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In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 124-124

Abstract: Introduction Limited stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), although different approaches are currently carried out, ranging from watch and wait to combined treatment. RT on involved lymph nodes allows eradication of the disease only in 40-50% of patients. Anti-CD20 monoclonal antibodies (MoAb), widely used in advanced stage FL, are likely to be effective in reducing the relapse risk, although no scientific evidence of their role has been provided. The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying patients unlikely to be cured by RT, for whom an immunotherapy-based consolidation could improve outcome. Methods 110 patients with stage I/II FL were enrolled. IFRT was administered to all patients at a dose of 24 Gy. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the Italian FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories: the presence of a BCL2/IGH rearrangement was investigated at baseline in all patients by nested PCR (NEST) and RQ-PCR (RQ), the latter according to the EuroMRD guidelines. In patients BCL2/IGH+ at baseline by both NEST and RQ in BM and/or PB, MRD was analyzed in both tissues after IFRT and every 6 months over a three-year follow-up period. Patients with positive MRD by both NEST and RQ in BM and/or PB after IFRT or who became positive during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab. The primary objective of the study was to define the efficacy of immunotherapy in obtaining the disappearance of BCL2/IGH rearranged cells. Results Preliminary data are available for 107 patients, 57 males, 50 females. Median age was 55 years (29-83). 17% had G1 FL, 32% G2, 40% G3A, 11% NOS. The FLIPI score was 0 in 59% of patients, 1 in 35%, 2 in 6%. 69% of patients had inguinal site involvement. Despite a negative BM biopsy, at baseline 30% of patients (n=32) had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM and/or PB; the concordance between compartments was 90%, with 10% of negative PB showing a positive BM. No significant differences were observed in relapse probability between patients with or without a molecular marker. All patients were submitted to IFRT and all obtained a clinical response, which was complete in 79 of the 101 evaluated patients (78%) and partial in 22 (22%). MRD evaluation after treatment revealed the persistence of BCL2/IGH rearranged cells in the PB and/or BM in 60% of patients. According to the design of the protocol, MRD-positive patients, either after IFRT (n=18) or in case of conversion to a positive signal during the follow-up (n=7), received 8 weekly administration of ofatumumab. A conversion to MRD negativity, evaluated in 23 treated patients, was obtained in 20 (87% - CI 65.1-97.1). This result was significantly superior to the expected 50%. One death occurred after IFRT, due to ischemic stroke. Adverse events likely correlated to ofatumumab occurred in 7/25 treated patients, consisting of infusion reactions in 5, leading to a permanent interruption of immunotherapy in 3. After a median follow-up of 18 months, all patients who achieved a MRD negativity with ofatumumab underwent a regular molecular follow-up and are still MRD-negative. Overall, clinical relapse or progression were observed in 17 patients: 13 (18%) among the 73 "no marker" patients; 2 relapses (16%) were observed among the 12 MRD-negative patients after IFRT and 2 relapses were observed among the 23 patients treated with the anti-CD20 MoAb (8.7%), 1 having achieved a MRD negativity and 1 not. No significant differences in event-free survival have so far been observed between the three groups. Conclusions The MRD data of this phase II trial for early stage FL indicate that RT alone is often insufficient to eradicate the disease, being capable of inducing a negative MRD only in 40% of evaluable cases, with a long-lasting effect only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved, obtaining the disappearance of BCL2/IGH rearranged cells in the majority of patients treated with ofatumumab. The strategy of an immunotherapy consolidation after IFRT in MRD-positive patients allowed to increase molecular responses. A longer follow-up and further studies on larger patient populations will allow to conclusively define the impact of this MRD-driven strategy also on clinical outcome. Disclosures Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Gilead: Speakers Bureau; Merk: Consultancy; Bristol Meyer Squibb: Speakers Bureau. Ferrero:Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Corradini:Roche: Honoraria; Novartis: Honoraria; kite: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcaini:Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ladetto:AbbVie: Honoraria; Roche: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; J & J: Honoraria; Celgene: Honoraria. Foà:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: The anti-CD20 MoAb Ofatumomab is employed to eradicate Minimal Residual Disease in early stage Follicular Lymphoma(FL). The drug is registered for Chronic Lymphocytic Leukemia, not for FL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123106

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 48-48

Abstract: Introduction Symptomatic patients with relapsed/refractory Waldenström Macroglobulinemia (RR-WM) treated with standard rituximab plus chemotherapy as second-line salvage therapy, generally show a 18-months progression free survival (PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi, a multicenter phase II study was designed to assess whether a combination of bendamustine, rituximab and bortezomib (BRB) (EudraCT Number:2013-005129-22) could be considered a promising new treatment in this setting. Patients and Methods This single-arm phase II study tested the hypothesis that 18-months PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan provided: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months (6 cycles). MYD88 L265P and CXCR4 S338X mutations were tested by ddPCR in bone marrow (BM), plasma and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). Results Median age was 66.8 years (8 patients were older than 75 years). Many patients had features of advanced disease such as cytopenia (anemia 71%, thrombocytopenia 20%), systemic symptoms (40%) and symptomatic splenomegaly (24%). Sixteen (42%) patients had at least one comorbidity, mostly cardiovascular disease (21%) or metabolic disorders (16%), such as diabetes mellitus. Thirty patients completed six cycles, 7 patients stopped therapy for toxicity and 1 for progressive disease. Overall response rate at the end of therapy was 82%, including 4 (11%) complete, 15 (39%) very good partial, 12 (32%) partial responses according to IWM response criteria. At 18, 24, and 30 months PFS was 84% (95% CI 68-92%), 81% (95%CI 65-91) and 79% (95%CI 62-89) respectively. At 18 months OS was 92% (95%CI 77-97%) and no deaths were observed between 18 and 30 months. Nineteen patients (50%) experienced grade ≥3 hematological toxicity, mainly thrombocytopenia, 12 patients (31.5%) developed grade ≥3 extra-hematological toxicity of which only one cutaneous toxicity related to bendamustine. Bortezomib-related nervous system disorders were observed in 6 patients (5 of grade 1-2 and 1 of grade 3), with no discontinuations. Mutational data were available for 21 patients: all patients scored MYD88 L265P in BM, 18/19 (95%) in plasma and only 18/21 (86%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. CXCR4 S338X was detected only in one patient at baseline. MRD negativization rates after treatment differed across investigated tissues: in detail, 5/17 (29%) in BM, 6/14 (43%) in plasma and 12/16 (75%) in PB. Overall, a good concordance was observed between BM and plasma (Cohen's kappa= 0.714), suggesting the possibility of avoiding BM aspiration for mutational screening and MRD analysis. Conclusion The final results of FIL BRB phase II trial showed that BRB regimen, used as second-line therapy, is an effective and well-tolerated salvage treatment for RR-WM patients. The deep anti-tumor activity of the novel combination is highlighted by an absolute increase of PFS rate in comparison to historical controls (30-months PFS of 79%), as well as by high rates of clinical response, with an ORR (CR+VGPR+PR) of 82% (95%CI 66-92). Moreover, MRD monitoring showed promising efficacy of BRB regimen in clearing the residual disease. Disclosures Benevolo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau. Ferrero: Morphosys: Research Funding; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Gaidano: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Vitolo: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-148424

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1607-1607

Abstract: BACKGROUND: Standard rituximab plus chemotherapy salvage treatment has shown moderate activity in patients with relapsed/refractory Waldenström's macroglobulinemia (RR-WM), with 18-months progression free survival (18-PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi (F.I.L.) we designed a multicenter phase II study to assess the efficacy of a combination of bendamustine, rituximab and bortezomib (BRB) in improving these results. METHODS and PATIENTS: This single-arm phase II study tested the hypothesis that 18-PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan was: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months. Patients with RR-WM after first line of therapy were enrolled in 18 F.I.L. centers, from October 2014 to November 2017. In the last 23 patients MYD88L265Pwas tested by the recently described droplet digital PCR (ddPCR) assay both on bone marrow (BM) and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). RESULTS: At the time of analysis, 29 patients completed the six cycles of therapy, six patients stopped therapy for toxicity, two patients died and one had just finished therapy and was not yet evaluated. 18-PFS was 84% (95%CI: 61-94%), with two progressions and two deaths without evidence of progression (one cerebrovascular accident during the fifth cycle and one pulmonary embolism at three months follow up). On an intention-to-treat analysis (N=37), overall response rate was 70%, (N=26) including 4 (11%) complete, 11 (30%) very good partial, 10 (27%) partial responses and 1 (3%) minimal response according to IWM response criteria. Overall, treatment was well tolerated, the most common adverse events of any grade included 13 patients (34%) experiencing grade 3-4 neutropenia, especially in cycle 4 (leading in four cases to treatment discontinuation). Peripheral nervous system toxicity was observed in five patients (13%; 4 of grade 1-2 and 1 of grade 3-4), with no discontinuations. Serious adverse events were observed only in three patients, mainly rash, all resolved. All the 23 patients assessed for MYD88L265Pat baseline scored positive in BM, while only 18/23 (78%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. Among the 21 patients monitored for MRD after treatment 5 scored MRD negative in BM and 13 in PB, highlighting the deep activity of the BRB regimen in clearing the disease. CONCLUSIONS: Among patients with RR-WM after first line of therapy, BRB regimen is a well-tolerated salvage treatment, resulting in high rates of PFS at 18 months. Moreover, the deep anti-tumor activity of this regimen is highlighted by the promising rates of both clinical and molecular responses. More complete and mature results will be presented during the meeting. (ClinicalTrials.gov number: NCT02371148). Disclosures Gaidano: AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114023

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 134-134

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) have a 40-50% cure rate when treated with cyclophosphamide-doxorubicin-etoposide-vincristine-prednisone (CHOEP) and hematopoietic stem cell transplantation (HSCT). Romidepsin, a histone deacetylase inhibitor, showed promising activity in relapsed or refractory PTCLs. Methods: On these premises, we designed a phase I/II trial (PTCL13 NCT02223208) to evaluate whether the addition of romidepsin to CHOEP improves the outcome of newly diagnosed PTCLs. In the phase Ib part of the study, we defined 14 mg/ms as the maximum tolerated dose of romidepsin when administered in combination with CHOEP (Ro-CHOEP). Thus, in the phase II part of the study we evaluated the efficacy of Ro-CHOEP followed by HSCT in young patients. The primary objective of the study was to demonstrate a 15% increase in 18-months progression-free survival (PFS) for the combination Ro-CHOEP plus HSCT (from 55% to 70%, planned sample size=110), compared to the previous Italian trial (Corradini P et al, Leukemia 2014). Patients aged 18-65 years with stage II-IV PTCL-NOS, angioimmunoblastic/T follicular helper (AITL/THF) and ALK negative anaplastic large cell lymphoma, were eligible. Treatment plan consisted of 6 courses of Ro-CHOEP every 21 days (14 mg/ms Ro day 1 and 8), followed by cisplatin-cytarabine-dexamethasone (DHAP) with stem cell harvest and HSCT. Patients in complete response (CR) after induction proceeded to autoHSCT, while those in partial response (PR), with an available HLA-matched donor, proceeded to alloHSCT upfront. Results: From September 2017 to October 2020, 86 patients were enrolled into the phase II part of the study; median age was 55 years (IQR 49;60); 78 (91%) had stage III-IV and 31 (36%) IPI score & gt;2. Pathological materials were collected at the time of diagnosis, and centrally reviewed by expert hemo-pathologists; subgroups were: 33 PTCL-NOS, 21 ALK negative, 31 AITL/THF, and one case not classified due to inadequate material. According to the statistical plan, an interim analysis was performed on the first 75 patients. At a median follow-up of 26 months, the 18-months PFS was 48% (95% CI: 0.36-0.58) and the OS was 75% (95% CI: 0.64-0.83). The 18-months PFS for PTCL-NOS versus ALK negative vs AITL/THF was 37% (95% CI: 0.20-0.54) vs. 51% (95% CI: 0.28-0.70) vs. 58% (95% CI: 0.36-0.74), p 0.118; the 18-months OS for PTCL-NOS vs. ALK negative vs. AITL/THF was 72% (95% CI: 0.51-0.85) vs. 76% (95% CI: 0.51-0.89) vs. 81% (95% CI: 0.60-0.92), p 0.957. All 86 patients completed the induction phase and were evaluable for response after 6 Ro-CHOEP: the overall response rate (ORR) was 71% (61 patients), with 62% (53 patients) CR. Four patients with ongoing treatment are not evaluable for response at the end of therapy, at the time of the analysis. Only 39 of 82 patients (48%) underwent HSCT and 43 did not: 28 due to progressive disease, 8 for poor mobilization, 7 for adverse events (1 sepsis, 2 cardiological events, 4 others). Among the 82 patients evaluable for response at the end of treatment, the final ORR after HSCT was 40% (33 patients), with 39% CR (32 patents). The most frequent toxicities during Ro-CHOEP treatment were hematological, with grade 3-4 neutropenia and thrombocytopenia in 33% and 34% of all the 459 cycles, respectively; severe febrile neutropenia was reported in only 4% of Ro-CHOEP courses. Severe non-hematological toxicities were observed in 35 (41%) of patients: cardiological in 5 patients (6%), gastrointestinal in 9 (10%), infections in 10 (12%), others in 11 (13%). Twenty-four deaths were recorded: 22 due to lymphoma progression, 1 due to transplant related mortality for a septic shock after alloSCT, 1 due to secondary malignancy. Conclusions: In the PTCL13 phase I part of the study we demonstrated the feasibility of the combination Ro 14 mg/ms plus CHOEP followed by high-dose chemotherapy and HSCT; in the phase 2 part of the study, the primary objective was not achieved, with a 18-months PFS of 48%. Based on these results, the enrollment of the trial was stopped due to inefficacy of the experimental combination. The benefit of adding romidepsin to chemotherapy was not observed neither in PTCL-NOS nor in AITL/THF. In conclusion, the addition of romidepsin to CHOEP did not ameliorate prognosis in newly diagnosis PTCLs eligible to HSCT. Disclosures Chiappella: Roche: Other: lecture fee, advisory board; Incyte: Other: lecture fee; Takeda: Other: advisory board; Celgene Bristol Myers Squibb: Other: lecture fee, advisory board; Clinigen: Other: lecture fee, advisory board; Novartis: Other: lecture fee; Janssen: Other: lecture fee, advisory board; Gilead Sciences: Other: lecture fee, advisory board; Astrazeneca: Other: lecture fee; Servier: Other: lecture fee. Flenghi: Roche: Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses. Zilioli: Gentilli: Consultancy, Speakers Bureau; Takeda: Consultancy, Other, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Italfarmaco: Consultancy. Cavallo: Servier: Speakers Bureau; Gilead: Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees. Musuraca: roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Varettoni: janssen: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Corradini: Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy. OffLabel Disclosure: Romidepsin is not registered in first line treatment. Romidepsin was provided free for the clinical trial.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153680

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: The Lancet Oncology, Elsevier BV, Vol. 15, No. 7 ( 2014-06), p. 730-737

Type of Medium: Online Resource

ISSN: 1470-2045

URL: Article

DOI: 10.1016/S1470-2045(14)70191-3

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 2049730-1

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 903-903

Abstract: Abstract 903 Introduction. R-CHOP21 is the standard treatment for untreated elderly DLBCL, however up to 40% of patients fail. There is a need to improve the efficacy of R-CHOP21; an option may be the addition of novel drugs in first line induction therapy. Lenalidomide has a complex mechanism of action as immunemodulation, antiangiogenesis, restoration of immunesynapses and direct antitumor effects. Lenalidomide monotherapy exhibits significant activity in patients with relapsed aggressive B-cell NHL and has in vitro synergy with rituximab and cytotoxic therapy. This rationale prompted FIL to conduct a prospective multicenter dose finding phase I-II trial aimed at evaluating toxicity and activity of lenalidomide plus R-CHOP21 (LR-CHOP21) in elderly untreated DLBCL (NCT00907348). In the dose-finding phase I study, 21 patients were enrolled, and 15 mg lenalidomide from day 1 to day 14 was identified as the maximum tolerated dose (MTD) in combination with R-CHOP21 (Vitolo, Ann Oncol 2011;22(4):331a). Patients and Methods. Based on the phase I results, 15 mg of lenalidomide in combination to R-CHOP21 was tested in a phase II study. Phase II was designed according to Simon's two stage design; primary endpoint was an improvement of overall response rate (ORR) of 15% in LR-CHOP21 compared to 70% of standard R-CHOP21 and the study would be considered of interest if at least 16/23 in step 1 and 39/49 in step 2 responses occurred. Response was evaluated according to 2007 Cheson criteria. PET scan was mandatory at the end of the treatment; patients in partial remission (PR) who underwent radiotherapy were considered as failure in progression free survival (PFS) analysis. Inclusion criteria were: age 60–80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; IPI at LI/IH/H risk. Treatment plan was: R-CHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. Mandatory supportive care included: GCSF or PegGCSF, cotrimoxazole as Pneumocystis Jiroveci prophylaxis and low molecular weight heparin or low dose aspirin as deep venous thrombosis prophylaxis. Results. From April 2010 to May 2011, 49 patients were enrolled in the phase II study including 9 patients treated at the MTD during phase I. Clinical characteristics were: median age 69 years (range 61–80); stage III/IV 43 (88%), performance status 〉 1 31 (63%), IPI IH/H 30 (61%). The step-1 of the trial showed an ORR of 22/23. At the end of 6 LR-CHOP21, ORR was 45/49 (92%). Complete remissions (CR) were 42 (86%) and PR 3 (6%); 3 patients (6%) did not respond and one (2%) died for violent death. At a median follow-up of 18 months, overall survival (OS) was 94% (95% CI: 82–98) and PFS was 75% (95% CI: 57–86). (Figure 1). Of the 294 planned courses of LR-CHOP21, 277 (94%) were administered, of which 221 (75%) with lenalidomide as planned, 40 (14%) with dose and/or day reduction and 16 (5%) without lenalidomide. Median dose of lenalidomide delivered in 49 patients was 1185 mg (IQR 900–1260), i.e. 94% of the planned dose (1260 mg). The most frequent cause of lenalidomide reduction or withdrawal was neutropenia. At least 90% of the planned dose of doxorubicine, cyclophosphamide and vincristine were administered, in: 91%, 95% and 83% of the R-CHOP21 courses, respectively. Median interval time between R-CHOP21 courses was 21 days (range 19–48). Hematological toxicity was mild: grade III/IV thrombocytopenia occurred in 13% of courses, anemia in 5% and neutropenia in 33%, with only 4% of febrile neutropenia. No grade IV extra-hematological toxicities were observed. Grade III non-hematological toxicities were reported in 7 patients: cardiologic, gastroenteric and renal in one patient respectively, grade III neurological toxicities, sensory and motorial neuropathy in two, thromboembolic event in one not receiving anti-thrombotic prophylaxis, and skin rash in one. No toxic deaths occurred during treatment. One patient died three months off therapy while in CR, due to aeromonas hydrophila sepsis and multi-organ failure. Conclusions. The addition of 15 mg lenalidomide on days 1–14 to R-CHOP21 is safe, feasible and effective in elderly untreated DLBCL. The primary objective of the phase II study was met, with 92% of ORR of which 86% CR and promising PFS rates. The addition of lenalidomide did not impair the administration of R-CHOP21. Based on these data, the efficacy of LR-CHOP21 needs to be investigated in a large phase III randomized trial in elderly DLBCL. Disclosures: Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Dreyling:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.903.903

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 850-850

Abstract: The standard treatment for elderly untreated diffuse large B-cell lymphoma (DLBCL) is RCHOP21, however up to 40% of patients experienced failures. Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 (Chiappella et al, Haematol 2013), FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL and identified 15 mg lenalidomide from day 1 to day 14 as the maximum tolerated dose in combination with RCHOP21. Patients and methods. The phase II trial REAL07 was designed based on Simon's two stage design to demonstrate an improvement of overall response rate (ORR) of 15% in LRCHOP21 compared to 70% of standard RCHOP21. Secondary endpoints were progression-free survival (PFS), overall survival (OS), event-free survival (EFS) and to correlate outcome with cell of origin (COO) profile. Response was evaluated according to 2007 Cheson criteria. Inclusion criteria were: age 60-80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; international prognostic index (IPI) at low-intermediate/intermediate-high/high (LI/IH/H) risk. Treatment plan was: RCHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. All cases were centrally reviewed by expert pathologist; COO profile analysis was conducted with immunohistochemistry according to Hans' algorithm and with gene expression profile (DASL assay). Results. From April 2010 to May 2011, 49 patients were enrolled. Clinical characteristics were: median age 69 years (range 61-80); stage III/IV 43 (88%), IPI IH/H 30 (61%). At the end of 6 LRCHOP21, ORR was 92%. Complete remissions (CR) were 42 (86%) and partial remission 3 (6%); 3 patients (6%) did not respond and one (2%) died for homicide. At a median follow-up of 28 months, 2-year OS was 92% (95% CI: 79-97), 2-year PFS was 80% (95% CI: 64-89) and 2-years EFS was 70% (95% CI: 55-81); 2-year PFS for IPI LI was 89% (95% CI: 62-97) and for IPI IH 76% (95% CI: 47-90) and for IPI H 72% (95% CI: 36-90). Hematological and extra-hematological toxicities were mild, with no grade IV extra-hematological events and no toxic deaths during treatment. Of the 294 planned courses of LRCHOP21, 277 (94%) were administered; median dose of lenalidomide delivered was 1185 mg (94% of the planned dose); at least 90% of the planned dose of each drug was administered in 91% of the RCHOP21 courses. Median interval time between RCHOP21 courses was 21 days (range 19-48). All 49 cases underwent central pathology review and diagnosis of DLBCL was confirmed. Regarding COO analysis, tissue block or stained slides were collected in 40/49 (82%), of which 32 were adequate for analysis. At the time of this abstract, COO analysis was reported according to immunohistochemistry data; DASL analysis is ongoing. Clinical characteristics between germinal center (GCB, 16 patients) and non-GCB (16 patients) were superimposable, excepted for a majority of H IPI risk in non-GCB group (p 0.067). ORR for GCB and non-GCB were 88% (CR 81%) and 88% (CR 88%), respectively. At a median follow-up of 28 months, 2-year PFS was 71% (95% CI: 40-88) in GCB-group and 2-years PFS was 81% (95% CI: 51-93) in non-GCB-group (Figure 1). Conclusions. In conclusion, LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup. These encouraging data warrant a future phase III randomized trial comparing LRCHOP21 vs. RCHOP21 in untreated non-GCB DLBCL. Disclosures: Off Label Use: lenalidomide in first line DLBCL is off lable. drug provided free by Celgene. Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.850.850

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Geriatric Oncology, Elsevier BV, Vol. 11, No. 1 ( 2020-01), p. 37-40

Type of Medium: Online Resource

ISSN: 1879-4068

URL: Article

DOI: 10.1016/j.jgo.2019.06.020

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2556813-9

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1-1

Abstract: Introduction. Previous uncontrolled studies have highlighted the activity of rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To better address this effect, a prospective randomized (1:1), multicenter, phase III study comparing treatment with dexamethasone alone (arm A) vs dexamethasone plus rituximab (arm B) was conducted from July 2005 through June 2007 for adult patients with previously untreated ITP and a platelet (PLT) count ≤20 × 109/L. Material and methods. Patients randomized to arm A received a single course of oral dexamethasone 40 mg on days +1, +2, +3, +4, while patients randomized to arm B received dexamethasone (as in arm A) in association with rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response and had a platelet count ≤20 × 109/L (from day +30 up to the end of 6 months) could receive salvage treatment with the experimental arm (dexamethasone plus rituximab). The primary objective of the study was to compare the sustained response (SR), i.e. PLT count 50 × 109/L at month + 6 of treatment. Secondary objectives were: evaluation of the safety, the initial response (PLT count 50 × 109/L) by day 30 after the initiation of treatment, the activity of salvage therapy with dexamethasone plus rituximab in patients non responding to dexamethasone monotherapy, the definition of clinical and laboratory factors predictive of response and to explore the pharmacokinetics parameters of rituximab and their potential relation with response. Results were analyzed by an intention to treat (ITT) and by a per-protocol (PP) analysis. Results. One-hundred-one patients (52 for arm A and 49 for arm B) and 64 patients (38 for arm A and 26 for arm B) represented the ITT and PP population, respectively. Demographic baseline data were in accordance to what expected for a population of ITP patients. No significant differences among the two groups of randomization were present. There was a female prevalence and the mean age was 47 and 49 years in arm A and B, respectively. Table 1 summarizes the ITT and PP efficacy results considering 3 different levels of response (i.e. PLT count 50 × 109/L, 100 × 109/L and 150 × 109/L). A significant advantage for arm B patients was documented. Table 1 Initial response Initial response Sustained response Sustained response Analysis Intention-to Treat Per-Protocol Intention-to Treat Per-Protocol Treatment Arm A Arm B P value Arm A Arm B P value Arm A Arm B P value Arm A Arm B P value Valuable patients 44 25 32 13 52 49 38 26 PLT 3 50×109/L 27% 68% .001 31% 69% .009 36% 63% .004 39% 85% & lt;.001 PLT 3 100×109/L 23% 48% .015 28% 46% .122 33% 53% .019 37% 77% & lt;.001 PLT 3 150×109/L 18% 36% .178 22% 38% .127 25% 43% .029 29% 65% .002 Twenty-seven patients initially allocated to arm A and who failed to achieve initial response or SR received salvage treatment with the dexamethasone plus rituximab. In this group, ITT and PP SR rate were 56% and 59%, respectively. No clinical or laboratory factors predictive of SR were identified. In arm B patients the serum concentrations of rituximab levels did not correlate with the rate of response. Twelve SR patients of arm A, 27 of arm B and 19 of salvage therapy group were systematically followed up beyond month 6 for a median period of observation of 18 months (range 10–34 months). The rate of SR loss (platelets & lt; 50 × 109/L) in these three groups was 25 % (3/12), 11% (3/27) and 10.5% (2/19). The safety profile was good with no substantial difference between the two arms of randomization. No patient died during the study period. Conclusion. The results of this study indicate that the association of dexamethasone plus rituximab improves patients outcome without worsening of the safety profile. This effect is characterized by prolongation of SR and reduction in relapse rate. The long period of relapse free survival registered in some patients suggests a possible curative effect. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.1.1

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 398-398

Abstract: Introduction: Management of elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL) is challenging. A simplified Comprehensive Geriatric Assessment (sCGA) based on ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales has demonstrated to be better than clinical judgement to stratify patients' outcome but has never been included in initial assessment. To further assess the impact of sCGA on patients' outcome, we conducted a prospective observational study on a large series of elderly patients with DLBCL. Methods: Patients were enrolled if 65 year old or older, with an untreated de novo DLBCL. sCGA was available at a web based platform that classified patients as FIT, UNFIT, and FRAIL, as shown in Table 1. Treatment choice was left at physician discretion. According to anthracycline dose, therapy was classified as curative (≥70% of full anthracycline dose), intermediate ( & lt;70%) or palliative (no anthracycline). Primary study endpoint was Overall Survival (OS). Results: From December 2013 to December 2017, 1353 patients have been registered by 37 centres and 1207 were eligible. Median age was 76 years (65-94), 68% had stage III-IV, and 55% had an International Prognostic Index(IPI) ≥3; 500 (42%), 304 (25%), and 403 (33%) were classified as FIT, UNFIT and FRAIL, respectively. Data on treatment were available in 1164 patients: rituximab was used in 96% of patients; treatment was curative in 89%, 53%, and 36% of FIT, UNFIT, and FRAIL patients, respectively; intermediate in 10%, 39%, and 31%, palliative in 0%, 8%, and 33% of patients. The OS was available in 1158 out 1164 cases. With a median follow up of 30 months (1-59) 3y-OS was 64% (95% CI 61% to 67%). According to sCGA the OS was significantly different among the 3 geriatric groups. Correlation with OS was improved when sCGA was integrated with age & lt; or ≥ 80 years to define 3 groups of patients (Table 2): FIT and UNFIT younger than 80 years (sCGA Group 1; 55%, 3 yr OS 75%), UNFIT ≥ 80 years and FRAIL younger than 80 years (sCGA Group 2: 28%, 3yr OS 58%), FRAIL ≥ 80 years (sCGA Group 3: 17%; 3yr OS 43%). Univariable and multivariable analysis for OS was conducted using the 3 sCGA groups and other clinical and laboratory features. The 3 sCGA groups were shown as independent prognostic factors with IPI and with anemia (Hb & lt; 12 g/dl). We used results of multivariable analysis to build a categorical prognostic index assigning different weights to prognostic features based on their Hazard Ratio (HR) (Table 3). The Elderly Prognostic Index (EPI) was defined as the score obtained from the sum of the weights and allowed to define 3 risk groups: Low Risk (LR: score 0-1; 23% of patients); Intermediate Risk (IR; score 2-4; 48%); High Risk (HiR; score 5-7; 29%). The 3 EPI risk groups had a different 3 year OS of 87%(95%CI 81-91), 69%(95%CI 63-73), and 42% (95%CI 36-49); HR for IR vs LR 2.57 (1.72, 3.84); HiR vs LR 6.21(4.17 -9.25), HiR vs IR 2.42 (1.91-3.05) (Figure1). Regarding treatment modality, curative, intermediate and palliative therapies were adopted in 89%, 10%, and 1% of the LR group; 70%, 24%, 7% of the IR group, and 37%, 35%, 28% of the HiR group. The model was internally validated by means of 1000 procedures confirming good performance (slope shrinkage 0.935 and c-Harrell 0.675 in validation sample compared with 0.682 in training sample). The EPI was also tested in an external validation data set that was identified from the pivotal study of sCGA in DLBCL (N=172 patients, Tucci A. et al, Leuk Lymph, 2015) (Figure 1). Conclusion: Using data from this large prospective observational study on elderly DLBCL patients we were able to build a new prognostic index that allows to identify 3 risk groups with significant differences in terms of 3 years OS. The EPI is the first index that integrates geriatric assessment with clinical features and contributes to improving management and clinical research in elderly patients with DLBCL. Disclosures Spina: Servier: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Sandoz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other; Roche: Other: lecture fee; Teva: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; GILEAD: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Celgene: Other: lecture fee; BMS: Other: lecture fee; Sanofi Genzyme: Other: lecture fee; CTI: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Menarini: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee, Research Funding; Takeda: Other: lecture fee; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Pfizer: Membership on an entity's Board of Directors or advisory committees. Merli:Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Cavallo:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J & J: Honoraria; Celgene: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Chiappella:Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Ferrero:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Luminari:ROCHE: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; GILEAD: Other: Lecturer; TAKEDA: Other: Travel Grant.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123027

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7