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Summary: The survival of acute myeloid leukaemia (AML) patients aged over 60 has been suboptimal historically, whether they are treated using hypomethylating agents, low‐dose cytarabine (LDAC) or venetoclax‐based regimens. Progress is being made, however, for subgroups with favourable molecular or cytogenetic findings. Arginine metabolism plays a key role in AML pathophysiology. We report the only randomised study of LDAC with recombinant arginase BCT‐100 versus LDAC alone in older AML patients unsuitable for intensive therapy. Eighty‐three patients were randomised to the study. An overall response rate was seen in 19.5% (all complete remission [CR]) and 15% (7.5% each in CR and CR without evidence of adequate count recovery [CRi]) of patients in the LDAC+BCT‐100 and LDAC arms respectively (odds ratio 0.73, confidence interval 0.23–2.33; p = 0.592). No significant difference in overall or median survival between treatment arms was seen. The addition of BCT‐100 to LDAC was well tolerated. [ABSTRACT FROM AUTHOR]

Summary: Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD. [ABSTRACT FROM AUTHOR]

Summary: Second‐generation immunomodulatory agents, such as lenalidomide, have a more favourable side‐effect profile than the first‐generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant‐ineligible myeloma (ND‐TNE‐MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND‐TNE‐MM. CRDa deepened response but did not improve progression‐free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND‐TNE‐MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual. [ABSTRACT FROM AUTHOR]

A recent report from the USA Children's Oncology Group (COG) acute myeloid leukaemia (AML)0531 trial1 described a surprisingly marked improvement in survival outcomes for children with ( I KMT2A i )-rearranged AML who received gemtuzumab ozogamicin (GO) with induction chemotherapy compared with those who did not. Gemtuzumab ozogamicin in (KMT2A)-rearranged adult acute myeloid leukaemia (AML) in the UK Medical Research Council AML15 and AML16 trials The 5-year relapse-free survival (RFS) for patients with I KMT2A i -rearrangements who did and did not receive GO was 45% and 36% respectively [hazard ratio (HR) 0-91, 95% confidence interval (CI) 0-41-2-02, I P i = 0-8, Fig 1]. [Extracted from the article]

The article offers information on the role of nucleated bone marrow (BM) cells for acute myeloid leukaemia (AML) patient. It discussed the increasingly standard to perform morphological tests and multiparameter flow cytometry (MFC) in parallel to assess remission; and also examine the data for discrepant response assessment by standard criteria.

Summary: Mantle cell lymphoma (MCL) is an aggressive form of non‐Hodgkin lymphoma that remains incurable for the majority of patients. Allogeneic stem cell transplantation (alloSCT) produces long‐term disease‐free remissions for around 30–40% patients, however it is reserved for the treatment of relapsed disease. This study examined the use of front line transplantation for young patients in an attempt to improve outcomes. Twenty‐five patients received an alloSCT using BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan)‐Campath conditioning following permissive induction therapy from both related and unrelated donors. This was a multi‐centre prospective trial. Twenty‐four of 25 patients engrafted with no non‐relapse mortality events by day 100. With a median follow‐up of 60·5 months, there have been six deaths (3 from MCL). The progression‐free survival (PFS) and overall survival were 68% and 80% at 2 years and 56% and 76% at 5 years. PFS was very similar for both sibling and unrelated transplants and there was no difference in PFS between patients with respect to remission status prior to transplantation. Nine (38%) patients experienced acute graft‐versus‐host disease (GVHD) and 14 (58%) experienced chronic GVHD, of which 8 were extensive. Front line alloSCT is feasible but should only be considered for patients at high risk of early progression following conventional therapy. [ABSTRACT FROM AUTHOR]

Many older patients with acute myeloid leukaemia ( AML) that receive standard intensive chemotherapy fail to achieve complete remission ( CR). Upfront identification of patients unlikely to benefit from standard induction chemotherapy would be important for exploration of novel therapies. This study evaluated if a flow cytometric assay measuring pre-treatment CD34+ CD38low blast frequency could predict therapeutic-resistance in 736 AML patients entered into the UK National Cancer Research Institute AML16 trial. High peripheral blood CD34+ CD38low blast frequency (>7% of leucocytes), present in 18% of assessable patients, conferred significantly reduced CR rates (38% vs. 76%, P < 0·0001) and poor survival, and was independently prognostic for all endpoints of treatment resistance by multivariate analysis. [ABSTRACT FROM AUTHOR]

P-glycoprotein (pgp), a membrane efflux pump, is recognized to have an anti-apoptotic function. Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) receptor are the most common mutations in acute myeloid leukaemia (AML). Both ITDs and pgp positivity confer an adverse clinical prognosis. FLT3 inhibitors induce variable apoptosis in cell lines transfected with FLT3 ITDs. We studied the effect of herbimycin A, AG1296 and PKC412 on primary AML blasts. All compounds showed significantly higher cell kill after 48-h incubation in samples with an ITD compared with wild type (Herbimicin P < 0.001; AG1296 P = 0.001, PKC412, P = 0.002). Pgp-positive samples were significantly less sensitive to herbimycin and AG1296 than pgp-negative samples, although neither molecule inhibited the efflux function of pgp. The concurrent incubation with the pgp inhibitor PSC833 resulted in an enhanced cell kill in 4/5 ITD pgp-positive samples versus two of nine ITD pgp-negative samples. PKC412 inhibited pgp function and induced cell death in FLT3 ITD/pgp-positive samples. We conclude that AML samples with a FLT3 ITD are more susceptible to these inhibitors than wild-type samples. However, the expression of pgp in cells with FLT3 ITDs can reduce their sensitivity to FLT3 inhibitors and therefore pgp expression should be assessed in clinical trials of FLT3 inhibitors. [ABSTRACT FROM AUTHOR]

BAT-25 and BAT-26 are mononucleotide microsatellites with quasi-monomorphic allele length distribution in healthy controls but unstable, shortened alleles in solid organ tumours with a mutator phenotype (RER+). Both markers are highly sensitive and specific for RER+ colorectal cancer. This study evaluated three mononucleotide microsatellites, BAT-25, BAT-26 and BAT-40 (a polymorphic mononucleotide microsatellite) in RER+ acute myeloid leukaemia (AML). Sixteen [six therapy-related AML (t-AML), 10 de novo AML] known RER+ AML, 22 healthy controls and five known RER− AML samples were analysed. In healthy controls and RER− AML, BAT-25 and BAT-26 were quasi-monomorphic and BAT-40 was polymorphic. Of the RER+ AML samples, 0 of 16 had microsatellite instability (MSI) at BAT-25, 0 of 16 had MSI at BAT-26 and three of 16 had MSI at BAT-40. We conclude that BAT-25, BAT-26 and BAT-40 microsatellites are insensitive to RER+ AML. Further studies are required to determine a consensus panel of sensitive microsatellites for use in AML. [ABSTRACT FROM AUTHOR]