AL amyloidosis

Bomsztyk et al. recently reported the utility of serum mass spectrometry-based free light chains assay (FLC-MS) in assessing the impact of negativity after treatment of 487 patients with immunoglobulin light chain (AL) amyloidosis in terms of overall survival (OS) and organ response rates. Along with this publication, Dispenzieri gives an interesting commentary. 290 (59%) and 349 (71.5%) patients had cardiac and renal involvement, respectively. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) patients were FLC-MS negative. At 12 months, the median OS for CR + FLC-MS negative was not reached versus 108 months in CR + FLC-MS positive (p=0.024). At 12 months, 70% of patients with FLC-MS negativity (versus 50% FLC-MS positive) achieved a cardiac response (p= 0.015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. Patients with no detectable FLC by FLC-MS have significantly better OS and organ response irrespective of conventional hematologic response. The assay used in this study is not currently commercially available and uses an MS that detects FLC rather than total light chains (those light chains bound to intact immunoglobulins plus FLC).

Monoclonal gammopathy of undetermined significance (MGUS)

Eythorsson et al. published the development of a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater bone marrow plasma cells (smoldering multiple myeloma [SMM] or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample. 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. This cohort included all persons with presumed MGUS randomly assigned to groups 2 and 3 of the iStopMM study (Iceland Screens, Treats or Prevents Multiple Myeloma, a prospective population-based screening study of MGUS; NCT03327597). The prediction model included MGUS isotype; M protein; free light chain (FLC) ratio; and total concentrations of IgG, IgA, and IgM as predictors. The c-statistic for SMM or worse was 0.85 (95% CI, 0.82-0.88) and calibration was excellent. At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. The prediction model will require external validation.

Online calculator 

Extranodal natural killer/T cell lymphoma (ENKTL)

ENKTL nasal type, is a rare and aggressive non-Hodgkin lymphoma frequently encountered in populations from Asia and South America, associated with Epstein-Barr virus infection. Patients with advanced ENKTL have a dismal prognosis despite receiving chemotherapeutic regimens. Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory ENKTL (phase 2 trial ORIENT-4). Tian et al. recently published results of a multicentre (in China), single-arm, phase 2 trial (NCT04127227), called SPIRIT, which assessed the safety and activity (primary endpoint was the complete response rate [CR]) of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for 34 eligible patients with advanced ENKTL. The median follow-up was 21 months (IQR 13-32). All patients attained an objective response, with a CR rate of 85% (29 of 34 patients, 95% CI 70-94). 24-month progression-free survival (PFS) was 64% (95% CI 48-86), and 36-month overall survival (OS) was 76% (95% CI 52-100). No severe adverse events occurred. Randomized phase 3 trials are necessary to explore the efficacy of this combination.

Chimeric antigen receptor T (CAR T) therapies

According to the results of a study by Grover et al., anti-CD30 CAR T-cell infusion as consolidation after carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous hematopoietic stem cell transplantation (HSCT) is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma (HL) at high risk of relapse. This phase 1 (NCT02663297) dose-escalation study was performed in patients with classical HL or non-HL with CD30+ disease who were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T-cells as consolidation after trilineage hematopoietic engraftment. 18 patients (11 with HL, 6 with T-cell lymphoma, and 1 with grey zone lymphoma) were infused with anti-CD30 CAR T-cells at a median of 22 days (range 16–44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2×10⁸ CAR T cells/m², was determined to be the maximum tolerated dose. Overall tolerability was good, with no treatment-related deaths, no toxicity-related discontinuations, no cytokine release syndrome above grade 1, and no neurotoxicity. Grade 3 or 4 cytopenias (anemia and neutropenia) were reported, attributed to tumor progression. Two patients developed secondary malignancies approximately 2 years and 2.5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48.2 months (IQR 27.5–60.7) post-infusion, the median progression-free survival (PFS) for all treated patients was 32.3 months (95% CI 4.6 months to not estimable), and the median PFS for treated patients with HL (n=11) has not been reached. For patients with T-cell lymphoma, results were more disappointing, with five relapses out of six patients treated.

Acute myeloid leukemia (AML)

Bazinet et al. performed a single-arm, phase 2 study (NCT04062266) in patients with a diagnosis of AML in complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive (n=35; 71% [cohort 1]) or low-intensity induction (n=10; 29% [cohort 2]) and not immediately eligible for hematopoietic stem cell transplantation (HSCT). Patients were assigned to maintenance therapy with azacitidine (50 mg/m2 intravenously or subcutaneously for 5 days) and venetoclax (400 mg orally for 7 days or 14 days). The primary outcome was relapse-free survival (RFS). 30 (86%) patients were enrolled in first CR, 3 (9%) were in first CRi, and two (6%) were in second remission following intensive or low-intensity induction, which allowed for previous venetoclax exposure. Most patients had European LeukemiaNet 2017 favorable or intermediate-risk disease. Eight patients (23%) proceeded to HSCT. The median RFS was not reached (95% CI 20.2 to not calculable) in the full cohort, not reached (95% CI 29.1 to not calculable) in cohort 1, and 30.3 months (95% CI 16.5 to not calculable) in cohort 2. The 2-year RFS was 65% (95% CI 50–85) in the full cohort, 71% (95% CI 53–94) in cohort 1, and 52% (95% CI 27–100) in cohort 2. The study was halted due to slow accrual (a common problem faced in maintenance trials in patients with AML). Prolonged administration of low-dose azacitidine and venetoclax is a promising maintenance strategy for patients with AML unable to immediately proceed to HSCT. The randomized, phase 3 study VIALE-M aimed to evaluate the addition of venetoclax to oral azacitidine as maintenance therapy in AML, but the results are not yet published.