In adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) genetic risk is usually combined with measurable residual disease (MRD) assignment to consolidation therapy. However, this combination is not uniform across trials and centralized assessment is not always performed. This study analyzed patients' outcomes using centrally assessed MRD and genetics. Patients with high genetic risk (HGR), those who required two induction cycles for complete remission (CR), and CR patients with end-of-induction (EOI) MRD ≥0.01% were assigned to allogeneic hematopoietic stem cell transplant (alloHSCT), while the remaining patients were assigned to delayed consolidation and maintenance. HGR for B-ALL included KMT2A rearrangements, low hypodiploidy and age >35 years, homozygous TP53 mutations/deletions, or concomitant IKZF1 and CDKN2A/B deletions. HGR in T-ALL included absence of NOTCH1/FBXW7 mutations and/or K/NRAS or PTEN alterations. Patients with early T-ALL (ETP) received a different induction regimen, and all were assigned to alloHSCT. Median (range) age of 436 patients was 39 (18-60) years, 332 with B-lineage ALL and 104 T-ALL. By intention to treat, 243 non-ETP patients (61%) were assigned to alloHSCT and 157 (39%) to CT. The 3-year overall survival (OS) probability (95% CI) was 64% (58%-69%). For patients with CR and EOI MRD<0.01% without HGR (n=109), the OS probability was 81% (70%-89%), compared with 50% (34%-63%) for MRD-negative patients with HGR (n=64). In patients with ETP-ALL the probability of 3-year OS was 61% (37%-79%). The combination of genetics and MRD allows accurate identification of adult Ph- ALL patients candidates to alloHSCT or chemotherapy. The trial was registered at www.ClinicalTrials.gov: NCT04179929.

Plasma cell leukemia (PCL) represents an exceptionally aggressive plasma cell malignancy defined by ≥5% circulating plasma cells in the peripheral blood of patients otherwise meeting the diagnostic criteria for multiple myeloma (MM), per the International Myeloma Working Group consensus. This ultrahigh-risk disease exhibits distinctive clinical features including frequent extramedullary involvement, severe cytopenias, hypercalcemia, renal insufficiency, and/or significantly elevated β2-microglobulin and lactate dehydrogenase levels. The molecular landscape includes high-risk cytogenetic abnormalities and mutations that promote accelerated proliferation, apoptotic resistance, immune evasion, and bone marrow microenvironmental independence through dysregulated adhesion molecule and chemokine receptor expression. Although autologous stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies improved historical outcomes, the therapeutic paradigm continues to evolve. Novel therapeutic approaches including B-cell maturation antigen-directed therapies (bispecific antibodies and chimeric antigen receptor T-cell therapy), G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted therapy, and B-cell lymphoma 2 (BCL-2) inhibition demonstrate promise in treating both primary and secondary PCL. Despite these advances, PCL remains inadequately studied, with treatment approaches predominantly extrapolated from MM trials in which patients with PCL have largely been excluded. This review synthesizes current evidence and presents illustrative clinical cases demonstrating practical treatment approaches, while highlighting critical knowledge gaps requiring dedicated prospective clinical trials to meaningfully improve outcomes in this challenging disease entity.

Diffuse large B cell lymphoma (DLBCL) is a highly heterogenous malignant disease that remains a major clinical challenge as relapsed and refractory disease is difficult to treat. Apoptosis evasion is a major feature of DLBCL. However, while the suppression of intrinsic apoptosis has long been recognized as a lymphoma-promoting event, the role of extrinsic apoptosis has remained poorly defined. Here, we demonstrated at the genetic level that expression of cFLIP, the most crucial, non-redundant inhibitor of extrinsic apoptosis, in B cells is necessary for the development of diffuse large B cell lymphoma (DLBCL) in an autochthonous murine model. Indeed, B cell-specific deletion of Cflar, the gene encoding for cFLIP, prevented lymphomagenesis mediated by oncogenic Myd88 and overexpression of BCL2. In human lymphoma cells, we showed that the absence of cFLIP sensitizes ABC- but not GCB DLBCL subtype cells to TRAIL- or LPS-induced, Caspase-8-mediated apoptosis. Furthermore, we unveiled a cell death-independent role of cFLIP in the suppression of pro-inflammatory cytokines at the transcriptional level, selectively in the ABC subtype.These results indicate that the suppression of intrinsic apoptosis can support lymphomagenesis only if extrinsic apoptosis is properly controlled. Moreover, licensing extrinsic apoptosis via cFLIP deletion can efficiently promote the death of DLBCL cells despite the suppression of the intrinsic pathway. Overall, these data provide the rationale for the development of cFLIP inhibitors for the treatment of ABC DLBCL and possibly other haematological cancers.