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Precise subclassification of myeloid malignancies per the World Health Organization (WHO) classification system and the International Consensus Classification of Myeloid Neoplasms and Acute Leukaemias (ICC) requires investigation and documentation of the presence of cytogenetic and/or molecular genetic changes. These ancillary studies not only help in diagnosis, but also the prognosis of disease; however, they take time to be completed. In contrast, morphological evaluation of material from the blood and bone marrow specimens of cases where myeloid malignancies are suspected is usually completed quickly. Cytomorphological assessment may predict genetic changes and can be helpful in triaging acuity. This is especially true in haematological emergencies such as acute promyelocytic leukaemia (APL), where prompt APL‐specific therapy can be life changing. Similarly, some morphological clues may help identify core binding factor leukaemias where a diagnosis of acute myeloid leukaemia (AML) could be rendered without reaching the 20% blast cutoff with immediate treatment‐decision implications, or even a subset of cases of AML with FLT3 ITD/NPM1 mutation(s) which show characteristic features. Even though FISH/cytogenetics and/or PCR are still required for establishing the final diagnosis, evaluation for the presence of specific cytomorphological features that help predict genetic changes can be a useful tool to help guide early therapy. [ABSTRACT FROM AUTHOR]

Pathogenic alterations of TP53 are an independent poor prognostic factor in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clinical course of TP53- altered myeloid neoplasms is dictated by genetic characteristics, such as TP53 allelic state and variant allele frequency (VAF), and not the blast count. Hence, it was recently proposed that MDS (with increased blasts) and AML with TP53 alterations may be best classified as a single molecular disease entity, TP53-mutated higher-risk (HR)-MDS/AML. TP53 mutations drive resistance to intensive chemotherapies and less intensive hypomethylating agents (HMA). Novel combinations incorporating BCL2 inhibitor venetoclax improve response rates for TP53-mutated subgroup, but the survival is not improved. Early clinical studies combining HMA with investigational agents demonstrated activity in TP53-mutated HR-MDS/AML, but updated results with larger samples, longer follow-up, or randomized trials were less impressive to date. Future research should focus on finding novel, potentially disease-modifying therapies to improve outcomes in patients with TP53-mutated HR-MDS/AML. [ABSTRACT FROM AUTHOR]

Patients with complex karyotype were significantly less likely to achieve either CR (OR 0.17; 95% CI 0.06-0.48; I p i <.0001) or CR/CRi (OR 0.26; 95% CI 0.09-0.72; I p i <.0001). Complete cytogenetic response (CCyR) in non-diploid patients was 65% with numerically improved response rates in non-diploid intermediate karyotype (non-diploid intermediate = 14/17 (82%); adverse = 16/29 (55%); I p i =.06) (Table 1). Compared to ND AML, patients with prior therapy for AML or antecedent hematological disorder were significantly less likely to achieve CR/CRi and had inferior OS and shorter EFS, regardless of karyotype. Acute myeloid leukemia (AML) is heterogenous in its pathogenesis as well as outcomes, which in turn is influenced by patient- and disease-related factors including age, ability to tolerate treatment, and cytogenetic features [[1]]. [Extracted from the article]

Summary: B‐cell lymphoma/leukaemia 11B (BCL11B) is an essential transcription factor for T‐cell lineage commitment and maturation. We investigated BCL11B expression by immunohistochemistry in T‐lymphoblastic leukaemia/lymphoma (T‐ALL/LBL) (n = 115). The majority (83%) of early T‐cell precursor T‐ALL/LBL (ETP‐ALL) cases showed negative BCL11B expression, while most (84%) of non‐ETP‐ALL/LBL were positive for BCL11B. A simplified three‐marker [BCL11B, cluster of differentiation 5 (CD5), CD13] immunophenotypic score discriminated reliably between ETP‐ALL and non‐ETP‐ALL/LBL. In ETP‐ALL, patients with positive BCL11B expression had a better overall survival than those with negative BCL11B (P = 0·009). In summary, BCL11B is a valuable marker for T‐ALL/LBL subtyping and serves as a potential prognostic marker in patients with ETP‐ALL. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). Methods: The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46‐89 years). Results: The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035‐0.593; P =.007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1‐ and 3‐year survival. Conclusions: aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients. Atypical chronic myeloid leukemia is characterized by specific mutational clonal dominance with a high frequency of codominant SRSF2 and SETBP1 mutations and other RAS pathway mutations present in minor clones at the time of diagnosis but associated with acute myeloid leukemia transformation. The incorporation of age, platelet counts, bone marrow blast percentages, and lactate dehydrogenase levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm that poses a substantial therapeutic challenge. Despite therapy, the patient's disease progressed and bone marrow evaluation in September 2019 showed persistent AML with 50% blasts and persistent FLT3 I - i ITD mutation. In the current case, I BCR-ABL1 i was not seen by karyotype in relapsed bone marrow specimen showing AML in May of 2019, but was seen in September of 2019 after the patient had been on single agent gilteritinib therapy for ~3 months. Less commonly, other mechanisms for I FLT3 i resistance such as secondary FLT3-F691L gatekeeper mutations or rarely I BCR-ABL1 i fusion can be seen at the time of progression on I FLT3 i inhibitor therapy [[3], [22]]. [Extracted from the article]

Lymphoplasmacytic lymphoma secreting IgG or IgA (non-IgM LPL) is rarely seen. Systematic studies of the clinical features and treatment outcomes are lacking in these patients. This study evaluated 17 patients with non-IgM LPL. The paraprotein secreted by these tumors was IgA (n = 8; 47%) and IgG (n = 9; 53%). The median serum level of paraprotein was 2,475 mg/dl (range = 747–5260) for IgA and 2580 mg/dl (range = 1900–7100) for IgG. The IgA-LPL group was more likely to present with B symptoms, a high beta2-microglobulin level and extramedullary involvement. Compared with patients with Waldenström macroglobulinemia (WM), patients with non-IgM LPL showed similar clinical and pathologic features, but a higher mortality within the first year after diagnosis (p < 0.001) and worse overall survival (p = 0.024), with no difference in progression-free survival and disease-specific survival. Rituximab alone or rituximab-based therapy was used frequently and was effective as either first-line or salvage therapy. [ABSTRACT FROM PUBLISHER]

Objectives: This session of the 2013 Society of Hematopathology/European Association for Haematopathology Workshop was dedicated to B-acute lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (LBL) with recurrent translocations and not otherwise specified. Methods: In this review, we summarize the cases discussed during the workshop, review the pertinent and most recent literature on the respective topics, and provide a few key points that may aid in the workup of patients with B-ALL/LBL. Results: Many of the submitted cases showed interesting diagnostic, immunophenotypic, or clinical aspects of B-ALL with BCR/ABL1, MLL-associated, and other recurrent chromosomal abnormalities. Several cases showed rare aberrancies such as coexistent IGH/BCL2 and MYC rearrangements and raised issues in classification. Other cases had unusual clinical presentations, including B-ALL with hypereosinophilia and therapy-related B-ALL. Several cases highlighted the role of flow cytometry immunophenotyping in distinguishing benign B-cell precursors from aberrant lymphoblasts, and other cases raised questions regarding the clinical importance of myeloperoxidase positivity in acute lymphoblastic leukemia. Conclusions: The complexity and spectrum of cases presented in this review highlight the importance of clinicopathologic correlation and the value of ancillary studies in the classification and workup of patients with B-ALL/LBL. B-acute lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (LBL) is a neoplasm of immature B-cell precursors that typically affects children younger than 6 years but is also encountered in older children and in adult populations. The estimated global incidence of B-ALL is around one to five per 100,000 persons per year. Patients with B-ALL usually have signs and symptoms of bone marrow (BM) failure, including cytopenias with or without leukocytosis. The diagnosis is established by immunophenotyping, commonly by flow cytometry (FC), which shows immature B lineage. Many cases of B-ALL harbor recurrent chromosomal abnormalities, including balanced chromosomal translocations, which are often critical determinants of prognosis. [ABSTRACT FROM AUTHOR]

Background: The prognostic importance of extramedullary involvement in patients with Waldenström macroglobulinemia (WM) at diagnosis and treatment options for these patients has not been well evaluated. In this study, we investigated the clinical manifestations, biological features, and effect of first-line therapy on the outcome of WM patients diagnosed with extramedullary involvement (EMWM) vs those with only bone marrow involvement (BMWM). Methods: We analyzed the clinical data of 312 WM patients diagnosed with EMWM (n = 106) and BMWM (n = 206) at The University of Texas MD Anderson Cancer Center from 1994 to 2014. EMWM was confirmed by biopsy, positron emission tomography-computed tomography, or magnetic resonance imaging, and clinical laboratory analyses. Results: Characteristics associated with EMWM were male sex (P = 0.027), age younger than 65 years (P = 0.048), presence of B symptoms (P < 0.001), high serum beta-2 macroglobulin (P < 0.001) level, low serum albumin level (P = 0.036), and cytogenetic abnormalities (P = 0.010). Kaplan-Meier survival analysis results showed that EMWM patients had a significantly shorter median overall survival (P < 0.001) and progression-free survival (PFS) (P < 0.001) than did BMWM patients. Chemotherapy combined with targeted therapy improved PFS for BMWM patients (P = 0.004) but not for EMWM patients. Additionally, initial treatment with rituximab significantly improved the PFS of BMWM patients (P = 0.012) but had no effect on EMWM patients. However, EMWM patients treated with nucleoside analogs attained a better PFS than those who did not (P = 0.021). Conclusions: We show that extramedullary involvement at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy with nucleoside analogs improved PFS for patients with EMWM. The study provides unique clinical and treatment observations in subtypes of WM patient. [ABSTRACT FROM AUTHOR]

3q26.2/ EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/ EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival. The study group included 12 cases of MDS/MPN with 3q26.2 rearrangements detected by conventional karyotyping. There were 7 men and 5 women with a median age of 67 years (range, 51–79 years) at time of initial MDS/MPN diagnosis. Ten cases were classified as chronic myelomonocytic leukemia (CMML) and 2 were MDS/MPN, unclassifiable. Among CMML cases, 5 (50%) were proliferative type and 5 (50%) were dysplastic type. Based on blast counts, these 10 CMML were: CMML-0 (n = 2), CMML-1 (n = 3), and CMML-2 (n = 5). Eleven (92%) patients had 3q26 rearrangements at the initial diagnosis. Inv(3)(q21q26.2) was most common, identified in 7(58%) patients, followed by t(3;21)(q26.2;q22) in 2 patients and 1 patient each with t(3;3)(q21;q26.2), t(2;3)(p21;q26-27), and t(3;6)(q26.2;q26). Six (50%) patients had 3q26.2 rearrangements as a sole cytogenetic abnormality and 6 (50%) patients had additional cytogenetic abnormalities. Molecular studies revealed DNMT3A mutations in all 3 patients assessed and RAS mutations in 2 of 8 (25%) patients. No mutations in ASXL1 (n = 3), TET2 (n = 3), FLT3 ITD/D835 (n = 10), and CEBPA (n = 7) were detected. Most patients received hypomethylating agent based chemotherapy. The median follow-up was 11.5 months (range, 1.5–24 months) and at time of last follow-up, 11 (92%) died with a median survival of 13.4 months (range, 1.5–24 months). The only patient alive had a relatively short follow-up of 2.4 months and showed disease progression at the last visit. In conclusion, 3q26.2/ EVI1 rearrangements are a rare event and usually present at time of initial diagnosis in MDS/MPN. The presence of 3q26.2/ EVI1 rearrangements in MDS/MPN is associated with rapid disease progression, poor response to treatment, and a poor prognosis. [ABSTRACT FROM AUTHOR]