Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): A randomised, double-blind, phase 3 study
Chanan-Khan A.,Mayo Clinic Cancer Center |
Cramer P.,University of Cologne |
Demirkan F.,Dokuz Eylul University |
Fraser G.,McMaster University |
And 26 more authors.
The Lancet Oncology | Year: 2016
Background: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Findings: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding: Janssen Research & Development. © 2016 Elsevier Ltd.
Salles G.,University of Lyon |
Seymour J.F.,University of Melbourne |
Offner F.,Ghent University |
Lopez-Guillermo A.,Hospital Clinic |
And 25 more authors.
The Lancet | Year: 2011
Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m2 every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9 (95 CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6 (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95 CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95 CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24) in the rituximab maintenance group and 84 (17) in the observation group (risk ratio 1·46, 95 CI 1·14-1·87; p=0·0026). Infections (grades 2-4) were the most common adverse event, occurring in 197 (39) and 123 (24) patients, respectively (risk ratio 1·62, 95 CI 1·35-1·96; p<0·0001). 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS. Groupe d'Etude des Lymphomes de l'Adulte (GELA) and F Hoffmann-La Roche. © 2011 Elsevier Ltd.
Montesinos P.,Hospital Universitario La Paz |
Rayon C.,Hospital Central de Asturias |
Vellenga E.,University of Groningen |
Brunet S.,Hospital Sant Pau |
And 20 more authors.
Blood | Year: 2011
The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventytwo patients (11%) were CD56+ (expression of CD56 in ≥20% leukemic promyelocytes). CD56+ APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56+ APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56- APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56+ APLalso showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin - derived regimens. This marker may be considered for implementing riskadapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278. © 2011 by The American Society of Hematology.
Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: Further improvements in treatment outcome
Sanz M.A.,Hospital Universitario La Paz |
Montesinos P.,Hospital Universitario La Paz |
Rayon C.,Hospital Central de Asturias |
Holowiecka A.,Center of Oncology of Poland |
And 16 more authors.
Blood | Year: 2010
A risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMALPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 × 109/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high-risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission afterATRAplus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in theLPA99 (26%;P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Registered at http://www.clinicaltrials.gov as NCT00408278. © 2010 by The American Society of Hematology.
Valsecchi M.E.,Medical Oncology |
Reviews on Recent Clinical Trials | Year: 2015
Breast cancer continues to be a major health problem. Both patients and clinicians demand faster access to drugs that could result in better outcomes. In part motivated by this necessity, there has been a change in the dominant paradigm regarding how drugs become approved. Complete pathological response (pCR), understood as the absence of remanent and viable tumor after a neoadjuvant treatment, is now considered by a large proportion of the medical community as a valid surrogate. The presumption is that patients achieving pCR are less likely to develop tumor recurrence. Consequently, if a drug can improve the number of patients achieving pCR it could then obtain approval by the regulatory agencies. Pertuzumab, an anti-HER- 2 monoclonal antibody, was granted accelerated approval based on this principle. The unprecedented approval of this drug is now an example that can help us to understand the advantages but also the potential risks associated with this new approach. In this review, we will discuss the results of the two clinical trials leading to the FDA-approval of pertuzumab in the neo-adjuvant setting. We will also analyze the outcomes from long term follow up of two important neoadjuvant clinical trials, the NeoALTTO and the NOAH studies. These last ones had provided further insights regarding the magnitude, the quality as well as some limitations of the relationship between pCR and harder endpoints such as event-free or overall survival. It seems evident that the acknowledgement of pCR as a potential surrogate endpoint represents an important step in the right direction. However, it still remains controversial whether this is applicable to all subtypes of breast cancers. Additional investigations may be necessary to safely generalize this concept. © 2015 Bentham Science Publishers.