Despite an increasing desire to use historical cohorts as “synthetic” controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012–2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) characterized by t(15;17) translocation, PML :: RARA rearrangement, a high risk of fatal hemorrhage, and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic-based therapy. 1 The white blood cell (WBC) count at

Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

BACKGROUND:Rheumatoid arthritis (RA) is a common autoimmune disease where methotrexate (MTX) is widely used as the first-line therapy. The combination of RA and MTX is associated with lymphoproliferative disorders (LPD). RA patients with Epstein-Barr virus (EBV) have impaired T-lymphocyte function, thus allowing an overgrowth of EBV-positive lymphoblastoid cells. We examined the association of EBV with LPD in immunosuppressed RA patients, particularly those treated with MTX.AIM:To review the relationship between RA, EBV-associated LPD and MTX use.METHODS:We reported two cases of RA patients with long-term MTX treatment who subsequently developed EBV-positive LPD, followed by a review of the relevant literature.RESULTS:Compared with normal population, RA patients have a higher risk of lymphoma, with diffuse large B-cell lymphoma being the most common subtype. MTX withdrawal can lead to lymphoma regression. Other biological therapies, such as abatacept and tocilizumab, are not associated with increased EBV-positive lymphoma diagnosis in RA patients.CONCLUSION:The association between EBV, lymphoma and MTX highlights the need to consider reducing or stopping MTX in patients who have had stable RA for many years.

Internal Medicine JournalVolume 51, Issue 2 p. 303-304 Letter to the Editor The role of intravenous immunoglobulin in treatment of refractory Felty syndrome c Minjoo Jeong, Minjoo Jeong chloe9265@hotmail.com orcid.org/0000-0002-0826-6247 Department of Immunology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorPeter Kolovos, Peter Kolovos Department of Haematology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorJohn Taper, John Taper Department of Haematology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorJames Yun, James Yun Department of Immunology, Nepean Hospital, Sydney, New South Wales, Australia Faculty of Medicine, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author Minjoo Jeong, Minjoo Jeong chloe9265@hotmail.com orcid.org/0000-0002-0826-6247 Department of Immunology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorPeter Kolovos, Peter Kolovos Department of Haematology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorJohn Taper, John Taper Department of Haematology, Nepean Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this authorJames Yun, James Yun Department of Immunology, Nepean Hospital, Sydney, New South Wales, Australia Faculty of Medicine, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 25 February 2021 https://doi.org/10.1111/imj.15180Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume51, Issue2February 2021Pages 303-304 RelatedInformation

Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML <60 years. A sub-group analysis of 46 patients with FLT3-ITD, indicated a trend for improved overall survival (OS) in the sorafenib (SOR) arm compared to placebo (PBO). Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR < or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3-4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3-4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.

Pomalidomide and low-dose dexamethasone prolongs progression-free and overall survival in patients with relapsed/refractory multiple myeloma following lenalidomide and bortezomib. As with other IMI...

BACKGROUND:Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. METHODS:This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. RESULTS:Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300 mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300 mg bid. CONCLUSION:Nilotinib 300 mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses.

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan–BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17–20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3–4, 54% bulk, and 54% International Prognostic Index 3–5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Abstract The TIDEL-II trial used imatinib (IM) upfront in patients (pts) newly diagnosed with chronic myeloid leukaemia in chronic phase (CML-CP), and switched selected pts to nilotinib (NIL) on the basis of IM intolerance or failure to achieve time-dependent molecular response. We previously reported major molecular response (MMR; BCR-ABL ≤0.1% IS) at 12 months (mths) and transformation-free survival (TFS) at 3 years. This abstract reports the final analysis with minimum follow-up of 60 months. Patients were enrolled across 27 Australasian sites in 2 equal and sequential cohorts. All started treatment with IM 600mg OD and dose escalated to IM 800mg OD if IM trough levels were <1000ng/mL on day 22. A series of time-dependent molecular targets were set: BCR-ABL (IS) ≤10% at 3 mths (early molecular response: EMR), ≤1% at 6 mths and ≤0.1% at 12 mths. In cohort 1 (C1), pts failing to meet these targets dose escalated to IM 800 mg OD. Pts who failed to improve molecular response after another 3 mths, or were already on IM 800mg OD, switched to NIL 400mg BID. In cohort 2 (C2), pts who failed these targets switched to NIL directly. In addition, pts with grade III/IV or persistent grade II toxicity were also allowed to switch from IM to NIL. Data analysed were limited to 60 mths of follow-up. The study enrolled 210 pts with a median age of 49.7 years (range 16-81); 42% were female. Baseline demographics and outcomes were similar across 2 cohorts. Forty pts had day 22 IM trough <1000ng/mL, and 31 had dose escalation. Switching to NIL occurred in 75 pts prior to 24 mths, 55 for failing TIDEL-II targets and 20 for IM intolerance. Table 1 summarises key results. In combination, 5 year overall survival (OS) and TFS and associated 95% confidence intervals, including withdrawn pts, were 95% (88-98%) and 92% (84-95%) respectively. Cumulative incidence by 60 mths of MMR was 86%, MR4 (BCR-ABL1 ≤ 0.01% IS) was 75% and MR4.5 (BCR-ABL1 ≤0.0032%) was 59%. Of the 181 pts achieving MMR on study, 44 (24%) did so after switching to NIL; of the 119 pts achieving MR4.5, 27 (23%) did so after switching to NIL. At 60 mths, 75 (36%) pts had withdrawn from study, and 14 were lost to follow up (including 12 with outstanding data queries). Of the 121 pts (58%) who remained on TIDEL-II until 60 mths, 33 were on NIL (30 in MMR), 77 on IM (76 in MMR); treatment was unknown for 11 (10 in MMR). The median dose of IM was 600mg OD. Of the 51 pts who dose escalated to IM 800mg OD (31 for low IM trough level and 20 for failing to achieve molecular targets), only 9 remained on this dose until mth 60 (5 and 4 pts form the respective groups). Eight pts transformed to accelerated or blastic phase; 5 within the 1st year, 2 in the 3rd and 1 in the 5th year; 2/8 occurred after study withdrawal. There were 14 deaths, mostly due to cardiac events (n=5) or progressive leukaemia (n=6). In all, 13/210 pts (6%) had cardiac, cerebral or peripheral vascular disease, 9 while on NIL and 4 having only had IM. Pts failing to meet molecular targets (analysed according to the 1st target failed) at 3, 6 and 12 mths numbered 25 (12%), 23 (11%) and 30 (14%) respectively with 19, 16 and 20 switching to NIL (subsequent molecular outcomes, Table 2). Pts failing to achieve EMR had poor achievement of MMR and MR4.5 (44% and 8% respectively by 60 mths). Of the 11 EMR failure pts who achieved MMR, only 4 remained in MMR at 60 mths. Pts failing to achieve BCR-ABL≤ 1% at 6 mths had similarly poor outcomes, with MMR and MR4.5 being 52% and 13% respectively. In pts failing to achieve MMR by 12 months, MMR and MR4.5 by 60 mths were 93% and 33% respectively. Twenty pts switched to NIL for IM intolerance prior to 24 mths: 9/20 already in MMR, and 3/20 already in MR4.5 at time of switching. For the remaining pts, MMR and MR4.5 were achieved by 100% and 88% after switching. The TIDEL-II strategy of combining IM and NIL compares favourably with other upfront treatment strategies, with MR4.5 of 59% by 60 mths. IM dose escalation to 800mg OD for target failure was not well tolerated: only 18% of pts who dose escalated maintained this dose at 60 mths. However, this did not appear to be detrimental to overall outcomes, which were similar in the 2 cohorts. Pts switching to NIL for IM intolerance, and for failing to achieve MMR by 12 months after meeting prior goals, had high rates of MMR, superior to those who failed their 3 and 6 mth targets. Early identification of pts at high risk of EMR failure who might benefit from more intensive or experimental therapies may be necessary to further improve outcomes. Disclosures Yeung: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. White:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Branford:Novartis: Honoraria, Research Funding, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Research Funding; Ariad: Research Funding; Bristol Myers-Squibb: Honoraria; Cepheid: Consultancy. Butcher:Janssen: Consultancy; Roche: Consultancy; Novartis: Consultancy. Gottlieb:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Indee: Membership on an entity's Board of Directors or advisory committees. Arthur:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Tam:Novartis: Honoraria. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Hughes:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

with cyclophosphamide. For AKI due to probable cast nephropathy, HCO HD with Fresenius Ultraflux ® EMiC ® 2 dialyser, 8 h/ session, 5 days/week was commenced. After 2 weeks of treatments, although κ-FLC Dear Editor, Cast nephropathy is the commonest cause of acute kidney injury (AKI) in patients with multiple myeloma (MM) [1] . There has been a recent interest in extended hemodialysis (HD) with high cut-off (HCO) dialysers for removal of immunoglobulinfree light chains (FLC), combined with effective chemotherapy to improve renal and patient outcomes [2, 3] . The conventionally used Gambro HCO 1100 dialyser is expensive. We report a patient with kappa (κ) FLC MM and AKI with significant reductions in κ-FLC levels using the cheaper Fresenius Ultraflux ® EMiC ® 2 dialyser. A 59-year-old Caucasian lady with a background of recurrent MM after autologous bone marrow transplant, treated with lenalidomide, monthly zoledronic acid infusions and later with bortezomib, presented with another relapse and AKI. She had previously had AKI due to biopsy proven cast nephropathy, acute tubular injury and eosinophilic interstitial nephritis secondary to zoledronic acid that was treated with steroids with near complete recovery of renal functions to a serum creatinine of 113 μmol/l. Bortezomib had to be withheld because of disseminated herpes zoster infection, but 4 months later, κ-FLC levels increased from 105 to 11,367 mg/l, with serum creatinine of 393 μmol/l at presentation. Bortezomib was recommenced along Received: March 14, 2016 Accepted: April 14, 2016 Published online: June 8, 2016

Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy.

s are available online only, free of charge, at www.karger.com/doi/10.1159/000446616 Basel · Freiburg · Paris · London · New York · Chennai · New Delhi · Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney Selected Abstracts from the 34th Vicenza Course on AKI & CRRT Vicenza, June 7–10, 2016

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.

Background Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy.Methods Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0.15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639.Findings 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4.2 years (IQR, 3.2-5.2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0.23 (95% CI 0.08-0.64, p=0.002) for freedom from relapse, 0.21 (0.07-0.59, p=0.001) for disease-free survival, 0.34 (0.16-0.69, p=0.002) for event-free survival, and 0.35 (0.14-0.91, p=0.02) for overall survival.Interpretation Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival.

Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) in poor prognosis DLBCL treated with R-CHOP immuno-chemotherapy (Stiff P et al., NEJM 2013). Furthermore, indiscriminate ASCT exposes those poor-risk patients destined to remain in CR with R-CHOP alone to unnecessary toxicity. Here, the role of interim PET/CT to risk-stratify is controversial. One confounding factor is that interim PET/CT is typically performed after 2 (or 3) cycles of chemotherapy when FDG-avidity likely reflects a mix of residual cancer cells and inflammation; in contrast, interim PET/CT after cycle 4 may be more representative of resistant lymphoma. We hypothesized that: 1. assessment of DLBCL patients by interim PET/CT after 4 cycles (iPET4) of R-CHOP-14 allows greater specificity of FDG-avidity; and, 2. for patients with iPET4-positivity, early treatment intensification with R-ICE chemotherapy followed by Zevalin-BEAM conditioning and ASCT results in 2-yr PFS that is equivalent to interim-PET/CT-negative patients treated with R-CHOP alone.