R-GDP then high-dose CT HDCT + ASCT) in adults aged ≤ 75 y with LBCL primary refractory to or relapsed ≤ 12 mo after first-line therapy and eligible for ASCT. Liso-cel arm pts underwent lymphodepletion followed by liso-cel (100 × 10 6 CAR + T cells). Bridging therapy was allowed. SOC arm pts received 3 cycles of CT; responding pts proceeded to HDCT + ASCT. Crossover to receive liso-cel was allowed for SOC arm pts if criteria were met. The primary endpoint was event-free survival (EFS) per independent review committee (IRC). Key secondary endpoints included CR rate and PFS per IRC, and OS. Endpoints were not statistically retested and are reported descriptively. Results: In total, 184 pts were randomized (92 per arm); baseline characteristics were reported (Abramson et al. Blood 2023). Median (range) FU was 33.9 mo (0.9–53.0). Median EFS, PFS, and duration of response (DOR) were longer for liso-cel vs SOC, similar to the primary analysis (Table). A total of 61 (66%) SOC arm pts crossed over to receive liso-cel. Median OS was not reached (NR) in either arm; 36-mo OS rates were numerically higher for liso-cel. Of 76 total deaths (liso-cel, n = 34; SOC, n = 42 crossover pts, n = 33), 10 occurred since the primary analysis (liso-cel, n = 6; SOC, n = 4 all crossover pts); most were due to disease progression or complications (n = 6). Safety results were consistent with the primary analysis. Cellular kinetics and B-cell aplasia will be presented. Conclusions: After median FU of 33.9 mo, liso-cel as 2L treatment in pts with primary refractory or early relapsed LBCL resulted in deepening of response and continued improvement in efficacy endpoints over SOC, confirming the ongoing benefit of liso-cel. Clinical trial information: NCT03575351 . Table: see text
Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide ...registry was developed for patients with cancer and COVID-19.
This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible.
Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years).
The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered.
•Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19).•This nationwide study investigated risk factors for fatal outcome of COVID-19.•Among 442 registered patients with cancer, 32.3% of patients died of COVID-19.•Haematological malignancy and lung cancer increased the risk of fatal outcome.•These results can guide treatment and vaccination decisions in patients with cancer.
Introduction Patients (pts) with high grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 gene rearrangements (double hit and triple hit (DH/TH)) have poor outcomes to standard R-CHOP. ...Retrospective studies reported improved disease-free survival (DFS) through intensification with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). This regimen was studied in a small prospective trial including 24 DH/TH and 19 single MYC rearranged (SH) lymphomas (Dunleavy, Lancet Haematol 2019). No prospective studies evaluating DA-EPOCH-R exclusively for pts with DH/TH HGBL have been reported. The HOVON-152 trial aimed to improve outcomes in untreated DH/TH HGBL pts by investigating the efficacy of the immune checkpoint inhibitor nivolumab as consolidation treatment in pts achieving complete metabolic response (CMR) after DA-EPOCH-R induction. Here, we present the efficacy and safety profile of the induction phase with DA-EPOCH-R. Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria were pts with newly diagnosed HGBL-DH/TH (according to the WHO 2016 classification), age ≥ 18 years, WHO performance status (PS) 0-3 and Ann Arbor stage II-IV. During the screening period for rearrangement status, pts could receive 1 cycle of R-CHOP or DA-EPOCH-R, followed by 5 cycles of DA-EPOCH-R. All pts received intrathecal CNS prophylaxis. All diagnostic lymphoma samples were centrally reviewed. PET-CT scans were performed at diagnosis, after 3 cycles and at end-of-induction (local review, central review will be reported at the conference). Pts in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceeded to nivolumab consolidation (480 mg every 4 weeks for one year). The HOVON-152 aimed to improve 12 months DFS of pts in CMR after induction from an expected 70% to 85% with nivolumab consolidation. Secondary objectives included evaluation of response rates, overall survival (OS) and safety. With a power of 0.90 a sample size of 97 pts was calculated. Here, we report efficacy (CMR rate) and safety of DA-EPOCH-R induction treatment. Logistic univariate analysis is used to analyze baseline characteristics associated with response. Adverse events (AEs) were defined according to the common terminology criteria for adverse events (CTC AE 5.0), counted by the highest grade per system organ class per patient. Results From August 2018 - March 2022, 97 pts have been enrolled (study inclusion completed). One patient was excluded due to CNS localization. The median age was 62 years (range 35-79); 90 (83%) pts had stage III-IV disease and 52 (54%) had (intermediate-)high international prognostic index (IPI) (Table 1). Central pathology review confirmed DH/TH in all pts. 65 pts (67%) had a BCL2 DH, 11 (12%) a BCL6 DH and 16 (17%) a TH. Dose adjustments were performed conform protocol. The maximum dose-level (DL) achieved was DL1 in 41 (43%), DL2 in 22 (23%), DL3 in 25 (25%), DL4 in 7 (7%) and DL5 in 1 (1%) of the pts. Vincristine dose was reduced in 28/81 (35%) pts. After DA-EPOCH-R induction, 63/96 (66%, 95% CI 55-75%) pts achieved CMR. WHO PS 2-3 (odds ratio (OR) 0.15, 95% CI 0.03-0.85, p=0.03), elevated LDH (OR 0.24, 95%CI 0.10-0.59, p=0.002) and bulky disease defined as ≥10 cm mass (OR 0.23, 95%CI 0.09-0.56, p=0.001), were significantly associated with a lower chance of achieving CMR. During treatment, 7 (7%) pts experienced a grade 5 AE (ileus, intestinal perforation, multi-organ failure/sepsis). Thereof, 4 patients died during DA-EPOCH-R and 3 patients died after DA-EPOCH-R. 31 (32%) experienced a grade 4 AE (e.g. sepsis, perforation, hemorrhage, thrombocytopenia and neutropenia), 21 (22%) a grade 3 AE (e.g. anemia, mucositis, infections and electrolyte disturbances) and 16 (17%) pts a grade 2 AE. Conclusion We report the largest prospective series of DH/TH HGBL patients treated with DA-EPOCH-R. DA-EPOCH-R induction was feasible, with toxicity and dose adjustments as previously described. The observed CMR rate of 66% was lower than previously reported in a prospective cohort of mixed DH/TH and SH patients (74%). For patients achieving CMR, the nivolumab consolidation phase is ongoing. Translational side studies investigating predictive factors to identify patients not achieving CMR are ongoing. For these patients, novel strategies to improve first-line treatment are warranted.
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