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In: American Journal of Hematology, Wiley, Vol. 98, No. 2 ( 2023-02)

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v98.2

DOI: 10.1002/ajh.26779

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 1492749-4

In: Hematological Oncology, Wiley, Vol. 36, No. 4 ( 2018-10), p. 624-632

Abstract: The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB‐related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life‐saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v36.4

DOI: 10.1002/hon.2503

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 2001443-0

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2946-2946

Abstract: Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL. Methods. Sixty-one fit CLL patients from 15 Italian institutions were enrolled in this front-line study and treated with the FC-O2 regimen based on the FC schedule (F 25 mg/sqm i.v. d1-3, C 250 mg/sqm i.v. d1-3) combined with 13 doses of O (300 mg i.v. d14; 1000 mg d21 at the first cycle; 1000 mg d1 and d15 at cycles 2-6 and d28 at cycle 6). As infection prophylaxis, patients received bactrim and peg-filgrastim in order to prevent granulocytopenia. CLL diagnosis, treatment requirement and response were assessed according to the 2008 iwCLL guidelines. Minimal residual disease (MRD) was evaluated by flow cytometry in the peripheral blood (PB) and bone marrow (BM), and also by RQ-PCR in flow negative cases. CT scan evaluation was included in the response assessment. Adverse events (AEs) were graded according to the NCI-CTCAE. Results. The median age of patients was 60 years (range 36-65), Binet stages B and C were recorded in 86% of cases, B-symptoms in 21%, increased β2M values in 74% and bulky nodes (≥5 cm) in 10%. An IGVH unmutated status was recorded in 60% of cases, deletion 13q in 37%, no aberrations in 33%, deletion 11q in 14%, trisomy 12 in 12%, 17p deletion and/or TP53 mutation were found in 10% of cases. At present, the median follow-up of patients is 7 months (range 1-20). Response to treatment has been assessed in 29 patients after a median number of 6 courses of treatment (range 2-6). The overall response rate is 90%, with a CR rate of 69% (20 patients). No evidence of MRD was observed by flow cytometry in both PB and BM in 15/20 CR patients (75%). To date, 11 patients with cytometric MRD negative CR have been evaluated by RQ-PCR and no residual disease was detected in 3. Grade 3-4 granulocytopenia was recorded in 4 patients (7%), a severe infection in 4 (7%) and 5 patients (8%) experienced a severe infusion-related reaction during ofatumumab administration. Treatment was discontinued in 8 patients as a result of toxicity (infection, 2 cases; FUO, 1; infusion-related toxicity, 1; autoimmune hemolytic anemia, 1; recurrent granulocytopenia, 1; tachyarrhythmia, 1; non-specified toxicity,1). A non-treatment-related death (traumatic aortic transaction due to a dislocated aortic endoprostheses) has been recorded in a patient after 2 months from treatment discontinuation and 1 showed a disease progression after 4 courses of FC-O2. Conclusions. Taken together, the first analysis of this ongoing front-line study suggests that the combination of FC with an increased dose of ofatumumab is well tolerated with acceptable and no unexpected toxicity. Our preliminary results show that the FC-O2 treatment is associated with a high rate of cytometric MRD-negative CR in young and fit patients with previously untreated CLL. Disclosures Carella: Seattle Genetics Inc.: Research Funding. Foà:Roche: Consultancy, Honoraria, 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.V126.23.2946.2946

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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. 3147-3147

Abstract: Introduction. Observational, real-life studies are relevant to understand whether data derived from prospective controlled trials (CTs) are reproducible in the day-to-day clinical practice. Within a named patient program (NPP), free and early access to ibrutinib was made available for the treatment of relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL) until this agent was approved in Italy. To define the efficacy and toxicity profile of patients treated with ibrutinib in this real-life setting, the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group carried out a retrospective analysis on the outcome of R/R patients with CLL who received ibrutinib in the NPP. Methods. Between April 2014 and January 2015, 216 R/R patients with CLL managed at 20 centers in Italy were included in the NPP. Patients were required to have R/R disease with disease progression within 24 months after prior chemo-immunotherapy. All patients received ibrutinib at the standard dose of 420 mg daily, continuously until disease progression or unacceptable toxicity. The period of observation included the duration of the NPP and was extended up to January 2016 for patients still on treatment with the commercial drug. Clinical data were reported retrospectively by the treating physicians using the Research Electronic Data Capture (REDCap) system. Results. The median age of patients was 58.3 years (range 27.5-81); 89% of patients were in Binet stage B-C. The median number of prior treatments was 3 (range 1-14). Thirty-seven % of patients was refractory to prior treatment. Deletion 17p and/or TP53 mutations were found in 54% of patients and deletion 11q in 11.6%. Seventy-eight % of patients had an unmutated IGHV gene profile. Prior atrial fibrillation (AF) was reported in 13 cases (6%), while 7 patients with AF (3.3%) were on anti-arrythmic treatment. Hypertension was recorded in 76 cases (35.2%). The median follow-up of patients was 24 months (range, 1-24 months. A response to ibrutinib was observed in 172 patients (79.6%) with a clinical CR/CRi in 34 (15.7%) and a PR/PR-L in 138 (63.9%). Similar response rates were observed in patients with an unmutated IGHV gene status (82.1%) and in those with deletion 17p/TP53 mutations (79.6%). The progression-free survival (PFS) and overall survival (OS) at 24 months were 64.6% (95%CI: 58.0-71.9) and 72.7% (95%CI: 66.5-79.4), respectively. No differences in PFS and OS were observed according to the IGHV mutational status (IGHV unmutated vs mutated: PFS, 65.2% vs 61.0%; p=0.7; OS, 65.2% vs 72.0%, p=0.6) and the presence of TP53 aberrations (TP53 aberrations, present vs absent: PFS, 64.8% vs 64.1%; p=0.6; OS, 69.8% vs 72.7%; p=0.8). Forty-eight patients (22.2%) discontinued ibrutinib within 12 months and 22 (10.2%) within 12-24 months from the start of ibrutinib. Progressive disease and Richter syndrome were the most common reasons for discontinuation that accounted for 16.2% (35 patients) and 1.8% (4 patients) of cases, respectively, and occurred after a median of 17 months from the start of ibrutinib. Treatment discontinuations due to adverse events (AEs) were recorded in 25 patients (11.6%) after a median time of 6 months from the start of treatment and included infections/febrile events in 7 cases, bleeding events in 3 (intracranial hemorrhage 1), sudden death in 3, acute myocardial infarction in 1, ischemic stroke in 2, second malignancy in 3, diarrhea in 1. AF occurred during treatment in 14 (6.5%) patients and was the reason of ibrutinib discontinuation in 2. AEs leading to discontinuation was not specified in 3 cases. Other reasons for ibrutinib discontinuation in 6 (2.8%) patients were ASCT in 4, unplanned surgery in 1, unknown in 1. Survival probability at 12 months from treatment discontinuation due to AEs or DP/RS was 38.2 and 37.2 months respectively (p= 0.6). Conclusions. The results of this real-life study show that in unselected patients with R/R CLL the clinical activity of ibrutinib was comparable to that reported in CTs. However, a third of patients discontinued ibrutinib within 24 months from the start of treatment. An earlier introduction of ibrutinib in the treatment approach of R/R patients, a careful surveillance and management of toxicities will optimise the clinical benefits of ibrutinib in CLL patients treated in the clinical practice. Disclosures Mauro: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: 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, Speakers Bureau. Zinzani:TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; MSD: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cortelezzi:novartis: Consultancy; roche: Consultancy; abbvie: Consultancy; janssen: Consultancy. Carlo-Stella:AstraZeneca: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Consultancy; ADC Therapeutics: Research Funding, Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Genenta Science: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Amgen: Speakers Bureau; MSD Italia: Speakers Bureau. Molica:Roche: Other: Advisory board; Gilead: Other: Advisory board; Jansen: Other: Advisory board; AbbVie: Other: Advisory board. Coscia:Janssen, Karyopharm: Research Funding; Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaja:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Gobbi:Ariad: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Amgen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Cuneo:janssen: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118280

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. 136, No. Supplement 1 ( 2020-11-5), p. 33-34

Abstract: INTRODUCTION. Richter syndrome (RS), the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, is a rare but a life threatening complication. Complex karyotype (CK), defined by the presence of ≥3 chromosomal lesions, is a heterogeneous cytogenetic category associated with a shorter survival in CLL, but its impact on the evolution into a RS has not been investigated. Among CK cases, those with≥5 lesions (highCK) and those with major structural abnormalities [type-2 CK (CK2)] display a more aggressive clinical course. The aim of this study was to assess the impact of CK subtypes on the risk of CLL evolution into a RS. METHODS. We performed a retrospective study in 3 Italian CLL centers. Stimulated cytogenetic with CpG+IL2 was performed in 540 patients within the first year after CLL diagnosis. CK cases with unbalanced translocations, additions, insertions, derivative or marker chromosomes were classified as type-2 CK (CK2). Instead, high-CK cases were those presenting at least 5 chromosome abnormalities. An IGHV gene sequence homology ≥98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). TP53 disruptions (TP53dis) included deletions and/or mutations. Time to Richter syndrome (TTRS) was calculated from CLL diagnosis to either histologically confirmed diffuse large B-cell lymphoma transformation or last known follow-up visit. Survival curves were compared with the log-rank test and p & lt;0.05 was considered as significant. Hazard ratio (HR) was calculated by multivariate analysis. RESULTS. Among the 540 patients, the median age at diagnosis was 63±12 years, 61% were males, 76% were at Binet stage A, 52% were U-IGHV, 11% had TP53dis, 20% harbored a CK. According to the qualitative classification of CK subtypes, 78/107 (73%) were CK2, whereas, with regards to the number of chromosome lesions, 52/107 (49%) were classified as high-CK. High-CK was present in 63% of CK2 patients. Seventeen % of patients died and 5% developed a RS over a median follow-up of 7 years. Overall, the rate of RS after 5 and 10 years from the diagnosis of CLL was 2.6% and 12%. We observed that patients who developed a RS were more commonly at a more advanced Binet stage at CLL diagnosis (46% vs 23%, p=0.0113) and displayed more frequently an U-IGHV status (79% vs 56%, p=0.0191), TP53 abnormalities (32% vs 10%, p=0.0043), CK2 (46% vs 13%, p & lt;0.0001) and a high-CK (39% vs 8%, p & lt;0.0001) profile, as compared to patients who did not developed RS. By univariate and multivariate analysis, the presence of a CK (overall), of a CK2 and of a high-CK subtypes were all significantly associated with a shorter TTRS, together with U-IGHV status, TP53dis, 11q- by FISH and Binet stage B-C. Patients with a CK2 (HR=5.6 p & lt;0.0001) and/or a high-CK (HR=6.9 p & lt;0.0001) harbored the highest risk of developing a RS, with a 10-year TTRS of 38% and 41%, respectively, vs 8% of patients without a CK. Other variables associated with TTRS at univariate and multivariate analysis were Binet stage B-C, U-IGHV, 11q-, TP53 dis. By integrating the statistically significant variables, we developed a hierarchical model based on HR values (Figure 1): 15% of patients were classified as high-CK and/or CK2, for whom the 10-year TTRS was 31% and the HR 13; 45% were U-IGHV/TP53dis/11q-/Binet B-C and showed a 10-year TTRS of 12% and the HR 3; 40% were M-IGHV without CK and TP53 wild-type, the 10-year TTRS was only 3%. This model was confirmed in multivariate analysis and internally validated (p & lt;0.0001). Moreover, our RS scoring system prove to better forecast the risk to develop RS that the hierarchical FISH score, the CLL-IPI and the Barcelona-Brno score, based both lower prediction error and Akaike index. CONCLUSIONS. We herein identified variables associated with a higher risk of developing a RS and recapitulated them into a RS scoring system. Remarkably, patients harboring a CK subtype at CLL diagnosis have the highest risk of developing a RS and should be carefully monitored during the clinical follow-up. Figure Disclosures Visentin: Gilead: 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, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin:Abbvie: Honoraria, 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, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro:Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Abbvie: 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, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trentin:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136605

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 30-31

Abstract: INTRODUCTION. Kinase inhibitors and glycoengineered monoclonal antibody, such as obinutuzumab (G), have significantly changed the treatment landscape of chronic lymphocytic leukemia (CLL). Both like the BTK inhibitor ibrutinib (IB) and obinutuzumab plus chlorambucil (G-CHL) are approved as first line therapy in CLL patients unfit for a fludarabine-base treatment. While IB has proved to be superior to bendamustine-rituximab in a phase 3 trial and an ongoing retrospective ERIC study, no head-to-head comparison has been done for IB vs G-CHL in a real-world evidence study. The aim of this study was to compared the clinical efficacy of the fixed duration G-CHL treatment vs continuous treatment with IB. METHODS. The inclusion criteria for this observational study were patients with a diagnosis of CLL, requiring treatment according to the iwCLL guideline (Hallek M, Blood 2018) and considered unfit for fludarabine-base therapy by the treating physician belonging to the Italian CLL campus. Patients received ibrutinib 420mg daily until progression or unacceptable toxicity, while G was administrated at 100mg on day 1, 900mg on day 2 and 1000mg on days 8 and 15 of the 1st cycle, then at 1000mg from cycles 2-6. Chlorambucil was administrated according to the local policy. An IGHV gene sequence homology ³98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). TP53 disruptions (TP53dis) included deletions and mutations. Progression-free survival (PFS), time-to-next treatment (TTNT) and overall survival (OS) were calculated according to the iwCLL 2018 guideline. Minimal residual disease (MRD), assessed by flow cytometry, was considered undetectable when & lt;10-4 (uMRD4). Survival curves were compared with the log-rank test and p & lt;0.05 was considered as significant. The study was approved by the ethic committee of Padua university hospital. RESULTS. We recruited 284 CLL patients from 16 hematologic centers, 104 were treated with G-CHL and 180 with IB as first-line treatment. Once TP53dis cases were excluded, 102 patients treated with G-CHL and 80 treated with IB were included for further analysis. Among patients managed with G-CHL the median age was 75 years and 20% were older than 80 years, 47% had a CIRS≥6 (range 2-18), 68% had a clearance creatinine & lt;70ml/min, 60% showed a Rai stage III-IV, 32% were U-IGHV and 11% harbored 11q deletion by FISH. Patients treated with IB displayed a better renal function (p=0.0011) and were enriched in U-IGHV cases (p=0.0001). After a median follow-up of 21 months, 23 patients relapsed (20 G-CHL, 3 IB), 16 required a subsequent treatment (14 G-CHL, 2 IB) and 17 died (10 G-CHL and 7 IB). Two patients in the IB arm developed Richter syndrome. After 8 months from the start of treatment, the overall response rates in the G-CHL and IB arms were 86% vs 77% (p=0.1480), including 25% vs 6% complete remissions (CR, p=0.0013) and 61% vs 71% partial responses (PR, p=0.6320). Remarkably, an uMRD4 by flow-cytometry was documented in 42% and 9% of G-CHL patients in the peripheral blood and bone marrow, respectively. The median PFS was 33 months for G-CHL arm, but not reached for IB patients. The 24months PFS, TTNT and OS was 67% vs 91% (p=0.0012), 83% vs 97% (p=0.0128) and 89% vs 95% (p=0.5314) for the G-CHL and IB arms, respectively. Interestingly, the depth of response influenced PFS only in the G-CHL arm both in terms of clinical response (the median PFS was 8, 29 and 38 months for no responding, PR and CR patients) and MRD status (the 24 months PFS was 82% vs 50% and 100% vs 58% for uMRD4 vs MRD+ evaluated on peripheral blood and bone marrow). While the PFS was significantly better with IB than with G-CHL in U-IGHV (p=0.007), it was superimposable for M-IGHV patients (p=0.1946). Dose reductions or discontinuations were recorded in 39% and 44% of patients in the G-CHL and IB arms. Atrial fibrillation and infections occurred in 2% and 6% (p=0.0442), and in 25% and 17% (p=0.1455) of patients in the G-CHL and IB arms, respectively. CONCLUSIONS. The Italian experience with G-CHL confirms the marked efficacy and safety of this combination, in particular for patients who reach a CR and/or an uMRD4. The continuous treatment with ibrutinib provides a better disease management in CLL patients unfit for fludarabine-base therapy, but some on them - particularly those with a M-IGHV status - can achieve a long-term disease control with a fixed duration obinutuzumab-based chemoimmunotherapy. Disclosures Visentin: Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Mauro:Takeda: Membership on an entity's Board of Directors or advisory committees; Octopharma: Consultancy; Astrazeneca: 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; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale:Janssen: Honoraria. Ciolli:Janssen: Honoraria; Abbvie: Research Funding. Sportoletti:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Murru:Gilead: 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, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gozzetti:Janssen: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria. Molica:Roche: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Marchetti:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Scarfo:Abbvie: 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, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: 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, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Laurenti:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Pizzolo:Abbvie: Speakers Bureau; janssen: Speakers Bureau. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Foà:Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: 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; Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: 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, Speakers Bureau. Trentin:Shire: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: 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-2020-136883

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300

Abstract: Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy. Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment. Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; 〉 65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; 〈 6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%). Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p 〈 0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL. Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3300.3300

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3240-3240

Abstract: Introduction. Elderly patients with chronic lymphocytic leukemia (CLL) and younger patients with comorbidities are often treated with chlorambucil (Chl), despite the relatively low response rates. The addition of anti-CD20 monoclonal antibodies to Chl substantially increases the response rates, without negatively affecting tolerability. Overall response rates (ORR) between 66% to 84% have been reported with these combinations, with complete responses (CR)ranging from 8% to 26%. Methods. We conducted a retrospective analysis on the use of the Chl-rituximab (R) combination as frontline treatment for elderly (≥65 years) and/or unfit (CIRS 〉 6) CLL patients treated at 15 different Italian hematologic centers. The main aim of the study was to further establish the safety and efficacy of the Chl-R protocol and investigate whether certain CLL patients for whom this protocol could be particularly effective could be identified. To this end, we performed a subgroup analysis stratifying patients according to FISH and IGHV results: high risk group (HR) included patients with 17p deletion, intermediate risk group (IR) patients with 11q deletion and/or unmutated IGHV, low risk group (LR) patients without 11q or 17p deletion and/or unmutated IGHV. Results. One hundred and two patients who underwent treatment between 2009 and 2011 were enrolled in the study. Patients' clinical and biologic characteristics are summarized in Table 1. Three patients discontinued treatment earlier than planned: 1 for an episode of autoimmune hemolytic anemia (AIHA) that developed after the 2nd cycle of Chl and before starting R treatment and 2 patients for disease progression after the 3rd and 5th cycle of Chl-R, respectively. The median number of Chl and R cycles administered in the 102 patients was 8 (range 2-12) and 6 (range 1-9), respectively. The planned treatment schedule was different among centers: the two main schedules used were Chl administered at 1 mg/kg for each cycle every 28 days, given at a fixed daily dose of 10 mg starting from day 1 and repeated for 8 cycles, and Chl administered at 8 mg/m2/day for seven days of each of eight 28-day-cycles. R was added to Chl from the 3rd cycle onwards and was administered on day 1 of each cycle at a dose of 375 mg/m2 during the first administration and 500 mg/m2 for the subsequent 5 cycles. On an intention to treat basis, the ORR was 87.1%. Thirty-two patients (31.7%) obtained a CR and 56 patients (55.4%) obtained a partial response (PR). Nostatistically significant differences were noted in terms of ORR for age above or below 70 years, fitness status, ECOG, bulky disease, cytogenetic risk abnormalities, IGHV mutational status, ZAP-70 or CD38 expression.Median progression-free survival (PFS) and time to retreatment (TTR) were reached at 43.7 and 72.3 months, respectively. Median overall survival (OS) was not reached; 86.1% and 81.2% of patients were alive at 48 and 60 months, respectively. The most frequent serious adverse event was grade 3-4 neutropenia, occurring in 13.7% of patients. Grade 3-4 extra-hematologic side effects were uncommon (9.8%). Subgroup analysis of the LR and IR patients (no HR patients were enrolled) showed that LR patients had a significantly better PFS than IR patients (65.8 months vs 35.2 months, p=0.001; Fig. 1),with 54.9% of patients remaining free from progression 60 months after treatment. Conclusions. Treatment of elderly and/or unfit CLL patients with the Chl-R regimen is associated with low toxicity, a high ORR and durable PFS. Particularly good results are achieved in CLL patients with a mutated IGHV profile and not carrying both 17p and 11q deletion, suggesting that in this low-risk subset of unfit patients Chl-R could represent the optimal therapeutic option, in consideration of safety, efficacy and costs. Disclosures D'Arena: Janssen-Cilag: Honoraria. Coscia:Gilead: Honoraria; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Mundipharma: Honoraria; Karyopharm: Research Funding. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Efremov:Gilead: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3240.3240

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 89, No. 5 ( 2014-05), p. 480-486

Abstract: In a phase II trial, we evaluated chlorambucil and rituximab (CLB‐R) as first‐line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28‐day cycles of CLB (8 mg/m 2 /day, days 1–7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4–8, 500 mg/m 2 ). Responders were randomized to 12 8‐week doses of R (375 mg/m 2 ) or observation. As per intention‐to‐treat analysis, 82.4% (95% CI, 74.25–90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60–64 years, 92.3%; 65–69, 85.2%; 70–74, 75.0%; ≥75, 81.0%). CLB‐R was well tolerated. After a median follow‐up of 34.2 months, the median progression‐free survival (PFS) was 34.7 months (95% CI, 33.1–39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB‐R represents a promising option for elderly CLL patients. Am. J. Hematol. 89:480–486, 2014. © 2014 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v89.5

DOI: 10.1002/ajh.23668

Language: English

Publisher: Wiley

Publication Date: 2014

detail.hit.zdb_id: 1492749-4

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 17, No. 10 ( 2017-10), p. S11-S12

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2017.09.039

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3