Acta Haematologica最新文献

Background: The entity of Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) accounts for approximately 20-30% of newly diagnosed adults with B-cell ALL cases in the USA. Compared to other B-cell subtypes, Ph-like ALL is associated with overall poor prognosis and inferior outcomes with high measurable residual disease rates following induction therapy, increased risk of treatment failure and relapse, as well as short event-free and overall survival.

Summary: Here we aim to highlight Ph-like ALL genetic subtypes and methods of genomic profiling for diagnosis and disease prognostication and to summarize current management approaches for frontline treatment including multiagent chemotherapy, immunotherapy, tyrosine kinase and small molecule inhibitors, and the role of allogeneic stem cell transplantation.

Key messages: Despite the improvement in the treatment outcomes of adult patients with newly diagnosed B-cell ALL, patients with Ph-like ALL continue to do poorly with standard therapy. Thus, tailored therapeutic studies are indeed warranted to refine frontline treatment approaches and to improve outcomes for patients with Ph-like ALL.

Background: Approximately half of newly diagnosed cases of acute lymphoblastic leukemia (ALL) occur in adults, but adults experience significantly higher rates of treatment failure and treatment-related mortality due to frequent presence of adverse disease biology and limited tolerability of conventional chemotherapy.

Summary: Here, we discuss recent data from clinical trials investigating new approaches for initial treatment of Philadelphia chromosome-negative ALL in older adults. These trials investigate the incorporation of novel agents including the anti-CD22 antibody-drug conjugate inotuzumab, the CD19-CD3 bi-specific T-cell engager blinatumomab, and the BCL2 inhibitor venetoclax into treatment regimens, with some studies attenuating or omitting chemotherapy. We also discuss the role of allogeneic stem cell transplantation consolidation for this population and highlight the possibility of frontline CD19-directed chimeric antigen receptor T-cell therapy consolidation approaches for B-ALL. Finally, we discuss improved understanding of the genetic diversity of ALL in older adults including occurrence of ALL with TP53 mutation, ALL with myeloid gene mutations, and therapy-related ALL.

Key message: Overall, we highlight progress for older adults with Ph-negative ALL with patients more frequently achieving a measurable residual disease-negative complete remission, but significant work remains to improve the safety of treatment as well as the depth and durability of treatment response.

Background: Assessment of measurable residual disease (MRD) assessment is an internal component of prognostication and management of acute lymphoblastic leukemia (ALL). A range of assays - differing in sensitivity, complexity, and clinical application - are available. As these technologies advance, clinicians face new challenges in selecting and interpreting MRD tests. Summary: MRD testing is essential for risk stratification and treatment guidance in pediatric and adult ALL. Key assay platforms include multiparameter flow cytometry, quantitative PCR, and next-generation sequencing (NGS) for clonal B- or T-cell receptor rearrangements. NGS MRD offers superior detection depth, especially in post-hematopoietic cell transplantation, and post-CAR T-cell therapy. In Philadelphia chromosome-positive ALL, persistent BCR::ABL1 may represent non-leukemic clones, warranting the use of lineage-specific assays. While bone marrow remains the standard MRD source, assessment of MRD in blood and cerebrospinal fluid are gaining support in select contexts. MRD assessment in T-cell ALL remains complex due to antigen heterogeneity and infrequent clonal targets. Key Messages: This review provides a practical overview of MRD testing in ALL, comparing available technologies and highlighting clinical implications of assay selection, sensitivity, and sample type.

Background: Allogeneic stem cell transplantation (ASCT) has been a cornerstone of acute lymphoblastic leukemia (ALL) treatment for decades, with significant improvements in patient survival. These advancements are linked to better therapies, refined conditioning regimens, and minimal residual disease monitoring. Despite progress, challenges remain in reducing relapse, treatment-related mortality, and toxicity.

Summary: This article explores recent advancements in ASCT for ALL, focusing on conditioning regimens, graft engineering, and post-transplant therapies. Key developments include identifying patients who benefit from reduced-intensity conditioning over myeloablative conditioning or reduction in dose of total body irradiation (TBI), leading to improved outcomes and lower toxicity. Innovative graft manipulation strategies, such as Orca-T and Orca-Q, aim to enhance graft-versus-leukemia effects while minimizing graft-versus-host disease (GVHD). Additionally, post-transplant therapies, including targeted treatments, immunotherapies, and CAR-T cells, are showing promise in preventing relapse. Advances in mismatched donor use and GVHD prophylaxis are broadening donor options and reducing adverse effects, improving ASCT's safety and effectiveness in ALL.

Key messages: ASCT remains a critical treatment for high-risk ALL, with advancements in conditioning, graft engineering, and post-transplant strategies. Future focus will be on optimizing patient selection, use in post-CAR-T consolidation, and refining graft manipulation, aiming to personalize ASCT and enhance survival and quality of life for ALL patients.

Chimeric antigen receptor T cell (CAR T) therapy was first approved for the treatment of children and young adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Since then, two additional CAR T products have been approved for adult R/R B-ALL. Through clinical trials and real-world evidence, we have learned that CAR T therapies generally lead to high upfront response rates with usually deep remissions, negative for measurable residual disease (MRD). Despite that, many patients eventually relapse, prompting a need for better prognostication and techniques to prolong remissions and maximize cures. Here, we focus our review on previously known and recently discovered prognostic factors for sustained remissions, and potential avenues for improved cure rates with CAR T therapy for ALL. Lastly, we comment on the importance of removing barriers to accessing CAR T cells for patients with ALL.

Introduction: Plasma cell neoplasms (PCNs) are a rare type of post-transplant lymphoproliferative disease (PTLD). Extramedullary plasmacytoma is a rare type of PCN, and is infrequently located in the retroperitoneum. According to the current literature, heart transplant recipients are considered at intermediate risk for developing PTLD.

Case presentation: We report a case of a 70-year-old patient with a history of heart transplantation, who was admitted to the hospital with back pain and swelling of the left lower limb. Imaging revealed a large retroperitoneal mass involving the left kidney, descending colon, left iliopsoas muscle, bladder, and prostate. Histopathological analysis confirmed the diagnosis of extramedullary plasmacytoma. Immunosuppressive therapy was reduced and chemotherapy was initiated; however, the patient passed away after two cycles of treatment.

Conclusion: To the best of our knowledge, only once has retroperitoneal plasmacytoma in a heart transplant recipient been previously reported. Our case should raise suspicion for recognizing and considering this rare diagnosis in similar clinical scenarios.

Introduction: The objective of our case series was to assess the change in hemoglobin for adults with myelodysplastic syndrome (MDS) started on a sodium glucose cotransporter 2 inhibitor (SGLT2i) for their diabetes, heart failure, or chronic kidney disease.

Case presentation: Five consecutive patients with bone marrow biopsy confirmed low or intermediate risk MDS were referred for consideration of SGLT2i between July 2024 and December 2024. The patients were followed prospectively and had a repeat complete blood count at least 3 months after starting empagliflozin at 10 mg daily. Four of the five patients provided written consent for their results to be published. Median age was 78 years (range 76 to 82 years), three of the four patients were men, and the median baseline hemoglobin was 11.6 g/dL (IQR 9.3-12.8). Over a median duration of 4 months of taking empagliflozin, the median repeat hemoglobin was 12.8 g/dL (IQR 10.3-13.7).

Conclusions: In our case series of four patients with MDS started on empagliflozin, we observed an increase in hemoglobin for all four patients. Larger studies are needed to assess whether the increase in hemoglobin is sufficiently robust and sustained to reduce a person's need for future red blood cell transfusion or other treatments for MDS.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive lymphoma with dismal outcome after disease progression. Individual risk assessment can stratify patients into different treatment strategies.

Methods: We retrospectively collected data from 326 DLBCL patients treated in a single center with RCHOP from 01/2000 to 06/2023. Immunohistochemistry by Han's algorithm was used to classify patients according to cell of origin (COO). The Kaplan-Meier estimator of survival and Cox regression analysis were used.

Results: Time to progression (TTP) and overall survival (OS) were not different according to COO. Univariate analysis reveals International Prognostic Index (IPI), b2-microglobulin ≥3.5 mg/L, bulky disease, and abnormal LDH, but not Han's defined COO, as the strongest predictors for progression. IPI score in multivariate analysis was the only prognostic factor for OS and together with high b2-microglobulin levels were independently prognostic factors for TTP. Accordingly, b2-microglobulin ≥3.5 mg/L was an independent prognostic factor for progression both in GC (hazard ratio [HR] 0.249 [(95% CI: 0.087-0.649), p = 0.004] and non-GC DLBCL patients (HR 0.380 [95% CI: 0.177-0.813], p = 0.011).

Conclusion: COO according to Hans index is not a significant prognostic factor for DLBCL patients, but b2-microglobulin ≥3.5 mg/L and IPI 2-5 in both GC and non-GC patients can predict individually a higher risk for progression.

Introduction: Relapsed/refractory (R/R) acute myeloid leukaemia (AML) is a life-threatening haematological malignancy without effective treatments. Anexelekto (Axl) and Mer receptor tyrosine kinases have emerged as important therapeutic targets in AML for their crucial role in survival of AML cells. Tamnorzatinib (ONO-7475) is a potent and highly selective inhibitor of Axl/Mer. We report first-in-human study of tamnorzatinib (NCT03176277) in patients with R/R AML.

Methods: Tamnorzatinib was administered as monotherapy (n = 20) to determine an appropriate biological dose of tamnorzatinib and then in combination (n = 22) with venetoclax to evaluate safety and clinical efficacy.

Results: Tamnorzatinib was safe and well tolerated as monotherapy (3, 6, and 10 mg) and in combination (6 mg) with venetoclax. No dose-limiting toxicities were observed at any dose level. Near-maximal Axl/Mer inhibition was observed following 6 mg tamnorzatinib alone and in combination therapy. No complete remission (CR) with partial haematologic recovery was observed with combination therapy. However, decreased transfusion dependency was observed; in the venetoclax-resistant subgroup (n = 14), 1 (7.1%) patient achieved CR with incomplete haematologic recovery and 1 (7.1%) patient achieved morphologic leukaemia-free state.

Conclusion: Tamnorzatinib alone and in combination with venetoclax was safe and well tolerated but failed to induce robust clinical efficacy in R/R AML.