Real-world effectiveness and safety of daratumumab, bortezomib and dexamethasone in relapsed/refractory multiple myeloma in Slovakia.

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) are limited. Daratumumab in combination with bortezomib and dexamethasone is a promising new treatment. The aim of this analysis was to assess the outcomes of daratumumab-bortezomib-dexamethasone (DVd) combination for the treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least two cycles of DVd treatment between December 2016 and July 2020 were identified. We analyzed the clinical characteristics and survival of 47 patients treated at 7 Slovak centers outside of the clinical trials. The median age was 65 years (range, 35 to 83). The median (range) number of lines of therapy per patient was 3 (2-6). All patients were previously exposed to PIs (proteasome inhibitors) and IMIDs (immunomodulatory drugs), the majority of patients (70.2%) had double refractory (IMIDs and PI) disease and 72.3% of patients were refractory to their last therapy. Most patients presented with high-risk characteristics, including 25.6% adverse cytogenetics and 25.5% extramedullary disease. The majority of patients responded with an overall response rate of 78%, we found complete response in 3, very good partial response in 22, partial response in 12, minor response or stable disease in 9, and progressive disease in 1 patient. After a median follow-up period of 8 months, the median progression-free survival was 10 months. There was a longer progression-free survival in those with 2 vs. >2 prior treatments, with equally good effectivity in standard-risk and high-risk cytogenetic groups. The adverse events were usually mild, none leading to permanent drug interruptions. Daratumumab-bortezomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting. This is the first analysis in Slovakia addressing the DVd combination outside of the clinical trial setting.

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial.

BACKGROUND: In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. METHODS: In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. FINDINGS: Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). INTERPRETATION: Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. FUNDING: Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

Chronic myeloid leukemia patients in prolonged remission following interferon-α monotherapy have distinct cytokine and oligoclonal lymphocyte profile.

Before the era of tyrosine kinase inhibitors (TKIs), interferon-alpha (IFN-α) was the treatment of choice in chronic myeloid leukemia (CML). Curiously, some IFN-α treated patients were able to discontinue therapy without disease progression. The aim of this project was to study the immunomodulatory effects of IFN-α in CML patients in prolonged remission and isolate biological markers predicting response. Due to rarity of patients on IFN-α monotherapy, a relatively small cohort of patients still on treatment (IFN-ON, n = 10, median therapy duration 11.8 years) or had discontinued IFN-α therapy but remained in remission for >2 years (IFN-OFF, n = 9) were studied. The lymphocyte immunophenotype was analyzed with a comprehensive flow cytometry panel and plasma cytokine levels were measured with multiplex bead-based assay. In addition, the clonality status of different lymphocyte subpopulations was analyzed by TCR γ/δ rearrangement assay. Median NK-cell absolute number and proportion from lymphocytes in blood was higher in IFN-OFF patients as compared to IFN-ON patients or controls (0.42, 0.19, 0.21×10(9)/L; 26%, 12%, 11%, respectively, p<0.001). The proportion of CD8+ T-cells was significantly increased in both patient groups and a larger proportion of T-cells expressed CD45RO. Most (95%) patients had significant numbers of oligoclonal lymphocytes characterized by T-cell receptor γ/δ rearrangements. Strikingly, in the majority of patients (79%) a distinct clonal Vγ9 gene rearrangement was observed residing in γδ(+) T-cell population. Similar unique clonality pattern was not observed in TKI treated CML patients. Plasma eotaxin and MCP-1 cytokines were significantly increased in IFN-OFF patients. Despite the limited number of patients, our data indicates that IFN-α treated CML patients in remission have increased numbers of NK-cells and clonal γδ(+) T-cells and a unique plasma cytokine profile. These factors may relate to anti-leukemic effects of IFN-α in this specific group of patients and account for prolonged therapy responses even after drug discontinuation.