News of the Week

Highlights:

• Induction chemotherapy has long been a key component of curative therapy for fit patients with acute myeloid leukemia (AML), despite its frequently severe side effects and substantial health care utilization.
• For patients who are ineligible for induction chemotherapy, hypomethylating therapy plus venetoclax is the standard  treatment owing to its efficacy and side-effect profile.
• In this clinical trial, azacitidine–venetoclax therapy led to significantly longer event-free survival (EFS) than induction chemotherapy among induction-eligible patients with AML.

In this multicenter, phase 2 trial (PARADIGM ClinicalTrials.gov number, NCT04801797), 172 previously untreated adults with AML who were eligible for induction chemotherapy were randomly assigned, in a 1:1 ratio, to receive either azacitidine plus venetoclax (n=86) or induction chemotherapy (n=86). Patients with  core binding factor fusions, mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3), or mutations in the gene encoding nucleophosmin-1 (NPM1; unless the patient was ≥60 years of age) were excluded. The primary end point was EFS.

The median age of the patients was 64 years. A total of 72% of the patients had adverse-risk disease according to the European LeukemiaNet 2022 classification. At a median follow-up of 21.9 months, the median EFS was 14.5 months (95% confidence interval [CI], 10.4 to 24.4) in the azacitidine–venetoclax group, as compared with 6.2 months (95% CI, 4.1 to 10.1) in the induction chemotherapy group, corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39 to 0.84; P=0.002 by the stratified log-rank test). Infection of grade 3 or higher occurred in 28% of the patients (95% CI, 19 to 39) receiving azacitidine–venetoclax and in 41% of those (95% CI, 30 to 52) receiving induction chemotherapy; hemorrhage of grade 3 or higher occurred in 2% (95% CI, 0.3 to 8) and 12% (95% CI, 6 to 20), respectively.

Highlights:

– Studies have shown that rasburicase is highly effective in rapidly lowering  plasma uric acid levels in patients with tumour lysis syndrome (TLS) However, no study has rigorously tested whether rasburicase improves clinical outcomes in such patients.

– In patients with TLS, early treatment with rasburicase was associated with a considerably lower risk of acute kidney injury requiring kidney replacement  therapy or death compared with delayed or no rasburicase treatment. This finding highlights the importance of prompt recognition of TLS and early treatment with rasburicase.

Among 1276 patients included in the analysis, 705 (55.3%) received rasburicase within 12 hours after TLS onset. Among patients treated within 12 hours of TLS onset, rasburicase was administered at a median  of 5.0 hours (interquartile range 3.1-7.5 hours).  Patients who received rasburicase had higher uric acid concentrations than those who did not (median 0.71 vs 0.59 mmol/L [11.9 vs 9.9 mg/dL]); however, severity  of illness was well balanced after applying inverse  probability of treatment weighting. Early rasburicase  treatment was associated with a lower risk of acute  kidney injury requiring kidney replacement therapy or  death (32.7% vs 42.0%; adjusted odds ratio (OR) 0.67, 95%  confidence interval [CI] 0.52 to 0.88; P<0.001). Results  were consistent across multiple sensitivity analyses  and for 90 day mortality (adjusted OR 0.71, 95% CI 0.54 to 0.94).

Key points:

• Follicular lymphoma has traditionally been considered an incurable malignancy characterized by repeated relapses. However, emerging long-term data are increasingly challenging this paradigm.
• With rituximab, median overall survival approaches 20 years, and only 35–40% of patients require more than one treatment line. Drawing on frameworks established in chronic viral infections and other hematologic malignancies, including chronic myeloid leukemia and multiple myeloma, this review examines the evolving concepts of cure and functional cure.
• The term “cure” lacks a universally accepted definition in medicine. The National Cancer Institute dictionary defines cure as the absence of cancer after treatment with no possibility of recurrence, emphasizing the notion of complete eradication of the disease, whereas the American Cancer Society considers cure as the total disappearance of cancer with no expectation of recurrence, although it acknowledges that absolute certainty is unattainable.
• Cure can be inferred when long-term survivors exhibit mortality comparable to their peers, even if microscopic disease persistence cannot be excluded.
• In recent years the concept of functional cure has been incorporated into different oncological and non-oncological diseases.
• Functional (or operational) cure refers to durable disease control with no clinically meaningful progression and restoration of life expectancy and quality of life comparable to the general population, achieved in the absence of ongoing disease-specific therapy.
• In hematologic malignancies, the concept of functional cure has been operationalized in settings where sensitive measurable residual disease (MRD) tools and highly effective targeted therapies are available, notably in chronic myeloid leukemia and multiple myeloma.
• The authors propose a framework supporting the probability of functional cure based on several observations (See Figure 1 in original paper):
• Durable remission following treatment discontinuation
• Absence of clinically meaningful progression
• Sustained deep remission defined by sensitive biomarkers including MRD and positron emission tomography/computed tomography. At present, MRD monitoring should primarily be performed within the context of prospective clinical trials, given the current limitations in assay standardization, interpretation, and clinical
• Normalization of survival relative to the general population and patient-reported quality of life.
• Early clinical milestones, such as event-free survival at 24 months and complete remission at 30 months, may also assist in identifying patients with particularly favorable long-term disease trajectories.

Key points:

• Diffuse Large B-cell lymphoma (DLBCL) is an aggressive lymphoma in which management is constrained by incomplete molecular characterization and the absence of sensitive markers of treatment response.
• Cell-free DNA (cfDNA) offers a noninvasive approach for tumor genotyping and minimal residual disease (MRD) monitoring. Nevertheless, technical challenges persist, including low cfDNA abundance and the discrimination of low allele fraction variants from background noise. See Table 1 in original paper for summary of ctDNA technologies in DLBCL.
• An unresolved question is how much analytical sensitivity is clinically meaningful. As assays become more sensitive, biological false positives will become increasingly relevant. Low-level B-cell clones, precursor lesions, or even physiological B-cell expansions may produce signals that resemble MRD.
• Tumor-informed assays tracking multiple genetic markers substantially improve sensitivity of disease monitoring. Standardization and prospective validation will facilitate routine clinical implementation.

Key points:

• Castleman disease (CD) comprises a heterogeneous group of rare lymphoproliferative disorders unified by characteristic lymph node histopathology but with substantial clinical, biologic, and therapeutic diversity.
• Major advances in disease classification, pathophysiologic understanding, and targeted therapy have reshaped the management of CD, particularly idiopathic multicentric CD (iMCD).
• The introduction of interleukine-6–directed therapy has transformed the management of iMCD by shifting treatment from empirical immunosuppression or cytotoxic chemotherapy toward a biologic-based approach, achieving durable disease control in most patients.
• Progress has also been made over the past several years in the anatomic, etiologic, and clinical classification of CD, enabling more individualized, severity-adapted treatment approaches across the disease spectrum. Emerging paradigms in CD management include the recognition of oligocentric CD (OligoCD) as an intermediate anatomic entity with distinct therapeutic implications, as well as the validation of idiopathic plasmacytic lymphadenopathy (IPL) as a clinically distinct subtype of iMCD.
• Patients with unicentric CD (UCD) and OligoCD may often be managed with localized therapy, although symptomatic unresectable UCD and a subset of patients with OligoCD may require systemic therapy.
• The recent paradigm of CD management emphasizes early identification of refractory disease and timely escalation beyond biologic therapy.