Induction Treatment In Patients Research Articles

Clinical outcomes of surgery after induction treatment in patients with pathologically proven N2-positive stage III non-small cell lung cancer.

To assess the effect of preoperative neoadjuvant therapy on resectability, downstaging, and the prognosis in patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). Eighty-four patients who underwent resections after induction therapy [76 with neoadjuvant chemotherapy (CTx) and 8 with induction chemoradiotherapy (CRTx)] for clinically evident [larger than 1 cm on computed tomography (CT)] and pathologically confirmed ipsilateral N2 positive NSCLC (stage IIIA) between January 2009 and July 2013 were reviewed retrospectively. Partial response (PR) was observed in 39 patients (46.4%). Standard lobectomy was performed in 63 cases (75.0%), and extensive resection was conducted in 21 cases (25.0%), including four pneumonectomies. Pathologic nodal downstaging (pN2 to pN0-1) was confirmed in 38 cases (45.2%). After induction therapy plus resection, 5-year progression-free survival (PFS) and overall survival (OS) in cases with radical resections were 37.9% and 34.2%, respectively. Patients who underwent lobectomy or pathologic nodal downstaging had better prognosis than those who had extensive resection or persistent N2 in PFS (P=0.036; P=0.025) and OS (P=0.023; P=0.024). On univariate analysis, lobectomy and pathological nodal downstaging were favourably predictive factors both in PFS and OS. Cox multivariate analyses identified only pathologic nodal downstaging to predict better PFS, and lobectomy to be significantly prognostic for OS. These data suggest that neoadjuvant therapy was feasible, and helpful for tumor and pathologic nodal downstaging with promising rates of survival in patients with stage IIIA-N2 NSCLC. After induction therapy, patients with potentially radical lobectomy were more likely to benefit from operation. Pathological nodal downstaging of pN2 to pN0-1, rather than clinical response was predictive of a favorable outcome, and was correlated with a better chance of survival.

Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials

ObjectiveChemoradiotherapy is often considered the ‘standard of care’ for patients with N2 disease. The aim was to evaluate survival outcomes of patients with N2 disease in multimodality trials of chemotherapy,...

176: Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials

176: Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials

Induction Therapy with Bortezomib, Thalidomide and Dexamethasone (VTD) in Caucasian Patients with Multiple Myeloma: A Single Center Experience

Objective: In clinical trials, the combination of bortezomib, thalidomide, and dexamethasone (VTD) has shown excellent results as induction treatment in patients with multiple myeloma. However, “real-life” data in unselected Caucasian patients are lacking. Methods: We retrospectively analyzed 41 patients treated with VTD between 2005 and 2014. Results: Post induction, the overall response rate was 78%, with ≥very good partial response (≥VGPR) in 54% and near complete/complete responses (nCR/CR) in 17% of the patients respectively. For patients proceeding to autologous stem cell transplantation (ASCT), post-transplant rates were 96% ≥VGPR and 48% nCR/CR. Median progression free survival (PFS) was 24 months and the estimated 1-year and 2-year overall survival (OS) rates were 95% and 76%, respectively. Subgroup analyses revealed significantly longer OS and PFS in patients with a ≥VGPR as first response status compared to those with a <VGPR [OS 44 vs. 25 months (p=0.036); PFS 29.5 vs. 16 months (p=0.011)], as well as in patients who underwent ASCT compared to not transplanted patients [OS 41 vs. 23.5 months (p=0.002); PFS 28 vs. 23 months (p=0.003)]. In 6 patients (15%) therapy was switched to another regimen due to lack of response (<PR, n=4), cardiac decompensation (n=1) or prolonged neutropenia (n=1). Non-hematological grade III/IV toxicities were peripheral neuropathy (2%), infections (7%), herpes zoster (5%), and thromboembolic events (2%). Dose reductions of thalidomide and/or bortezomib were necessary in 24% of the patients because of peripheral neuropathy. Conclusion: The VTD regimen was found to be a highly effective and well tolerated induction regimen for multiple myeloma patients outside clinical trials.

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial

Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.

Recent clinical trials in lupus nephritis.

Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil.

Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group

Relapse is the main cause of therapeutic failure in follicular lymphoma (FL). We set out to evaluate the role of consolidation with Yttrium-90 ibritumomab tiuxetan in patients with intermediate- and high-risk FL after four cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) and two cycles of CHOP. Thirty patients were included. The overall response rate after consolidation therapy was 93%. Of the 18 patients who presented with a partial response after induction treatment, 11 had a complete response after consolidation treatment. The complete clinical response rate was 76.6%. The most important grade 3–4 toxicity was hematological, with 46% thrombopenia and 56% neutropenia. With a median follow-up of 26 months, the means for progression-free survival and overall survival were not reached. Our data support consolidation with Yttrium-90 ibritumomab tiuxetan as an effective treatment, which provides long progression-free and overall survival, in first line after a response to induction treatment in patients with intermediate- and high-risk FL.

Induction Chemotherapy or Chemoradiotherapy Followed by Radical Esophagectomy for T4 Esophageal Cancer: Results of a Prospective Cohort Study

We hypothesized that the survival rate of patients undergoing R0 esophagectomy after induction chemotherapy or chemoradiotherapy for unresectable T4 esophageal cancer (URT4) would be similar to that of patients undergoing esophagectomy for immediately resectable esophageal cancer with no unfavorable prognostic factors (RNU). Between April 2002 and June 2012, 87 of 283 patients with esophageal cancer who presented at the University Hospital of the Ryukyus were enrolled in this prospective cohort study. Tumors were classified as RNU and URT4 in 44 and 43 of the 87 patients, respectively. Outcomes of treatment for URT4 patients were compared with those of RNU patients. The R0 resection rate (61 %) and in-hospital mortality rate (20 %) of URT4 patients were significantly poorer than those of RNU patients (98 and 2.3 %, respectively), although the morbidity rate was similar in the two groups (63 and 52 %, respectively). The 5-year survival rate (35 %) of URT4 patients was significantly poorer than that of RNU patients (67 %) in the intention-to-treat analysis. However, no significant difference was noted between the two survival curves for cases of R0 resection (5-year survival rate, 60 % vs. 69 %). Multivariate analysis revealed R status as the only significant independent prognostic factor for URT4 patients (P < 0.001; hazard ratio = 8.279). Satisfactory survival rates can be achieved if R0 resection is performed after induction treatment in patients with T4 esophageal cancer, although secondary radical esophagectomy is associated with a higher risk of in-hospital mortality.

Increased risk of central venous catheter–associated thrombosis in acute promyelocytic leukemia: a single‐institution experience

Patients with acute leukemia and in particular, acute promyelocytic leukemia (APL), are felt to be at high risk for developing venous thromboembolism. The presence of central venous catheters (CVCs) increases this risk; however, reports have varied regarding the frequency of this complication. Current guidelines do not recommend the routine use of prophylactic anticoagulation for patients with CVC. We suspected an increased incidence of CVC thrombosis in patients with APL and therefore conducted a retrospective survey of 473 patients who were treated for acute leukemia at our institution. The overall rate of symptomatic CVC thrombosis was 6.8%. We found a significantly (P < 0.001) increased rate of symptomatic CVC thrombosis (32%) in patients with APL as compared with patients with acute lymphocytic leukemia and acute myeloid leukemia (6.4% and 4%, respectively). CVC thrombosis was most prevalent following induction treatment and was associated with higher platelet counts in patients with APL. Following this observation, 13 additional newly diagnosed patients with APL were treated with low molecular weight heparin prophylaxis during the recovery phase after chemotherapy. None had a thrombotic event. Although our treatment group was small, we suggest considering prophylaxis for CVC thrombosis during platelet recovery after induction treatment in patients with APL.

Increased Risk of Central Venous Catheter Associated Thrombosis in Acute Promyelocytic Leukemia.

AbstractAbstract 2588▪▪This icon denotes a clinically relevant abstract Background:Patients with acute leukemia and in particular, patients with acute promyelocytic leukemia (APL), are considered to be at high risk for the development of venous thromboembolism. The presence of central venous catheters (CVC) increases the risk of thrombotic complications; however, previous reports have varied as to the frequency of this complication. Current guidelines do not recommend the routine use of prophylactic anticoagulation for patients with CVC. Design and methods:We have suspected an increased incidence of CVC thrombosis in patients with APL and therefore conducted a retrospective survey of 473 patients who were treated for acute leukemia at our institution. Results:The overall rate of symptomatic CVC thrombosis was 6.8%. We found a significantly (p< 0.001) increased rate of symptomatic CVC thrombosis (32%) in patients with APL as compared with patients with acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) (6.4% and 4% respectively) as shown in Figure 1. CVC thrombosis was most prevalent following induction treatment, during the period of recovery of blood counts, and was associated with significantly higher platelet counts in patients with APL compared to other AML patients. We therefore relate this higher thrombosis rate to the disease pro-coagulants, the treatment with all-trans-retinoic-acid and the high platelet counts at the time of induction recovery.Subsequently, following this observation, we treated 13 newly diagnosed patients with APL with low molecular weight heparin prophylaxis during the induction recovery phase of blood counts. None of these patients had a thrombotic event, nor a bleeding complication. Conclusions:Although our treatment group was small, we suggest considering prophylaxis for CVC thrombosis during platelet recovery after induction treatment in patients with APL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Upfront Consolidation Combining Yttrium-90 Ibritumomab Tiuxetan and High Dose Therapy with Stem-Cell Transplantation in Poor Risk Patients with Diffuse Large B-Cell Lymphoma

AbstractAbstract ▪812▪This icon denotes a clinically relevant abstract Background:High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is considered as a relevant option for upfront consolidation in patients with poor risk aggressive lymphomas (Fitoussi, hematologica 2011; 96(8):1136-1143). Adding Y90-Ibritumomab Tiuxetan to BEAM regimen would improve outcomes in relapse or refractory lymphomas. We evaluated the safety and efficacy of standard-dose Y90-Ibritumomab Tiuxetan combined with high-dose BEAM after first line induction treatment in patients under 65 years of age with poor prognosis diffuse large B-cell lymphoma (DLBCL). (clinicaltrials.gov: NCT00689169). Methods and Patients:Pathologically proven CD20+ DLBCL patients, 18–65 years of age, with IPI ≥ 2, in CR, CRu or PR according to the IWG 1999 criteria after rituximab-containing induction therapy were included. Patients received Rituximab 250 mg/m2 on d-21, Rituximab 250 mg/m2 followed by Y90-Ibritumomab Tiuxetan 0.4mCi/kg on d-14, BEAM started on d-7 followed by ASCT. FDG-PET scans evaluated using Juweid criteria were performed before transplant in all patients, but were not decisional. Patients were analyzed by immunochemistry for CD10, BCL6, MUM1 and BCL2 expression. End of treatment assessment was done at day 100 (D100). The primary end point was event-free survival (EFS) at 2 years. Results:Seventy five consecutive patients were enrolled from August 2007 to December 2008. Median age was 49 years (19–64) with 7 pts (9%) older than 60 years. The IPI score was 2 in 28 pts (37%) and >2 in 47 pts (63%), bulky disease ≥ 10 cm in 29 pts (39%) and mediastinal involvement in 20 pts (26%). Thirty six patients received 4 (14 pts) or 6 (22 pts) cycles of R-CHOP and 39 had 4 cycles of R-ACVBP as induction treatment. After induction, 63 patients (84%) were in CR or CRu and 12 (16%) were in PR, 21 pts (28%) presented with positive PET. Four pts progressed before they completed the treatment including 2 with positive PET. Median follow-up was 34 months for the 71 patients eligible for analysis. Median time to reach a neutrophil count > 500/μL and platelet count > 20 000/μL was 11 days. Neutropenic fever (100%) and mucositis (78%) occurred in most patients. Other adverse events (AE) were usually mild to moderate in severity. Twenty three AE were reported as serious, mostly infection (n=9). One of them was fatal due to septic shock. The 2-yr EFS and overall survival (OS) was 79% (95% CI: 67–88%) and 83% (95% CI: 70–88%) respectively. Fourteen pts relapsed including 9 before D100. The Overall Response Rate (CR+CRu+PR) was 83%, 59 patients (81%) achieved a CR/CRu, 2 pts were in PR. The 2-year DFS was 91% (95% CI: 80% – 96%). There were no differences in OS (p=0.9) and EFS (p=0.8) between patients in CR/Cru or in PR. Positive PET imaging before transplant did not predict treatment failure. Nineteen pts with positive PET after induction were consolidated with Y90-Ibritumomab Tiuxetan and BEAM, one died of sepsis, 18 achieved a CR/CRu and 3 relapsed at 9, 14 and 20 month. Mediastinal involvement, non-GCB phenotype and high BCL2 expression did not affect outcome. IPI score (2 v >2) and bulky disease at diagnosis appeared to be prognosis factors for OS: 96% v 75% (p = 0.02) and 91% v 70% (p=0.02) respectively, but not for EFS: 2 years EFS 89% v 73% (p = 0.09) and 84% v 70% (p=0.1) respectively. Conclusions:Adding Y90 Ibritumomab Tiuxetan to BEAM is safe without an increase in transplant-related toxicity. First line consolidation with Y90 Ibritumomab Tiuxetan and HDT induced high rates of EFS and OS in poor prognosis patients with DLBCL irrespectively of PET status after induction treatment and warrants randomized study. Disclosures:Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

Impact of t (11;14) on the outcome of autologous hematopoietic cell transplantation (Auto-HCT) in multiple myeloma.

8040 Background: Approximately 15-20% of patients with multiple myeloma (MM) present with t(11;14)(q13;q32) involving IgH and CCND1-XT genes. In this study, we report the impact of the t(11;14) on the outcome of patients with MM. Methods: We performed a retrospective chart review on patients with MM who underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between 2/2000 and 8/2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available before transplant. The primary objective was to compare the progression free survival (PFS) and overall survival (OS) of patients with t(11;14) to patients without chromosomal abnormalities. Results: CC or FISH studies were available for 1239 patients: 863 normal, 28 with t(11;14), 348 with other abnormalities. Concurrent high-risk abnormalities on CC or FISH were seen in 15/28 patients with t(11;14): del(13q) in 11 , del(17p) in 3, and t(14;16)(q32;q23) in 1. Induction treatment in patients with t(11;14) was: bortezomib + dexamethasone +/- thalidomide/lenalidomide : 15 (53%), thalidomide or lenalidomide + dexamethasone: 11 (39%), others 2 (8%); they received auto-HCT after a median of one line (1-7) of therapy. Median follow up in surviving patients was 39 months. There was no significant difference in median time from diagnosis to auto-HCT from diagnosis (6.9 vs. 7.7 months, p=1.0), disease status at auto HCT (&gt;PR1: 82 vs. 76%, &lt;PR1: 7 vs. 11%, relapsed 10 vs. 13%), complete remission (CR: 21% vs. 32%; p=0.30), very good partial remission (VGPR: 29% vs. 21%; p=0.23) or overall response (75% vs. 85%; p=0.18) between patients with t(11;14) and normal karyotype. Median PFS in patients with t(11;14) and normal karyotype was 15.7 months and 35.9 months, respectively (p=0.017). Median OS in patients with t(11;14) and normal karyotype was 51.4 months and 88.4 months, respectively (p=0.03). There was no difference in PFS (p=0.25) or OS (p=0.71) in patients with t(11;14), with or without other high-risk chromosomal abnormalities. Conclusions: In this large single center study with a long follow up, we demonstrated that t(11;14) in MM is associated with a shorter PFS and OS in the context of auto-HCT.

Risk-benefit Assessment of Adalimumab and Certolizumab Pegol as Induction Treatment for Crohnʼs Disease

Purpose: Benefit and risk of a treatment can be quantified by calculating number needed to treat (NNT) and number needed to harm (NNH)1. Relative to a comparator, treatments with smaller NNTs are more effective and those with smaller NNHs are more toxic; negative NNHs indicate reduced risk of an adverse event. We quantified the benefit-risk profile of adalimumab (ADA) and certolizumab pegol (CZP) by calculating NNT for clinical remission and NNH for serious adverse events (SAE) during induction treatment of patients (pts) with moderate to severe Crohn's disease (CD). Methods: Data were evaluated from induction studies of ADA (CLASSIC-I [bionaïve pts]2 and GAIN [infliximab-exposed pts]3) and CZP (bionaïve pts)4. Efficacy and safety data (Table 1) from randomization through the study's primary endpoint (ADA: 4 weeks; CZP: 6 weeks) were evaluated for intent-to-treat pts receiving ADA (160 mg/80 mg at Weeks 0 and 2), CZP (400 mg at Weeks 0, 2, 4) and corresponding placebo (pbo) to calculate NNT for clinical remission (CDAI<150) and NNH for SAE. Point estimates and two-sided 95% confidence intervals (CI) were derived for the treatment effect (NNT) and risk difference (NNH) between drug and pbo.Table 1: Data from ADA and CZP induction trialsResults: Point estimates for NNT and NNH are shown in Table 2. The NNT for ADA was 5 for bionaïve pts and 8 for infliximab-exposed pts (both values statistically significant); the NNT for CZP was not significantly different from placebo. The 95% CI values for NNHs for both compounds included ∞, indicating no statistically significant difference between drug and pbo for SAE. Because of differences in trial designs, patient populations, and study endpoints, comparisons of efficacy and safety from different clinical trials is not appropriate.Table 2: Point estimates for NNT and NNHConclusion: For adalimumab, the NNT value for remission induction was 5 for bionaïve patients and 8 for infliximab exposed patients, and NNH values did not differ significantly from placebo, indicating a favorable risk-benefit profile.

Early allo-SCT for AML with a complex aberrant karyotype—results from a prospective pilot study

In AML, a complex aberrant karyotype is associated with poor response to chemotherapy and dismal prognosis. We prospectively studied the concept of allogeneic haematopoietic SCT (HSCT), performed early and regardless of response to induction treatment in patients with complex karyotype AML (CK-AML). The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later. In vivo T-cell depletion by anti-thymocyte globulin was used to protect from early GvHD, and prophylactic donor lymphocyte transfusion was given from day+120 to augment the GvL effect, once tolerance was established. Eighteen consecutive patients with CK-AML (median age: 53 years) received HSCT from related (n=7) or unrelated (n=11) donors. Before FLAMSA-RIC, nine patients each had received one and two induction courses. Stage at start of FLAMSA-RIC was CR/CRi (n=8) or persistent disease (n=10). Following HSCT, 16 patients achieved CR. After a follow-up of 51 months, 11 patients are alive in CR, whereas seven have died in remission (n=3), or from leukaemia (n=4). Cumulative incidence of relapse, non-relapse mortality, acute GvHD≥II and chronic GvHD were 0.222±0.098, 0.235±0.104, 0.367±0.120 and 0.481±0.123, respectively. Four-year survival from HSCT is 61%. Early HSCT following FLAMSA-RIC may improve the outcome of this unfavourable AML subgroup.

Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis

Class V lupus nephritis (LN) occurs in one-fifth of biopsy-proven cases of systemic lupus erythematosus. To study the effectiveness of treatments in this group of patients, we pooled analysis of two large randomized controlled multicenter trials of patients with diverse ethnic and racial background who had pure class V disease. These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points. Weighted mean differences, pooled odds ratios, and confidence intervals were calculated by using a random-effects model. A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. Hence we found that the response to MMF as induction treatment of patients with class V LN appears to be no different from that to IVC.

Mycophenolate Mofetil in Low Doses Stabilizes and Improves Antineutrophil Cytoplasmic Antibody-associated Vasculitis and Lupus Nephritis

Clinical experience with mycophenolate mofetil (MMF) in glomerulonephritis still remains limited. In order to assess the experience of one center with the efficacy and tolerability of MMF in patients with glomerulonephritis, we performed a retrospective 6-year analysis of 68 patients treated by MMF for glomerular disease, mainly anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV: n=34) and systemic lupus erythematosus and lupus nephritis (SLE: n=24). Indications were maintenance treatment in 40% of patients, induction treatment in patients not tolerating cyclophosphamide in 27%, and disease relapse in 33%. Mean treatment duration was 11.5 months. Efficacy endpoints were serum creatinine, urinary protein excretion, and steroid dose. In AAV patients, MMF was associated with significant improvement in 18%, partial improvement in 26%, stabilization in 29%, and disease progression in 12%; adverse event dropouts totalled 15%. In SLE, the respective figures were 30, 22, 9, and 22%, with 17% adverse event dropouts. The most frequent side effects were gastrointestinal events (n=7) and infections (n=3). None was life-threatening and there were no deaths. MMF, in the relatively low doses used, was safe and effective, stabilizing or improving AAV in 73% of patients and SLE in 61%. Further prospective randomized controlled trials with MMF in renal vasculitis and lupus nephritis are clearly warranted.

Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement

We performed a single-centre non-blinded clinical trial to compare the clinical efficacies of mycophenolate mofetil (MMF) and intermittent cyclophosphamide (CTX) pulse therapy as induction treatments in patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis (AAV) and moderate renal involvement. Patients with active AAV and serum creatinine <500 micromol/L received either MMF treatment (MMF group) or monthly CTX pulse therapy (CTX group) for 6 months. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). The disease activity, remission rate, renal function and adverse reactions were compared between the two groups. A total of 35 patients (15 male, 20 female: aged 49.1 +/- 12.2 years) were enrolled, with 18 in the MMF group and 17 in the CTX group. Of the 35 patients, 28 were MPO-ANCA positive and 2 were PR3-ANCA positive. Four patients were lost to follow-up in the CTX group. At Month 6, BVAS scores were much lower in the MMF group than in the CTX group (0.2 +/- 0.89 versus 2.6 +/- 1.7, P < 0.05). In the intent-to-treatment analysis, 14 of 18 patients (77.8%) treated with MMF and 8 of 17 patients receiving CTX (47.1%) had complete remission with an absolute difference of 30.7%. Eight of 18 patients (44.4%) in the MMF group and 2 of 17 patients (15.4%) in the CTX group recovered renal function. Serum ANCA decreased to normal in 41.7% of patients in the MMF group and in 16.7% in the CTX group. Side effects in the MMF group were pneumonia (1), herpes zoster (1) and gastrointestinal symptoms (2), and in the CTX group were leukocytopenia (1), gastrointestinal distress (4) and pneumonia (1). Our study suggests that MMF effectively ameliorates disease activity and considerably improves renal function in patients with AAV. Further large-scale multicentre prospective randomized controlled trials will be needed to confirm these findings.

VELCADE/Dexamethasone (Vel/Dex) Versus VAD as Induction Treatment Prior to Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM): An Interim Analysis of the IFM 2005-01 Randomized Multicenter Phase III Trial.

ASCT is considered the standard of care for patients up to 65 years of age with MM. The optimal induction treatment prior to ASCT is still unknown. VAD is a commonly used regimen but is associated with a number of toxicities, administrative inconvenience, and a complete remission (CR) rate of typically less than 10%. Recently the combination thalidomide/Dex was reported to induce a higher overall response rate than Dex alone in newly diagnosed patients, but with significantly more toxicities, especially deep vein thrombosis, and a 4% CR rate (Rajkumar et al, J Clin Oncol 2006;24:431–6). In a phase II trial we have evaluated the combination of Vel 1.3mg/m2 D1, 4, 8, 11 with Dex 40mg/D D1-4, D9-12, for 4 consecutive 21-D cycles (Dex only on D1-4 during cycles 3–4). This combination was well tolerated and yielded a 21% CR/nCR rate with successful stem cell harvest and engraftment (Harousseau et al, Haematologica 2006). In 2005, the IFM initiated a multicenter randomized phase III trial comparing Vel/Dex with VAD as induction treatment of patients with newly diagnosed MM up to the age of 65. The primary objective of the study is the CR (negative immunofixation) plus nCR (CR but positive immunofixation) rate after 4 cycles. A secondary objective is to evaluate the role of consolidation with 2 courses of DCEP (Dex, cyclophosphamide, etoposide, cisplatin). Patients were randomized at diagnosis among 4 arms (A1: 4 cycles of VAD; A2: 4 cycles of VAD + 2 cycles of DCEP; B1: 4 cycles of Vel/Dex; B2: 4 cycles of Vel/Dex + 2 cycles of DCEP); stratification was by cytogenetics and β2 microglobulin. Stem cell collection was performed between cycle 3 and cycle 4 after priming with G-CSF (10μg/kg/D × 6 D). At the end of induction (± DCEP consolidation) treatment, patients received melphalan 200mg/m2 plus ASCT. Enrollment of 480 patients is planned, to detect a 10% higher CR/nCR rate with Vel/Dex (20% vs 10%) with 80% power (two-sided test, significance level 0.05). An interim analysis is planned when 222 patients have been evaluated for response at the end of induction. As of July 2006, 304 patients have been enrolled. Randomization of the 222 patients to be considered for interim analysis was completed on May 19th. Baseline characteristics include: median age 55y; 140M, 82F; β2 microglobulin >3mg/L in 54%; del13 by FISH in 45%. The occurrence of serious adverse events (SAEs) was similar between the VAD and Vel/Dex arms (31% with VAD, 33% with Vel/Dex). The most frequent SAEs were pneumopathy (5.3% VAD, 4.0% Vel/Dex), thrombosis (2.7% VAD, 3.3% Vel/Dex), and peripheral neuropathy (1.3% VAD, 3.3% Vel/Dex). We intend to present results from the interim analysis.

Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol

AbstractBetween 1996 and 2000, 90 newly diagnosed adult patients with T-acute lymphoblastic leukemia (T-ALL) were registered in the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acuta Limfoide (LAL) 0496 protocol. Cases were centrally processed for morphology, immunophenotype, cytogenetics, molecular biology, and multidrug resistance (MDR). Twenty-two patients were females and 68 were males. Four percent of cases were pro-T, 47% pre-T, 39% cortical T, and 10% mature T-ALL. Fifty-six percent of patients with pro-T + pre–T-ALL achieved complete remission (CR) compared with 91% for cortical + mature cases (P = .002). CD34 expression was associated with a significantly lower CR rate: 54% versus 84% (P = .009). Thirty-one (36.5%) of 85 patients had an abnormal karyotype, the most common abnormality (15%) being a partial del(6q). The cytogenetic profile did not impact on CR achievement. MDR1 function, present in 26% of cases, correlated significantly with CR achievement (P = .004). A highly significant (P = .001) difference in CR rate was observed between patients who did not express the CD13/CD33/CD34 antigens and were MDR functionally negative (96%) compared with patients positive for at least one of these markers (57%). Multivariate analysis showed an impact on CR achievement for CD33 expression and MDR1 function. An extensive biologic workup of adult T-ALL cases at presentation is recommended in order to design tailored therapeutic strategies aimed at improving CR rates.

Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up

AbstractShortly before the all-transretinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m2 IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m2 IDA daily for 4 days combined with 200 mg/m2 Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR (P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively (P = .0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone (P = .0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/μL (P = .0001) and increasing age (P = .0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.