First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

[Myelodysplastic/myeloproliferative neoplasia: a diagnostic and therapeutic challenge]. / Wenn die Dysplasie und die Proliferation zusammen kommen: MDS/MPN.

Myelodysplastic/myeloproliferative neoplasia: a diagnostic and therapeutic challenge Abstract. Myelodysplastic/myeloproliferative neoplasia is a WHO defined group of hematologic diseases. Difficulties diagnosing a distinct entity within this group are related to the resemblance of changes due to inflammation or dysplasia and proliferation. In addition, treatment is aiming to control the proliferation but should not aggravate dysplasia related cytopenia. In the article, we present an overview with a special focus on CMML as well as MDS/MPN-RS-T.

The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase II study SAKK 33/14.

The ß-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a ß-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569).

sIL2R ratio as early marker for response in hairy cell leukemia and the prognostic relevance of IL28B genotype to interferon-α therapy.

Interferon-α (IFNα) was the first effective drug therapy for hairy cell leukemia (HCL). Nowadays, it is used as an alternative treatment in selected patients. Due to unlimited treatment time, monitoring and early prediction of response are important. Moreover, IFNα is used in the therapy of chronic hepatitis C, where a single nucleotide polymorphism of interleukin-28B gene (IL28B) correlates with therapy response. The role of this polymorphism in therapy response of IFNα-treated patients with HCL is unknown. Thirty-seven HCL patients treated between 1978 and 2014 were included in this study. Treatment strategy and response parameters (blood cell counts, soluble interleukin-2 receptor (sIL2R), and bone marrow examination) have been assessed. Relative decrease of sIL2R was correlated with outcome parameters. Response parameters of IFNα-treated patients were correlated with IL28B polymorphism. Twenty-one patients were analyzed for the correlation of sIL2R ratio and outcome. After 1 and 3 months of therapy (IFNα or cladribine (CDA)), the median sIL2R level showed a relative decrease of 79 and 91%. These decreases significantly correlate with time to complete remission (CR, p = 0.029 and p = 0.018). Correlation analyses of IL28B genotype with outcome parameters are not significant. Six patients (16%) were diagnosed with secondary malignancies, and one death was registered (median follow-up time 14 years). IFNα is a safe, effective, and well-tolerated long-term treatment in HCL. Relative decreases of sIL2R levels correlate with time to CR and are useful as early predictor for response. There is no significant correlation between IL28B polymorphism and treatment response to IFNα. Graphical abstract.

Prognostic Significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in Patients with Myelofibrosis: A Retrospective Study.

In myelofibrosis, comorbidities (CMs) add prognostic information independently from the Dynamic International Prognostic Scoring System (DIPSS). The Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) offers a simple tool for CM assessment as it is calculable after having performed a careful history and physical examination, a small routine chemistry panel (including creatinine and liver enzymes) and a limited set of functional diagnostics. To assess the prognostic impact of the MDS-CI in addition to the DIPSS and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70, we performed a retrospective chart review of 70 MF patients who had not received allogeneic stem cell transplantation (primary MF, n = 51; secondary MF, n = 19; median follow-up, 40 months) diagnosed at our institution between 2000 and 2020. Cardiac diseases (23/70) and solid tumors (12/70) were the most common CMs observed at MF diagnosis. Overall survival (OS) was significantly influenced by the MDS-CI (median OS MDS-CI low (n = 38): 101 months; MDS-CI intermediate (n = 25): 50 months; and high (n = 7): 8 months; p < 0.001). The MDS-CI added prognostic information after inclusion as a categorical variable in a multivariate model together with the dichotomized DIPSS or the dichotomized MIPSS70: MDS-CI high HR 14.64 (95% CI 4.42; 48.48), p = 0.0002, and MDS-CI intermediate HR 1.97 (95% CI 0.96; 4.03), p = 0.065, and MDS-CI high HR 19.65 (95% CI 4.71; 81.95), p < 0.001, and MDS-CI intermediate HR 1.063 (95% CI 0.65; 4.06), p = 0.2961, respectively. The analysis of our small and retrospective MF cohort suggests that the MDS-CI represents a useful tool to identify MF patients with an increased vulnerability due to comorbidities. However, analyses of larger cohorts are necessary to define the value of the MDS-CI as a prognostic tool in comparison with other comorbidity indices.