ALBERT

Description: Key Points In older patients with AML who are not suitable for intensive treatment, clofarabine doubles remission rates Survival is not improved compared with low-dose Ara-C

Description: Introduction The efficacy of rasburicase vs allopurinol for the prevention of hyperuricemia (HU) of tumor lysis syndrome (TLS) has been demonstrated in clinical trials, yet studies evaluating these therapies in real-world clinical practice are lacking. Here, we evaluate the real-world use and clinical impact of rasburicase and allopurinol for the prevention of chemotherapy-induced HU. Methods Data were collected from a proprietary aggregated Electronic Medical Records database containing data from 21 healthcare organizations and 26 million patients in the US. Inclusion criteria included patients at high risk (HR) of TLS (Table 1) and diagnosed with acute lymphocytic leukemia, acute myeloid leukemia, Burkitt's Lymphoma, chronic lymphocytic leukemia, or diffuse large B-cell lymphoma, and receiving chemotherapy between 01/01/2017 and 06/30/2018. Baseline measures were those within 6 months but closest to and before the start of chemotherapy. Patients were followed until death or 6 months from the start of chemotherapy. Statistical analyses included Student's t-test for continuous variables and Chi-squared, Fisher's exact, or McNemar's test for categorical variables. Multivariate analyses were conducted to assess association of variables and to generate scores for propensity score matching (PSM). Results Of the patients who qualified for the study, 74% (991) received allopurinol, 7% (92 patients) rasburicase, and 19% (248) did not receive a urate-lowering therapy. Patients receiving rasburicase were more likely to be male, with pre-existing TLS at chemotherapy drug initiation, and previously treated with rasburicase or both urate-lowering therapies. The TLS risk population receiving rasburicase presented with higher mean baseline uric acid level (9.0 mg/dL) compared with patients receiving allopurinol (6.9 mg/dL), and over half had baseline uric acid levels 〉7.5 mg/dL (56% vs 35% for allopurinol). Multivariate analysis further indicated that a greater fraction of patients receiving rasburicase had renal impairment (glomerular filtration rate [GFR]

Description: Abstract 4560 Introduction: About 15% of acute myelogenous leukemia (AML) patients will have disruption of the core binding factor (CBF) transcription factor as indicated by the detection of t(8;21) or inv(16) on metaphase cytogenetic analysis. In general, patients with CBF-AML are younger and regarded as having a favorable outcome when treated with anthracycline-based induction chemotherapy and multiple cycles of high-dose cytarabine consolidation. Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are usually perceived as unnecessary in the management of CBF-AMLs. However, most data indicating the favorable prognosis of CBF-AML with non-HSCT management originates from young selected patients participating in clinical trials and information on relapse treatments is often lacking. We performed a retrospective analysis of consecutive patients diagnosed with CBF-AML at a regional leukemia center over the last twelve years to assess long term survival of unselected patients and the likelihood of therapeutic success without ever requiring HSCT. Methods: The study cohort was identified through a search of all AML reports issued by the institutional clinical cytogenetics laboratory since the introduction of electronic records (1998-2010). We subsequently reviewed the charts of all patients with CBF-AML (irrespective of other cytogenetic abnormalities) to extract demographic, treatment, and outcome information. Survival status and subsequent treatments in other institutions were determined by contacting the patient, attending physician or review of public death records. Data collection and analysis were approved by the Institutional Review Board. Results: Thirty patients with CBF-AML were identified, 14 with t(8;21) and 16 with inv(16) AML. Median follow up for survivors in this series is 35.3 months (range 6.4–117.4) with all survivors currently in remission. Median age at diagnosis was 43 years (range 18–69) with 10 (33%) patients older than 55. All patients initially received therapy with curative intent with anthracycline-based induction chemotherapy. Only 47% of the patients were treated on clinical trials. There was 1 death during induction therapy and 22/29 patients (73.3%) achieved a complete remission with initial induction therapy. Overall 13 patients (43.3%) have required some modality of HSCT. Six patients received HSCT in CR1 due to perceived high risk of relapse (5 autologous, 1 allogeneic). None of the 6 patients who underwent HSCT in CR1 (5 autologous, 1 allogeneic) have relapsed. Among the 16 patients receiving non-transplant consolidation in CR1, 6 have subsequently relapsed and required a HSCT (3 autologous, 3 allogeneic) and 3 of these patients are alive 20.9–117.4 months from the initial diagnosis. Seven patients received HSCT in CR2 or in relapse (4 autologous, 3 allogeneic) and 6 of these patients are long-term survivors. Estimated 5 year overall survival for the entire cohort is 58.8 +/− 10.8%, comparable to what has been described for younger patients entering clinical trials (Grimwade et al, 2010). However, the likelihood of survival at 5 years without requiring HSCT was only 28.1+/− 8.8% (Figure). Conclusions: The favorable outcome previously reported for CBF-AMLs was reproducible in unselected patients. However, only a minority of patients were long term survivors relying exclusively on conventional chemotherapy. In the near future, strategies for molecular risk stratification of CBF-AML patients need to be coupled with risk-adapted therapy, likely including early use of HSCT for high-risk patients. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: The safety and efficacy of rurioctocog alfa pegol (BAX 855, SHP-660, TAK-660; Adynovate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in patients with severe hemophilia A has been reported previously (Konkle BA et al., Blood 2015, 126:1078-85; Brand B et al., Haemophilia 2016, 22:e251-8; Mullins ES et al., Haemophilia 2017, 23:238-46); however, research describing patient experience with extended half-life (EHL) recombinant factor VIII (FVIII) products outside clinical trials is limited. The objective of this study was to assess real-world utilization of TAK-660 in patients with hemophilia A and describe their clinical profiles before and after switching to TAK-660. Factor consumption and bleed outcomes stratified by age (

Description: The MRC AML15 Trial is primarily for patients with any form of AML who are under 60 years. One of the questions addressed was whether the addition of the immunoconjugate, Gemtuzumab Ozogamicin (GO) to induction (course 1) and/or consolidation (course 3) is beneficial. In induction patients are randomised to receive either DA (Daunorubicin/Ara-C) or ADE (Ara-C/Daunorubicin/Etoposide) or FLAG-Ida (Fludarabine/Ara-C/Idarubicin/G-CSF) and in consolidation either MACE (Amsacrine/Etoposide) or HD Ara-C (3.0g/m2 or 1.5g/m2 per dose). Our prior pilot trial had shown that GO 3mgs/m2 could be safely added to day 1 of each of these treatments (Kell et al Blood102, 4277–4283). Here we report the preliminary results of the effect of combining GO with induction chemotherapy. This randomisation achieved its recruitment target and was closed on 30 June 2006. All other comparisons in the trial, including GO in consolidation, remain open. Patients: A total of 1115 patients were randomised between July 2002 and June 2006. The median age was 49 (range 0–71) years: 53% of patients were male: 92% (n=1027) had de novo disease: 95% had WHO performance score of 30 x 109/l and LFT’s 〉 normal were initially excluded but admitted from March 2004. APL patients were not eligible for entry. 15% of patients with data had favourable 71% intermediate, and 14% adverse cytogenetics. Over 83% were CD33 positive. Results: The overall remission rate was 85% with no differences between the arms for GO vs no GO in CR (85% vs 85%) induction death (8% vs 7%) or resistant disease (7% vs 8%). There was a modest increase in mucositis on the GO arm in course 1 only (p=0.04) and increased AST and Alt toxicity in C1 (p=.002; p=.03) but no difference in bilirubin grades. GO patients used more platelets (19 vs 14; p

Description: The UK MRC AML12 Trial in Acute Promyelocytic Leukaemia was conducted between 1994 and 2002 and involved the simultaneous administration of ATRA with standard chemotherapy (Daunorubicin/Etoposide/Ara-C) until complete remission. This approach resulted in an overall survival at 5 years of 80% for patients given long ATRA; however it was associated with prolonged periods of neutropenia, days on antibiotics and hospitalisation. In the successor trial, AML15, which recruited 291 patients between May 2002 and June 2007 from 90 treatment centres, the same treatment was compared with the Idarubicin/ATRA approach developed by the Spanish PETHEMA Group. Patients under 60 years of age were randomised to receive either the MRC Arm (four treatment courses ADE/ADE/MACE and MidAC with ATRA given for the first 60 days of treatment) or the Spanish Arm (two courses of Idarubicin/ATRA followed by two courses of Mitoxantrone/ATRA, and then 18 months of maintenance. In course 3 of each arm patients are randomised to receive, or not, Gemtuzumab Ozogamicin (GO) on day 1. Since it was considered unlikely that sufficient patients would be available to demonstrate any effectiveness difference the primary endpoints were toxicity, neutropenic days, days on antibiotics, hospitalisation, supportive care requirements and Quality of Life which was measured at baseline, and 3, 6, 12 and 24 months from entry using the EORTC QLQ30, plus leukaemia module, and Hospital Anxiety and Depression Score. Results: No difference in CR was seen (91% MRC vs 93% Spanish; OR 0.73, 95%CI 0.30–1.77, p=0.5); 10 vs 8 patients died during induction and 1 patient in each arm had resistant disease. Five (MRC) vs 6 (Spanish) patients have relapsed. More patients (n=11) in the MRC arm died in CR than in the Spanish arm (n=2) (p=0.009). Overall survival, with a median follow up of 24 months, was not significantly different (85% Spanish vs 81% MRC at 4 years; HR 0.57 95% CI 0.29–1.11, p=0.10). The MRC treatment was significantly more myelosuppressive which resulted in significantly greater need for blood product support, days on antibiotics and hospitalisation, particularly in the second course (p

Description: EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD50 (the concentration of EB1089 required to kill 50% of cells) value (± SD) of 2.1 × 10−8 M (± 1.4 × 10−8 M). Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (P = .1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression, but this was evident only in the apoptotic cells. In contrast, the expression of Bax, p21, and p53 was not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 mitogen–activated protein (MAP) kinase and suppression of extracellular signal–regulated kinase (ERK) activity, and this was associated with downstream activation of caspase-3. The pancaspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.

Description: Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%,P 

Description: Abstract 484 On behalf of the NCRI AML Working Group, United Kingdom There is a general acceptance that survival in younger patients (75% relapse remains a problem. Optimisation of induction and defining the schedule and duration of post-induction chemotherapy remains important even as novel approaches such as antibody directed therapy or small molecule therapy are added. The MRC AML15 compared 3 induction chemotherapy schedules and 4 post induction options. In induction patients were randomised to two course of DA or ADE or FLAG-Ida. In each case patients were also eligible to be randomised to receive Gemtuzumab Ozogamicin (GO) or not, which has been separately reported. In consolidation patients were randomised to MRC schedule (MACE/MidAC) or two courses of High Dose Ara-C and for those randomised to Ara-C to a dose of 3g/m2 or 1.5g/m2. Finally patients could be randomised to receive, or not, a 5th course comprising Ara-C. Between October 2002 and January 2009, 1982 patients were randomised between DA (n=994) and ADE (n=988); up to May 2007, patients could also be randomised to FLAG-Ida; the randomised comparison with ADE recruited 1266 patients (FLAG-Ida n=635, ADE n=631). For part of the trial patients could be randomised to GO or not (306 patients in the DA v ADE and 297 in the FLAG-Ida v ADE comparisons were randomised). The median age of patients in the randomised comparisons was 49 years. Overall the ORR was 85% (CR 80%, CRi 5%) and the OS at 5 years is 43%. The randomisations were balanced for age, sex, performance status, de Novo/secondary disease, cytogenetics, white cell count, and GO allocation. With the exception of a suggestion of greater benefit on ORR with FLAG-Ida among patients given GO, overall outcomes were not affected by GO treatment. In consolidation 1445 patients were randomised between MRC (n=723) and HD Ara-C (n=722). Of the 723 Ara-C patients, 328 were randomised to 3g/m2 and 329 to 1.5g/m2: 227 of the 1619 patients who received 4 courses were randomised for a 5th course with 112 allocated 5 courses. Conclusions: There were no significant differences in the response rate between induction treatments. FLAG-Ida resulted in a reduced relapse rate but this was balanced by increased myelosuppression and deaths in CR resulting in no overall benefit in survival. No survival differences were seen in any of the post induction comparisons, but the MACE/MidAc arm produced more myelosuppression and required more supportive care, and led to increased death in remission. Disclosures: No relevant conflicts of interest to declare.

Description: Inclusion of CAMPATH-1H as part of a Fludarabine/Melphalan conditioning regimen is effective at preventing GVHD and reducing non-relapse mortality (NRM)following allogeneic stem cell transplantation. However, these benefits are offset by high rates of infection and potentially a loss of graft-versus-tumor effects. When used at a total dose of 100mg, CAMPATH-1H antibody can still be detected at levels in excess of those required to induce ADCC for several weeks. We reasoned that a reduction in the dose of CAMPATH-1H would permit improved immune reconstitution post-transplantation. We report here the analysis of a national, multi-center trial in which the total dose of CAMPATH-1H was reduced step-wise in separate cohorts from 60mg to 20mg prior to HLA-identical sibling transplantation (n=106). Eligibility criteria included patients with haematological malignancies who were aged 18–65, who had a life expectancy 〉3 months and who were not suitable for standard myeloablative conditioning. Primary endpoints included PK data, chimerism, NRM and incidence of GVHD or infection. The study received IRB approval and all patients gave informed consent. Four total doses of CAMPATH-1H were tested in consecutive cohorts: group 1, 60mg split between d-2 and d-1 (n=26); group 2, 40mg split between d-2 and d-1 (n=27); group 3, 30mg d-1 (n=28); and group 4, 20mg on day -1 (n=25). 97/106 patients recruited to the study are evaluable with a median follow up of 12 months. Median age was 50 (range 19–64). No major differences were identified in patient characteristics between each cohort. 1-year OS and PFS for the whole population was 80.8% and 67.2% respectively. Peak CAMPATH-IH levels (ug/ml) measured by ELISA on day 0 (n=5 each group) were 7.7 ±1.1 in group 1, 4.3 ±0.7 in group 2, 4.9 ±0.8 in group 3 and 2.7± 0.7 in group 4 (p