Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment

Although CEBPA double-mutated (CEBPA^{DM}) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPA^{DM} patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus a C-terminal loss-of-function in-frame indel mutation (CEBPA^{Classic-DM}), but approximately one-third of cases have one or more non-classic mutations, with diverse combinations reported, and there is little information on the consequences of such mutants. We evaluated outcome in a cohort of 104 CEBPA^{DM} patients, 79 CEBPA^{Classic-DM} and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% vs. 46%; P=0.05), particularly post relapse (41% vs. 0%; P=0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As CEBPA^{DM} cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a CEBPA^{Classic-DM} methylation signature from a preliminary cohort of 10 CEBPA^{DM} (including 8 CEBPA^{Classic-DM}) and 30 CEBPA wild-type (CEBPA^{WT}) samples, and independently validated the signature in 17 CEBPA^{Classic-DM} cases. Assessment of the signature in 16 CEBPA^{DM} cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to CEBPA^{Classic-DM} whereas for 69% the profile was either intermediate between CEBPA^{Classic-DM} and CEBPA^{WT} or equivalent to CEBPA^{WT}. These results suggest that CEBPA^{DM} cases with non-classic mutants may be functionally different from those with CEBPA^{Classic-DM} mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under ISRCTN17833622 and AML15 under ISRCTN17161961)

Whole body‐diffusion weighted imaging for the assessment of treatment response in hairy cell leukaemia: A positive first step

Abstract We present the case of a patient diagnosed with hairy cell leukaemia (HCL) who subsequently developed biopsy confirmed bone lesions and underwent multiple lines of therapy. The reported incidence of bone lesions in HCL is 3%, and bony involvement can be associated with high tumour burden and aggressive disease. The commonly lytic bone lesions in HCL are difficult to accurately assess for response. Whole body diffusion weighted imaging (WB‐DWI) has been used clinically in multiple myeloma; we postulate clinical utility in HCL, where hypercellularity also applies. In our case, WB‐DWI appears to discriminate sites of active disease from bone response. We present the salient radiological and pathological images. To our knowledge, this is the first description of WB‐DWI in HCL; we support research of WB‐DWI in the staging, prognostication and response assessment of HCL

ASXL1 mutations are infrequent in young patients with primary acute myeloid leukemia and their detection has a limited role in therapeutic risk stratification

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

Guidelines on the diagnosis and management of Waldenström macroglobulinaemia-A British Society for Haematology guideline.

SCOPE The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. METHODOLOGY This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström('s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(-related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents

Patient reported outcome measures in Waldenström macroglobulinaemia: A real‐world data analysis from the WMUK Rory Morrison Registry

Abstract Waldenström macroglobulinaemia (WM) is an incurable chronic B‐cell malignancy, but highly responsive to treatment. Treatments include fixed‐duration chemotherapy and continuous oral chemoimmunotherapy. In this expanding field, it is important to have reliable information on the impact of the various therapies on patients’ quality of life (QoL). Patient reported outcome measures (PROMs) are increasingly recognised as important to understand patient experience of disease beyond traditional clinical outcome measures. Four QoL questionnaires (EORTC QLQ‐C30 [European Organisation for Research and Treatment of Cancer quality of life core questionnaire], BIPQ [Brief Illness Perception Questionnaire], HADS [Hospital Anxiety and Depression Scale], EQ‐5D‐5L [EuroQoL 5‐dimensional descriptive system questionnaire]) are embedded in the UK national WM registry, the Rory Morrison Registry. We reviewed the results from a snapshot of PROMs. As of November 2021, 155 patients completed PROM data with 98% completion rate across all 58 questions. Complete clinical information was available for 52 patients. The majority of QoL questions (69%) failed to elicit a notable median response. Only four questions elicited statistically significant responses when comparing groups, and these were exclusively found in the EuroQoL‐5D‐5L and HADS questionnaires. Our data suggest that widely used questionnaires may not be suitable for patients with WM. We advocate the development of WM‐specific outcome measures to overcome this