Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p

Proteomic markers with prognostic impact on outcome of chronic lymphocytic leukemia patients under chemo-immunotherapy: results from the HOVON 109 study

Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25–60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients

Induction of TAp73 by platinum-based compounds to overcome drug resistance in p53 dysfunctional chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment

Homing and clonogenic outgrowth of CD34+ peripheral blood stem cells: A role for L-selectin?

Objective. After transplantation of hematopoietic stem cells, adhesion molecules play a major role in the multistep process of engraftment in which L-selectin is suggested to be of relevance. A positive correlation previously was found between the number of reinfused L-selectin+ stem cells and platelet recovery. In the present study, we determined the role of L-selectin in different engraftment steps, i.e., adhesion to endothelial cells, migration, and clonogenic outgrowth by in vitro assays that closely mimic the in vivo situation. Materials and Methods. Flow adhesion and migration experiments were performed using the human bone marrow endothelial cell line 4LHBMEC and isolated peripheral CD34+ cells with or without blocking of L-selectin-ligand interaction. Various clonogenic assays, including serum-free colony-forming unit-megakaryocytes (CFU-MK) and burst-forming unit-megakaryocytes (BFU-MK), were performed with sorted L-selectin+L-selectin- cells or in the presence of antibodies. Results. Blocking of L-selectin on CD34+ cells did not significantly affect rolling over and firm adhesion to 4LHBMEC. In addition, no role for L-selectin was found in transendothelial migration experiments. Finally, in clonogenic outgrowth of sorted or anti-L-selectin monoclonal antibody-incubated CD34+ cells, no key role for L-selectin expression could be defined in BFU-MK and CFU-MK assays. Conclusion. Using in vitro assays for CD34+ stem cell adhesion, migration, and clonogenic capacity, we were not able to define a major role for L-selectin. © 2002 International Society for Experimental Hematology. Published by Elsevier Science Inc

Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-11 CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells

Induction of TAp73 by platinum-based compounds to overcome drug resistance in p53 dysfunctional chronic lymphocytic leukemia

In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironmen

Obinutuzumab pretreatment abrogates tumor lysis risk while maintaining undetectable MRD for venetoclax + obinutuzumab in CLL

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment