The 2022 European LeukaemiaNet acute myeloid leukemia (AML) classification allocates AML with t(8;21) RUNX1::RUNX1T1 fusion and AML with inv(16) or t(16;16) CBFB::MYH11 fusion (collectively, core-binding factor AML), AML with NPM1 without FLT3-ITD mutation and AML with CEBPA bZIP in-frame mutation into the favorable-risk strata based on initial molecular diagnostics. Generally, these entities have a relatively low risk of relapse (< 30%-40%) and many patients (> 50%-60%) survive long-term with intensive chemotherapy alone. However, there is growing literature that patterns of co-mutation, and more importantly, postremission measurable residual disease (MRD) status, modify these risks dynamically; necessitating an adaptive approach to optimize patient outcomes. In this review, we summarize evidence on how molecular and MRD features could assist clinicians in identifying high-risk patients within these favorable-risk subgroups, and where escalation of therapy, including with allogeneic transplantation in first remission, may be beneficial.

Background:Next generation sequencing (NGS) of cell free tumour DNA (ctDNA) provides a snapshot of lymphoma mutations correlating with tumour burden. We evaluated the ability of ctDNA to molecularly profile and track disease burden in patients with aggressive-B-cell lymphoma. Methods:Patients were prospectively recruited from the 'standard-of-care' clinic based on high-risk clinical features. Using error-corrected, capture-based NGS of ctDNA, we profiled 17 patients receiving treatment for diffuse large B-cell lymphoma to determine the utility of molecular profiling and dynamic response assessment through to measurable residual disease (MRD) states. Results:Somatic mutations were detected at baseline in 17/17 patients, including 13 with phased variants that could be leveraged for enhanced assay sensitivity. Early molecular response (EMR; ≥ 2 log10 reduction in ctDNA during cycle 1) was predictive of end-of-treatment complete metabolic response (CMR; EMR rate 100% vs. no EMR 12.5%, p = 0.0014) and 24-month progression free survival (PFS; no progression events for those in EMR vs. no EMR 4.57 months, p = 0.015). Only 1/12 MRD-negative patients relapsed. Interestingly, all three late relapses demonstrated histological infidelity and potential clonal evolution based on ctDNA results. Conclusion:These data further support the potential utility of molecular lymphoma profiling by ctDNA analysis and the predictive value of EMR as reported by independent groups. We also posit that ctDNA alone is insufficient to diagnose late relapses, where shared mutations may associate with differential histopathology.

ABSTRACT:Despite the use of FMS-like tyrosine kinase 3 (FLT3) inhibitors, outcomes for patients with FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) remain suboptimal because of high rates of relapse. We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO), and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3mut AML in the UK National Cancer Research Institute AML19 trial. A total of 195 patients were randomized to receive DA with either 1 or 2 doses of GO (DAGO1 and DAGO2). Overall, 77 had an FLT3 mutation and received midostaurin for 2 weeks after each chemotherapy course and then as maintenance for 1 year unless they received a transplant. A total of 39 patients received DAGO1+m and 38 DAGO2+m. Their median age was 51 years (range, 20-74), and 16 (20%) were aged >60 years. The overall response rate was 91%. Day 60 mortality was 0%, with no increase in toxicity compared with patients treated contemporaneously with DAGO1 and DAGO2 without midostaurin. Two-year overall survival was 77%. Two-year event-free survival and cumulative incidence of relapse were 62% and 31%, respectively. Measurable residual disease (MRD) clearance was enhanced compared with patients with FLT3mut AML treated with DAGO without midostaurin. Overall, 81% of evaluable patients were NPM1 MRD negative in the peripheral blood after course 2 (76% with DAGO1+m, and 86% with DAGO2+m), 79% were MRD negative in the bone marrow by FLT3-ITD next-generation sequencing, and all patients had FLT3-MRD levels <0.01%. DAGO+m appears safe and effective. DAGO2+m will now be evaluated in a randomized study. This trial was registered at www.isrctn.com as #ISRCTN78449203.

BACKGROUND:After pharmaceutical benefits scheme approval of midostaurin for fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukaemia (AML) in 2018, the Australasian Leukaemia & Lymphoma Group (ALLG) proposed a consensus approach to AML induction with 7+3 chemotherapy (7 days of infusional cytarabine with three doses of anthracycline) to align with future clinical trial protocols. AIMS:To determine the efficacy and safety of idarubicin-based 7+3 induction ± midostaurin (per ALLG recommendations) in a real-world, tertiary hospital setting. METHODS:Data were prospectively collected for all patients assessed for front-line AML treatment. Disease risk and response assessments were defined by European LeukaemiaNet 2017 guidelines. Efficacy and safety endpoints included complete remission (CR) rates, composite CR rates, event-free survival (EFS), overall survival (OS), induction mortality, duration of cytopenias and intensive care unit (ICU) utilisation. Analysis was planned following completion of ≥50 inductions and 5-year aggregated experience. RESULTS:Between 2018 and 2023, 58 patients (median age 49 years) received 7+3 induction with CR and induction mortality rates of 88% (95% confidence interval (95% CI): 77-95%) and 1.7% (95% CI: 0-9%) respectively. At a median of 24.6 months of follow-up, median OS was 17.6 months for adverse-risk versus not reached for non-adverse-risk patients (P = 0.03). FLT3-mutated patients demonstrated an 89% CR rate (95% CI: 67%-99%) with comparable 4-year EFS (65%) and OS (68%) to FLT3-wild-type patients. Safety across 58 induction and 139 consolidation cycles was acceptable, with a single death and a 21% ICU admission rate (95% CI: 11%-33%) during induction. CONCLUSIONS:Idarubicin-based 7+3 induction with contemporary supportive care yields good safety and CR rates, including in midostaurin-treated FLT3-mutated patients. Survival outcomes for adverse-risk AML patients remain suboptimal.

Vox SanguinisEarly View INTERNATIONAL FORUM International Forum on the Use of Irradiated Blood in Patients With Haematological Malignancy: Responses Xiao-Yin Zhang, Xiao-Yin ZhangSearch for more papers by this authorMichael Murphy, Michael MurphySearch for more papers by this authorGraham P. Collins, Graham P. CollinsSearch for more papers by this authorVernon J. Louw, Vernon J. LouwSearch for more papers by this authorGamuchirai Y. Tadzimirwa, Gamuchirai Y. TadzimirwaSearch for more papers by this authorSatyam Arora, Satyam Arora orcid.org/0000-0002-9048-5624 Search for more papers by this authorNita Radhakrishnan, Nita RadhakrishnanSearch for more papers by this authorCarlos Gonzalez, Carlos GonzalezSearch for more papers by this authorRyan A. Metcalf, Ryan A. Metcalf orcid.org/0000-0001-6074-7147 Search for more papers by this authorErica Swenson, Erica SwensonSearch for more papers by this authorMaria A. Nuñez, Maria A. NuñezSearch for more papers by this authorEdgardo Saa, Edgardo SaaSearch for more papers by this authorArwa Z. Al-Riyami, Arwa Z. Al-Riyami orcid.org/0000-0001-8649-0650 Search for more papers by this authorAli Tabatabaey, Ali TabatabaeySearch for more papers by this authorYulia Lin, Yulia Lin orcid.org/0000-0002-5562-9020 Search for more papers by this authorAditya Tedjaseputra, Aditya TedjaseputraSearch for more papers by this authorErica M. Wood, Erica M. Wood orcid.org/0000-0001-7527-2340 Search for more papers by this authorAlexandra Pedraza, Alexandra PedrazaSearch for more papers by this authorCristina Sanz, Cristina Sanz orcid.org/0000-0002-0370-3436 Search for more papers by this authorCorentin Streel, Corentin StreelSearch for more papers by this authorVéronique Deneys, Véronique DeneysSearch for more papers by this authorAmalia G. Bravo, Amalia G. BravoSearch for more papers by this authorKarla Maldonado, Karla MaldonadoSearch for more papers by this authorLuiz Amorim, Luiz AmorimSearch for more papers by this authorThais Ferraz, Thais FerrazSearch for more papers by this authorYoshihiko Tani, Yoshihiko TaniSearch for more papers by this authorNaoko Goto, Naoko GotoSearch for more papers by this authorFanny Delettre, Fanny DelettreSearch for more papers by this authorPierre Tiberghien, Pierre TiberghienSearch for more papers by this authorJaap Jan Zwaginga, Jaap Jan ZwagingaSearch for more papers by this authorTheodora Foukaneli, Theodora FoukaneliSearch for more papers by this authorPaul Kerr, Paul KerrSearch for more papers by this authorSamclide Mbikayi Mutindu, Samclide Mbikayi MutinduSearch for more papers by this authorAlphonse Mosolo Nganzele, Alphonse Mosolo NganzeleSearch for more papers by this authorRichard Schäfer, Richard SchäferSearch for more papers by this authorNancy Dunbar, Corresponding Author Nancy Dunbar [email protected] Search for more papers by this author Xiao-Yin Zhang, Xiao-Yin ZhangSearch for more papers by this authorMichael Murphy, Michael MurphySearch for more papers by this authorGraham P. Collins, Graham P. CollinsSearch for more papers by this authorVernon J. Louw, Vernon J. LouwSearch for more papers by this authorGamuchirai Y. Tadzimirwa, Gamuchirai Y. TadzimirwaSearch for more papers by this authorSatyam Arora, Satyam Arora orcid.org/0000-0002-9048-5624 Search for more papers by this authorNita Radhakrishnan, Nita RadhakrishnanSearch for more papers by this authorCarlos Gonzalez, Carlos GonzalezSearch for more papers by this authorRyan A. Metcalf, Ryan A. Metcalf orcid.org/0000-0001-6074-7147 Search for more papers by this authorErica Swenson, Erica SwensonSearch for more papers by this authorMaria A. Nuñez, Maria A. NuñezSearch for more papers by this authorEdgardo Saa, Edgardo SaaSearch for more papers by this authorArwa Z. Al-Riyami, Arwa Z. Al-Riyami orcid.org/0000-0001-8649-0650 Search for more papers by this authorAli Tabatabaey, Ali TabatabaeySearch for more papers by this authorYulia Lin, Yulia Lin orcid.org/0000-0002-5562-9020 Search for more papers by this authorAditya Tedjaseputra, Aditya TedjaseputraSearch for more papers by this authorErica M. Wood, Erica M. Wood orcid.org/0000-0001-7527-2340 Search for more papers by this authorAlexandra Pedraza, Alexandra PedrazaSearch for more papers by this authorCristina Sanz, Cristina Sanz orcid.org/0000-0002-0370-3436 Search for more papers by this authorCorentin Streel, Corentin StreelSearch for more papers by this authorVéronique Deneys, Véronique DeneysSearch for more papers by this authorAmalia G. Bravo, Amalia G. BravoSearch for more papers by this authorKarla Maldonado, Karla MaldonadoSearch for more papers by this authorLuiz Amorim, Luiz AmorimSearch for more papers by this authorThais Ferraz, Thais FerrazSearch for more papers by this authorYoshihiko Tani, Yoshihiko TaniSearch for more papers by this authorNaoko Goto, Naoko GotoSearch for more papers by this authorFanny Delettre, Fanny DelettreSearch for more papers by this authorPierre Tiberghien, Pierre TiberghienSearch for more papers by this authorJaap Jan Zwaginga, Jaap Jan ZwagingaSearch for more papers by this authorTheodora Foukaneli, Theodora FoukaneliSearch for more papers by this authorPaul Kerr, Paul KerrSearch for more papers by this authorSamclide Mbikayi Mutindu, Samclide Mbikayi MutinduSearch for more papers by this authorAlphonse Mosolo Nganzele, Alphonse Mosolo NganzeleSearch for more papers by this authorRichard Schäfer, Richard SchäferSearch for more papers by this authorNancy Dunbar, Corresponding Author Nancy Dunbar [email protected] Search for more papers by this author First published: 25 March 2025 https://doi.org/10.1111/vox.70014Read 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. 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BackgroundWe discuss a case of an immunocompetent patient who presented with fever and tachypnoea, found to have Candida parapsilosis bone marrow infection, cultured on bone marrow aspirate sample. Candida parapsilosis is an opportunistic yeast pathogen that typically affects immunocompromised individuals, or occurs in patients with apparent introduced source; neither of these factors were present for this case. Bone marrow aspirates and trephines are not regular investigations for fever; however they can be useful diagnostic aids as evidenced in this case.Case ReportAn 83-year-old woman presenting with fevers and tachypnoea was being treated for a systemic bacterial infection, however was unresponsive to empirical antibiotic therapy. To exclude an occult malignancy, an 18-fluorodeoxyglucose positron emission tomography scan was conducted. Significant bone marrow uptake was noted, prompting a bone marrow aspirate and trephine to investigate for a hematological malignancy. While the trephine biopsy was benign, a culture of the aspirate grew Candida parapsilosis. Intravenous antifungal therapy was initiated; however, the patient did not improve despite targeted therapy likely due to delays in diagnosis, and was palliated.ConclusionOur case seeks to demonstrate a novel case whereby a bone marrow aspirate culture provided a conclusive diagnosis of invasive Candida parapsilosis bone marrow infection, and guided treatment in an immunocompetent patient. It is important for clinicians to consider invasive fungal infections in febrile patients regardless of immune status. Additionally, when performing a bone marrow aspirate and trephine on a febrile patient, we recommend including aspirate fungal cultures to investigate for an invasive fungal infection.

Molecular measurable residual disease (MRD, e.g., by real-time quantitative polymerase chain reaction, RT-qPCR), is an integral part of response assessment in acute myeloid leukaemia (AML) with established prognostic and evolving therapeutic significance. MRD failure can occur through several pathways (namely MRD persistence at the end of treatment at a high level, MRD progression from a low level or MRD re-emergence during follow up; the latter two constitute MRD relapse as defined by the European Leukaemia Net) and is clinically actionable, with survival benefit reported in AML subgroups. Selection of pre-emptive therapy at MRD failure relies upon an integrated clinico-molecular assessment and is subset-specific. In acute promyelocytic leukaemia, arsenic trioxide-based regimen for MRD failure following frontline treatment with all-trans-retinoic acid plus chemotherapy represents standard of care, while hypomethylating agents (e.g., azacitidine), salvage chemotherapy (e.g., FLAG-IDA) and venetoclax-based regimens are effective in NPM1-mutated AML. Specific inhibitors of FLT3 have emerging use in FLT3-mutated AML and are associated with minimal toxicity. Furthermore, immunotherapeutic approaches such as donor lymphocyte infusions and interferon-⍺ are efficacious options in the post-allogeneic-HSCT settings. Enrollment into clinical trials with genomic-guided assignment of pre-emptive therapy at MRD failure should be prioritized. Finally, with the emergence of novel agents (e.g., menin inhibitors) and approaches (e.g., adoptive cellular and immunological therapy), an exciting future lies ahead where a broad array of highly active therapeutic options will likely be clinically applicable to a wide range of AML subsets.

Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection of residual leukaemia (RL; blasts ≥5%) typically results in the administration of a second induction course. However, whether D21-BM results predict for RL at the end of first induction has not been systematically assessed. This study evaluates the predictive role of D21-BM morphology in detecting RL following first induction. Between August 2018 and March 2022, all patients with FLT3-AML receiving 7+3 plus midostaurin, with D21-BM performed, were identified. Correlation between D21-BM morphology vs D21-BM ancillary flow/molecular results, as well as vs D28-BM end of first induction response, were retrospectively reviewed. Subsequently, D21-BMs were subjected to anonymised morphological re-assessments by independent haematopathologists (total in triplicate per patient). Of nine patients included in this study, three (33%) were designated to have RL at D21-BM, all of whom entered complete remission at D28-BM. Furthermore, only low-level measurable residual disease was detected in all three cases by flow or molecular methods at D21-BM, hence none proceeded to a second induction. Independent re-evaluations of these cases failed to correctly reassign D21-BM responses, yielding a final false positive rate of 33%. In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.

Background: In the registration trial for midostaurin (RATIFY) in intensively-treated FLT3-mutated acute myeloid leukaemia (FLT3-AML), day-21 bone marrow biopsy (D21-BMB) was protocolled. Those with persistent leukaemia (PL), as defined by a morphologic blast count ≥ 5% in a cellular (> 20%) marrow received a second induction (∼25% of participants).1 However, a similar D14-BMB early response assessment strategy is known to poorly predict overall induction outcomes.2 Our study aimed to assess the predictive value of D21-BMB on induction outcomes of our local FLT3-AML population treated intensively plus midostaurin. Methods: Between August 2018 and March 2022, all patients with newly diagnosed FLT3-AML at Monash treated with 7+3 (idarubicin) plus midostaurin who had D21-BMB (± 24H) were included in the analysis. To improve objectivity, D21-BMBs were morphologically assessed by two independent haematopathologists blinded to the original diagnostic reports. The predictive value of D21-BMBs was assessed against final induction remission status; determined from results of D21 or D28-BMB (where available), whichever was done later, in conjunction with peripheral blood count recovery and blast clearance. The RATIFY definition of PL was strictly used, while the 2022 ELN response criteria3 was used to designate complete remission (CR), CR with incomplete haematologic recovery (CRi), morphologic leukaemia-free state (MLFS) and non-evaluable marrows. This study was approved by the Monash Health Ethics Committee (RES-21-0000015Q-72713). Results: 15/144 newly diagnosed AML during the study period were FLT3-mutated and treated with 7+3+midostaurin: 9/15 had D21-BMB assessments (7/9 had a repeat D28-BMB) while 6/15 did not (1 induction death, 5 done at later time-points). Amongst the D21 original reports, 3/9 (33%) were classified as having PL, 4/9 CRi or MLFS and 2/9 non-evaluable due to marrow aplasia. Independent, duplicated, blinded review of D21-BMBs of the 3 patients originally assigned to have PL yielded an overall concordance of 89% (100%, 100%, 67%). At D28, all 7 patients, including the 3 original PL cases (who were not prescribed re-induction, based on review of ancillary flow cytometry and molecular results) attained CR as their final induction outcome. With the 2 patients with only D21-BMBs achieving subsequent count recovery and blast clearance, all 9 patients achieved CR at the end of 7+3+midostaurin induction.

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

Aditya Tedjaseputra , James A. Kuzich, Nisha Thiagarajah, Tse-Chieh Teh, Julia McClelland, Marzia Rahman, Rowena Brook, Chong Chyn Chua, Doen Ming Ong, Shuh-Ying Tan, Robin Filshie, Chun Yew Fong, Pasquale Fedele, Ashish Bajel, Jake Shortt and Andrew H. Wei The Alfred Hospital, Melbourne, Australia; Monash Haematology, Melbourne, Australia; St. Vincent’s Hospital Melbourne, Melbourne, Australia; Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Australia; Austin Health, Melbourne, Australia; Eastern Health, Melbourne, Australia; Western Health, Melbourne, Australia; Northern Health, Melbourne, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia; School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia

Abstract Background Transformation of Chronic Lymphocytic Leukaemia (CLL) or Small Lymphocytic Lymphoma (SLL) to high-grade disease (Richter's Transformation; RT) carries a poor prognosis. Despite the advent of novel therapies, published data indicates that chemoimmunotherapy remains the standard of care for RT. This project evaluated real-world outcomes in patients with RT across eight Australian centres to validate known prognostic factors, as well as identify new predictors of survival in this cohort of patients. Our aims were also to determine if prior BTK inhibitors (BTKi), BCL 2 inhibitors (BCL2i), or escalation of treatment regimen impacted these patients' outcome. Methods This was a retrospective multicentre study conducted by members of the Australasian Lymphoma Alliance in 8 centres across 4 Australian states. Consecutive patients with biopsy proven Diffuse Large B-Cell Lymphoma (DLBCL) or Hodgkin Lymphoma (HL) type RT between 2010 and 2019 were identified using institutional databases. Patients' diagnoses were confirmed by review of local pathology reports. Patients' characteristics, treatment received, and outcomes were recorded and analysed. Univariate comparisons were made using Cox regression analysis. Kaplan Meier curves were used for analysis of overall survival (OS) measured from diagnosis of high-grade disease. Results Seventy-eight patients (55 with CLL and 23 with SLL) were included in the analysis. The majority had low Rai stage at diagnosis (stage 0 in 41% of patients, 1 in 39%, 2 in 16%, 3 in 3%, and 4 in 1%). 25% had prior treatment of low-grade disease with a BTKi and 18% with a BCL2i. At the time of low-grade diagnosis, 54/78 (69%) of patients (pts) had had mutational analysis: 24% (13/54) had a 17p deletion, 78% (17/22) were IgHv unmutated, and 33% (6/18) had a TP53 mutation. Median time to transformation from CLL diagnosis was 4.8 years (range 0-24). 42% had received 2 prior lines of treatment for CLL/SLL at the time of transformation (range 0-5). The predominant histology was DLBCL (71 pts with DLBCL; 6 pts with HL, 1 pt had HL and DLBCL concurrently). Majority of the pts had ECOG<2 (0-1, 76%; 2, 23%). 50% had transformed disease in extra-nodal sites, 27% with bone marrow involvement, and 6% had CNS involvement. 15/18 pts (83%) had clonally related disease proven by IgHv testing. 71 pts (91%) received curative intent treatment, with the rest receiving palliative radiotherapy and/or steroids. 54 patients were treated with standard therapy (R-CHOP or similar), 13 pts were treated with an intensive regimen (R-HyperCVAD, OFAR, R-EPOCH14, or R-ICE), and 4 were treated with novel therapies (BTKi + PD1 combination, and BiTEs). There was no significant difference seen between the standard and intensive therapy groups in terms of treatment completion (61% in standard vs 62% in intensive, p=0.82) or CR rates (50% in standard vs 62% in intensive; p=0.80). Overall, 48/76 (64%) of patients died with a median OS of 15 months (median OS 11 months in DLBCL; median OS not reached in HL). Surviving pts had a median follow up of 33 months. There was no difference in OS between pts that received standard or intensive regimens (HR 1.49 CI 0.75-2.94). Patients with prior lines of treatment for CLL (HR 3.71; CI 1.73-7.98), elevated LDH (>1.5x ULN) (HR 3.0; CI 1.6-5.8), 17p deletion (HR 2.34; CI 1.12-4.91), or bone marrow involvement by high grade disease (HR 2.99; CI 1.5-5.9) had an inferior OS. Prior low-grade treatment with a BTKi (HR 1.67; CI 0.88-3.18) or a BCL2i (HR 1.79; CI 0.92-3.45) did not impact outcome following transformation. Conclusions This is the largest Australian report on patient outcome following RT. Whilst prior CLL treatment was associated with worse outcome after transformation, prior BTKi or BCL2i use did not seem to have an impact on survival. Furthermore, elevated LDH >1.5 ULN and bone marrow involvement with RT were also predictors of poor patient outcome, with the latter not previously described. Finally, intensive chemotherapy regimens were found not to be superior to R-CHOP chemotherapy, suggesting that RCHOP remains the treatment of choice in this population. The OS for patients with RT is poor, and research into more effective therapies is needed. Figure 1 Figure 1. Disclosures Lewis: Roche: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: Conference attendance; Novartis: Patents & Royalties: Conference attendance; AstraZeneca: Consultancy, Honoraria. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cheah: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy.

Background Graft-versus-myeloma (GvM) effect from allogeneic-SCT potentially affords long-term disease control in multiple myeloma (MM). A salvage program incorporating chemotherapy followed by tandem autologous + non-myeloablative allogeneic-SCT (TAA-SCT) may offer a survival advantage over chemotherapy alone (ChA) Method Consecutive patients with relapsed MM (R-MM) salvaged with chemotherapy followed by TAA-SCT at the Alfred between Jan-08 and Dec-19 were identified. A 2:1 comparator cohort salvaged with ChA (iMiD agent/PI available) matched for age/sex/ISS-stage, was extracted from the Myeloma and Related Diseases Registry (MRDR). All patients received autologous-SCT as part of their upfront treatment. Survival was assessed by Kaplan-Meier method and compared using log-rank test. Prognostic variables were adjusted using Cox-regression. Results 48 patients received TAA-SCT following salvage chemotherapy during the study period; 35% met criteria for high-risk myeloma at diagnosis (ISS-III and/or adverse CG/FISH) with a median age at salvage of 57 [range: 32-68] and 2 prior therapy lines [range: 1-7]. Preceding TAA-SCT, salvage chemotherapy yielded ≥ PR in ~95% of cases; iMiD® and/or PI were used in ~85%. 87 matched patients were identified from the MRDR as the ChA cohort. Baseline characteristics were comparable, except that the TAA-SCT cohort was more heavily pre-treated (p < 0.001). With a median follow-up of 60 months, the estimated 5-year OS were similar: TAA-SCT 63% (95%CI: 48%-75%) vs. ChA 53% (95%CI: 34%-68%). However, after adjusting for number of prior therapy lines, an OS advantage was observed in the TAA-SCT relative to the ChA cohort (HR 0.33, 95% CI:0.13-0.82, p = 0.001). In addition, PFS was also improved in the TAA-SCT cohort (Figure 1, p < 0.001), with a 5-year PFS of 25% (95%CI: 14%-38%) vs. 1% (95%CI: 0-6%) for the ChA cohort. Conclusion In the iMiD® and PI era, TAA-SCT following chemotherapy remains an effective salvage strategy in selected patients with R-MM, providing an immunological platform for a GvM effect with OS and PFS advantage over chemotherapy alone. Graft-versus-myeloma (GvM) effect from allogeneic-SCT potentially affords long-term disease control in multiple myeloma (MM). A salvage program incorporating chemotherapy followed by tandem autologous + non-myeloablative allogeneic-SCT (TAA-SCT) may offer a survival advantage over chemotherapy alone (ChA) Consecutive patients with relapsed MM (R-MM) salvaged with chemotherapy followed by TAA-SCT at the Alfred between Jan-08 and Dec-19 were identified. A 2:1 comparator cohort salvaged with ChA (iMiD agent/PI available) matched for age/sex/ISS-stage, was extracted from the Myeloma and Related Diseases Registry (MRDR). All patients received autologous-SCT as part of their upfront treatment. Survival was assessed by Kaplan-Meier method and compared using log-rank test. Prognostic variables were adjusted using Cox-regression. 48 patients received TAA-SCT following salvage chemotherapy during the study period; 35% met criteria for high-risk myeloma at diagnosis (ISS-III and/or adverse CG/FISH) with a median age at salvage of 57 [range: 32-68] and 2 prior therapy lines [range: 1-7]. Preceding TAA-SCT, salvage chemotherapy yielded ≥ PR in ~95% of cases; iMiD® and/or PI were used in ~85%. 87 matched patients were identified from the MRDR as the ChA cohort. Baseline characteristics were comparable, except that the TAA-SCT cohort was more heavily pre-treated (p < 0.001). With a median follow-up of 60 months, the estimated 5-year OS were similar: TAA-SCT 63% (95%CI: 48%-75%) vs. ChA 53% (95%CI: 34%-68%). However, after adjusting for number of prior therapy lines, an OS advantage was observed in the TAA-SCT relative to the ChA cohort (HR 0.33, 95% CI:0.13-0.82, p = 0.001). In addition, PFS was also improved in the TAA-SCT cohort (Figure 1, p < 0.001), with a 5-year PFS of 25% (95%CI: 14%-38%) vs. 1% (95%CI: 0-6%) for the ChA cohort. In the iMiD® and PI era, TAA-SCT following chemotherapy remains an effective salvage strategy in selected patients with R-MM, providing an immunological platform for a GvM effect with OS and PFS advantage over chemotherapy alone.

AbstractMonitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD−; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.

BACKGROUND:Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There are minimal data on HT in the Australian setting.AIMS:To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital.METHODS:All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed using the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model.RESULTS:A cohort of 45 patients was identified with a median age of 66 years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score ≥3). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) induction was used in 69%, with an overall response rate of 82% (complete response (CR), 75%). Sixty-one percent of these induction responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs 54%, P = 0.057) and 5-year OS (82% vs 46%, P = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction responders.CONCLUSIONS:Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naïve at HT.

Acute monocytic leukaemia (French-British-American classification: AML-M5b) is characterised by a predominance of cells of the monocytic lineage on bone marrow examination. Furthermore, a discerning feature is its tendency for tissue infiltration. While gum hypertrophy and hepatosplenomegaly are common, ocular involvement is rare. Here, we present a case of a 75-year-old man referred with proptosis and monocytosis-subsequently diagnosed as AML-M5b, whose disease course was distinguished by extensive tissue invasion (ocular, pulmonary, liver, spleen). Cytogenetics and molecular tests were consistent with blastic transformation of previously undiagnosed chronic myelomonocytic leukaemia, supported by the presence of long-standing, low-grade monocytosis. Notably, a BRAF V600E mutation was also detected-an oncogenic driver previously reported in de novo and therapy-related, but not chronic myelomonocytic leukaemia-transformed, AML-M5b. While an initial response to cytoreductive treatment was observed, his tissue-invasive disease soon progressed with worsening pulmonary infiltrates, disseminated intravascular coagulation and renal failure, resulting in death.