INTERIM ANALYSIS OF CENTRAL REVIEW OF END-OF-THERAPY PET IN FOLL12 TRIAL FOR FOLLICULAR LYMPHOMA

2019 ◽  
Vol 37 ◽  
pp. 393-393
Author(s):  
L. Guerra ◽  
F. Bergesio ◽  
A. Versari ◽  
A. Franceschetto ◽  
S. Peano ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Interim Analysis

scholarly journals Safety Profile of Idelalisib in Patients with Refractory Follicular Lymphoma: Interim Analysis of a Noninterventional Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-50
Author(s):  
Gilles Salles ◽  
Ka Lung Wu ◽  
Sofya Kovalchuk ◽  
Santiago Mercadal ◽  
Annalisa Chiarenza ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Safety Profile ◽  
Interim Analysis ◽  
Research Funding ◽  
Stage Iii ◽  
Disease Stage ◽  
Stevens Johnson Syndrome ◽  
Risk Of Death ◽  
Registration Trial ◽  
Grade 3

Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

POLATUZUMAB VEDOTIN (POLA) + OBINUTUZUMAB (G) + LENALIDOMIDE (LEN) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) FOLLICULAR LYMPHOMA (FL): PHASE IB/II INTERIM ANALYSIS

2019 ◽  
Vol 37 ◽  
pp. 175-176 ◽  
Author(s):  
C. Diefenbach ◽  
B. Kahl ◽  
L. Banerjee ◽  
A. McMillan ◽  
R. Ramchandren ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Interim Analysis ◽  
Phase Ib

Chimeric Anti-CD20 Monoclonal Antibody (Rituximab; Mabtheraâ) in Remission Induction and Maintenance Treatment of Relapsed /Resistant Follicular Non-Hodgkin’s Lymphoma : A Phase III Randomized Intergroup Clinical Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 586-586 ◽  
Author(s):  
Marinus H.J. Van Oers ◽  
Martine Van Glabbeke ◽  
Ivana Teodorovic ◽  
Cynthia Rozewicz ◽  
Richard Klasa ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Follicular Lymphoma ◽  
Interim Analysis ◽  
Hodgkin’S Lymphoma ◽  
Maintenance Treatment ◽  
Initial Diagnosis ◽  
Hodgkin's Lymphoma ◽  
Phase Iii ◽  
Remission Induction ◽  
Non Hodgkin's Lymphoma

Abstract Background. In view of a) the efficacy of Rituximab (R) monotherapy in relapsed low grade lymphoma; b) the feasibility to combine R with cytostatic drugs c) the potential of such combinations to clear minimal residual disease, in 1999 we started a phase III clinical trial in patients with relapsed follicular non-Hodgkin’s lymphoma, with 2 main objectives. First: to compare CHOP and R-CHOP as to response rate and response quality. Second: to establish the effect of maintenance treatment with R on progression-free survival (PFS ). Study design. Patients with stages III or IV follicular lymphoma at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg /m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment or maintenance treatment with R (375 mg/m2 once every 3 months until relapse or for a maximum period of two years). Results. In February 2004, a preplanned second interim analysis by the IDMC was performed. At that time 461 patients had been included. Of these, 369 could be evaluated for response (188 CHOP; 181 R-CHOP). The groups did not differ as to age, sex, performance status, time from initial diagnosis, number and type of, and best overall response to prior chemotherapy. Both treatment arms yielded similar PR rates: CHOP 53.7%; R-CHOP 52.5 %. However, there was a highly significant difference in CR rates: CHOP 18.1% versus R-CHOP 30.4 % (p=0.0004). 319 patients have been randomized for maintenance treatment. Of these, 268 were evaluable (132 observation; 136 R maintenance). 1 year and 3 year PFS were 54.9% and 31.2% respectively in the observation arm, and 80.2 % and 67.7% in patients with R maintenance treatment (p< 0.0001). There is as yet no impact on OS: the observed difference (in favor of R maintenance) was not significant for an interim analysis (p=0.03). There were no differences in toxicity between CHOP and R-CHOP induction treatments. Maintenance treatment was associated with minimal toxicity. Because the planned second interim analysis revealed that the primary endpoints for both the induction and maintenance part of the study had been reached, the formal criteria for stopping the trial have now been met. Conclusion. In patients with relapsed/resistant follicular lymphoma R-CHOP remission induction results in a highly significant increase in CR rate as compared to CHOP. Moreover, this is the first trial to show that in these patients Rituximab maintenance treatment achieves a considerable improvement in PFS.

Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1576-1576 ◽  
Author(s):  
Laurie H Sehn ◽  
David A Macdonald ◽  
Sheldon H. Rubin ◽  
Morel Rubinger ◽  
Kevin R Imrie ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Standard Dose ◽  
Single Agent ◽  
Acceptable Level ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Grade 3

Abstract Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

Final Results of a Randomized Phase 2 Multicenter Study of Two Bortezomib Schedules In Patients with Recurrent or Refractory Follicular Lymphoma. Groupe d'Etude Des Lymphomes De l'Adulte (GELA) Study FL-05

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 768-768 ◽  
Author(s):  
Vincent Ribrag ◽  
Herve Tilly ◽  
Olivier Casasnovas ◽  
Andre Bosly ◽  
Reda Bouabdallah ◽  
...  
Keyword(s):  
Clinical Study ◽  
Follicular Lymphoma ◽  
Interim Analysis ◽  
Research Funding ◽  
Optimal Schedule ◽  
Dose Schedule ◽  
Open Label ◽  
Qualitative Comparison ◽  
Duration Of Response ◽  
Indolent Lymphomas

Abstract Abstract 768 Background: Bortezomib has previously demonstrated activity in indolent lymphomas including follicular lymphoma (FL). However, the optimal schedule, dose and precise activity of bortezomib in FL remain to be investigated. Aims: To evaluate the efficacy and tolerability of bortezomib in the treatment of advanced FL, but also using a qualitative comparison of two different dose schedules, based on safety, efficacy and dosing convenience to recommend a dose schedule for further clinical studies. Methods: This prospective, randomized, sequential, international, multicenter, 2-arm, non-comparative, open-label, clinical study was conducted from 08–2005 to 09–2008. The eligible subjects (follicular lymphoma grade 1–3, no CNS involvement, in relapse or refractory to previous therapy, ECOG 0–2, Absolute neutrophil count > 1000 cells/mL; Platelets > 50,000 cells/mL, Aspartate transaminase < 3 × ULN; Alanine transaminase < 3 × ULN; Total bilirubin < 2 × ULN; Creatinin level < 150 μmol/L, without known previous HIV serology) were randomized to receive either treatment in a 1:1 ratio. Treatment arm A patients (pts) received 1.5 mg/m2 bortezomib administered biweekly on days 1, 4, 8, and 11 of a 21-day cycle for 8 cycles. Treatment arm B pts received 1.6 mg/m2 bortezomib administered weekly on days 1, 8, 15, and 22 of a 35-day cycle for 6 cycles. Treatment allocation was stratified according to number of prior therapies (1 or 2 versus > 2) and time to progression (TPP) for the last given anti-lymphoma therapy (≤ 12 months versus > 12 months). Responses were assessed using 1999 IWG criteria. An interim analysis was planned after 15 evaluable pts randomized in each treatment arm; if only 5 subjects or fewer respond, the treatment arm was concluded to be ineffective and the treatment arm closed to inclusion; otherwise this treatment arm proceeded to include 50 pts. Results: 87 pts (51 [59%] men and 36 [41%] women) with median age of 65 years (range:40 to 77) were treated with bortezomib. Prior therapies were >2 in 62% and progression <12 months from last therapy in 49%. 30% previously received HDT with ASCT, and all of them were previously treated with immunotherapy. Arm B was closed to inclusion after interim analysis. After this interim analysis, the 6 patients still on therapy in this arm completed therapy according to arm A. 15/50 pts (32%) in arm A (bortezomib 1.5 mg/m2) and 8/37 pts (23%) in arm B (bortezomib 1.6 mg/m2) achieved a complete, unconfirmed complete or partial response at the end of treatment. Median duration of response was 16 (range 1–45) and 15 (1-39) months and PFS was 6 and 7.5 months for arms A and B, respectively. Most drug-related AEs (all grades, all cycles) were mild. AEs > grade 3 observed in more than 5% of pts were lymphopenia (25% both arms), thrombocytopenia (19% and 25% in arms A and B, respectively) and neutropenia (8% both arms). One pt died of possibly drug-related cardiac failure associated with hyponatremia. Conclusions: This study demonstrates tolerability and durable clinical benefit of bortezomib when given at 1.5 mg/m2 biweekly on a 21 days cycle in pts with recurrent or refractory FL. These results suggest recommending this dose schedule for further clinical study. Disclosures: Ribrag: LFB: Honoraria, Research Funding; servier: Research Funding; celgene: Research Funding; pfizer: Honoraria; novartis: Honoraria. Tilly:Amgen: Honoraria. Feugier:roche: Consultancy, Honoraria.

Chimeric Anti-CD20 Monoclonal Antibody (Rituximab;Mabthera) in Remission Induction and Maintenance Treatment of Relapsed /Resistant Follicular Non-Hodgkin’s Lymphoma: Final Analysis of a Phase III Randomized Intergroup Clinical Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 353-353 ◽  
Author(s):  
Marinus H.J. Van Oers ◽  
Martine Van Glabbeke ◽  
Ivana Teodorovic ◽  
Cynthia Rozewicz ◽  
Richard Klasa ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Interim Analysis ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Remission Induction ◽  
Induction Treatment ◽  
Rituximab Maintenance ◽  
Study Results

Abstract Background. Last year we reported interim results of a randomised phase III trial in patients with relapsed/refractory stage III/IV positive follicular NHL, demonstrating that the addition of rituximab (R) to CHOP chemotherapy for remission induction as well as rituximab maintenance treatment significantly improves the clinical outcome (Blood2004;104:169a). Based on these interim results, randomisation to the induction part of the trial was halted and the protocol was amended. Study design. Patients with stages III or IV follicular lymphoma at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg /m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment (observation) or maintenance treatment with R (375 mg/m2 once every 3 months) until relapse or for a maximum period of two years. Results. At the time of the preplanned second interim analysis (February 2004) 461 patients had been included. Of these, 369 could be evaluated for response (188 CHOP; 181 R-CHOP). Both treatment arms yielded similar partial response rates (CHOP: 53.7% - R-CHOP: 52.5%), but highly significant different CR rates (CHOP: 18.1%; R-CHOP: 30.4%; p=0.0004). Of 319 patients randomized for maintenance treatment, 268 were evaluable (132 observation; 136 R maintenance). A highly significant advantage was observed in progression free survival in patients randomized to R maintenance, when compared with the observation arm (median PFS 38 vs.15 months; p&lt;0.0001). At that time there was no impact on OS: the observed difference (in favor of R maintenance) was not significant for an interim analysis. Toxicity of CHOP and R-CHOP induction was similar, and R maintenance was associated with minimal toxicity. These results of the planned second interim analysis showed that the formal criteria for stopping the trial had been met. It was concluded that this is the first trial to show that: 1) in patients with relapsed/resistant follicular lymphoma R-CHOP remission induction results in a highly significant increase in CR rate as compared to CHOP; 2) rituximab maintenance treatment significantly improves PFS in patients responding to induction treatment. The final analysis of the study results will be performed in September 2005, with an additional follow-up of at least 18 months. The final results will be presented at the meeting.

scholarly journals A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3984-3984
Author(s):  
Zhong Zheng ◽  
Li Wang ◽  
Shu Cheng ◽  
Pengpeng Xu ◽  
Weili Zhao
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Group Performance ◽  
De Novo ◽  
Phase Ii Study ◽  
Eastern Cooperative Oncology Group ◽  
Elevated Serum ◽  
Newly Diagnosed ◽  
Grade 3

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis Zhong Zheng1, Li Wang1,2, Shu Cheng1, Peng-Peng Xu1, Wei-Li Zhao1,2 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China Abstract Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Rituximab plus chemotherapy for FL significantly improves the outcome of the patients, nevertheless, most patients ultimately relapse. Therefore, novel agents along with Rituximab have been applied to increase treatment efficacy in this subset of iNHL patients. Tumor immune eascape plays a crucial role in lymphoma progression. Through modulating tumor microenvironment, lenalidomide, are emerging as effective therapeutic approaches to affect tumor immunity and inhibit lymphoma cells proliferation. However, its anti-tumor activity activity has not yet been assessed in de-novo chinese FL patients. This prospective phase II study is to evaluate the efficacy and safety of lenalidomide in combination with Rituximab (R2) in newly diagnosed FL patients (NCT 03715309). Methods: Patients with newly diagnosed FL (grade 1 to 3a), aged 16 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m2 on day 0, lenalidomide 25mg from day 1 to day 10 every 3 weeks for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: To date, eighty-six patients have been enrolled, with median age of 48 years (range, 22-73). At diagnosis, Seventy-seven patients (89.5%) presented advanced Ann Arbor stage and 19 cases (22.0%) showed elevated serum LDH level. Twenty-nine patients (33.7%) had multiple extra-nodal sites involving bone marrow, bone, gastrointestinal, and spleen. Twenty-one patients (24.4%) had IPI scores ≥ 3. For Sixty-four patients available for response evaluation, the CR rate was 81.2% (52/64) and the ORR was 90.1% (58/64). Grade 3-4 neutropenia was found in 18 cases (20.9%). No grade 3-4 thrombocytopenia and grade 3-4 anemia were observed. For non-hematological AEs, cutaneous reactions and tumor flare reaction were observed in 12 cases (13.9%) and in 1 case (1.16%), respectively, while no grade 4 non-hematological AEs were presented. Conclusion: Lenalidomide Plus Rituximab as first-line therapy for de novo patients with FL showed encouraging response and good tolerability. Disclosures No relevant conflicts of interest to declare.

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