Clinical trial in advanced-stage classical Hodgkin lymphoma (HL): BrECADD versus eBEACOPP.

Highlight(s): A phase 3 trial demonstrated that PET-guided BrECADD after two cycles was better tolerated and more effective (in terms of progression-free survival [PFS])  than eBEACOPP in first-line treatment of adult patients with HL.

Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical HL (e.g., Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone), guided by positron emission tomography (PET) after two cycles (PET-2). Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by PFS. An additional test of superiority of PFS was to be done if non-inferiority had been established (NCT02661503).  

1482 patients were included in the intention-to-treat analysis. The median patient age was 31 years (interquartile range 24–42).  Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0.72 [95% confidence interval [CI] 0.65–0.80]; p<0.0001). At a median follow-up of 48 months, BrECADD improved PFS with a hazard ratio (HR) of 0.66 (0.45–0.97; p=0.035). Test for superiority in the final analysis  was positive showing patients assigned to BrECADD had a 4-year PFS rate of 94.3% (95% CI 92.6–96.1) whereas those assigned to eBEACOPP had a rate of 90.9% (88.7–93.1; HR 0.66 [95% CI 0.45–0.97]; p=0.035). 4-year overall survival rates were 98.6% (97.7–99.5) and 98.2% (97.2–99.3), respectively. PET-2-guided BrECADD achieves high response rates, and most patients can be treated with four cycles. Hight rates of gonadal function recovery in female and male patients were observed, as well as high numbers of childbirths with BrECADD, which is most likely linked to the omission of procarbazine.

Low-Dose Planned Glucarpidase Allows Safe Outpatient High-Dose Methotrexate  (HD-MTX )Treatment for central nervous system (CNS) Lymphoma. A  prospective nonrandomized study.  

Highlight(s): Outpatient HD-MTX with glucarpidase is safe and well-tolerated and has the potential to alter standard treatment for CNS lymphoma. These findings could allow for the expansion of outpatient HD-MTX protocols, allowing patients to avoid repeated and prolonged hospital admissions for CNS lymphoma treatment.

Eligible patients had CNS lymphoma, creatinine <1.3 mg/dL, and previously tolerated HD-MTX. Patients could re-enroll for subsequent doses of HD-MTX as eligibility and slots permitted. MTX 3.5 g/m² was administered once over 2 hours, preceded by standard hydration and followed by an additional 2 hours of dextrose 5% in water with NaHCO3 75 mEq at 150 cc/h. Glucarpidase 2000u was administered once in the clinic 24 hours later. The primary end point was MTX level 48 hours after HD-MTX. Twenty doses of outpatient HD-MTX with glucarpidase were administered to seven patients. After 20 of 20 (100%) treatments, serum MTX levels were reduced to <100 nmol/L. Treatments were well-tolerated, and no admissions were required. One patient received additional outpatient hydration for elevated creatinine. Development of antiglucarpidase antibody was rare and did not affect treatment. The treatment was overall well tolerated with only one grade 3 event of decreased lymphocyte count and one patient required additional contact with the health care system for outpatient intravenous hydration because of grade 2 creatinine elevation.

Mitral regurgitation (MR) is associated with similar loss of von Willebrand factor (VWF)  large multimers, but lower frequency of anemia compared with aortic stenosis (AS).

Highlight(s): Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.

Moderate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed. At baseline, the mean hemoglobin level was 12.9 ±1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%), less than in patients with severe AS. The rate of MR patients having anemia was far less compared with that of AS patients, which could be due to having less angiodysplasia.

A systematic review and meta-analysis of nonrelapse mortality (NRM) after chimeric antigen receptor (CAR) T-cell therapy.

Highlight(s): Comprehensive evidence-based recommendations that guide infection prevention and management following CAR T-cell therapy are required due to the crucial role that infections play as the primary cause of NRM across CAR T-cell products and disease types.

In this systematic review and meta-analysis, the authors searched for reports of nonrelapse mortality (NRM) after CAR T-cell therapy in lymphoma and multiple myeloma up to March 2024. After extraction of causes and numbers of deaths, NRM point estimates using random-effect models was analyzed. 7604 patients across 18 clinical trials and 28 real-world studies were identified. NRM point estimates varied across disease entities and were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%) and indolent lymphoma (5.7%). Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%).  The infections predominated as the cause of death even more in the real-world setting (64.4%, 217 of 337) than in clinical trials (59.1% 75 of 127), which remained true even when excluding COVID–19-related deaths. Conversely, the CAR T-cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome, and hemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths (cumulatively 11.5%). Considering the clinical significance of fatal infections, detailed and structured reporting of infectious events should be a mandatory requirement in clinical trials.

How I Treat: Differentiation Therapy in Acute Myeloid Leukemia (AML).

Differentiation syndrome (DS), characterized predominantly by systemic inflammatory response system (SIRS)-like features of dyspnea, pulmonary infiltrates, pleural and pericardial effusions, unexplained fevers, hypotension, edema and/or weight gain ≥5kg, and renal insufficiency (diagnosis if ≥ 1 signs or symptoms; Frankel et al. 1992). An increasing number of AML therapeutics have been developed, not as cytotoxic therapies, but rather as targeted agents able to restore the aberrant and leukemogenic "block" in normal differentiation. The underlying pathogenesis of DS remains incompletely characterized but is thought to stem from exuberant cytokine production in differentiating and maturing leukemic cells, leading to a hyperinflammatory state.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are classic examples of differentiating agents for treatment of acute promyelocytic leukemia (APL); newer therapies functioning through differentiation include isocitrate dehydrogenase (IDH) 1 and 2 inhibitors, FMS-like tyrosine kinase 3 (FLT3) inhibitors, and menin inhibitors. When systemic inflammatory response system features develop 6 weeks into salvage therapy of a multiply refractory AML with FLT3 and IDH1-mutations receiving an IDH1 or FLT3 targeted agent, they can often be mistakenly assumed to be due to an undiagnosed infection or persistent/progressive disease, both of which are equally plausible etiologies (and may even be occurring in tandem). The incidence of DS with FLT3 inhibitors (not with midostaurin, likely related to the use of midostaurin in combination with intensive chemotherapy, where DS is minimized) is less frequent than with ATRA or IDH inhibitors.

Prompt consideration of DS, rapid initiation of systemic corticosteroids (e.g., dexamethasone at a dose of 10mg BID, for at least 3 days and then tapered once symptoms resolve), and early cytoreduction (e.g., hydroxyurea, gemtuzumab ozogamicin, and/or cytarabine whenever the white blood cell count is >25 ×10⁹/L [or >10 ×10⁹/L for APL]), to minimize additional complications of leukostasis) in the setting of concomitant hyperleukocytosis, are essential for optimal management.