Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma

Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial

[EN]The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse

Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy

BACKGROUND: C.E.R.A. (Continuous Erythropoietin Receptor Activator) is an innovative agent with unique erythropoietin receptor activity and prolonged half-life. This study evaluated C.E.R.A. once weekly (QW) or once every 3 weeks (Q3W) in patients with anemia and advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: In this Phase II, randomized, open-label, multicenter, dose-finding study, patients (n = 218) with Stage IIIB or IV NSCLC and hemoglobin (Hb) ≤ 11 g/dL were randomized to one of six treatment groups of C.E.R.A. administered subcutaneously for 12 weeks: 0.7, 1.4, or 2.1 μg/kg QW or 2.1, 4.2, or 6.3 μg/kg Q3W. Primary endpoint was average Hb level between baseline and end of initial treatment (defined as last Hb measurement before dose reduction or transfusion, or the value at week 13). Hematopoietic response (Hb increase ≥ 2 g/dL or achievement of Hb ≥ 12 g/dL with no blood transfusion in the previous 28 days determined in two consecutive measurements within a 10-day interval) was also measured. RESULTS: Dose-dependent Hb increases were observed, although the magnitude of increase was moderate. Hematopoietic response rate was also dose dependent, achieved by 51% and 62% of patients in the 4.2 and 6.3 μg/kg Q3W groups, and 63% of the 2.1 μg/kg QW group. In the Q3W group, the proportion of early responders (defined as ≥ 1 g/dL increase in Hb from baseline during the first 22 days) increased with increasing C.E.R.A. dose, reaching 41% with the highest dose. In the 6.3 μg/kg Q3W group, 15% of patients received blood transfusion. There was an inclination for higher mean Hb increases and lower transfusion use in the Q3W groups than in the QW groups. C.E.R.A. was generally well tolerated. CONCLUSION: C.E.R.A. administered QW or Q3W showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 μg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Simvastatin and purine analogs have a synergic effect on apoptosis of chronic lymphocytic leukemia cells

Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs—fludarabine and cladribine—in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis

Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia

In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis

Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies