Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of matched targeted therapies in people with relapsed or metastatic cancer in phase I, II and III trials.

Background Procarbazine-containing chemotherapy regimens associate with cytopenias and infertility, suggesting stem cell toxicity. Procarbazine in eBEACOPP (escalated dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity, although limited genomic and clinical data support this substitution. Methods To assess mutagenic and clinical consequences of dacarbazine-procarbazine substitutions, we compared mutational landscapes in haematopoietic stem and progenitor cells (HSPCs) from patients treated with different Hodgkin regimens and children, sperm and bowel tissue from procarbazine-treated patients. We compared efficacy and toxicity data of a multicentre eBEACOPDac-treated patient cohort, with eBEACOPP clinical trial and real-world datasets. Results eBEACOPP-treated patients exhibit a higher burden of point mutations, small insertions and deletions in HSPCs compared to eBEACOPDac and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-treated patients. Two novel mutational signatures, SBSA (SBS25-like) and SBSB were identified in HSPCs, neoplastic and normal colon from only procarbazine-treated patients. SBSB was also identified in germline DNA of three children conceived post-eBEACOPP and sperm of an eBEACOPP-treated male. The dacarbazine substitution did not appear to compromise efficacy; 3-year progression-free survival of 312 eBEACOPDac patients (93.3%; CI95=90.3-96.4%) mirrored that of 1945 HD18-trial eBEACOPP patients (93.3%; CI95=92.1-94.4%). eBEACOPDac-treated patients required fewer blood transfusions, demonstrated higher post-chemotherapy sperm concentrations, and experienced earlier resumption of menstrual periods. Conclusions Procarbazine induces a higher mutational burden and novel mutational signatures in eBEACOPP-treated patients and their germline DNA raising concerns for hereditary consequences. However, replacing procarbazine with dacarbazine appears to mitigate gonadal and stem cell toxicity while maintaining comparable clinical efficacy.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThe study was funded by the Addenbrooke's Charitable Trust. The study was funded by the Wellcome Trust.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Health Research Authority of England and Wales gave ethical approval for this work. The Public Benefit and Privacy Panel of Scotland gave ethical approval for this work. The NHS Research Ethics Committee gave ethical approval for this work (REC reference 18/EE/0199, IRAS 149581).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

Internationally it has become increasingly common practice to modify escalated BEACOPP (eBPP) by replacing procarbazine with dacarbazine to reduce haematopoietic stem cell and gonadal toxicity in Hodgkin lymphoma (HL) patients. A similar replacement of procarbazine in COPP (to COPDac) has reduced gonadal toxicity and conferred comparable long-term event-free survival in children (EuroNet-PHL-C1 trial; Mauz-Körholz et al. Lancet Oncol 2021). Using a real-world multi-centre dataset of 25 UK, Ireland and France centres we have 2.5 years median follow-up of 311 high risk advanced stage HL patients treated with first-line escalated BEACOPDac (eBPDac). We have compared toxicity data with 73 UK patients treated with eBPP and outcome data with 2073 patients treated in the German HD18 trial. We show eBPDac patients have a reduced blood transfusion requirement and earlier return of menstrual periods compared with real-world eBPP patients (Figure 1A). We have observed 16 relapses, 3 non-lymphoma deaths and an estimated 3 yr PFS of 92.4% with progression-free survival (PFS) and overall survival (OS) comparable to HD18 (Figure 1B). Through collaboration with the GHSG we are performing a case matched analysis with the HD18 cohort and will present the results at 17-ICML. The differential impact of procarbazine and dacarbazine-containing regimens on stem cell genomic toxicity was investigated by whole genome sequencing (WGS) of haematopoietic stem and progenitor cell (HSPC) colonies from patients treated with eBPP, eBPDac and ABVD. We found that HSPCs from ABVD and eBPDac-treated patients had similar minor excess somatic mutation burdens compared to age-matched normal HSPCs of 183 (CI95% = 110–256) and 291 (CI95% = 242–340) mutations respectively. In contrast, the HSPCs from eBPP-treated patients had a dramatically increased excess mutation burden of 1153 (CI95% = 937–1369). Analysis of the mutational profiles revealed that every patient who received procarbazine had a clear SBS25-like mutational signature, demonstrating that SBS25 is attributable to procarbazine. We have also identified the SBS25 signature in malignant and non-malignant non-haematopoietic tissue in patients previously exposed to procarbazine, suggesting this drug induces the SBS25 signature in multiple somatic tissues. To determine whether procarbazine also induces SBS25 in germ cell DNA we performed duplex sequencing of sperm from an eBPP-treated male, and WGS of buccal DNA from 3 children with pre-conception maternal exposure to eBPP × 6 cycles. Reassuringly, SBS25 was not found in the germline of all 3 children, while the results of the sperm mutation analysis are expected imminently. The research was funded by: Addenbrooke's Charitable Trust Keywords: Chemotherapy, Hodgkin lymphoma, Late Effects in Lymphoma Survivors Conflicts of interests pertinent to the abstract. A. Santarsieri Educational grants: Takeda

With survival outcomes ever improving for patients with a wide range of lymphoma histologies, the focus on reducing long-term complications of therapy has increased. Recently published, complimentary population and retrospective series have highlighted the importance of considering bone health in patients treated for lymphoma. Fracture-related events or the requirement for secondary bone prophylaxis, likely linked to glucocorticoid-induced osteoporosis (GIO) are substantial and clinically meaningful in a significant minority of patients following routinely employed steroid-containing immunochemotherapy. In this review, we describe the pathophysiology of GIO, the risk of GIO in observational front-line lymphoma studies and efficacy of prophylactic measures from several prospective clinical trials are summarized. Finally, areas of importance for future research are discussed and recommendations for GIO risk assessment and management in lymphoma are provided based on the current available literature.

To optimise management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection identifying high-risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS-CoV-2 infection. SARS-CoV-2 was diagnosed before/during first-line treatment in 64 patients, during follow-up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first-line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high-dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID-19). Vaccination was associated with lower pneumonia incidence and in-hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6-month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow-up died from COVID-19, requiring similar measures as infected subjects in the general population.

IMPORTANCE Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. OBJECTIVE To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. DESIGN, SETTING, AND PARTICIPANTS The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients ( >= 18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. EXPOSURES SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. MAIN OUTCOMES AND MEASURES The primary end point was all-cause mortality within the primary hospitalization. RESULTS Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38%(966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) andmyeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19-related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). CONCLUSIONS AND RELEVANCE The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

Background:Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)-based studies. Objectives:To assess for an association between clinically validated TTS and COVID-19 vaccination. Methods:We used the self-controlled case series method to assess the risks of clinically validated acute TTS after a first COVID-19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results:One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02-31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18- to 39-year-olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4- to 27- and 28- to 41-day periods (RI, 1.52; 95% CI, 0.88-2.63; and (RI, 1.70; 95% CI, 0.73-3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS-CoV-2 test occurred across all age groups and exposure periods. Conclusions:We demonstrate an increased risk of TTS in the 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS-CoV-2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

Introduction When treating Hodgkin lymphoma (HL), it is common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. A similar replacement of procarbazine in COPP (to COPDac) has reduced gonadal toxicity and conferred a comparable long-term event-free survival to children (EuroNet-PHL-C1 trial; Mauz-Körholz et al Lancet Oncol 2021). Our own retrospective study has shown that adults treated with first-line escalated BEACOPDac (eBPDac) have a reduced blood transfusion requirement and earlier return of menstrual periods compared with real-world eBPP patients (pts) with no loss of clinical efficacy compared to HD18 eBPP pts (Santarsieri et al Blood 2021). To better understand the toxicity differences, we performed this study to compare the haematopoietic stem and progenitor cell (HSPC) mutational burden in pts who have received procarbazine and dacarbazine containing regimens. Chemotherapeutic agents are known to damage DNA and this mutational process likely causes many of the long-term chemotherapy toxicities. Little is known about the mutational signatures and mutation burdens caused by HL therapies, although a novel mutational signature (SBS25) has recently been described in two HL cell lines (Petljak et al Cell 2019). Methods We whole genome sequenced 6-8 single-cell derived HSPC colonies from each of 12 advanced stage HL pts (n = 91; mean sequencing depth 26X). The pts were all in remission > 6 months and had been previously treated with either eBPDac (6 cycles (n=2); 4 cycles (n=2)), eBPP (6 cycles (n=3); 5 cycles (n=1); 4 cycles (n=1)) or ABVD (n=3; all 6 cycles). Single HSPC somatic mutation burdens and mutation spectra from these chemotherapy exposed individuals were compared to those from our previously published normal cohort (n = 110; mean sequencing depth 24X) (Mitchell et al Nature 2022). In addition we have updated the outcomes of our retrospective multi-centre study of pts treated with eBPDac including additional pts and longer follow-up of the entire cohort. Mutational analysis The somatic single nucleotide variant mutation burden in normal adult HSPCs ranges from approximately 400 aged 20yr to 1500 aged 80yr; an average of 18 mutations accumulate with every year (Figure 1A). The HSPCs from ABVD and eBPDac-treated pts had similar minor excess somatic mutation burdens compared to aged-matched normal HSPCs of 183 (CI95%= 110-256) and 291 (CI95%= 242-340) mutations respectively. In contrast, the HSPCs from eBPP-treated pts had a striking and significantly increased excess mutation burden of 1153 (CI95%= 937-1369). Of the eBPP pts, the single patient who received 4 cycles had the lowest number of excess mutations, but noting the inter-patient variation, we cannot yet conclude that eBPP cycle number correlates with the number of mutations. Descriptive analysis of the mutational profiles (Figure 1B) revealed that every patient who received procarbazine had a clear SBS25-like mutational signature, characterised by T>A base substitutions, demonstrating for the first time that this DNA mutational signature is directly attributable to procarbazine. Clinical data analysis The clinical data presented last year have been updated with more pts and longer follow-up (n=288; median 2.3 yr). With this high-risk group of advanced stage pts, our data suggest that the eBPDac pts have reduced red cell transfusion requirements, reduced hospitalisation, improved menstrual period recovery and improved sperm count preservation compared with eBPP pts. The eBPDac 24-month PFS is similar to HD18 3-yr PFS (94.9% vs 92.3%) and appears superior to RATHL 5-yr PFS (81.4%). The eBPDac 24-month OS estimate is 99%. Conclusions We have shown that dacarbazine-containing regimens (ABVD and eBPDac) confer a lower mutation burden to HSPCs compared with procarbazine-containing eBPP and that procarbazine is the agent responsible for the SBS25 mutational signature. This work provides a model example of how genomic analysis could be used to inform therapeutic decision making in cancer. Our retrospective analysis provides strong supportive evidence that eBPDac is a highly efficacious HL treatment and noting the clear benefits in terms of HSPC genomic health, we would encourage clinicians offering eBPP to HL pts to consider replacing procarbazine with dacarbazine. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BACKGROUND:Venous thromboembolism (VTE) in patients with thrombocytopenia represents a complex management challenge.OBJECTIVES:To describe practice, document outcomes, and compare management to national guidelines.METHODS:We present a prospective multicenter cohort of 105 patients with hematological cancer, VTE within 28 days, and platelets <50 × 109 /L from May 14, 2019 to April 24, 2021 from 20 sites.RESULTS:Median age was 64 and median initial platelet count 28 × 109 /L. Thromboses were: 46% catheter-associated, 11% lower limb, 33% pulmonary emboli (PE), and 10% other sites. Management was according to International Society on Thrombosis and Haemostasis (ISTH) guidance in 30 (47%) of 64 patients with high-risk thrombosis and 2 (5%) of low-risk thrombosis (catheter-associated or asymptomatic subsegmental PE). Twelve patients (11%) received no anticoagulation. At 28 days mortality was 15%, 8% experienced VTE progression, 7% experienced major bleeding, and 25% experienced clinically relevant non-major bleeding. Four inferior vena cava filters were placed, two were later removed. The median number of platelet units transfused was 5 (range 0-53). Twenty-seven percent of patients had a change of management strategy by 28 days. There was no clear relationship among platelet transfusion threshold, anticoagulant dose reduction threshold, and risk of thrombosis progression or major bleeding.CONCLUSIONS:This data set demonstrates the heterogeneity of approaches used in patients presenting with severe thrombocytopenia and acute thrombosis and confirms the high rates of bleeding in this cohort with thrombosis progression rates similar to the wider cancer-associated thrombosis population. Randomized data is required to inform the optimal management.

Figure 1: Kaplan-Meier estimates of progression-free survival and overall survival of the eBPDac-treated patients compared with intention-to-treat set in the HD18 trial and 18-59y RATHL patients. Table of patient characteristics and treatment outcomes. When treating advanced stage Hodgkin lymphoma, it is common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3). This is a retrospective study of patients treated with first line escalated BEACOPDac (eBPDac) at 23 centres updated since ASH 2021. With a median follow-up of 28 months, the 24-month progression-free survival (PFS) is 95% (CI 92.2–98.0%). Of 268 eBPDac patients, 226 were treated as per HD18 protocol and 42 as per AHL2011. Survival outcomes were compared with 2073 eBPP patients in the HD18 trial and 1088 patients aged 18-59y in the RATHL trial. The eBPDac patients were younger than the HD18 and RATHL patients but had higher risk and more stage 4 disease. Of the eBPDac patients 76% achieved iPET Deauville score (DS) ≤3, similar to RATHL (DS≤3:83.7%) and HD18 (DS≤3:76%). One patient had primary refractory disease and twelve have relapsed at 6 to 36 months. Three patients have died of non-lymphoma causes. The eBPDac 24-month PFS is similar to HD18 3-year PFS (95% vs 92.3%) and appears superior to RATHL 5-year PFS (81.4%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The eBPDac 24-month OS estimate is 99%. Toxicity was compared between eBPDac patients and 68 matched real-world eBPP patients over the first 4 cycles. There were no significant differences in age, sex or stage, but more eBPP patients had high risk disease (IPS3+). Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count was lower in eBPDac patients with D9 GCSF. eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.88 vs 3.83 units, p<0.001) and had fewer non-elective days of inpatient care (mean 3.49 vs 5.66; p=0.021). Of the women aged <35y who completed ≥4 cycles chemotherapy, 52/52 had return of menstrual periods after eBPDac, compared to 25/28 after eBPP. eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.71 vs 8.89 months, p=0.002). However, eBPP patients received more cycles of chemotherapy. To compare haematopoietic stem cell toxicity, peripheral blood mononuclear cells were isolated from 4 eBPDac, 5 eBPP and 3 ABVD patients. Haematopoietic progenitor cells were grown in culture and the colonies harvested have undergone whole genome sequencing. The data is imminent and we will present the mutation burden and mutational signatures associated with these regimens.

Introduction. A number of recent studies have described outcomes of patients (pts) with hematological malignancies affected by SARS-CoV-2, however data according to a particular tumour type and its specific treatments are lacking. Aggressive non-Hodgkin lymphomas for which dose intensity is crucial, represent one of the most common and vulnerable populations infected by SARS-CoV2. Herein, we report data from an international real world study of pts with primary central nervous system lymphoma (PCNSL) and concurrent SARS-CoV-2 infection. Methods. Key data on clinical presentation, management and outcome of pts were collected and analyzed to determine the impact of SARS-CoV-2 infection on the delivery of anti-lymphoma treatment and overall outcome. SARS-CoV-2 infection was defined by naso-pharyngeal swab or by broncho-alveolar lavage. Pts were grouped in 1st, 2nd and 3rd pandemic waves using July 31, 2020 and January 1, 2021 as cut-offs for SARS-CoV-2 diagnosis. Results. Ninety-one pts from 27 centers of 5 countries (France, Israel, Italy, United Kingdom, USA) were registered. The enrolled cohort was dominantly in the pre-vaccination era, but subsequently included 16 vaccinated pts. SARS-CoV-2 was diagnosed before/during 1st-line PCNSL treatment in 64 (70%), during follow-up in 21 (23%), and during salvage therapy in 6 (7%) pts. Thirty-eight (59%) of the 64 pts infected before/during first-line developed pneumonia; this complication was more common if (1) non-vaccinated, (2) steroids before viral infection for at least two weeks or with a cumulative dose >100 mg of dexamethasone, and (3) high-dose cytarabine before virus detection. Eighteen (47%) pts with pneumonia cleared the virus; 15 of whom resumed anti-lymphoma treatment, with a median delay of 30 days, and 17 were alive at the last visit. Seventeen of the 20 pts with pneumonia who did not clear virus died early (<30 days) of COVID-19 or related infections. Twenty (77%) of the 26 pts without pneumonia cleared virus and resumed/initiated first line therapy, with a median delay of 22 days; 15 of whom were alive at the last follow up. Overall, 43 (67%) pts initiated/resumed or completed first-line treatment, with a median delay of 22 (range 0-116) days. Resumption of anti-lymphoma treatment was more common among those who did not develop pneumonia, cleared the virus and/or did not receive steroids during infection. Resumption of chemo despite viral persistence was associated with a poorer survival, with a 6-month OS of 70% (95%CI= 67-73%) for the 23 pts who initiated/resumed chemo despite viral persistence and 87% (95%CI= 86-87%) for the 20 pts who waited the virus clearance (p= 0.07). Eight (38%) of the 21 pts infected during lymphoma follow-up developed pneumonia; all cleared virus and 20 of 21 were alive at last follow-up. Conversely, 4 (67%) of the 6 pts with relapsed PCNSL infected during salvage therapy died of COVID-19 or related infections. At a median follow-up since virus detection of 185 days (18-534), 61 pts cleared virus and 59 (65%) are alive, with tumor remission in 34. The 1- and 6-month OS were 80% (95% CI= 79-81%) and 66% (95% CI= 64-68%), respectively; virus persistence and pre-COVID-19 steroid therapy were independently associated with poor OS. Mortality during the 3 considered waves was not significantly different. Notably, however, deaths in the 3rd wave occurred exclusively in non-vaccinated pts (p= 0.0009). Moreover, overall outcome of the 16 pts infected after November 2021, when Omicron variant became prevalent appears favourable: 14 of these patients were vaccinated, all of them are alive and resumed/completed chemotherapy with a median delay of 3 days (range 0-28); there were only 2 COVID-19-related deaths, which occurred in the 2 non-vaccinated pts. Finally, this study did not show a significant association between comorbidities and COVID-19-related mortality. Conclusions. COVID-19 was a strong outcome-defining event, especially in pts receiving anti-PCNSL treatment and in those who had received a cumulatively high steroid dose before viral infection. Vaccination was associated with a lower incidence of pneumonia and in-hospital mortality. Chemo initiation or resumption during active infection should be indicated cautiously. For pts in follow up, SARS-CoV-2 was not associated with severe symptoms and did not affect OS. These data will inform clinical management of pts with PCNSL in the context of SARS-CoV-2 infection.

Abstract Background: In the treatment of advanced Hodgkin lymphoma, it is increasingly common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the "escalated BEACOPDac (eBPDac)" regimen are very limited. Methods: This is a retrospective study of 225 patients from 20 centres in the UK, Ireland and France who were treated with eBPDac first line for advanced stage Hodgkin Lymphoma. Toxicity outcomes were compared with 58 matched patients treated with eBPP at 4 UK centres and survival outcomes were compared with 2073 eBPP patients in the HD18 trial 1 and with 1088 patients aged 18-59y in the RATHL trial 2,3. Most eBPDac patients were treated as per HD18 protocol. The 34 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Toxicity outcomes: Toxicity was compared between eBPDac patients (n=225; median follow-up 22.1 months) and matched real-world UK eBPP patients (n=58; median follow-up 52.7 months) over the first 4 cycles. eBPP and eBPDac patients were well matched with no significant differences in age (median 23 y vs 26 y), sex, stage (stage 3/4 82% vs 83%) and international prognostic score (IPS 3+ 74% vs 65%). 55% of eBPDac patients received only 4 cycles (vs 12% of eBPP patients; p<0.001) reflecting publication of HD18 trial data. Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count tended to be lower in eBPDac than eBPP patients (2.04 vs 2.45; p=0.072; G-CSF given D9), however it increased to 6.48 in eBPDac patients given GCSF from D4. There were fewer non-elective days of inpatient care for eBPDac compared with eBPP (mean 3.35 vs 5.84; p=0.022), and eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.79 units vs 4.16 units; p<0.001). Women aged <35, who completed ≥4 cycles of eBPDac/eBPP had a similar rate of return of menstrual cycles (eBPP 22/25; eBPDac 41/41), although eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.64 months vs 9.12 months, p=0.0026). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.60; p<0.001). The use of Goserelin to suppress ovulation varied between centres. Disease outcomes: The eBPDac patients (n=225) were younger than the HD18 patients (median age 26 y vs 35 y, p<0.001) and the RATHL patients (median age 26 y vs 31 y). However, they had higher risk disease than HD18 (IPS 4+ 36% vs 16%, p<0.001) and RATHL patients (IPS 3+ 65% vs 33%, p<0.001) and more stage 4 disease than HD18 (66% vs 36%, p<0.001) and RATHL (66% vs 28%, p<0.001). Of the 225 patients who started eBPDac, 77% achieved iPET2 Deauville score (DS) ≤3, similar to RATHL (DS ≤3: 83.7%) and HD18 (DS ≤3: 76%). Of the eBPDac patients, one patient had primary refractory disease, and ten have relapsed at 6 to 36 months. One 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1 and one 34-year-old with alcoholic liver disease died 8 months after treatment while still in remission. There have been no lymphoma-related deaths to date. Figure 1 shows Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS). The PFS at 22 months (median follow-up) of eBPDac patients was 94.9% (91.7-98.3%) which is similar to HD18 3 year PFS of 92.3% (91.1-93.5%) and appears superior to RATHL 5 year PFS 81.4% (78.9-83.7%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The OS rates with all 3 regimens are excellent, with 22 month eBPDac OS estimate of 98.9% (97.4-100%). Summary/Conclusion: Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. Despite the clear preference of clinicians to offer this regimen to high-risk advanced stage patients, with nearly 2 years median follow-up we have observed similar PFS and OS compared to HD18 but superior survival estimates compared with 18-59y RATHL patients, suggesting that eBPDac is highly efficacious for the treatment of Hodgkin lymphoma. References: 1Borchmann P et al. Lancet 2017; 390:2790-2802 2Johnson P et al. NEJM. 2016; 374:2419-2429 3Russell J et al. Ann Hematol 2021; 100:1049-1058 Figure 1 Figure 1. Disclosures Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Menne: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. Osborne: Roche: Other; Takeda: Other; Pfizer: Other; Servier: Other; Gilead: Other; Novartis: Other; MSD: Other. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees; Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding. Collins: Pfizer: Honoraria; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Celgene: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Davies: Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding. Furtado: Abbvie: Other: Conference support. Gallop-Evans: Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Iyengar: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Linton: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; University of Manchester: Current Employment; Celgene: Research Funding; BeiGene: Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Calle: Abbvie: Other. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nagumantry: Takeda, Alexion, Abbvie: Other. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttenthal: Jazz: Other; Takeda: Other; Roche: Other. McMillan: Pfizer: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abvie: Membership on an entity's Board of Directors or advisory committees. Follows: Janssen, Abvie, Roche, AZ: Other.

AVENuE - Avelumab in the frontline treatment of advanced classic Hodgkin lymphoma - a window study Background Response adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has become a standard of care in many countries for advanced stage classic Hodgkin Lymphoma (cHL), as investigated in the RATHL study: following 2 cycles of ABVD patients with negative (Deauville 1-3) interim PET (iPET2) proceeded to 4 cycles of AVD; those with positive (Deauville 4-5) iPET2 intensified therapy to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (escBEACOPP) or BEACOPP every 14 days. Overall this strategy was associated with a 3-year progression free survival (PFS) of 82.6%, and outcomes for patients with positive iPET2 were disappointing with 3y progression-free survival (PFS) of 67.5%. More intensive treatment such as upfront use of escBEACOPP has been reported to produce higher PFS (89% at 5 years), but it is unclear whether overall survival (OS) is improved. More intensive treatment is, however, associated with higher risk of toxicity. Inhibitors of programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have established efficacy in relapsed / refractory cHL with response rates of 55-87%. In the front line setting PD-1 inhibitors have a reported complete metabolic response (CMR) rate of 18-37%. Response to PD-L1 inhibitors in the frontline setting has not been explored. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment because PET interpretation with checkpoint inhibitors is often complex. In the context of PD-1 inhibition, PD-1 expression by immunohistochemistry (IHC) and 9p24.1 copy gain by fluorescence in situ hybridisation (FISH) are reported to correlate with response. Methods AVENuE is a Phase II single-arm multicentre study with sites in the UK and Australia assessing the safety and efficacy of 2 cycles (4 doses) of the PD-L1 inhibitor avelumab for untreated high-risk stage II-IV cHL prior to the iPET2 response adapted approach described above. Eligible patients must be 16-60 years, ECOG 0-1, and have adequate organ function. Patients with; compressive symptoms from lymphoma, autoimmune disorders or immunosuppressive treatment within 2 months are excluded. The primary endpoint is the centrally reviewed PET CMR rate to avelumab. Secondary endpoints are: the safety and tolerability of sequential avelumab and combination chemotherapy as assessed by CTCAE v 5.0; the iPET2 CMR rate after avelumab and 2 cycles of ABVD; PFS and OS at one year. Using a single stage A'hern design, target recruitment is 47 patients to give 90% power at a 0.05% one sided alpha to exclude an overall response rate (ORR) to 2 cycles of avelumab of < 20%; an ORR of 40% would be considered worthy of further study. Recruitment has continued during the COVID-19 pandemic. 29 patients have been enrolled. Exploratory endpoints include correlating disease response with baseline PD-1 copy number by FISH and PD-1 expression by IHC. Serial serum TARC is being explored as an aid to response assessment and changes in peripheral blood immune cell subset are being investigated as possible biomarkers of response. Trial funder: Pfizer Ltd in alliance with Merck KGaA Pfizer Ltd is providing funding as part of an Alliance between Pfizer and Merck KGaA Clinical trials.gov NCT03617666 EUDRACT No.: 2018-002227-42 Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Regeneron: Speakers Bureau; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy. Barrington: Bristol Myers Squibb international corporation: Research Funding; Pfizer Inc: Research Funding; Amgen Ltd: Research Funding; Takeda Speakers Bureau: Honoraria. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Iyengar: Janssen: Other: conference support, Speakers Bureau; Abbvie: Other: conference support; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd..: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Avelumab prior to frontline chemotherapy in advanced stage classic Hodgkin lymphoma.

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 10 9 /L, platelets < 75 × 10 9 /L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

Background: Relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL) has a poor outlook with chemotherapy alone (long-term survival 10-20%). In fit patients, non cross-reacting salvage regimens and high dose chemotherapy with autologous stem cell transplant (ASCT) improve 5 year freedom from second failure (FF2F) to 42%. Progressive disease, toxicity of salvage therapy and failure to harvest stem cells are common barriers to ASCT. The most discriminating reported prognostic factor for ASCT outcome is pre-transplant response by PET (3-5 year PFS >70% if PET negative; 25-30% if PET positive). Programmed cell death protein 1 (PD-1) inhibitors have established efficacy in R/R cHL, with overall response rates (ORR) of 69-72% and complete metabolic response rates (CMR) of 16-37%. PD-1 inhibitors warrant exploration as salvage therapy because ORR appears to be at least as good as with cytotoxic chemotherapy or brentuximab vedotin, they are not typically myelosuppressive, helping preserve fitness, and responses are relatively durable allowing time for transplant. PD-1 expression by immunohistochemistry (IHC) and 9p24 copy gain by FISH are reported to correlate with response to PD-1 inhibitors. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment. Methods: ANIMATE is a Phase II single-arm multicentre study in the UK assessing the safety and efficacy of 4-8 doses of nivolumab 240 mg every 14 days as second or third line therapy for R/R cHL in ASCT-fit patients. Eligible patients must be ≥ 16 years, and about to receive or be receiving first or second line therapy (£ 14 days after last treatment in cycle 2 (cycle 3 or 4 if receiving brentuximab vedotin)). Patients with autoimmune disorders, colitis, inflammatory bowel disorders or pneumonitis are excluded. Trial treatment eligibility, assessments and patient progress are shown in Fig 1. The primary endpoint is ORR by PET after 4-8 cycles of nivolumab. The study is powered to exclude an ORR <40% for which we require 30 nivolumab-treated patients (A’Hern single arm design, 80% power and a one-sided 0.1 alpha). We expect to register 75-120 patients during salvage treatment. Secondary endpoints are: safety and tolerability of nivolumab (including safety of subsequent allogeneic transplant); progression free survival and overall survival at one year. Exploratory endpoints include: correlating disease response with baseline PD-1 copy number, PD-1 expression by IHC, immune profiling of tumour and peripheral blood by flow and gene expression profiling; and assessment of whether response assessment can be improved by combining PET with serum biomarkers e.g. TARC. Since December 2018, 38 patients have been registered, of whom 16 have been PET positive at the end of their current salvage therapy and eligible for nivolumab. Clinical trials.gov No. NCT03337919 ANIMATE trial schema. PET CT Positorn emission tomography with contrast enhanced computed tomography *indeterminate Response modified form Lymphoma Response to immunomodulatory Therapy Criteria of Cheson et al., 2016 The research was funded by: Bristol Myers Squibb Keywords: Ongoing Trials Conflicts of interests pertinent to the abstract S. Barrington Honoraria: Roche, Takeda Educational grants: Takeda C. Burton Consultant or advisory role: Celgene, Bristol Myers Squibb Foundation Honoraria: Roche, Takeda G. P. Collins Consultant or advisory role: Roche, Takeda, Incyte, Pfizer, MSD, Celgene, Beigene, Daiichi Sankyo, Celleron therpeutics, ADC therapeutics Honoraria: Roche, Takeda, Gilead Sciences, Pfizer, Novartis, Daiichi Sankyo, Incyte, Celleron Therapeutics, MSD Oncology, BeiGene, ADC Therapeutics Research funding: MSD Oncology, Celegene, Celleron Therpeutics, Bristol Myers Squibb, Amgen Educational grants: Roche, Takeda

In the treatment of advanced Hodgkin lymphoma, it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with IV dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the “escalated BEACOPDac (eBPDac)” regimen are limited. From 2009, 205 patients were treated first line with either eBPP (n = 58) at 4 UK centres, or eBPDac (n = 147) at 16 centres in the UK, Ireland and France with median follow up 51.3 months and 22.9 months respectively. Patients were well matched with no significant differences in age (median: 23 y vs 27 y), sex, stage (stage 3/4: 81% vs 83%) and IPS (IPS3+: 74% vs 65%). 51% of eBPDac patients received only 4 cycles (vs 12% eBPP patients; p < 0.001) reflecting publication of HD18 trial data. In total, 74% patients achieved iPET2 Deauville score ≤3 and 90% achieved PET negative remission by end of treatment. 77% of eBPDac patients achieved iPET2 Deauville ≤3 which was statistically similar to the eBPP cohort (67%; p = 0.181) and matched the 76% iPET D2/3 reported in HD18. Of 205 patients, 202 are alive and 197 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months and the latter died of refractory disease. One eBPDac patient had primary refractory disease, and three have relapsed at 2, 7 and 24 months. One 56-year-old eBPDac patient with high IPS died of bowel perforation during cycle 1 and one 34-year-old with alcoholic liver disease died 8 months after treatment while in remission. Toxicity was compared over the first 4 cycles. Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count was lower in eBPDac than eBPP patients (1.81 vs 2.45; p = 0.067; G-CSF given D9), however it increased to 5.61 in eBPDac patients given GCSF from D4. There is a trend toward fewer non-elective days of inpatient care for eBPDac compared with eBPP (mean 3.74 vs 5.83; p = 0.118), and eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.93 units vs 4.16 units; p < 0.001). Women aged <35, who completed ≥4 cycles of eBPDac/eBPP had a similar rate of return of menstrual cycles (eBPP 22/25; eBPDac 29/29), although eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.48 months vs 9.12 months, p = 0.0026). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.60; p < 0.001). The use of Goserelin varied between centres. Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. Despite a predominance of high risk advanced stage patients, with nearly 2 years median follow up we have observed only 2 deaths and 4 progression events from 147 patients treated with eBPDac, suggesting this regimen is highly efficacious in Hodgkin lymphoma. EA – previously submitted to regional or national meetings (up to 1000 attendees) and EHA 2021. Keywords: Hodgkin lymphoma Conflicts of interests pertinent to the abstract A. Santarsieri Honoraria: Janssen P. Brice Other remuneration: Takeda France, Millenium Takeda, BMS T. F. Menne Other remuneration: Kite/Gilead, Amgen, Novartis, Celgene, Daiichi Sankyo, Takeda, Roche, Janssen, Astra Zeneca, Jazz, Pfizer, Bayer, Kyowa Kirin W. Osborne Other remuneration: Roche, Takeda, Pfizer, Servier, Gilead, MSD, Novartis K. M. Ardeshna Other remuneration: Gilead, Celgene G. P. Collins Other remuneration: Gilead K. Cwynarski Other remuneration: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssen M. Furtado Educational grants: Abbvie S. Iyengar Other remuneration: Takeda, Janssen, Gilead, Abbvie, Roche N. Martinez-Calle Other remuneration: Abbvie P. McKay Other remuneration: Epizyme S. K. Nagumantry Other remuneration: Takeda, Alexion, Abbvie N. Shah Other remuneration: Abbvie B. J. Uttenthal Other remuneration: Roche, Takeda, Jazz A. K. McMillan Other remuneration: Pfizer, F Hoffman-La Roche Ltd, BMS, Celgene, Novartis, Gilead, Sandoz, MSD G. A. Follows Other remuneration: Janssen, Abbvie, Roche, Astra Zeneca

SummaryPatients with haematological malignancies have a high risk of severe infection and death from SARS‐CoV‐2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS‐CoV‐2 infection and active haematological cancer. The primary end‐point was all‐cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti‐CD19/anti‐CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS‐CoV‐2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti‐CD19/anti‐CD20 treatments.