Nicola Cascavilla

Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma

BACKGROUND Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. METHODS We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. RESULTS The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. CONCLUSIONS MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

BACKGROUND Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma

BACKGROUND Bortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma. PATIENTS AND METHODS Sixty-four patients were treated for a median of four 28-day cycles (1-6). Bortezomib was given at 1.3 mg/m(2) (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1-4); 34 patients receive doxorubicin at 20 mg/m(2) (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m(2) (day 1). RESULTS Fifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76-1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3-4 cardiac heart failure. CONCLUSIONS PAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.

Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes

Thirty‐seven anaemic subjects with low‐to‐intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long‐acting erythropoiesis‐stimulating molecule darbepoetin‐alpha (DPO) at the single, weekly dose of 150 μg s.c. for at least 12 weeks. Fifteen patients (40·5%) achieved an erythroid response (13 major and two minor improvements, respectively, according to International Working Group criteria). Such results are currently maintained after 7–22 months in 13 of the responders, one of whom required iron substitutive therapy during the treatment. One patient relapsed after 4 months. Another responder died after 5 months because of causes unrelated to the treatment. No relevant side‐effects were recorded. At multivariate analysis, significant predictive factors of response were baseline serum levels of endogenous erythropoietin <100 IU/l, absent or limited transfusional needs, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low‐intermediate risk MDS and may be effective in a significant proportion of these patients.

Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease

Regulatory T-cells (Treg) actively maintain immunological self-tolerance and play a significant role in the progression of cancer. Treg cell numbers have been evaluated in 80 patients with previously untreated chronic lymphocytic leukemia (CLL) and in 40 normal healthy volunteers. Treg cells are higher in CLL patients than in controls and correlate with disease status (more advanced clinical stage, peripheral blood B-cell lymphocytosis, absolute CD38+ B-cell number, and more elevated LDH levels). No correlation was found with ZAP-70 expression, IgVH mutational status and cytogenetic abnormalities. This data shows that Treg cell number is abnormal in CLL patients.

Clinico-prognostic implications of simultaneous increased serum levels of soluble CD23 and β2-microglobulin in B-cell chronic lymphocytic leukemia

Abstract:  Soluble CD23 (sCD23) and beta‐2 microglobulin (β2‐m) are reliable prognostic parameters in B‐cell chronic lymphocytic leukemia (CLL); however, their merit over well‐established clinical variables such as clinical stages, bone marrow (BM) histology and lymphocyte doubling time (LDT) remains to be defined. Furthermore, information dealing with the impact on overall survival of the simultaneous increase of either β2‐m or sCD23 are lacking. In this prospective study based on 106 B‐cell CLL patients, we propose a combination of β2‐m and sCD23 as a strong prognostic system whose statistical significance was mainly due to an excess of deaths in the subgroup displaying increased serum levels of either β2‐m or sCD23. Multivariate survival analysis confirmed the important dominant role of such a finding, thus excluding features with a high degree of codependence (i.e. clinical stages, LDT) and including variables with low association (i.e. BM histology) in the final regression model. The presence of increased serum levels of β2‐m/sCD23 and diffuse BM histology signified high‐risk disease, whereas the absence of any adverse variable was associated with prolonged survival; in between there was a subgroup with only 1 characteristic which displayed an intermediate pattern of survival. Finally, on the basis combined increased serum levels of β2‐m and sCD23, a better stratification of low‐ and intermediate‐risk patients could be obtained, thus allowing the formulation of a clinico‐biological staging for CLL.

CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia.

CD38 identifies a surface molecule with multi-functional activity. Its prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is currently under investigation in view of the fact that two different groups have recently indicated that CD38 expression could be an independent prognostic marker in B-CLL. We analyzed the clinico-biological features of 61 immunologically typical (CD5+CD23+) B-CLL patients stratified according to the CD38 expression. Twenty-two (36%) patients expressed CD38 in more than 30% of CD19-positive cells and were considered as CD38-positive B-CLL. Atypical morphology (p 0.02), peripheral blood lymphocytosis (p 0.01) and diffuse histopathologic bone marrow pattern (p 0.003) were findings found to be closely associated with CD38 expression. On the other hand, A and B Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005) were more represented in the CD38-negative B-CLL group. Trisomy 12 was detected more frequently in the CD38-positive B-CLL group, while 13q14 deletions mainly occurred in CD38-negative group (p 0.005). Finally, median survival of CD38-positive B-CLL patients was 90 months, while it was not reached at 180 months in CD38-negative patients. Taken together, our data strongly suggest that the evaluation of CD38 expression may identify two groups patients with B-CLL greatly differing in their clinico-biological features.

Quantitative flow cytometry for the differential diagnosis of leukemic B-cell chronic lymphoproliferative disorders

We have investigated whether the quantitative flow cytometry is an useful tool to better characterize B‐cell chronic lymphoproliferative disorders (CLDs). Peripheral blood samples from 104 patients with leukemic B‐cell disorders and 20 healthy donors were analyzed. Directly phycoerythrin‐conjugated CD19, CD20, CD22, CD23, CD79b, and CD5 monoclonal antibodies (MoAbs) and QuantiBRITE pre‐calibrated beads were used to calculate the number of antigen molecules per cell, expressed as antibody binding capacity (ABC). As compared to normal controls, in chronic lymphocytic leukemias (CLL) all MoAbs tested, with the exception of CD23 and CD5, showed lower ABC levels. In prolymphocytic leukemias (PL), CD5 and CD23 antigens were constantly absent while lower CD19 and CD22 ABC levels were observed. Hairy cell leukemias (HCL) displayed very high levels of CD20 and CD22. Of interest, splenic lymphomas with villous lymphocytes (SLVL) could be discriminated from HCL for higher CD79b and lower CD19 ABC values. Finally, higher CD20 levels were detected in follicular lymphomas (FL), whereas higher CD79b and CD5 levels characterized mantle cell lymphomas (MCL). Seven out of 61 CLL cases were defined as morphologically atypical. When compared with typical forms, lower levels of CD19 and CD23 and higher CD20 and CD22 ABC values were detected. However, we failed to demonstrate quantitative differences between atypical CLL and MCL. Our results suggest that quantitative flow cytometry may be a useful additional tool to better identify some types of B‐cell CLDs. Am. J. Hematol. 64:275–281, 2000.

Rituximab for warm‐type idiopathic autoimmune hemolytic anemia: a retrospective study of 11 adult patients

Warm‐type idiopathic autoimmune hemolytic anemia (AIHA) is a relatively common hematologic disorder resulting from autoantibody production against red blood cells. Steroids represent the first‐line therapeutic option, and immunosuppressive agents as well as splenectomy are used for refractory cases. Recently, the anti‐CD20 monoclonal antibody rituximab has been shown to control autoimmune hemolysis in patients with refractory chronic disease. We report results from a retrospective analysis of 11 adult patients receiving rituximab for steroid‐refractory AIHA of the warm type at a mean age of 55 yr (range 23–81 yr). All patients were given methyl‐prednisolone as first‐line treatment and some of them also received azathioprine and intravenous high‐dose immunoglobulins. One patient underwent splenectomy. All patients were considered refractory to steroids and/or immunosuppressive drugs and all were then given weekly rituximab (375 mg/m2) for four consecutive weeks. An increase in hemoglobin (Hgb) levels in response to rituximab, with a mean increment of 3.3 g/dL (95% CI 2.1–4.4), was observed in all cases. Four patients required packed red cell transfusions before starting rituximab and all became transfusion‐free. At a mean follow‐up of 604 d (range 30–2884 d) since the treatment of AIHA with rituximab, all patients are alive, eight (73%) of them in complete remission (CR) and three (27%) in partial remission (PR). A moderate hemolysis still persisted in six (54%) patients. In conclusion, our experience clearly demonstrates that anti‐CD20 monoclonal antibody rituximab is an effective and safe alternative treatment option for idiopathic AIHA, in particular, for steroid‐refractory disease.

Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma

Purpose: To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a “lead compound” of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC). Experimental Design: The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, “wound” healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels. Results: Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 μmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways. Conclusions: This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM. Clin Cancer Res; 17(7); 1935–46. ©2011 AACR.