A modern view of LGL leukemia [Review]

Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative chronic disorder characterized by the expansion of either T or natural killer (NK) cytotoxic cells. In contrast to Epstein-Barr virus-induced aggressive NK-LGLL, chronic T-LGLL, and NK-LGLL are indolent diseases affecting older patients. LGLL is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. The JAK-STAT pathway is crucial in LGL pathogenesis by promoting survival, proliferation, and cytotoxicity. Recent advances have identified multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and cross-talk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that most patients eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate, and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting, and hypomethylating agents, opening new developments in a still-incurable disease. The Figures in this article are highly illustrative.

Figure 1 describes the pathogenesis: from a polyclonal expansion through an oligoclonal phase to leukemia and tissue infiltration.

Figure 3 of the original article has a great graph illustrating the clinico-mutational correlation.

Figure 4 summarizes the diagnostic approach; it starts with:

1.       Compatible clinico-biological context (neutropenia, recurrent infection, splenomegaly, autoimmune disorders) AND

2.       Chronic LGL count > 0.5 x 10⁹/L

Subsequently, the blood immunophenotyping with the following markers CD3/5/4/8/16/56/57:

1.       CD3posCD8pos = T-LGL [85% of cases] or

2.       CD3posCD56pos/CD16pos= NK-LGL [15%]).

Figure 5 summarizes the therapeutic approach.

Risk prediction for clonal cytopenia: multicenter real-world evidence [Retrospective study]

Highlight(s): The clonal cytopenia risk score (CCRS) offers precise clonal cytopenia of undetermined significance (CCUS) risk assessment for patient management and clinical trial eligibility.

This study of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 critical adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 10⁹/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5)  groups. The CCRS effectively predicted a 2-year cumulative incidence of myeloid neoplasm (MN) for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (p< 0.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (p = 0.005) in stratifying the cumulative incidence of MN. Although the CCUS cohort was assembled exclusively from academic centers and may represent a predominantly high-risk population, the reliability of results is expected to be robust because all cases also underwent bone marrow biopsy verification.

The use of direct oral anticoagulants in the secondary prevention of venous thromboembolism in patients with severe thrombophilia: communication from the ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia [Narrative review]

Highlight(s): Given the paucity of available evidence, this communication advises caution when utilizing low-dose direct oral anticoagulants (DOACs) in the context of thrombophilias.

DOACs are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. Current evidence is based only on cohort or single-center studies, and poor data are available on patients' compliance in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs. warfarin, ranging from 0.3 to 0.75. Treatment failure is more significant in those with severe protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. The current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists.

Assessment of fitness for bleomycin use and management of bleomycin pulmonary toxicity in patients with classical Hodgkin lymphoma: A British Society for Haematology Good Practice Paper [Guideline]

Bleomycin, originally developed as an antibiotic in the 1960s, has been a cornerstone of therapy for classical Hodgkin lymphoma (HL) since Bonadonna et al. first published results of its use in combination with doxorubicin, vincristine, and dacarbazine (ABVD) in 1975.

Bleomycin frequently causes a decline in pulmonary function, and it should be used with caution in patients with pre-existing pulmonary disease in whom this could be clinically relevant. The use of bleomycin should be limited to a maximum of 2 cycles in patients >60 years old with HL, and it should usually be omitted in patients older than 70 years. In all patients, baseline pulmonary imaging will usually be performed as part of routine HL staging, and renal function should be checked before every cycle of bleomycin. The role of pulmonary function tests in predicting bleomycin-associated lung toxicity is, at best, uncertain and should be reserved for patients with baseline pulmonary comorbidities where a decline in pulmonary function may not be tolerated. To see all recommendations, visit the link.

Acute Promyelocytic Leukemia: Long-Term Outcomes from the HARMONY Project [Retrospective study]

Highlight(s): This study reaffirms the superiority of ATRA-ATO  all-trans-retinoic acid – arsenic trioxide) over ATRA-chemotherapy in acute promyelocytic leukemia (APL) patients, regardless of patient age and Sanz-risk score.

Leveraging the HARMONY Platform, the authors analyzed 1438 newly diagnosed (between 1999 to 2022) APL patients. Patient data was derived from the 2 international multicenter GIMEMA-APL0406 and NCRI-AML17 trials and 4 European registries (HOVON, AMLSG, Swedish AML Registry, and SAL). The study cohort included 721 males and 717 females, with a median age of 50.5 years (range 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO and 747 AIDA (ATRA with idarubicin)-like chemotherapy. Early death occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz-risk score (odds ratio [OR]:1.06, 95% confidence interval [CI]: 1.04-1.08, and OR: 4.65, 95% CI: 2.55-8.51, respectively). The median follow-up was 5.5 years (interquartile range= 3.2-7.5). ATRA-ATO regimen was associated with the best outcome, reaching a 91% 7-year overall survival (vs. 81% for AIDA-like, hazard ratio [HR]:2.14, 95%CI: 1.51-3.05), 89% event-free survival (vs. 71% for AIDA-like, HR:2.72, 95%CI: 2.01–3.69) and 3% relapse (vs. 13% for AIDA-like, HR:4.19, 95%CI: 2.38–7.39, p<0.001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients’ age, Sanz-risk score, and treatment scenario.