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Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800–999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of

This study used a real-world population as a synthetic comparator for the single-arm TRANSCEND NHL 001 study (TRANSCEND; NCT02631044) to evaluate the efficacy of lisocabtagene maraleucel (liso-cel) compared with conventional (noncellular) therapies in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Inclusion and exclusion criteria for the real-world study closely matched the enrollment criteria in TRANSCEND. The analytic comparator cohort was created by matching and balancing observed baseline characteristics of real-world patients with those in TRANSCEND using propensity score methodology. Efficacy outcomes comparing liso-cel– (n = 257) and conventional therapy–treated (n = 257) patients, respectively, significantly favored liso-cel: overall response rate (74% vs 39%; p < 0.0001), complete response rate (50% vs 24%; p < 0.0001), median overall survival (23.5 vs 6.8 months; p < 0.0001), and median progression-free survival (3.5 vs 2.2 months; p < 0.0001). These results demonstrated a statistically significant and clinically meaningful benefit of liso-cel in patients with third- or later-line R/R LBCL relative to conventional therapies. Clinical trial registration: ClinicalTrials.gov identifier: NCT02631044.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine (Ara-C), but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared to cells with monoallelic mutation. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients.

Background: novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population.Methods: this was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 μg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235.Findings: between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 μg/kg and 45 μg/kg for patients with classical Hodgkin lymphoma and 80 μg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81).Interpretation: these results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma.Funding: ADC Therapeutics.

Background: Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G, et al. Lancet Oncol 2020, Duell J, et al. Haematologica 2021). Here, we report the final, 5-year follow-up of L-MIND. Data cut-off was Nov 14, 2022. Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, 1-3 prior systemic therapies (including a CD20-targeting regimen), and ECOG PS 0-2. Tafasitamab (12 mg/kg) was given for up to 12 cycles in combination with LEN (25 mg), then as monotherapy until disease progression (PD) or unacceptable toxicity. The primary endpoint was best objective response rate (ORR; complete response [CR] or partial response [PR], by independent radiology committee). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). Exploratory analyses evaluated efficacy endpoints by prior lines of therapy (pLoT). Results: Of 81 pts enrolled, 80 were treated (full analysis set [FAS]). The ORR (FAS) of 57.5% [95% CI: 45.9-68.5], with CR of 41.2% [30.4-51.6] (n=33) and PR of 16.2% [8.9-26.2] (n=13), was generally consistent with the primary and 3-year analyses. Median DoR was not reached (NR) with median follow up (mFU) of 44.0 months [29.9-57.0]. Median PFS was 11.6 months [5.7-45.7] (mFU 45.6 [22.9-57.6]) and median OS was 33.5 months [18.3-NR] (mFU 65.6 [59.9-70.3]). At data cut-off, OS was >60 months in 21 pts (18 with best response of CR, 1 PR, 1 stable disease and 1 PD), including 14 with 1 pLoT and 7 with ≥2 pLoT. Pts with 1 pLoT (n=40) in the FAS had higher ORR (67.5%; 52.5% CR [n=21] and 15% PR [n=6]) compared to pts with ≥2 pLoT (n=40; 47.5%; 30% CR [n=12] and 17.5% PR [n=7]). However, median DoR was not reached for both subgroups, indicating similar long-term efficacy for responders. AEs were consistent with previous reports and manageable; incidence declined after transition from combination to tafasitamab monotherapy and again with monotherapy >2 years. Conclusion: The final, 5-year analysis of L-MIND showed prolonged durable responses with tafasitamab + LEN combination therapy, followed by long-term tafasitamab monotherapy, in pts with R/R DLBCL ineligible for ASCT, with median DoR not reached after 44 months mFU. No new safety signals were identified, confirming the tolerability profile observed with earlier data cuts. These long-term data suggest that this immunotherapy may have curative potential that is being explored in further studies. Citation Format: Johannes Duell, Pau Abrisqueta, Marc Andre, Marinela Augustin, Gianluca Gaidano, Eva González Barca, Wojciech Jurczak, Nagesh Kalakonda, Anna Marina Liberati, Kami J. Maddocks, Tobias Menne, Zsolt Nagy, Olivier Tournilhac, Abhishek Bakuli, Aasim Amin, Konstantin Gurbanov, Gilles Salles. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT022.

SUMMARYSARS-CoV-2 vaccination protects against COVID-19. Antibodies and antigen-specific T-cell responses against the spike domain can be used to measure vaccine immune response. Individuals with lymphoma have defects in humoral and cellular immunity that may compromise vaccine response. In this prospective observational study of 457 participants with lymphoma, 52% of participants vaccinated on treatment had undetectable anti-spike IgG antibodies compared to 9% who were not on treatment. Marked impairment was observed in those receiving anti- CD20 antibody within 12 months where 60% had undetectable antibodies compared to 11% on chemotherapy, which persisted despite three vaccine doses. Overall, 63% had positive T-cell responses irrespective of treatment. Individuals with indolent B-cell lymphoma have impaired antibody and cellular responses that were independent of treatment. The significant reduction and heterogeneity in immune responses in these individuals emphasise the urgent need for immune response monitoring and alternative prophylactic strategies to protect against COVID- 19.

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study (NCT04858568) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60%53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients.

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Background:\ud Hickman-type tunnelled catheters (Hickman), peripherally inserted central catheters (PICCs), and totally implanted ports (PORTs) are used to deliver systemic anticancer treatment (SACT) via a central vein. We aimed to compare complication rates and costs of the three devices to establish acceptability, clinical effectiveness, and cost-effectiveness of the devices for patients receiving SACT.\ud Methods:\ud We did an open-label, multicentre, randomised controlled trial (Cancer and Venous Access [CAVA]) of three central venous access devices: PICCs versus Hickman (non-inferiority; 10% margin); PORTs versus Hickman (superiority; 15% margin); and PORTs versus PICCs (superiority; 15% margin). Adults (aged ≥18 years) receiving SACT (≥12 weeks) for solid or haematological malignancy from 18 oncology units in the UK were included. Four randomisation options were available: Hickman versus PICCs versus PORTs (2:2:1), PICCs versus Hickman (1:1), PORTs versus Hickman (1:1), and PORTs versus PICCs (1:1). Randomisation was done using a minimisation algorithm stratifying by centre, body-mass index, type of cancer, device history, and treatment mode. The primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up. This study is registered with ISRCTN, ISRCTN44504648.\ud Findings:\ud Between Nov 8, 2013, and Feb 28, 2018, of 2714 individuals screened for eligibility, 1061 were enrolled and randomly assigned, contributing to the relevant comparison or comparisons (PICC vs Hickman n=424, 212 [50%] on PICC and 212 [50%] on Hickman; PORT vs Hickman n=556, 253 [46%] on PORT and 303 [54%] on Hickman; and PORT vs PICC n=346, 147 [42%] on PORT and 199 [58%] on PICC). Similar complication rates were observed for PICCs (110 [52%] of 212) and Hickman (103 [49%] of 212). Although the observed difference was less than 10%, non-inferiority of PICCs was not confirmed (odds ratio [OR] 1·15 [95% CI 0·78–1·71]) potentially due to inadequate power. PORTs were superior to Hickman with a complication rate of 29% (73 of 253) versus 43% (131 of 303; OR 0·54 [95% CI 0·37–0·77]). PORTs were superior to PICCs with a complication rate of 32% (47 of 147) versus 47% (93 of 199; OR 0·52 [0·33–0·83]).\ud Interpretation:\ud For most patients receiving SACT, PORTs are more effective and safer than both Hickman and PICCs. Our findings suggest that most patients receiving SACT for solid tumours should receive a PORT within the UK National Health Service.\ud Funding:\ud UK National Institute for Health Research Health Technology Assessment Programme.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we performed a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identified a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identified a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N=1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology by identifying putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5’-azacitidine (5’-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5’-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5’-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5’-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.Key PointsMutant TET2 allele dosage affects response to 5’-azacitidine in acute myeloid leukemia in vitro and in a xenograft model.Our data highlight the importance for screening of biallelic mutations to predict response to therapy in acute myeloid leukemia.

Tafasitamab; B-cell lymphoma Tafasitamab; Linfoma de células B Tafasitamab; Limfoma de cèl·lules B Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months’ follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months’ follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.

Introduction: Chimeric Antigen Receptor T-cell therapy (CAR-T) is a potentially life-saving treatment for refractory haematological malignancies. Many UK CAR-T services are in their infancy. Patient perspectives on service delivery, treatment toxicity and impact on health related quality of life (HRQoL) are lacking. This qualitative evaluation aimed to explore the patient and carer experience of CAR-T and identify areas for service improvement. Methods: Patients who received CAR-T between April 2019 and March 2021 at the Freeman Hospital, Newcastle-upon-Tyne, who attended primary or follow-up appointments between December 2020 and March 2021 were asked if they wanted to take part in the evaluation. 16 semi-structured qualitative interviews were carried out with 10 patients and 4 carers at specific time points in the patient journey: hospital admission prior to CAR T-cell infusion, day 28 postinfusion and routine follow-up appointments after treatment (8, 9, 12 and 18 months). Five patients completed 2 interviews (pre-infusion and day 28). Results: The mean age of the patients was 54 and 60% were female. Nine patients had diffuse large B-cell lymphoma and one had primary mediastinal B-cell lymphoma. Inductive thematic analysis identified three main themes. The importance of the CAR-T nurse specialist as a point of contact was consistently identified by patients and carers as vital to navigating the treatment process. The continuity of care and approachability associated with this role were linked to patient satisfaction and perceived level of support received. Reported treatment toxicity centred on fatigue, poor appetite/weight loss and problems with memory and cognition. Patients and carers were well prepared for side effects in the acute treatment phase but some felt less prepared for prolonged impact on physical function and cognition after discharge. CAR-T therapy was viewed as a 'lifeline,' but the uncertainty of treatment outcome caused significant anxiety, disruption to employment and family life, and made it difficult to make future plans. Many responses were framed by the COVID-19 pandemic which increased feelings of isolation and vulnerability and had a significant, negative impact on HRQoL. Conclusions: To our knowledge this is the first qualitative work exploring the views of CAR-T patients and carers at multiple points in the patient journey, including perspectives on long-term treatment impact. Considerations for service creation and development nationally and internationally include: the importance of a dedicated nurse specialist, preparing patients for and supporting them with prolonged treatment side effects, and the psychological challenges associated with prognostic uncertainty. Expanding indications of CAR-T therapy mean there is an urgent need for multi-centre studies incorporating patient-reported outcome data to inform patient centred care and service delivery.

Introduction The phase 3 ECHELON-2 study (NCT01777152) demonstrated that frontline treatment with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL) (Horowitz S, et al. Lancet 2019). With a median follow-up of 36.2 months for progression-free survival (PFS), the hazard ratio (HR) (0.71 [95% confidence interval {CI}: 0.54, 0.93], P=0.01) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. With a median follow-up of 42.1 months for overall survival (OS), the HR (0.66 [95% CI: 0.46, 0.95], P=0.02) also favored A+CHP over CHOP. Median OS was not reached for either arm. With these results, A+CHP was the first treatment regimen to show an OS benefit over CHOP in this pt population. Herein, we report results with a median follow-up of 44.3 months for PFS and 55.5 months for OS. Methods ECHELON-2 is a phase 3, randomized, double-blind, double-dummy, placebo-controlled, active-comparator, multicenter study. Eligible adult pts with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) were randomized to A+CHP or CHOP for six or eight cycles. Randomization was stratified by histological subtype and international prognostic index score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this updated analysis. Key secondary endpoints were OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR). Subsequent therapies, including BV or BV-containing regimens, were permitted. Results A total of 452 pts were enrolled and randomized 1:1 with 226 pts in each arm. The study included pts with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]); given target enrollment, most pts (316 [70%]) had sALCL (218 [48%] anaplastic lymphoma kinase [ALK]-negative and 98 pts [22%] ALK-positive). With additional follow-up, the HRs for PFS per investigator (0.70 [95% CI: 0.53, 0.91], P=0.0075) (Figure 1) and OS (0.74 [95% CI: 0.54, 1.02], P=0.0688) continue to favor A+CHP over CHOP. The median PFS was 63.5 months (95% CI: 42.0, not evaluable) versus 23.8 months (95% CI: 13.6, 55.9) for A+CHP and CHOP, respectively. The estimated 5-year PFS was 50.9% (95% CI: 42.1, 59.1) for the A+CHP arm versus 42.7% (95% CI: 35.3, 49.8) for the CHOP arm. Median OS was not reached for either arm. The estimated 5-year OS was 68.7% (95% CI: 61.3, 75.0) for the A+CHP arm versus 60.3% (95% CI: 52.8, 67.0) for the CHOP arm. The PFS analyses for key prespecified subgroups were generally consistent with the overall study results (Figure 2). In the subset of pts with sALCL, the HR for PFS (0.55 [95% CI: 0.39, 0.78]) also favors A+CHP over CHOP, with an estimated 5-year PFS of 59.8% (95% CI: 48.0, 69.7) for the A+CHP arm versus 48.1% (95% CI: 39.1, 56.6) for the CHOP arm. A total of 23 pts (10%) in the A+CHP arm (16 pts with sALCL, 4 pts with PTCL not otherwise specified, and 3 pts with angioimmunoblastic T-cell lymphoma) and 51 pts (23%) in the CHOP arm received subsequent systemic therapy with BV. In the A+CHP arm, the median time to retreatment was 12.3 months (range, 3, 51); 15 pts (ORR: 65%) had CR (9 pts) or partial remission (6 pts) after retreatment with BV monotherapy (21 pts) or BV-containing regimen (2 pts). With additional follow-up in pts with treatment-emergent peripheral neuropathy (PN) (117 pts A+CHP and 124 pts CHOP), 68% of pts in the A+CHP arm had either resolution or improvement of these events compared with 77% of pts in the CHOP arm. Of the pts with ongoing PN events at last follow-up, 73% in A+CHP arm and 74% in the CHOP arm had grade 1 events, 25% and 23% of pts, respectively, had grade 2 events, and 2% of pts in each arm had grade 3 events. Conclusions At 5 years, frontline treatment with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, including ongoing remission in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of PN. Additional 5-year results, including data from prespecified subgroups, will be presented. Disclosures Horwitz: C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Affirmed: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; ASTEX: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding. Pro:Verastem Oncology: Research Funding. Illidge:Takeda: Current Employment, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Iyer:Legend Biotech: Consultancy; Rhizen: Research Funding; Spectrum: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Bartlett:BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy; Forty Seven: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; BMS/Celgene: Research Funding; Roche/Genentech: Consultancy, Research Funding. Christensen:Odense University Hospital: Current Employment; Seattle Genetics, Inc.: Research Funding. Morschhauser:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Domingo-Domenech:Takeda: Consultancy, Other: Travel, accomodations and expenses , Research Funding; Bristol-Myers Squibb: Other: Travel, Research Funding; Roche: Other: Travel, accomodations and expenses ; Janssen: Other: Travel, accomodations and expenses ; Seattle Genetics, Inc.: Research Funding. Rossi:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Kim:Donga: Research Funding; Joihnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Research Funding; Celltrion: Research Funding. Feldman:Celgene: Honoraria, Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Rhizen: Research Funding; Janssen: Speakers Bureau; Pharmacyclics: Honoraria, Other, Speakers Bureau; AstraZeneca: Consultancy; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Pfizer: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Trillium: Research Funding; Portola: Research Funding; Corvus: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding. Menne:Daiichi Sankyo: Honoraria; Kyowa Kirin: Other: Travel expenses; Pfizer: Honoraria, Other; Roche: Honoraria; Bayer: Other: Travel expenses; Kite/Gilead: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel expenses; Takeda: Honoraria; Atara: Honoraria; AstraZeneca: Research Funding; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding. Belada:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding. Illés:Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharma: Consultancy, Honoraria; Solasia: Honoraria; SymBio: Consultancy; Takeda: Consultancy, Honoraria; HUYA Bioscience: Consultancy, Honoraria; Eisai: Honoraria; Yakult: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Chugai Pharma: Consultancy, Honoraria. Tsukasaki:Ono Pharma: Consultancy; Mundy Pharma: Honoraria; HUYA: Consultancy, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Eizai: Research Funding; Seattle Genetics: Research Funding. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Shustov:Seattle Genetics: Research Funding. Hüttmann:Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment. Savage:Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Zinzani:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miao:Takeda: Current equity holder in publicly-traded company. Bunn:Seattle Genetics: Research Funding; Takeda: Current Employment. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Puhlmann:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Truemper:Janssen: Consultancy; Mundipharma: Research Funding; Nordic Nanovector: Consultancy; Roche: Research Funding; Seattle Genetics: Research Funding; Takeda Europe: Consultancy, Research Funding.

Aim: The objective of this study was to establish the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of talazoparib. Patients & methods: This Phase I, two-cohort, dose-escalation trial evaluated talazoparib monotherapy in advanced hematologic malignancies (cohort 1: acute myeloid leukemia/myelodysplastic syndrome; cohort 2: chronic lymphocytic leukemia/mantle cell lymphoma). Results: Thirty-three (cohort 1: n = 25; cohort 2: n = 8) patients received talazoparib (0.1–2.0 mg once daily). The MTD was exceeded at 2.0 mg/day in cohort 1 and at 0.9 mg/day in cohort 2. Grade ≥3 adverse events were primarily hematologic. Eighteen (54.5%) patients reported stable disease. Conclusion: Talazoparib is relatively well tolerated in hematologic malignancies, with a similar MTD as in solid tumors, and shows preliminary anti leukemic activity. Clinical trial registration: NCT01399840 (ClinicalTrials.gov), Lay abstract The objective of this study was to define the highest dose of talazoparib that people with various types of leukemia (mainly various blood cancers) could tolerate. People were assigned into two cohorts based on their type of leukemia: cohort 1 included 25 people with acute myeloid leukemia or myelodysplastic syndrome; cohort 2 included 8 people with chronic lymphocytic leukemia or mantle cell lymphoma. Similar to what researchers observed for people with solid tumors, the highest tolerated dose was 1.35 mg per day in cohort 1, and it was estimated to be ∼0.9 mg per day in cohort 2. Side effects that occurred during the study were expected, given the types of leukemia being treated. Talazoparib also showed promising anti leukemic effects in some patients., Tweetable abstract In this Phase I talazoparib trial in hematologic malignancies (cohort 1: AML/MDS, n = 25; cohort 2: CLL/MCL, n = 8), the maximum tolerated dose was exceeded at 2.0 and 0.9 mg/day in cohorts 1 and 2, respectively. Stable disease and transfusion independence were also observed.

IntroductionEvent free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30-50%, with 5-year survival for adult patients only 20%. A large proportion of patients with newly diagnosed and relapsed ALL harbour somatic mutations that activate the RAS-signalling cascade. Steroids are a backbone of all induction blocks of ALL therapy, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886), results in a potent synergistic anti-cancer effect.Methods and analysisThe SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Münster, Germany; Paris, France; and Utrecht, Netherlands. Paediatric centres are all part of the Innovative Therapies for Children with Cancer consortium. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are ≥18 years old, ECOG ≤2 and paediatric Ethics and disseminationMedical ethical committees of all the participating countries will approve the study protocol. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registration numberThe trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.GovNCT03705507, and ITCC-063 study.Strengths and limitations of this studyNovel combination of the MEK1/2 inhibitor, selumetinib, with dexamethasoneSeamless phase I/II Bayesian trial design with a Continual Reassessment Method for dose escalation in phase IParallel cohort trial design of adult and paediatric patients within one protocolAvailability of CAR T-cell therapy since this trial started recruitment has competed for the same patient populationOffers a bridging treatment option for patients awaiting CAR T-cell therapy outside clinical studies or at relapse after CAR-T treatment

Content: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can have serious complications. In this disorder, autoantibodies bind to antigens on red blood cells leading to phagocytosis and destruction of the cells. This is mediated by Fcg receptors on macrophages through a spleen tyrosine kinase (SYK)-dependent pathway. Fostamatinib is a potent, oral SYK inhibitor approved for the treatment of chronic immune thrombocytopenia. Fostamatinib prevents platelet destruction by inhibition of platelet phagocytosis mediated through Fcg receptor and SYK in macrophages. Fostamatinib was evaluated for wAIHA in an open-label, multicenter, phase 2 study (NCT02612558). This study demonstrated markedly improved hemoglobin levels in 11 of 25 patients (44%) after fostamatinib treatment. Adverse events (AEs) were consistent with the safety database (>4000 patients across multiple diseases). Based on this phase 2 study, a randomized, double-blind, placebo-controlled, global phase 3 study (NCT03764618) was initiated in wAIHA patients to investigate the safety and efficacy of fostamatinib. The phase 3 study began enrolling patients at 103 sites in 22 countries (North America, Europe and Australia) in 2020 with a goal of enrolling approximately 90 patients. This is the first phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA. Inclusion criteria include: age ?18;documented diagnosis of primary or secondary wAIHA;failure of ?1 prior wAIHA treatment;haptoglobin below normal or total bilirubin above normal or lactate dehydrogenase above normal;and baseline hemoglobin ?9 g/dl or, if hemoglobin >9 g/dl and 1.5 x normal. Randomization of eligible patients will be 1:1 to fostamatinib or placebo for 24 weeks. Randomized patients will be stratified by concomitant steroid use and baseline anemia severity. Fostamatinib is started at 100 mg BID and increased to 150 mg BID at Week 4, if tolerated. The dose may be reduced for AEs. Patients may continue selected concurrent wAIHA therapies (maximum of 2) throughout the study. A steroid taper will be allowed in patients with a hemoglobin response. Rescue therapy will also be allowed. Patients who complete the study can rollover to an open-label extension. Efficacy endpoints will include hemoglobin response, ( ?10 g/dl with a ?2 g/dl increase from baseline without rescue therapy);duration of hemoglobin response;and the need for rescue therapy. Safety endpoints will be the recording of AEs. Patients will be evaluated in the clinic at two-week intervals. Using the Cochran Mantel Haenszel test at a two-sided significance level of 0.05, to detect a difference in response between the active and placebo groups with 80% power would require 90 subjects randomized 1:1. The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. As of 11 January 2021, 62 sites are open to screening (subject to local COVID-19 regulations), and 64 patients have been randomized.