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PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline β2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

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.

We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.

Outcome after failure of initial therapy in younger adult patients with acute myeloid leukaemia (AML) is highly variable. Cytogenetics, length of first remission (CR1) before relapse, and allogeneic transplantation are known prognostic factors, but the contribution of leukaemic genotype is less clear, particularly in resistant disease. Of 5,651 younger adult patients entered into UK MRC/NCRI AML trials between 1988 and 2014 with available FLT3ITD and NPM1 genotype, 326 (6%) had resistant disease and 2338 (41 %) relapsed after achieving CR1. Overall survival (OS) was significantly higher in relapsed compared to resistant disease (p = 0·03). Independent favourable prognostic factors for OS in resistant disease included lower blast cell percentage after two courses of induction therapy (p = 0.0006) and NPM1 mutant (NPM1MUT) (p = 0.04). In relapsed disease, longer CR1 was a favourable independent factor for attainment of CR2 (p

ObjectivesTo estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer.MethodsWe employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England.ResultsDeclines in urgent referrals (median=−70.4%) and chemotherapy attendances (median=−41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=−44.5%) and chemotherapy attendances (median=−31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity.ConclusionsDramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

Background: Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors. Methods: We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data. Results: Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with ≥1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with ≥1 comorbidity. Conclusion: We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.

Background Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. Patients and methods Eligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). Results A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0). Conclusions This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. Trial Registration ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)., Highlights • R-CODOX-M/R-IVAC is an effective regimen for treatment of high-risk DLBCL and high-grade B-cell lymphoma (IPI score 3–5). • Treatment was well tolerated in patients aged

IntroductionOutcomes after frontline treatment of Burkitt lymphoma (BL) have improved with the introduction of dose‐intense chemotherapy regimens, such as CODOX‐M/IVAC. While rituximab has increased survival rates for most forms of high‐grade B‐cell lymphoma, there has previously been hesitancy about incorporating it into BL treatment, partly due to concerns about increased toxicity. Prospective data using the standard dose CODOX‐M/IVAC regimen in combination with rituximab are lacking. We conducted a single‐arm phase 2 trial to assess the efficacy and toxicity of R‐CODOX‐M/R‐IVAC.MethodsEligible patients were aged 18–65 years, with newly diagnosed BL with MYC rearrangement as the sole cytogenetic abnormality, and high‐risk disease, defined by an International Prognostic Index (IPI) score of 3‐5. Patients received two cycles of R‐CODOX‐M chemotherapy alternating with two cycles of R‐IVAC, followed by two further cycles of rituximab alone. The primary endpoint was 2‐year progression‐free survival.ResultsThirty‐eight patients were registered but after central pathology review, 27 patients had confirmed BL and commenced study treatment. Median age was 35 years, 14.8% patients had central nervous system involvement and 18.5% were HIV positive. Twenty‐two (81.4%) patients completed four cycles of chemotherapy. There were two treatment‐related deaths (7.4%). Two‐year progression‐free and overall survival rates were 77.2% (90% confidence interval [CI]: 56.0‐89.0) and 80.7% (90% CI: 59.6‐91.5), respectively.ConclusionsThis prospective trial demonstrates excellent survival rates with R‐CODOX‐M/R‐IVAC in a high‐risk BL cohort. It provides reassuring evidence regarding the feasibility of this regimen and also provides a benchmark for future studies.

Risk-stratification and treatment intensification according to minimal residual disease (MRD) analysis has improved outcomes of patients with acute lymphoblastic leukemia (ALL).[1][1],[2][2] However, a significant proportion of patients with T-cell ALL (T-ALL) still experience early relapse or

INTRODUCTION We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR-T immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL. Cumulatively, this data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Recently, CAR-T therapy has been explored in indolent lymphomas such as follicular (FL) and mantle cell lymphoma (MCL), but a high incidence of toxicity including Grade 3-4 ICANS has been reported. We have initiated testing of AUTO1 in the setting of indolent and high-grade B-NHL and CLL (NCT02935257). METHODS Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m 2 x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x10^6 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x10^6 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. RESULTS As of 17th May 2021, we recruited 13 patients: 7 with FL, 4 with MCL, 1 DLBCL and 1 CLL. Apheresis and product manufacture was successful in all 13 patients and 9 patients were infused: 7 with FL and 2 with MCL. Three patients (1 DLBCL, 1 CLL and 1 MCL) were pending infusion at time of data cut-off and 1 patient (MCL) died due to Covid-19 prior to infusion. Patients treated with AUTO1 had a median age of 56 years (range 39-68y), had received a median of 3 prior lines of treatment (range 2-5) and all patients had stage IV disease at screening. Grade 1 CRS was reported in 4/9 and Grade 2 CRS in 1/9. 1/9 developed MAS which resolved with anakinra/dexamethasone. No ICANS was observed on study. Excellent CAR engraftment was observed and 9/9 patients were in CMR by 18FDG PET-CT post-treatment. At a median of 6.1 months (range 4.0-8.1m), 8/9 patients were disease free at last follow-up. One patient died in CMR at month 5.6 of COVID-19. CONCLUSION AUTO1 has a tolerable safety profile in adult patients with r/r B-NHL despite high disease burden. Early data shows 100% complete remission rates and excellent CAR engraftment/expansion. Additional MCL, CLL and DLBCL patients, updated data and longer follow up will be presented. Disclosures Roddie: Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau. Hartley: Astra Zeneca: Ended employment in the past 24 months; ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Farzaneh: Autolus: Consultancy, Current equity holder in publicly-traded company. Lowdell: Autolus: Consultancy, Current equity holder in publicly-traded company. Linch: Autolus: Consultancy, Current equity holder in publicly-traded company. Pule: Autolus: Current Employment, Current equity holder in publicly-traded company. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company.

TO THE EDITOR: Addition of the CD33-targeted immunoconjugate gemtuzumab ozogamicin (GO; Pfizer) has been shown to improve the response to standard-induction chemotherapy and results in better long-term survival in adult patients with acute myeloid leukemia (AML).[1][1] The greatest impact was

Introduction: Prognosis for adult B-cell Acute Lymphoblastic Leukaemia (B-ALL) is poor and there is currently no licensed CD19 Chimeric Antigen Receptor (CAR) therapeutic. We developed a novel CD19 CAR (CAT-41BBz CAR) with a fast off-rate, designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. We describe updated data from the Phase I ALLCAR19 (NCT02935257) study of AUTO1 in relapsed/refractory adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leukapheresate. The first 6 products were generated using a standard dynabead/WAVE bioreactor process and subsequent products using a semi-automated closed process. Study design: Patients aged >16y underwent lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) followed by split dose CAR T-cell infusion (Day 0: if ≥20% Bone Marrow (BM) blasts, infuse 10 x 106 CAR T-cells; if Results: As of 13 May 2020, 24 patients have been leukapheresed, 23 products manufactured and 19 patients received at least 1 dose of AUTO1. The median age was 43y (range 18-62), 26% had prior blinatumomab, 47% had prior inotuzumab ozogamicin and 63% had prior hematopoietic stem cell transplantation (HSCT). At the time of pre-conditioning, 42% had ≥50% BM blasts. No patients experienced ≥Grade 3 CRS (Lee criteria), 3/19 (16%) experienced Grade 3 ICANS that swiftly resolved with steroids. Of 19 infused patients, 16/19 (84%) achieved Minimal Residual Disease (MRD) negative complete response (CR). Currently 6 patients have died, none related to AUTO1. 11/19 (58%) patients remain on study and continue in MRD negative remission at a median follow up of 12.2 months (range 0.6-24.4m). To date, only 2 patients underwent HSCT whilst in remission. For all treated patients, the event-free survival (EFS) at 6 months was 62% and 76% for those whose products were manufactured using the closed process. Patients exhibited robust CAR expansion (mean peak CAR T levels 716,769 copies/µg DNA). Conclusions: AUTO1 has a tolerable safety profile in adult patients with r/r B-ALL despite high disease burden. Early data shows high remission rates with 84% achieving MRD negative CR. This preliminary data supports the further development of AUTO1 as a standalone treatment in patients with r/r B-ALL. Data from additional patients and longer follow up will be presented. Furthermore, data from extension cohorts of patients with low- and high- grade B-cell Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia will be presented. Figure Disclosures Roddie: Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Linch:Autolus: Consultancy. Pule:UCLB: Patents & Royalties; Mana Therapeutics: Other: entitled to share of revenue from patents filed by UCL; Autolus: Current Employment, Other: owns stock in and receives royalties, Patents & Royalties. Peggs:Autolus: Consultancy.

Summary This phase II trial was designed to determine the safety and efficacy of a modified paediatric risk‐stratified protocol in young adults (18–30 years) with classical Hodgkin Lymphoma. The primary end‐point was neurotoxicity rate. The incidence of grade 3 neurotoxicity was 11% (80% CI, 5–19%); a true rate of neuropathy of >15% cannot be excluded. Neuropathy and associated deterioration in quality of life was largely reversible. The overall response rate was 100% with 40% complete remission (CR) rate. Twelve months disease‐free survival (DFS) was 91%. We demonstrate that a risk‐stratified paediatric combined modality treatment approach can be delivered to young adults without significant irreversible neuropathy.

Haematological engraftment was assessed in 804 autologous transplants. Neutrophil recovery occurred in over 99% within 14 d but platelet recovery was delayed beyond this time in 14·8%. Time to recovery was dependent on the progenitor cell dose infused. The minimum CD34+ cell threshold adopted in this study (2 × 106 /kg) was safe although recovery was faster with a dose >5 × 106 /kg. CD34+ cell doses of between 1 and 2 × 106 /kg were also acceptable if either the granulocyte-macrophage colony-forming cell dose exceeded 2 × 105 /kg or this dose was due to splitting a higher yield harvest. Prompt neutrophil recovery affords important quality assurance for laboratory processing.

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7·2 years the 5-year progression-free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.

Diffuse large B-cell lymphoma with secondary involvement of the central nervous system (SCNS-DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS-DLBCL treated with R-IDARAM (rituximab 375 mg/m(2) IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m(2) /day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1-3; cytosine arabinoside 1000 mg/m(2) /day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m(2) IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation ('new disease'), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded - 6 (26%) complete response, 8 (35%) partial response. Grade 3-4 haematological toxicity was seen in all cycles, with no grade 3-4 or long-term neurological toxicity. Median follow-up for surviving patients was 49 months. At 2 years, estimated progression-free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5-year estimated PFS of 50% and OS 75%. R-IDARAM is a well-tolerated regimen with encouraging efficacy in patients with SCNS-DLBCL, although patients with relapsed or refractory disease continue to fare poorly.

Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P

Cell cycle status may play an important role in directing patient therapy. We therefore determined the cell cycle status of leukaemic cells by immunophenotypic analysis of bone marrow trephine biopsies from 181 patients with acute myeloid leukaemia (AML) and correlated the results with biological features and clinical outcome. There was considerable heterogeneity between patients. The presenting white cell count significantly correlated with the proportion of non-quiescent cells (P < 0·0001), of cycling cells beyond G1 (P < 0·0001) and the speed of cycling (P < 0·0001). Profiles in acute promyelocytic leukaemia (APL) differed from non-APL and were consistent with more differentiated cells with reduced proliferative potential, but no significant differences were observed between non-APL cytogenetic risk groups. NPM1 mutations but not FLT3 internal tandem duplication (FLT3ITD ) were significantly associated with a higher proportion of cells beyond G1 (P = 0·002) and faster speed of cycling (P = 0·003). Resistance to standard cytosine arabinoside and daunorubicin induction chemotherapy was significantly related to a slower speed of cycling (P = 0·0002), as was a higher relapse rate (P = 0·05), but not with the proportion of non-quiescent cells or actively cycling cells. These results show a link between the cycling speed of AML cells and the response to chemotherapy, and help to identify a group with a very poor prognosis.

Background Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I–IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a ‘high-risk’ extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Some studies have suggested that cases of acute myeloid leukemia (AML) with low levels of FLT3 internal tandem duplications (FLT3(ITD)) do not have a worse prognosis if there is a concomitant NPM1 mutation, although this is controversial. To clarify this therapeutically important issue, we have analyzed FLT3(ITD) and NPM1(MUT) levels in 1609 younger adult cases of cytogenetically intermediate-risk AML. The cumulative incidence of relapse was increased in NPM1(MUT) cases by the presence of a FLT3(ITD), but did not differ markedly according to FLT3(ITD) level. This remained true when allowance was made for poor leukemic cell purity by adjustment of the FLT3(ITD) level to the measured NPM1(MUT) level. If consolidation therapies are to be determined by relapse risk, then NPM1(MUT) cases with low-level FLT3(ITD) should not be considered as good risk without further studies. AML 12 and AML 15 are registered at http://www.controlled-trials.com under ISRCTN17833622 and ISRCTN17161961, respectively.

Purpose The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity. Patients and Methods Sixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had borderline ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension. Primary end point was overall response rate at the end of treatment. Results Thirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response [CR], n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population. Conclusion Our phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.

Introduction: 2nd generation CD19 CAR T cells show unprecedented efficacy in B-ALL, but several challenges remain: (1) scaling manufacture to meet patient need and (2) feasibility of generating products from lymphopenic patients post allogeneic stem cell transplant (allo-SCT). To overcome these issues we propose: (1) use of the CliniMACS Prodigy (Miltenyi Biotec), a semi-automated cGMP platform that simplifies CAR T cell manufacture and (2) the use of matched donor T cells to overcome the challenge posed by patient lymphopenia, albeit this may come with a heightened risk of graft versus host disease (GvHD). CARD (NCT02893189) is a Phase I study of matched donor derived CD19 CAR T cells generated on the CliniMACS Prodigy in 14 adult patients with relapsed/refractory (r/r) B ALL following allo-SCT. We additionally explore the requirement for lymphodepletion (LD) in the allogeneic CAR T cell setting and report on the incidence of GvHD with this therapy. Methods: Manufacturing: CARD utilises non-mobilised matched donor leucapheresate to manufacture 2nd generation CD19CAR T cells using a closed CliniMACS® Prodigy/ TransACTTM process. Study design: Eligible subjects are aged 16-70y with r/r B ALL following allo SCT. Study endpoints include feasibility of CD19CAR T cell manufacture from allo-SCT donors on the CliniMACS Prodigy and assessments of engraftment and safety including GvHD. To assess the requirement for LD prior to CD19CAR T cells in lymphopenic post-allo-SCT patients, the study is split into Cohort 1 (no LD) and Cohort 2 (fludarabine (30 mg/m2 x3) and cyclophosphamide (300mg/m2 x3)). To mitigate for the potential GvHD risk, cell dosing on study mirrors conventional donor lymphocyte infusion (DLI) schedules and is based on total CD3+ (not CAR T) cell numbers: Dose 1=1x106/kg CD3+ T cells; Dose 2= 3x106/kg CD3+ T cells; Dose 3= 1x107/kg CD3+ T cells. Results: As of 26 July 2019, 17 matched allo SCT donors were leukapheresed and 16 products were successfully manufactured and QP released. Patient demographics are as follows: (1) median patient age was 43y (range 19-64y); (2) 4/17 had prior blinatumomab and 5/17 prior inotuzumab ozogamicin; (3) 7/17 had myeloablative allo SCT and 10/17 reduced intensity allo SCT of which 6/17 were sibling donors and 12/17 were matched unrelated donors. No patients with haploidentical transplant were enrolled. To date, 12/16 patients have received at least 1 dose of CD19CAR T cells: 7/16 on Cohort 1 and 5/16 on Cohort 2 (2/16 are pending infusion on Cohort 2 and 2/16 died of fungal infection prior to infusion). Median follow-up for all 12 patients is 22.9 months (IQR 2.9-25.9; range 0.7 - 25.9). At the time of CAR T cell infusion, 7/12 patients were in morphological relapse with >5% leukemic blasts. Despite this, CD19CAR T cells were administered safely: only 2/12 patients experienced Grade 3 CRS (UPenn criteria), both in Cohort 1, which fully resolved with Tocilizumab and corticosteroids. No patients experienced ≥Grade 3 neurotoxicity and importantly, no patients experienced clinically significant GvHD. In Cohort 1 (7 patients), median peak CAR expansion by flow was 87 CD19CAR/uL blood whereas in Cohort 2 (5 patients to date), median peak CAR expansion was 1309 CD19CAR/uL blood. This difference is likely to reflect the use of LD in Cohort 2. CAR T cell persistence by qPCR in Cohort 1 is short, with demonstrable CAR in only 2/7 treated patients at Month 2. Data for Cohort 2 is immature, but this will also be reported at the meeting in addition to potential mechanisms underlying the short persistence observed in Cohort 1. Of the 10 response evaluable patients (2/12 pending marrow assessment), 9/10 (90%) achieved flow/molecular MRD negative CR at 6 weeks. 2/9 responders experienced CD19 negative relapse (one at M3, one at M5) and 3/9 responders experienced CD19+ relapse (one at M3, one at M9, one at M12). 4/10 (40%) response evaluable patients remain on study and continue in flow/molecular MRD negative remission at a median follow up of 11.9 months (range 2.9-25.9). Conclusions: Donor-derived matched allogeneic CD19 CAR T cells are straightforward to manufacture using the CliniMACS Prodigy and deliver excellent early remission rates, with 90% MRD negative CR observed at Week 6 in the absence of severe CAR associated toxicity or GvHD. Peak CAR expansion appears to be compromised by the absence of LD and this may lead to a higher relapse rate. Updated results from Cohorts 1 and 2 will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Qasim:Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; UCLB: Other: revenue share eligibility; Servier: Research Funding; Bellicum: Research Funding; CellMedica: Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if Results: As of 24 July 2019, 16 patients have been leukaphresed, 14 products manufactured (one failed leukaphresis and one currently in manufacture) and 13 patients have received at least 1 dose of AUTO1. Of the 16 patients, median age was 35.5 (range 18-63), 10/16 (63%) had prior blinatumomab or inotuzumab ozogamicin and 12/16 (75%) had prior HSCT. At the time of pre-conditioning, 9/13 (69%) patients were in morphological relapse with >5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (median peak expansion 172 CAR/uL blood). Of the 13 patients dosed (1/13 pending 28 day follow up), 10/12 (83%) achieved MRD negative CR at 1 month and all patients had ongoing CAR T cell persistence at last follow up. Two patients experienced CD19 negative relapse (one at M3, one at M6), 1 patient died on D17 before first response evaluation, 1 died in molecular CR from sepsis, and 1 died from persistent disease. Currently, 7/12 remain on study and continue in flow/molecular MRD negative remission with a median follow up of 9.0 months (range 1.2-14.8). Conclusions: AUTO1 delivers excellent early remission rates with initial data showing 83% MRD negative CR and robust CAR expansion and persistence. Despite high tumour burden, the safety profile compares favourably to other CD19 CARs, with no cases of severe CRS and only one case of Gr3 neurotoxicity. This is consistent with experience in the paediatric cohort. Updated results will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

ASXL1 mutations are recurrent in acute myeloid leukemia (AML), but it is unclear whether ASXL1 genotype might influence patient management. We analyzed frequency and impact in younger (15-59 years) and older (≥ 60 years) patients with primary or secondary disease. Overall, 9% had truncating mutations. Incidence was significantly lower in younger patients with primary than with secondary disease (4%, 12%; p = 0.03). In older patients it did not differ significantly (11%, 15%; p = 0.5). In univariate analysis, ASXL1-mutated patients had a worse outcome (5-year relapse 83% vs. 56%, p = 0.01; overall survival [OS] 6% vs. 22%, p = 0.02). However in multivariate analysis, ASXL1 mutations had no prognostic significance (for OS, p = 0.3), because age was a major confounding factor. The low incidence of mutations in younger patients with primary disease and the lack of significance in multivariate analysis indicate that there is a limited role for screening at diagnosis for ASXL1 mutations for the purpose of prognostic stratification.

Background: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. Methods: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages

Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer in the UK, and represents a heterogeneous group of malignancies. This article will give an overview of lymphoid neoplasms, concentrating on the common subtypes of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Clinical outcomes in B-cell NHL have significantly improved in the past decade, largely due to the availability of the monoclonal antibody, rituximab. However, some aggressive lymphomas, including many T-cell disorders, still carry a poor prognosis.

GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA-double mutations. To explore their impact on this favourablerisk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/ CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPAdouble/ FLT3-inernal tandem duplication-negative patients.

Objectives Elderly patients with diffuse large B cell lymphoma (DLBCL) without prohibitive co-morbidities may be cured with standard immuno-chemotherapeutic regimens, as used in younger patients. Less is known about the survival prospects in older people, if first-line therapy fails. This study aimed to provide additional information regarding prognosis in this group. Materials and Methods Databases were collated from three randomized trials of first-line therapy in those aged 60 and over, deemed fit enough for standard therapy. Overall survival from the point of treatment failure was calculated and comparisons were made between age groups and types of treatment failure. Results Overall survival (OS) at 2 years in 862 patients was 46%, 38%, 37% and 23%, respectively, for those aged 60–64, 65–69, 70–74 and > 74. Type of treatment failure impacted on 2 year OS as follows: initial partial remission (PR): 48%; complete response (CR) with late relapse: 37%; CR with early relapse: 17%; and less than PR to initial therapy: 12%. Conclusion Older patients failing first-line therapy for DLBCL should be counseled differently regarding prognosis depending upon age and type of treatment failure. The chance of survival was greater in those achieving PR or CR with relapse more than 12 months from diagnosis. This data may support the consideration of aggressive salvage therapy in fit patients in these categories, regardless of biological age per se. Palliative management may be more appropriate for those achieving less than PR to initial therapy or who enter CR but relapse within one year of diagnosis.

PURPOSE: The primary aim was to compare the diagnostic performance of PET/MRI (performed with basic anatomical MRI sequences) in detecting sites of disease in adult patients with lymphoma compared with the current standard of care, PET/CT. Secondary aims were to assess the additional value of diffusion-weighted imaging to PET/MRI in disease detection and to evaluate the relationship between the standardized uptake value on PET/MR and the apparent diffusion coefficient on diffusion-weighted imaging. METHODS: Sixty-eight studies in 66 consecutive patients with histologically proven Hodgkin or non-Hodgkin lymphoma were prospectively evaluated. Each patient had whole body PET/CT, followed by whole body PET/MR. Two experienced readers independently evaluated the PET/MRI studies, and two other experienced readers independently evaluated PET/CT. Site of lymphoma involvement and SUVmax at all nodal sites more avid than background liver were recorded. Readers provided stage (in baseline cases) and disease status (remission vs active disease). The apparent diffusion coefficient mean value corresponding to the most avid PET site of disease was recorded. RESULTS: Ninety-five nodal and 8 extranodal sites were identified on both PET/CT and PET/MRI. In addition, 3 nodal and 1 extranodal sites were identified on PET/MRI. For positive lesion detection, reader agreement in PET/MR was perfect between the 2 readers and almost perfect between PET/CT and PET/MR (k > 0.978). Intermodality agreement between PET/CT and PET/MRI was also near perfect to perfect for staging/disease status k = (0.979–1.000). SUVmax from PET/CT and PET/MRI correlated significantly (Spearman rho correlation coefficient, 0.842; P < 0.001). Diffusion-weighted imaging did not alter lesion detection or staging in any case. A negative correlation was demonstrated between ADC mean and SUVmax (Spearman rho correlation coefficient r, -0.642; P < 0.001). CONCLUSIONS: PET/MRI is a reliable alternative to PET/CT in the evaluation of patients with lymphoma. Diffusion-weighted imaging did not alter diagnostic accuracy. With comparable accuracy in detection of disease sites and added benefit of radiation dose reduction, PET/MRI has a potential to become part of routine lymphoma imaging.

The impact of human leukocyte antigen (HLA) mismatch after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIT) using unrelated donors (UD) is unclear, and may be modulated by T-cell depletion. We therefore examined outcomes of 157 consecutive patients undergoing RIT after uniform conditioning with fludarabine, melphalan, and alemtuzumab (FMC). Donors were 10/10 HLA-matched (MUDs, n = 107) and 6 to 9/10 HLA-matched (MMUDs, n = 50), with no significant differences in baseline characteristics other than increased cytomegalovirus seropositivity in MMUDs. Rates of durable engraftment were high. Graft failure rates (persistent cytopenias with donor chimerism) were similar (8% vs 3%, P = .21), though rejection (recipient chimerism) was more frequent in MMUDs (8% vs 0%, P < .01). There were no significant differences between donors in the incidences of acute graft-versus-host disease (GVHD; 20% vs 22% grade 2-4, respectively, P = .83), chronic extensive GVHD (3-year cumulative incidence [CI] 23% vs 24%, P = .56), or treatment-related mortality (1-year CI 27% vs 27%, P = .96). Furthermore, there was no difference in 3-year overall survival (OS; 53% vs 49%, P = .44). Mismatch occurred at the antigenic level in 40 cases. The outcome in these cases did not differ significantly from the rest of the cohort. We conclude that RIT using HLA-mismatched grafts is a viable option using FMC conditioning.

Involved field (IF) radiation was compared with extended field (EF) radiation in Hodgkin lymphoma (HL) to ascertain whether reduced radiation fields would reduce the late sequelae of radiation without compromising disease control and survival. A total of 603 patients with stage I or II HL were entered into this trial; laparotomy was carried out in 380 (63%) patients. Stage I or IIA disease patients were randomised to receive IF or EF comprising a mantle or inverted Y fields alone. Stage I and IIB patients were randomised between mantle or inverted Y fields and total nodal irradiation (TNI). The dose was 35Gy to uninvolved sites and 40Gy to involved sites. The median follow-up of surviving patients was 25.2 years with only 3.3% lost to follow-up. The treatment failure rate at 25 years in stage IA and IIA was 44% after EF and 54% after IF ( P =0.01); in stage I and IIB this was 80% (EF) and 82% (TNI) at 25 years. No difference in overall survival between the randomised groups was seen. The incidence of second malignancies was 21% after IF and 20% after EF with a slight excess of lung cancer in the EF group. No significant differences in the causes of death between the randomised arms have emerged. In conclusion, IF radiotherapy for stage I and IIA HL results in a 11% greater risk of relapse compared with EF but has no effect on overall survival, risk of second malignancy or cause of death at 25 years.

Six patients with severe combined immunodeficiency were transplanted with bone marrow from their HLA haploidentical parents. T-lymphocytes were removed by complement mediated lysis with a monoclonal antibody (CAMPATH-I) followed by rosetting with sheep erythrocytes. The patients were pre-conditioned with marrow ablative chemotherapy, using busulphan and cyclophosphamide. There was graft take in five patients, with evidence of transient acute graft-versus-host disease only. Three patients are alive and well greater than 5 months after transplant, and one who is 12 months post graft has full reconstitution of cell mediated and humoral immunity, including specific antibody response to immunization. Transplantation across major histocompatibility barriers can be successfully achieved using this method of treatment of donor marrow.

Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients.

Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission.We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction.Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status.The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).

Purpose To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. Patients and Methods Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. Results Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. Conclusion This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.

Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.

The diagnosis of Burkitt Lymphoma (BL) and B-cell lymphomas unclassifiable with features intermediate between Diffuse Large B-cell Lymphoma and BL (BLU) in adults remains problematic even with immunophenotyping and MYC gene analysis. Gene expression profiling may improve categorization but is not routinely available. BL and its variants should be treated with specific regimens incorporating intensive courses of chemotherapy with fractionated alkylating agents and cell cycle phase-specific agents that readily cross the blood brain barrier. Subsequent courses should be given as soon as haematological recovery occurs, with the whole course completed within a few months. A number of regimens have been developed that encompass these principles but there have been no comparative randomized trials. The results from several studies suggest that the addition of rituximab is highly efficacious and this may be particularly valuable in older patients. It is usual to employ 'risk-adapted' strategies in the treatment of BL but these must be continually re-evaluated, and 'response-adapted' approaches should be explored. The role of transplantation is limited and largely confined to autologous transplants in patients who only achieve a partial response on front-line therapy or who have a chemosensitive relapse. Further advances will be greatly facilitated by randomized trials, which will require international collaboration.

PURPOSE: This multicentre, prospective, randomised-controlled trial compared efficacy and toxicity of differing radiotherapy doses in non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Patients with any histological subtype of NHL, requiring radiotherapy for local disease control, whether radical, consolidative or palliative, were included. Three hundred and sixty one sites of indolent NHL (predominantly follicular NHL and marginal zone lymphoma) were randomised to receive 40-45Gy in 20-23 fractions or 24Gy in 12 fractions. Six hundred and forty sites of aggressive NHL (predominantly diffuse large B cell lymphoma as part of combined-modality therapy) were randomised to receive 40-45Gy in 20-23 fractions or 30Gy in 15 fractions. Patients with all stages of disease, having first-line and subsequent therapies were included; first presentations of early-stage disease predominated. RESULTS: There was no difference in overall response rate (ORR) between standard and lower-dose arms. In the indolent group, ORR was 93% and 92%, respectively, (p=0.72); in the aggressive group, ORR was 91% in both arms (p=0.87). With a median follow-up of 5.6years, there was no significant difference detected in the rate of within-radiation field progression (HR=1.09, 95%CI=0.76-1.56, p=0.64 in the indolent group; HR=0.98, 95%CI=0.68-1.4, p=0.89 in the aggressive group). There was also no significant difference detected in the progression free or overall survival. There was a trend for reduced toxicities in the low-dose arms; only the reduction in reported erythema reached significance. CONCLUSION: In a large, randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24Gy in indolent NHL and 30Gy in aggressive NHL, compared with previous standard doses of 40-45Gy.

Purpose Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse. Patients and Methods This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse. Results Three-year donor lymphocyte–related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients. Conclusion These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.

Introduction: Patients with Acute Myeloid Leukaemia (AML) who harbour a FLT3-ITD mutation have a worse prognosis characterised by increased early relapse. Outcomes following relapse in such patients are typically poor, not only because of earlier relapse, but also because of worse performance post-relapse than those who have the same remission duration but are FLT3-ITD WT. In a single centre retrospective study among relapsed patients, Ravandi et al [1] found a remission rate of 24% and median survival of only 13 weeks. There are therefore twin challenges in this population: first to reduce the early relapse rate, and also to develop more effective treatments post relapse. In the recent QUANTUM-R trial [2] for patients with relapsed or refractory disease, single agent quizartinib (AC220) was found to significantly improve median survival from 20.4 weeks to 27 weeks when compared to "doctor's choice" treatment (low-dose ara-C, MEC or FLAG-Ida). There is however, no directly comparable data for the population in the QUANTUM-R trial. To contextualise these results, especially given the potentially different outcomes by control treatment, we looked at outcomes in the UK NCRI AML15,16,17 trials in patients satisfying the eligibility criteria of QUANTUM-R. Methods: Patients aged 18+ in the UK NCRI AML15,16,17 trials were identified who harboured a FLT3 ITD mutation, were treated with intensive chemotherapy, and were either refractory to two courses of induction therapy, or relapsed within six months of transplant, or did not receive a prior transplant and had a remission duration of 6 months or less. Patients were grouped hierarchically as refractory, relapsed post transplant, or relapsed without prior transplant. Eligibility was established at the point a patient first became eligible for analysis. The primary outcome was overall survival (OS), measured from point of eligibility, with subsequent remission with or without count recovery as secondary outcome. A sensitivity analysis was performed excluding those who died within 21 days of eligibility to eliminate patients who might be thought of as too unwell to enter a post-relapse trial. Cox regression was used to identify prognostic factors for survival. Results: A total of 264 patients were identified (refractory n=58, relapsed post SCT n=49, relapsed without SCT n=157). The median age was 51 (range 18-84); 25% of patients were aged 60 or older; 44% were male, 95% had intermediate cytogenetics; 11% had secondary disease. Split by age, among those under 60 45 were refractory, 44 relapsed post SCT and 110 relapsed without SCT; for ages 60+ the figures were 13 vs 5 vs 47. Overall 17% of patients experienced a subsequent remission; with median survival of 86 days and 1 year OS of 13%. If deaths within 21 days were excluded, the remission rate improved to 21%; with a median survival of 133 days and 1 year OS of 16%. In multivariable Cox regression, age group HR for age>60 1.81 (1.33-2.47) p=0.0002) and route to eligibility (HR refractory vs relapsed no SCT 0.77 (0.55-1.07); relapsed post SCT vs no SCT 1.58 (1.11-2.25) p=0.003) were the only factors affecting survival - in particular sex, secondary disease, and ITD allelic burden were not significant. In the sensitivity analyses, only age was significant (HR 1.77 (1.24-2.53) p=0.001); with route to eligibility not significant (p=0.14). Among patients with post-relapse treatment information, 65% were treated intensively, 8% non-intensively, and 20% with palliation - other patients received experimental therapies. When restricting attention to those treated intensively, median survival was 130 days with 17% 1 year OS. Figures were not materially changed if early death was excluded. Of 215 patients who had not relapsed post transplant, 53 (25%) received a transplant post-eligibility. In these 56 patients, median survival was 301 days with 42% alive at one year. Conclusions: In relapsed/refractory AML, outcomes for FLT3-ITD mutated patients are generally poor and worse for older patients. Applying the eligibility criteria of QUANTUM-R and excluding early deaths gives outcomes comparable to the control group of the QUANTUM-R study. In the 25% of patients who proceeded to transplant survival was extended indicating that a treatment which can deliver patients to transplant has the potential to improve patient outcomes. References: [1] Ravandi F, et al. Leuk Res. 2010;34(6):752-756; [2] Cortes et al. EHA 2018, Abstr LB2600. Table. Table. Disclosures Hills: Daiichi Sankyo: Consultancy, Honoraria. Russell:Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau.

Introduction: The increasing delineation of acute myeloid leukemia (AML) has identified a number of genetic mutations which may be amenable to targeted therapies. However, such mutations typically only occur in a minority of patients, and this relative paucity presents challenges in drug development. Even for more common mutations such as FLT3 ITD, randomised trials can take many years to complete, and there is the issue of how to deal with patients who are tested but not eligible. Earlier phase trials therefore tend to be single arm studies, and often recruit in the relapsed/refractory population, where eligibility is known up front, and it is possible to obtain an early read out for efficacy. Such is the case for the recent evaluations of enasidenib and ivosidenib in IDH1/2 mutated patients. However, with single-arm studies there a need to contextualise results. We therefore looked at outcomes from the United Kingdom NCRI trials of AML for patients with IDH1/IDH2 mutations who were relapsed or refractory to therapy. Methods: A database search identified patients within the UK NCRI AML trials with an IDH1/IDH2 mutation, who had received intensive induction and who were either: in second relapse, relapsed post-transplant, refractory to two courses of induction, or who relapsed within 1 year of remission. Outcomes were measured from the point of eligibility: patients who were multiply eligible were included only once, at their first point of eligibility. The primary outcome was overall survival, with achievement of complete remission, with or without peripheral count recovery, as secondary outcome. Cox regression analysis was used to identify prognostic factors within the cohort of patients. Cytogenetics are evaluated using the MRC classification. Results: A total of 757 patients were identified with IDH1/2 mutation (IDH1 alone n=247; IDH2 alone n=504, both n=6). Of these 211 patients satisfied the relapsed/refractory criteria (IDH1 alone n=81; IDH2 alone n=128; both IDH1/2 n=2; refractory n=28; relapsed post SCT n=34; relapsed within 1 year with no SCT n=138; second relapse n=11 - Table). Median age was 54 years (range 22-77); 51% were male; and 95% of patients had intermediate risk cytogenetics. Remissions were achieved in 43/211 patients (20%; refractory 50%; relapsed post SCT 15%; relapsed within 1 year 17%; second relapse 9% - Table). Patients with IDH1 mutations had a remission rate of 23%; for IDH2 mutated patients, the rate was 18%. Median survival was 4.4 months for IDH1 mutated patients, and 6.6 months for IDH2 mutations; 2 year survival was 17%, 21% respectively. Split by age, median survival was 4.0 and 9.4 months respectively (2-year survival 19%; 27%) for patients aged Conclusions: These results give context to the recent findings in single arm studies of ivosidenib for relapsed/refractory IDH1 mutated patients, and enasidenib for patients harbouring an IDH2 mutation. In the two studies reported, median survival was respectively 8.8 and 9.3 months, compared to 4.4 and 6.6 months in a younger group of patients identified from the UK NCRI AML trials treated with a variety of therapies. In both monotherapy trials the median survival was extended: however, reported one-year survival was not greatly improved (enasidenib 1 year survival 39% vs 34% for the NCRI cohort; ivosidenib, approximately 35% vs 32%). The difference in survival for IDH2 mutated patients in the NCRI cohort, by age and route to eligibility indicates that the interpretation of the results of single arm studies, in a heterogeneous condition such as AML, is fraught with difficulties. Ideally the magnitude of benefit should be assessed using randomised data from large scale collaborations and platform trials. Table: Outcomes for IDH1/IDH2 mutated relapsed/refractory patients in the UK NCRI AML trials. Disclosures Hills: Daiichi Sankyo: Consultancy, Honoraria. Russell:Daiichi Sankyo: Consultancy; Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Background: The International Prognostic Index (IPI) was first described in 1993 and is the most widely used prognostication tool in diffuse large B-cell lymphoma (DLBCL). Five independent risk factors for OS: age (≤60 yrs versus >60 yrs), stage (I/II versus III/IV), number of extranodal (EN) sites (≤1 versus >1), performance status (PS) (0-1 versus ≥2) and serum lactate dehydrogenase (LDH) (normal versus elevated) were used to design a prognostic model which stratified patients into 4 prognostic groups according to the number of risk factors present: low (0-1), low-intermediate (2), high-intermediate (3), and high-risk (4-5); predicting 5-yr OS rates of 73%, 51%, 43% and 26% and 5-yr relapse-free survival (RFS) rates of 70%, 50%, 49%, 40% respectively. For patients aged ≤60 yrs 3 risk factors (stage, PS and LDH level) remained independently significant for OS, and an age-adjusted (aa) model (the aa-IPI) was proposed which predicted 5-yr OS for the low (0), low-intermediate (1), high-intermediate (2) or high-risk (3) groups of 83%, 69%, 46% and 32% respectively (Shipp et al, 1993). The British Columbia Cancer Agency re-evaluated the role of IPI in the rituximab era in their registry-based cohort of 365 patients in 2007. Although the IPI remained predictive, only 2 (rather than 4) prognostic groups were identified and the authors recommended use of the Revised-IPI (R-IPI) where redistribution of the absolute number of IPI risk factors better stratified patients into 3 prognostic groups: very good (0) good (1,2) and poor (3-5) (Savage et al, 2007). However, a subsequent analysis of pooled data from 3 prospective trials (Ziepert et al, 2010) confirmed that the IPI remained highly predictive of outcomes in the rituximab era. Here we report an evaluation of prognostic indices within the UK NCRI R-CHOP 14 vs 21 prospective trial cohort (Cunningham et al, 2013). Methods: The IPI and R-IPI were applied to the R-CHOP 14 versus 21 trial cohort (n=1,080) and for the subgroup of patients aged ≤60 yrs (n=515) and correlated with OS and progression-free survival (PFS). For patients aged ≤60 yrs the aa-IPI was applied in addition. It was not possible to evaluate the NCCN-IPI in our cohort as absolute LDH values were not collected at enrolment. The association between baseline clinical factors (age, gender, PS, stage, presence of >1 EN site of disease, presence of an elevated LDH, disease bulk and B symptoms) and patient outcomes were investigated in univariable and multivariable analysis (MVA). Performance of the prognostic indices was compared using the Concordance Probability Estimate (CPE) and Akaike's Information Criterion (AIC): CPE evaluates discriminatory power to assess the strength of statistical models (higher values indicate better discrimination); AIC estimates the quality of statistical models relative to each other in terms of fitting the data (lower values indicate a better model fit). Results: After a median follow-up of 6.5 years, both the IPI and R-IPI were significantly associated with OS (Figure 1) and PFS; the IPI performed better than the R-IPI for OS and PFS in terms of discrimination and model fit (Table 1). All IPI factors were significantly associated with OS, and remained in MVA with the exception of disease stage. For patients aged ≤60 yrs, the IPI, R-IPI and aa-IPI were all strongly associated with OS and PFS; the IPI performed best overall of the 3 prognostic indices in terms of discrimination and model fit (Table 2). All individual IPI risk factors, excepting stage, were again found to be significantly associated with OS in MVA for patients aged ≤60 yrs. Conclusion: For the entire DLBCL cohort both the IPI and R-IPI identified meaningful prognostic groups for OS and PFS. Although the IPI outperformed the R-IPI, neither index identified a patient subgroup with an OS of Disclosures Cunningham: Roche pharmaceuticals: Research Funding. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck KGA: Research Funding; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Celgene: Other: Advisory board, Research Funding; Takeda: Other: Speaker fee; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Pocock:Kent & Canterbury Hospital: Employment. Ardeshna:Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Radford:Celgene: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; BMS: Consultancy, Speakers Bureau; Pfizer: Research Funding. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Johnson:Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Boeringher Ingelheim: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Novartis: Honoraria; Celgene: Honoraria; Eisai: Research Funding; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy.

Purpose To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein α (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact. Patients and Methods The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing. Results Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA–wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively). Conclusion Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.

We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy. This study is registered at http://www.controlled-trials.com under ISRCTN17833622.