News of the Week

Highlights:

• Current treatment of newly diagnosed multiple myeloma (NDMM) involves lenalidomide maintenance therapy given until disease progression. The appropriate duration of maintenance therapy with lenalidomide has been unclear.
• In this phase 3 trial involving patients with standard-risk NDMM who were not undergoing up-front autologous stem-cell transplantation (ASCT), indefinite-duration maintenance therapy after induction therapy did not result in significantly longer overall (OS) survival than fixed-duration maintenance therapy.

In this phase 3 trial (ENDURANCE ClinicalTrials.gov, NCT01863550), patients with standard-risk NDMM who were not undergoing up-front ASCT were enrolled. After induction treatment with a proteasome inhibitor–lenalidomide combination,  patients were randomly assigned to receive indefinite-duration (continuous) lenalidomide or fixed-duration lenalidomide (for 2 years). The primary end point was OS. At the end of induction, 516 patients were randomly assigned to the indefinite-duration group (n=260) or the fixed-duration group (n=256). At a median follow-up of 86 months, OS did not differ significantly between the groups.   With 80 deaths in each group, OS at 7 years was 68.6% in the indefinite duration group and 69.0% in the fixed-duration group (difference, −0.4 percentage  points; 95% confidence interval [CI], −9.0 to 8.3; P=0.93). Progression-free survival at  7 years was 36.1% in the indefinite-duration group and 29.7% in the fixed-duration  group (difference, 6.4 percentage points; 95% CI, −2.6 to 15.4). The 5-year cumulative  incidence of second primary cancers, excluding nonmelanoma skin cancer, was 11.2% with indefinite-duration lenalidomide and 8.3% with fixed-duration lenalidomide.  More adverse events occurred with indefinite-duration lenalidomide; the incidence  of nonhematologic events of grade 3 or higher was 48.2% with indefinite-duration  therapy and 31.5% with fixed-duration therapy.

Highlights:

• Although the YEARS diagnostic algorithm is a safe and efficient way to rule out acute pulmonary embolism (PE), robust evidence on its accuracy in patients with cancer is lacking, and current guidelines suggest proceeding directly to computed tomographic pulmonary angiography (CTPA).
• In patients with cancer and suspected PE, a diagnostic strategy using the YEARS diagnostic algorithm was as safe as using CTPA only, thus, obviating the need to perform CTPA in of 22% of patients.

The Hydra study was a multicenter, international, open-label, randomized, non-inferiority trial from 2019 to 2025. Patients with active cancer and suspected acute PE were recruited from hospital emergency departments/medical units. Patients were randomly assigned in a 1:1 ratio to receive diagnostic management by the YEARS algorithm (n=352)—consisting of assessing YEARS items, D-dimer levels, and performing risk-dependent CTPA—or by CTPA only (n=346).

The primary outcome was centrally adjudicated symptomatic venous thromboembolism or (possible) PE-related death within 90 days after ruling out PE at baseline. A total of 698 patients were randomized (median age, 65 years [interquartile range, 56-72 years],

and 104 patients (15%) had PE diagnosed at baseline. In the intention-to-diagnosis analysis, the absolute risk difference between the YEARS algorithm and CTPA only was−2.6% (99.9% confidence interval,−7.5% to 2.4%; P=5.9×10⁻⁴ for noninferiority). No difference in the proportion of negative CTPA (P =0.93) was observed between the groups.

Highlights:

• Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) face an unfavorable prognosis once first-line treatment fails; therefore, there is an unmet need for new treatment options.
• Pola-R-GemOx (polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin) significantly improved overall survival (OS) compared with R-GemOx (rituximab, gemcitabine, and oxaliplatin), offering an additional treatment option in patients with transplant-ineligible R/R DLBCL.

The phase III POLARGO trial was a randomized, open-label, global study. Following a Pola-R-GemOx safety run-in (n=15), patients with R/R DLBCL (not otherwise specified or transformed indolent lymphoma) ineligible for autologous stem cell transplant were randomly assigned 1:1 to receive Pola-R-GemOx or R-GemOx alone every 21 days for up to eight cycles. The primary end point was OS. In total, 255 patients were randomly assigned to receive Pola-R-GemOx (n=129) or R-GemOx (n=126). After a median follow-up of 24.6 months, patients receiving Pola-R-GemOx versus R-GemOx had a significantly lower risk of death (hazard ratio, 0.6 [95% confidence interval (CI), 0.43 to 0.83]; P=0.0017) with a median OS of 19.5 months (95% CI, 13.3 to not estimable) versus 12.5 months (95% CI, 8.9 to 15.8).

The most common grade 3/4 adverse events (AEs) were thrombocytopenia and neutropenia. Peripheral neuropathy was more common with Pola-R-GemOx (n=73 [57%]) versus R-GemOx (n=36 [29%]) and was primarily grade 1. Fatal AEs occurred in 15 (12%) and five (4%) patients in the Pola-R-GemOx and R-GemOx groups, respectively, and were largely driven by infections (including COVID-19).

In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of transfusion-dependent β-thalassemia (TDT) patients

Key points:

– Clinical management of TDT patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic stem cell transplantation (HSCT) potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years.

– The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT).

–  The lower age limit. For the time being, they strictly follow the regulatory authority (The Food and Drug Administration and European Medicines Agency) indications as follows: Gene addition (GA) therapy to patients ≥4 years and gene editing (GE) therapy to patients ≥12 years of age. See Figure 1 in original paper.

– The upper age limit. The panel recommends limiting access to GT for patients above the age of 35 years. The panel agrees that any GT approach beyond the age of 35 years (upper age limit in clinical trials of GE therapy) should be treated as an exceptional case, under the principle of gradualness only in selected centers with large experience and qualification in the delivery of GT and/or HSCT in TDT.

– The best transplant outcomes in β-TDT are achieved in patients <14 years old with an HLA-identical donor (related or unrelated).

– In TDT patients, haploidentical transplantation is an emerging alternative, requiring further studies to optimize protocols and to optimize long-term safety and efficacy.

– Advances in graft-versus-host disease prophylaxis strategies continue to refine transplantation approaches, which may, in the future, result in broader access to HSCT for patients without an HLA-matched donor.

– Outcomes of HSCT in adulthood require improvements even in the context of a fully matched sibling, and a careful case-by-case discussion.

– Beta and alpha globin genotypes must be assessed in all patients prior to proceeding with GT.

– Patients should not be excluded from GT therapy based on beta genotypes.

– Currently, patients with alpha globin gene multiplication should not be considered as eligible for GT.

– Ineligible patients (See Table 2 in original paper).

– Patients with liver fibrosis and iron overload within the following characteristics:

—Liver stiffness measurement (LSM )≥8kpPa independently from liver iron concentration (LIC).

—LSM <8kPa and LIC >7–14mg/dry weight (dw) without a 6–12-month period of regular and consistent iron chelation to decrease LIC ≤7 mg/g dw.

—LSM <8kPa and LIC ≥15mg/g dw (situation to be re-evaluated by liver biopsy, temporarily not eligible)

• Patients with severe myocardial iron overload demonstrated by a T2 magnetic resonance imaging <10ms documented in the previous 6 months.
• Pulmonary hypertension (determined by cardiac catheterization).
• Patients with chronic organ damage, hepatopathy, insulin-dependent diabetes, nephropathy and positive thrombophilic status.