Combination Of Thalidomide Research Articles

Bortezomib Plus Dexamethasone (VD)Versus Reduced-dose bortezomib Plus Thalidomide Plus Dexametasone (vTD) as Induction Treatment Prior to Autologous Stem-Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM).

Abstract 354▪▪This icon denotes an abstract that is clinically relevant. IntroductionThe Intergroupe Francophone du Myelome (IFM) has shown that induction tteatment prior to ASCT with VD is superior to VAD in terms of complete response (CR) or CR plus very good partial response(VGPR) both before and after ASCT (Harousseau 2008 Joint ASH/ASCO session). The Italian group has presented impressive results with the three-drug combination VTD.(Cavo Blood 2008;112:)However in both studies, peripheral neuropathy (PN)was the most frequent adverse event (9% Grade 3) Patients and Methods.The IFM has conducted a randomized trial comparing four 21-day cycles of induction with VD(V1.3 mg/m2/d on days 1,4,8,11 plus D 40mg:d on days 1-4 and 8-11 for the first 2 cycles, on days 1-4 for the last 2 cycles) or vTD (v 1mg/m2 /d on days 1,4,8,11 plus thalidomide 100mg:d d1-21 plus dexamethasone same dosing as for VD). Results were assessed after cycle 2 and 4 and after ASCT. Responses were evaluated according to IMW uniform criteria . Samples for serum and urine electrophoreses were centralized (HAL,CHU Nantes). In the vTD arm, if after cycle 2, the response was. ResultsFrom 03/2008 to 01/2009, 205 patients with newly diagnosed symptomatic MM and up to 65 years of age were recruited and randomized at diagnosis (stratification according to β-2 microglobulin and presence of del(13) by FISH). The two groups were well balanced as regards initial prognostic parameters : age, ISS,β-2microglobulin,hemoglobin,calcium and creatinine levels, incidence of del(13),t(4.14) and del(17p.).As of August 15th, 191 patients are evaluable for response after cycle 4 ( 95 VD,96 vTD). According to investigators'assessment,the efficacy results are the following (VD vs vTD): CR rate 12%vs 14% (p = 0.68), ,≥VGPR 36%vs 50 % (p=0.047), ≥PR 81%vs 91%(p = 0.06),stable disease 12%vs 5%, progression/failure 7%vs 4%.In the vTD arm the doses of v and T were increased due to ≥3 6 %vs 2 % (p=0.17) ConclusionThe combination of reduced-dose bortezomid and thalidomide induces significantly more CR+VGPR than the VD with usual doses of V.Despite the addition of thalidomide, the incidence of PN was markedly reduced In the vTD arm with only 2% Grade ≥3 PN. vTD should be considered a new standard for induction treatment prior to ASCT Disclosures:Harousseau:Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:janssen cilag: Honoraria; celgene: Honoraria. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Lenalidomide IS Able to Restore Immune SYSTEM IN MULTIPLE MYELOMA PATIENTS.

Abstract 4909LENALIDOMIDE IS ABLE TO RESTORE IMMUNE SYSTEM IN MULTIPLE MYELOMA PATIENTSAnnalisa Chiarenza, Nunziatina Parrinello, Piera La Cava, Eleonora Spina, Daniele Tibullo, Cesarina Giallongo, Maide Cavalli, Alessandra Romano, Paolo Fiumara, Giuseppe A. Palumbo, Francesco Di Raimondo BackgroundMultiple myeloma (MM) is a malignant plasma-cell proliferative disorder associated with dysfunctional T-cell responses. The immunomodulatory Thal derivative (IMiD) CC-5013 (lenalidomide) appears to be a promising agent for the treatment of myeloma. Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated to be responsible for it's activity (inhibition of angiogenesis, direct antiproliferative and proapoptotic effects on MM cells, suppression of pro-inflammatory cytokines, modulation of myeloma-stromal cells adhesive interactions). In addition, it has been demonstrated that lenalidomide in vitro is able to enhance T cell proliferation and to promotes ADCC.In this study we evaluated if MM patients have a deficit of T-reg (CD4+, CD25+, and FOXP3+) and of T lymphocytes bearing CD200 (a tolerogenic molecule) and the effect of lenalidomide treatment on these parameters. In addition, we investigated whether lenalidomide could improve ex vivo the ADCC against myeloma cells. Materials and methodsEight patients with previously untreated MM (median age 56 years) were treated with lenalidomide plus dexamethasone as first line therapy. Lenalidomide was given orally 25 mg daily on days 1 to 21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1, 8, 15, 22 of each cycle. All patients were evaluable for response and toxicity.Peripheral blood mononuclear cells (PBMNc) were obtained from MM patients using density gradient centrifugation (Fycoll) under sterile condictions, at the beginning of treatment and after 4 cycles of therapy. The percentage of T-reg (CD4+CD25+FOXP3+) and the expression of CD200 on T- lymphocytes were evaluated by cytometry. Twelve healthy subjects were used as control.Moreover, PBMNc (effector cells, E) were incubated with MM cells line ARH-77 (target cells, T), previously labelled with CFDA,SE (carboxyfluorescein diacetate, succinimidyl ester) as a tracing fluorescent marker, in culture medium (RPMI-1640, 10%FCS, 1%penicillin/streptomycin) at different concentration (T/E ratio 1:20, 1:40). After 18-24 h co-colture cells were analyzed by flow cytometry and MM plasma cells cytotoxicity was calculated as the percentage of positive CFDA,SE/propidium cells. Myeloma cell viability was determined by tripan blue esclusion and apoptosis was also evaluated using Annexin V/propidium assay. Two MM patients treated in first line with a combination of Velcade, Thalidomide and Dexamethasone (VTD) were used as control and the experiments were performed in duplicate. ResultsMM patients have a significantly lower rate of CD4+/CD25+/FOXP3+ and CD200+/CD3+ than normal (28,3±14,9/mmc and 37,8±24,7 /mmc vs 79,3±27,8 and 79,5± 48,9)(p=0,0001 and p=0,01 respectively). In our study, lenalidomide treatment resulted in an increase both of Treg cells and T-lymphocytes espressing CD200. This improvement is not statistically significant probably due to the low number of patients examined (tab I).More important, we observed that PBMC derived from patients treated with lenalidomide showed an increase ability to kill a target MM cell line compared to PBMC collected at diagnosis (CFDA,SE/propidium cells 11% vs 68%). This effect was more prominent in patients treated with lenalidomide than in MM patients treated with VTD (CFDA,SE/propidium cells 12% vs 39%), Fig.1. ConclusionsOur data emphasize the role of lenalidomide in modulating the endogenous tumor-specific immune response and underline the anti-myeloma activity of these new class of drugs.TABLE IPTS (n) 8CD3+CD200+ /mmcCD4+CD25+FOXP3+/mmcCycleMeansStand devTest t (p)meansStand devTest t (p)I100100II426,20330,640,040235,40154,260,027III364,79405,980,086279,25146,440,013IV459,85459,420,077214,00143,470,053Post IV376,25273,330,068225,25163,790,123 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens.

Abstract 1873Poster Board I-898Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep-vein thrombosis (DVT) and pulmonary embolism (PE). The VTE risk in MM is increased by various patient- and disease-related factors; however, type of anti-MM therapy represents a key factor, with a substantially elevated risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide (thal) or lenalidomide (len) in combination with dexamethasone (dex) and/or chemotherapy (Palumbo et al, Leukemia 2008); VTE risk with len-dex (RD) is further increased with concomitant erythropoietin (EPO). By contrast, treatment with the proteasome inhibitor bortezomib (btz), either alone or in combination, does not increase VTE risk. In the VISTA phase 3 trial of melphalan-prednisone (MP) vs btz plus MP (VMP) in previously untreated MM patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008), data from an updated safety analysis showed similar rates of DVT (VMP: 5/340 [1%], four grade 3; MP: 6/337 [2%], two grade 3) and PE (VMP: 4/340 [1%], two grade 4; MP: 3/337 [1%], one grade 3, two grade 4) between arms; as reported by Richardson et al (IMW 2009), rates of DVT/PE were not affected by use of erythropoiesis-stimulating agents, including EPO. These findings reflect those from the APEX phase 3 trial of single-agent btz vs high-dose dex in relapsed MM (Lonial et al, Br J Haematol 2008); rates of DVT/PE were low (0.6% vs 2.7%) and unaffected by concomitant EPO use, and VTE risk appeared lower with btz vs dex, controlling for EPO use (odds ratio 0.207, p=0.046). As previously reported, btz shows anti-hemostatic effects in patients with relapsed or refractory MM, resulting in a decrease in platelet count and significant reductions in agonist-induced platelet aggregation (Zangari et al, Haematologica 2008); these findings support btz exerting anti-thrombotic actions and thus potentially providing a protective effect in combination with regimens with elevated VTE risk. A review of data from phase 3 trials of btz- and/or IMiD-based therapy in frontline MM and other studies of novel combination regimens supports this hypothesis. Despite the confounding effect of variable VTE prophylaxis, btz-based regimens are associated with DVT/PE rates of 0–4% (Figure), similar to those seen with MP and dex alone (Palumbo et al, Leukemia 2008), whereas IMiD-based btz-free regimens are generally associated with substantially higher rates. Direct comparisons of regimens of thrombogenic potential with/without btz demonstrate lower VTE risk with btz; as previously reported, DVT rates of 0% vs 10% (p=0.0006) were seen with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) with vs without btz in an analysis of patients enrolled on two University of Arkansas trials (Zangari et al, ASH 2004). Palumbo et al (EHA 2009) also reported lower rates of VTE events with btz, thal, dex (VTD, ∼4.5%) and VMP—thal (VMPT, ∼2.7%) vs TD (7%) in a phase 3 randomized trial of aspirin, low molecular weight heparin, and warfarin as VTE prophylaxis, while in another phase 3 study Rosiñol et al (ASH 2008) showed a lower rate of thrombotic events with VTD vs TD (1.7% vs 13%, p=0.02, no prophylaxis). Indirect, between-study comparisons of VTE risk support these findings; in six phase 3 studies, TD was associated with 5.5–23% DVT/PE, while in two phase 3 studies, the rate with VTD was 1.7–4%. Similarly, rates were 6–12% in five phase 3 studies of MP-thal (MPT) vs 4% with VMPT (Palumbo et al, EHA 2009). Finally, len-low-dose dex (Rd) and RD resulted in DVT/PE rates of 12–27% in two phase 3 studies, whereas a rate of only 4% was reported in a phase 1/2 study of btz-RD (RVD) by Richardson et al (IMW 2009). Taken together, these findings confirm the low VTE risk associated with btz and support a potential protective effect of btz in combination with IMiD-based regimens associated with elevated VTE risk. [Display omitted] Disclosures:Zangari:Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Fink:DOD Radioprotectants: Research Funding.

Infection Complications in Patients with Multiple Myeloma Treated with New-Drug Combinations Including Thalidomide.

Abstract 2828Poster Board II-804Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined.We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis.Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%).Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component > 2 g (p=0.021), platelets < 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component > 2 g (p=0.015 HR= 1.8) and platelets < 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset.In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures:Off Label Use: Thalidomide, Bortezomib and Doxil.

Phase II Multicenter Study of Association of Arsenic Trioxide (ATO) and Ascorbic Acid in Myelodysplastic Syndrome.

Abstract 943 Introduction:Arsenic trioxide (ATO) inhibits angiogenesis, induces apoptosis and differentiation in variety of malignant cells. Two multicenter phase II studies have documented that ATO has as a moderate activity both in low and high risk myelodysplasia with 19-21% haematological improvement. Ascorbic acid in “vitro” increases in tumor cells the activity of ATO by depleting GSH and inhibiting NF-kb. High EVI-1 levels have been reported to predicted the response to arsenic trioxide and thalidomide combination therapy. We report the results of a multicenter phase II study with combination of arsenic trioxide and acid ascorbic in myelodysplastic patients. Patient eligibility included:a) pts with 3q26 rearrangement or high EVI-1 levels; b) non-RAEB pts at low-intermediate/1 risk who failed a previous therapy; c) RAEB or high-intermediate-2 risk patients not elegible to chemotherapy and/or bone marrow transplant. Study design:Arsenic trioxide was administrated intravenously over 1 hour at the loading dose of 0.30 mg/kg/day for 5 consecutive days, followed by0.25 mg/kg/day twice weekly for 15 weeks. Ascorbic acid 1000 mg was given IV within 30 minutes after each arsenic trioxide infusion. Response evaluation was scheduled after two and four months of treatment according to the IWG criteria (Cheson 2000) Patients:44 pts were enrolled .Median age was 71 years (range 47–80). WHO categories were non-RAEB (15 pts), RAEB-1 (12 pts), RAEB-2 (17 pts). 23 patients had a low/intermediate-1 IPSS score; 18 had a high/intermediate-2 risk. Risk category, could not be assessed in 3 pts lacking of cytogenetic data. Before starting therapy EVI-1 was highly expressed in 13 out of 34 evaluated pts (38%); high WT-1 levels was documented in 25 out of 35 pts (71%). 31 pts (57%) were transfusion dependent at baseline. Results:Ten out of 44 evaluable patients obtained a response (23%). They included 1 complete remission, 2 major erythroid hematologic improvement (HI-E major), 3 minor HI-E, 2 major neutrophil improvemet (HI-N) and 2 major trilineage responses. Response rate was 35% in lower risk IPSS patients and 6% in higher risk pts (p 0.05).Only 3 pts with high EVI-1 expression achieved a response. In 8 out of ten responders, the response was evident within the first 8 weeks of treatment. Twenty three (52%) patients discontinued treatment because disease progression (11%), severe adverse events (32%), drug unrelated adverse events (5%), withdrawal of consent (5%). Severe neutropenia and thrombocytopenia were observed respectively in 45% and 23% pts. The other G3-4 adverse events observed were: ATRA-like syndrome (9%), cardiotoxicity (11%) infection (11%), hepatotoxicity (9%). No toxic death was observed. Summary and Conclusions:The combination of ATO and ascorbic acid is tolerable and it is active in about 25% of MDS patients. The addition of ascorbic acid to ATO does not increase neither the toxicity nor the response rate to ATO. The tolerability of this regimen is reduced in elderly and high risk patients. In our study high EVI-1 transcript levels were not confirmed to predict the response to ATO. Disclosures:Off Label Use: Arsenic trioxide is yet approved for the treatment of MDS, even if its efficacy has been shown in other phase II studies.

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study

The clinical efficacy and safety of a four-drug combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone was assessed for patients with relapsed or refractory multiple myeloma. Seventy patients received at least two cycles of treatment with bortezomib 1.3 mg/m(2) intravenously on days 1, 4, 8, and 11; cyclophosphamide 150 mg/m(2) orally on days 1-4; thalidomide 50 mg/day orally every day; and dexamethasone 20 mg/m(2) intravenously on days 1, 4, 8, and 11. The overall best response rate was 88%, with 46% complete response, 9% very good partial response, and 33% partial response. After a median follow-up of 12.6 months, the median progression-free survival (PFS) was 14.6 months with a 3-year PFS of 14% and the median overall survival (OS) was 31.6 months with a 3-year OS of 47%. Grade 3 or 4 adverse events included thrombocytopenia (12%), neutropenia (4%), peripheral sensory neuropathy (3%), with thrombosis being very rare (<1%). Bortezomib combined with cyclophosphamide, thalidomide, and dexamethasone is a highly effective salvage therapy with manageable toxicity for patients with relapsed or refractory multiple myeloma.

Clinical Outcomes in Metastatic Gastroenteropancreatic Neuro-endocrine Tumors (NETs) with Temozolomide and Thalidomide Combination Therapy

Purpose: Gastroenteropancreatic NeuroEndocrine Tumors (NETs) are heterogenous group of neoplasms which have limited response rates and significant toxicity with standard chemotherapy. Temozolomide is considered as a less toxic alternative for NETs. Combination with thalidomide is postulated to increase the efficacy by inhibiting the angiogenic pathways, but there is limited data available. Methods: The study was a retrospective study of patients with metastatic NETs, who received an oral thalidomide and temazolamide combination. Clinical data including patient's age, gender, race, type of cancer, previous therapies, clinical, radiological and tumor marker response to chemotherapy and toxicity was recorded. Results: The study group consisted of 12 patients with metastatic NETs, of which 5 were males and 7 females. The median age of diagnosis was 67 yrs (Range 47-79 yrs). Six patients had NET and 6 had carcinoid tumors. The primary sites of the tumor were pancreas ( n=4), small bowel (n=4), colon (n=2) and lung (n=2). The tumor markers secreted were as follows: chromogranin(n=10), serotonin (n=6), gastrin (n=2) and pancreatic polypeptide(n=1). The median chromogranin level at diagnosis was 47 Units/L (Range 5-122,000). Sites of metastases were liver (n=12), omentum (n=6), lungs (n=5) and bones (n=2). All patients had received sandostatin and received prior chemotherapy ranging from 1 to 3 regimens. Patients received a median of 1.5 (Range 1-9) cycles of temozolomide and thalidomide combination. Six patients came off thalidomide for toxicity and remained on temozolomide for another 4 cycles. Clinical, radiological and marker response could be evaluated in 8 patients; four patients were too early for response evaluation. Clinical best response was as follows: partial response (n=3), stable disease (n=4) and progression (n=1). Best radiographic response was as follows: partial response (n=2), stable disease (n=5) and disease progression (n=1). Tumor marker response was recorded as follows: partial response (n=2), stable disease (n=5) and progression (n=1). The reasons for discontinuation of regimen were toxicity (n=7) and disease progression (n=1). The most frequent treatment related adverse events were lymphopenia (n=4), abnormal LFTs (n=3), venous thromboembolism (n=2), peripheral neuropathy (n=2) and cardiomyopathy (n=1). Median survival was not obtained as 11 patients were still alive. Conclusion: The temozolomide and thalidomide combination regimen is effective in patients with metastatic NETs refractory to conventional chemotherapy and is worthy of further study. This regimen has treatable toxicities and patients should be monitored closely.

Thalidomide-induced heart block in a dialysis patient.

Sir, We report the case of a patient with thalidomide-induced third-degree heart block when used in context of myeloma and acute renal failure. An 88-year-old female patient was commenced on thalidomide 50 mg daily along with pulsed dexamethasone for treatment of newly diagnosed multiple myeloma. After 3 weeks of treatment, the dose of thalidomide was increased to 100 mg daily. Electrocardiogram (ECG) at baseline presentation and on 50 mg od showed normal sinus rhythm with a ventricular rate of 83/min. There was no evidence of delayed atrio-ventricular conduction (PR interval 130 ms) and normal QRS. After 3 days of 100 mg thalidomide, the patient started feeling light-headed on minimal exertion. A repeat ECG showed third-degree heart block with a ventricular rate of 31 beats per minute and left bundle block. The patient had no history of ischaemic heart disease. Serum electrolytes, thyroid function tests, cardiac enzymes and chest x-ray were within normal limits. We observed this patient for 24 h, and the ECG abnormality did not improve. After counselling about the need for ongoing treatment with thalidomide treatment for her myeloma and the risks of infections with a permanent pacemaker, she went on to have a permanent pacemaker fitted. Due to its anti-angiogenesis activity thalidomide has been used for the treatment of multiple myeloma. The combination of thalidomide and dexamethasone, often in combination with cylcophosphamide, is now one of the most common regimens for patients with newly diagnosed multiple myeloma [1]. As thalidomide predominately undergoes pH-dependent spontaneous hydrolysis in all body fluids into multiple metabolites and is passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function. Hence, no dose reduction is recommended for patients with renal impairment or those on dialysis. Thalidomide has a number of well-recognized side effects such as teratogenicity, skin rash, peripheral neuropathy, pneumonitis and venous thromboembolism (VTE). However, the incidence of heart block has been rarely reported. There have been similar case reports of conduction abnormalities with thalidomide [2]. We conclude that cardiac monitoring should be instituted and screened for when treating patients with this drug. Regular ECGs should be performed when rate disturbance is noted on this therapy. Conflict of interest statement. None declared.

Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer

Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

Bortezomib in combination with dexamethasone and subsequent thalidomide for newly-diagnosed multiple myeloma: A Chinese experience

ObjectiveBortezomib–dexamethasone–thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology 2007;12(3):235–9), but this regimen has not been tested in the Chinese patients. We report here our results testing with this combination in the Chinese population and to investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. MethodsBetween June 2006 and March 2008, 20 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3mg/m2 IV on days 1, 4, 8 and 11 and dexamethasone at 20mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100mg to 200mg. Fourteen patients were male and 6 were female. Median age was 59 years (range 43–86 years). 11 patients were stage 2 according to the International Staging System, 8 were stage 3, only 1 patient was stage 1. All patients received a median of two cycles of therapy (range 1–6). The EBMT criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. Results16 out of 20 patients (80%) achieved PR and 3 (15%) achieved CR; therefore the overall response rate was 95%. With a median follow-up duration of 7.8 months (4–22 months), no patients died. Grade 3–4 toxicities included fatigue (3/20), thrombocytopenia (10/20) diarrhea (5/20) and orthostatic hypotension (3/20) Grade 2 neuropathy occurred in four out of 20 patients and herpes zoster occurred in four out of 20 patients. Routine anticoagulation or anti-thrombosis was not used. Only 1 patient suffered from DVT/PE. ConclusionsOur preliminary experience in Chinese patients indicated that bortezomib–dexamethasone–thalidomide is highly effective in newly-diagnosed MM. Grade three and 4 toxicities are rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in the Chinese patients with MM are being cautiously observed.

Survival from lung cancer not improved with thalidomide

Thalidomide in combination with chemotherapy does not improve survival of patients with small cell lung cancer, but is associated with an increase in the risk of thrombotic events.

Treatment of Malignant Pheochromocytoma

Pheochromocytoma (PCC) is a rare disease, mainly sporadic, but also associated with some familial disorders, with a malignancy frequency of approximately 10%. Only the presence of distant metastases, derived from large pleomorphic chromaffin cells, is widely accepted as a criterion of malignancy. Variable symptoms may be caused by production and release of catecholamines. Since there is no curative treatment for malignant PCC and due to its unfavorable prognosis, assuring quality of life is one of the main therapeutic objectives. Besides a long-term medical treatment of symptoms using selective alpha-1 blockers and nonselective, noncompetitive alpha- and/or beta-blockers, debulking surgery is the first treatment step. In case of a sufficient uptake of (123)I-MIBG treatment with targeted radiation therapy, use of (131)I-MIBG is an option as an adjuvant therapy, following debulking surgery. Chemotherapy should be applied to patients without positive MIBG-scan, with no response to (131)I-MIBG or progression after radionuclide treatment, and especially in cases with high proliferation index. The most effective chemotherapy regimen appears to be the CVD-scheme, including cyclophosphamide, vincristine, and dacarbazine. The so-called targeted molecular therapies with treatment combinations of temozolomide and thalidomide, or sunitinib monotherapy, and novel therapeutic somatostatin analogues have shown promising results and should thus encourage clinical trials to improve the prognosis of metastatic PCC. Within this review the current treatment modalities and novel molecular strategies in the management of this disease are discussed and a treatment algorithm is suggested.

Anti-angiogenic Therapy Using Thalidomide Combined With Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Cancer cells rely on angiogenesis for growth and dissemination, and small cell lung cancer (SCLC) is a highly angiogenic tumor. We evaluated thalidomide, an anti-angiogenic agent, when combined with chemotherapy and as maintenance treatment. A total of 724 patients (51% with limited and 49% with extensive disease) were randomly assigned to receive placebo or thalidomide capsules, 100-200 mg daily for up to 2 years. All patients received etoposide and carboplatin every 3 weeks for up to six cycles. Endpoints were overall survival, progression-free survival, tumor response rate, toxicity, and quality of life (QoL). Hazard ratios (HRs) for comparing thalidomide against placebo were estimated using Cox regression modeling. Statistical tests were two-sided. The median overall survival was 10.5 months (placebo) and 10.1 months (thalidomide) (HR for death = 1.09, 95% confidence interval [CI] = 0.93 to 1.27; P = .28). Among patients with limited-stage disease, there was no evidence of a survival difference (HR for death = 0.91, 95% CI = 0.73 to 1.15), but among patients with extensive disease, survival was worse in the thalidomide group (HR for death = 1.36, 95% CI = 1.10 to 1.68). Progression-free survival rates were also similar in the two groups (HR = 1.07, 95% CI = 0.92 to 1.24). Thalidomide was associated with an increased risk of having a thrombotic event, mainly pulmonary embolus and deep vein thrombosis (19% thalidomide vs 10% placebo; HR = 2.13, 95% CI = 1.41 to 3.20; P < .001). There were no statistically significant differences between treatments in hematological and nonhematological toxic effects, except more patients in the thalidomide group had rash, constipation, or neuropathy. Overall, QoL scores were similar in the two treatment groups, but thalidomide was associated with less insomnia and diarrhea and more constipation and peripheral neuropathy. In this large randomized trial, thalidomide in combination with chemotherapy did not improve survival of patients with SCLC but was associated with an increased risk of thrombotic events.

Pilot study of topotecan and thalidomide in patients with recurrent malignant gliomas

e13019 Background: Adults with glioblastoma multiforme (GBM) treated with radiation and chemotherapy have median survival of less than 12 months from diagnosis. Topotecan is a topoisomerase-1 inhibitor with activity in brain tumors and very little nonhematologic toxicity. Continuous infusion has been shown to have decreased hematologic toxicity. Thalidomide has antiangiogenic and immnunomodulatory effects. The combination would offer a multitargeted approach with no overlapping toxicity. Methods: Single-center prospective phase II study of 10 patients (median age 50, range 38–70) with high-grade recurrent glioma treated at Rush University Medical Center between 2002 and 2006 following IRB approval. All patients had failed at least one standard therapy and received a combination of the two drugs: topotecan by continuous infusion for 21 days, every 28 days at 0.4 mg/m2/day through a permanent in-dwelling catheter and thalidomide with starting oral dose of 100 mg/day, escalated by 100 mg/day per week to maximum of 400 mg/day by day 28. Dose reductions were made for grade 3 and 4 hematologic or nonhematologic toxicities. All patients received coumadin 1 mg/day DVT/PE prophylaxis. Assessment of response was done every 8 weeks by MRI and MRS. Results: Median number of cycles of study drugs = 3; median time to progression = 4 months; median survival = 12 months; DVT/PE = 40% of patients with low-dose coumadin prophylaxis. Conclusions: The combination of topotecan and thalidomide is feasible and shows moderate activity. The study is limited by small size and thromboembolic complications likely related to thalidomide in 40% of patients. Low-dose coumadin prophylaxis was not adequate in preventing thrombosis. [Table: see text] No significant financial relationships to disclose.

Erythropoiesis-stimulating agents in cancer patients: ESMO Recommendations for use

Erythropoiesis-stimulating agents in cancer patients: ESMO Recommendations for use

Age 40 Years and Under Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transmplant

Multiple myeloma (MM) rarely occurs in patients 40 years of age and younger. This young age has been reported to correlate with improved survival in patients with MM. The objective of this study is to describe presenting features and outcomes of patients < or =40 years of age with MM who undergo autologous stem cell transplantation (ASCT) as first-line treatment, and compare overall survival (OS) and progression free survival (PFS) to patients aged 41-65 years. We performed a retrospective institutional review of all patients < or =40 years of age and 41-65 years of age at the time of diagnosis of MM who had undergone upfront ASCT from January 1, 1990, to July 31, 2007. Thirty-eight patients < or =40 years of age and 608 patients aged 41-65 were identified. There was a high rate of plasma cell leukemia (PCL) in young patients at 11% compared to the reported rate of 2%-4%. At diagnosis, there was an increased rate of renal failure in the young cohort compared to patients aged 41-65 years at 25% versus 16% and Bence Jones proteinuria at 81% versus 51%. The rate of complete or partial response was similar between the groups at 79% and 83% in the young and older cohorts, respectively. Median PFS post-ASCT was 22.0 months (95% confidence interval [CI]: 16.1, 28.0), versus 26.9 months (95% CI: 24.0, 29.8) for patients aged 41-65 years (P = .66). Median OS from date of ASCT was also similar to those over 40 years: 68.1 months (95% CI: 39.0, 97.2) versus 80.7 months (95% CI: 68.1, 93.4); P = .90. Treatment-related mortality (TRM) was low at 2.6% and 2.3% in the young and older cohorts, respectively. Despite previous reports that young age is a positive prognostic marker, our study found OS post-ASCT is equivalent to those aged 41-65 years. This study emphasizes the importance of developing strategies to better the outcomes of young patients with MM.

A Combination of Thalidomide and Augmentin Protects BALB/c Mice Suffering from Klebsiella pneumoniae B5055-Induced Sepsis

Despite extensive research, the mortality associated with sepsis in hospitals remains very high. We have evaluated the protective immunomodulatory effect of thalidomide alone or with Augmentin in Klebsiella pneumoniae B5055-induced sepsis in BALB/c mice. The mouse model of sepsis was developed by placing K. pneumoniae B5055 entrapped in fibrin and thrombin clots in the peritoneal cavity of mice. The septic mice were treated with thalidomide alone (30 mg/kg/day/po), Augmentin alone (20 μg/ml/ip) and with their combination. The thalidomide-alone treated mice showed 75% survival whereas 60% of the Augmentin-alone treated group survived. Combination treatment provided 100% survival. Treatment with thalidomide alone significantly (p<0.05) decreased interleukin-1 α (IL-1α), nitric oxide (NO) and malondialdehyde (MDA) levels in the serum without significantly (p<0.05) decreasing the bacterial count in blood. Augmentin alone only decreased the bacterial load in blood significantly (p<0.05). However, a combination of thalidomide with Augmentin significantly (p<0.05) decreased both the bacterial count and inflammatory mediators.

Thalidomide suppressed the growth of 4T1 cells into solid tumors in Balb/c mice in a combination therapy with the oncolytic fusogenic HSV-1 OncdSyn

The anti-tumor properties of thalidomide or in combination with an oncolytic herpes virus (OncdSyn) was investigated in a mouse model of human breast cancer. To determine if thalidomide could act alone, 4T1 cells were injected into Balb/c mice. Tumors were sized, and the mice were fed chow or chow-containing thalidomide. After 4 days the tumor volumes were compared. To determine if thalidomide could act with the virus, tumors of mice were injected with phosphate buffered saline (PBS), or fed thalidomide with injections of PBS, or fed thalidomide with injections of OncdSyn, or received injections of OncdSyn. Thalidomide alone suppressed tumor growth. The most significant treatment occurred in thalidomide-fed-OncdSyn-injected mice. Compared to PBS controls, there was a significant difference in the number of metastatic nodes in the lungs. Thalidomide alone delayed tumor growth, but the combination of thalidomide with OncdSyn appeared to produce the best results.

Oncology: Treatment of Multiple Myeloma in the Targeted Therapy Era

To review the clinical trials that have impacted treatment standards of multiple myeloma (MM). A PubMed search (1980-June 2008) restricted to English-language publications was conducted using the key words multiple myeloma, clinical trials, targeted therapy, thalidomide, lenalidomide, bortezomib, dexamethasone, melphalan, autologous stem-cell transplantation, and tumor biology. Abstracts emanating from the meetings of the American Society of Clinical Oncology and American Society of Hematology from June 2002 to June 2008 were also reviewed. Although hematopoietic stem-cell transplantation has improved the response rate and duration of overall survival, MM remains an incurable disease. However, focused research aimed at the molecular basis of the disease has led to a number of new treatment strategies. Evidence from clinical trials indicates that each of the 3 novel agents, thalidomide, lenalidomide, and bortezomib, is remarkably effective as first-line therapy. The data also suggest that clinicians may need to reevaluate the role of stem-cell transplantation in the disease. Thalidomide, lenalidomide, or bortezomib in combination with dexamethasone have replaced traditional chemotherapy such as melphalan, doxorubicin, and vincristine as initial therapy of patients with MM who are eligible for stem-cell transplantation. Furthermore, these novel drugs can be incorporated into regimens used to treat transplant-ineligible patients or those with relapsing disease.

Refractory Plasmablastic Type Myeloma with Multiple Extramedullary Plasmacytomas and Massive Myelomatous Effusion: Remarkable Response with a Combination of Thalidomide and Dexamethasone

A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology.