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In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9375-9377

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-159949

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 16-17

Abstract: Background and Aims. Prediction of treatment efficacy is an active and growing field of pharmacology. In the Fondazione Italiana Linfomi (FIL) MCL0208 phase III trial (NCT02354313), a 24 months lenalidomide maintenance (LM, 15 mg days 1-21 every 28 days) after high-dose immuno-chemotherapy followed by autologous transplantation (ASCT) in 300 frontline mantle cell lymphoma (MCL) patients showed substantial clinical activity in terms of Progression-Free Survival (PFS) vs observation (OBS). However, this benefit seemed not uniform across patient series. To deeper investigate the differential pattern of response to lenalidomide, a wide analysis of the host pharmacogenomics (PG) background was planned, in order to dissect whether specific germline polymorphisms of transmembrane transporters, metabolic enzymes or cell surface receptors (ABCB1, ABCG2, VEGFA, FCGR2A, NCF4, GSTP1, CRBN) might predict the drug efficacy. Actually, several single nucleotide polymorphisms (SNPs) of ABCB1 exert an effect on substrate affinity of lenalidomide for the transmembrane transporter. Moreover, VEGFA is involved in the anti-angiogenic activity of lenalidomide and might eventually upregulate ABCB1 expression, too. Patients and methods. Genotypes for SNPs were obtained through allele-specific (ASO) probes on germline DNA from peripheral blood. Minor allele frequencies (MAFs) were obtained and the Hardy-Weinberg equilibrium (HWE) was checked. Genotypes were used to infer individual haplotypes by Arlequin and Haploview softwares. Minimal residual disease (MRD) was assessed with ASO primers on either IGH or BCL-1/IGH rearrangements by RQ-PCR in bone marrow samples. TP53 disruption was identified by NGS targeting resequencing and copy number variation analysis. Clinical-biological correlations were screened by automated machine learning methods and validated by both Kaplan-Meier at univariate level and Cox models for multivariate analysis (MV). A logistic regression was implemented to investigate correlations between polymorphisms and MRD kinetics. Results. 278 out of 300 patients (93%) were fully genotyped. The MAF values of the SNPs were very similar to published data and the HWE was confirmed. Most notably, ABCB1 c.2677G & gt;T/A(W) and VEGFA c.2055A & gt;C were significantly associated to outcome and are thus described in this abstract. In the case of ABCB1, the three loci were in strong linkage disequilibrium (p & lt;0.001). 31% of patients were homozygous for ABCB1 wild type alleles (GG, "WT"), 53% heterozygous (GW, "HET") and 16% polymorphic on both chromosomes (WW, "POL"). 20% were VEGFA WT (AA), 47% HET (AC) and 33% POL (CC). PG did not impact on induction therapy and randomization rates of this trial, as superimposable polymorphism frequencies were described between the enrolled and randomized population. Conversely, both ABCB1 HET and POL and VEGFA HET/POL associated with higher MRD clearance rates vs WT after 6 months of LM (93% vs 71% and 91% vs 67%, respectively). Interestingly, the risk of MRD reappearance during LM was 86% lower for patients harboring either polymorphism vs WT (odds ratio 0.14, 95% CI 0.02-0.99; p & lt;0.05). Actually, ABCB1 HET/POL predicted for a more favorable PFS vs WT in LM (3yPFS 85% vs 69% p & lt;0.05, Fig.1A), as well as VEGFA HET/POL (3yPFS 85% vs 59% p & lt;0.01, Fig.1B). The two polymorphisms co-occurred in 57% of patients, being 12% ABCB1 HET/POL only, 23% VEGFA HET/POL and 8% ABCB1/VEGFA WT. Interestingly, patients with either polymorphism had superimposable outcome to patients in whom both co-occurred (Fig.1C). Finally, MV showed that either polymorphism was protective for PFS among randomized patients (HR=0.42; 95% CI 0.20-0.85; p & lt;0.05). According to this hypothesis, among the 17 ABCB1/VEGFA WT patients LM did not improved PFS vs OBS (Fig.1D), independently from TP53 disruption. Conclusions. The first PG data on LM after ASCT in MCL suggested that: 1) ABCB1 and VEGFA polymorphisms did not impact on the chemotherapeutic efficacy of FIL-MCL0208 trial; 2) both polymorphisms favored sustained MRD clearance during LM; 3) either polymorphism conferred a survival advantage during LM. Taken together, these observations hint that a variable excretion of lenalidomide through ABCB1 (heralded by SNPs), as well as an altered VEGFA pathway, could predict treatment efficacy. This observation might be very useful in the future to tailor lenalidomide therapy to MCL patients. Disclosures Ferrero: Servier: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Maria:Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses; BMS: Consultancy; MSD: Consultancy; Janssen: Consultancy, Other: travel, accomodations, expenses; Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding. Ferreri:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Hutchinson: Research Funding; BMS: Research Funding. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. OffLabel Disclosure: Lenalidomide maintenance in mantle cell lymphoma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134875

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. 128, No. 22 ( 2016-12-02), p. 2985-2985

Abstract: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context. Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. Disclosures Cascavilla: Janssen-Cilag: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; 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.V128.22.2985.2985

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 2 ( 2023-02), p. 433-440

Abstract: The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18–65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0–56.7), and the 18-month overall survival was 73.1% (95%CI:61.6–81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-022-01780-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2008023-2

In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. S3 ( 2023-08), p. e8994203-

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/01.HS9.0000967796.89942.03

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2023

detail.hit.zdb_id: 2922183-3

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6538-6539

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-163824

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 154-154

Abstract: Abstract 154 Background Follicular lymphoma (FL) has an indolent course during which patients (pts) receive multiple lines of active treatments ranging from single-agent chemotherapy (CHT) or monoclonal antibodies (MoAb), to high-dose therapy with stem cell transplantation (HSCT). In relapsed patients the efficacy of salvage treatments may be affected by the type and the intensity of the previous treatments and it is currently not known whether a definite sequence of treatments throughout the course of the disease could optimize the outcome of patients. Since randomized trials can hardly be designed to answer this important clinical question, the Fondazione Italiana Linfomi (FIL) launched an observational, multicenter, retrospective study (REFOLL) to analyze if combinations of different first-line and salvage treatments could be identified, able to achieve a better long-term outcome. Patients and Methods Of 582 pts with FL at first relapse between 2000 and 2008 registered from 25 Institutions, 548 were included in the study. They had received either alkylating- (AA) (22%), or anthracycline- (AC) (61%) or nucleoside analogues-based (NA)(17%) CHT as first-line treatment, with the addition of rituximab (R) in 284 (52%). AA pts were older (P 〈 .001), but they had less stage III-IV (P=.011) and FLIPI high-risk disease (P=.02), and had received maintenance R after first-line CHT more often (P 〈 .001) compared to pts receiving AC- or NA-based CHT. At relapse 21 pts received radiotherapy and 4 palliation and were excluded. Salvage treatment of the other 523 pts were either the same first-line CHT programs (AA: 20%; AC 18%; NA: 14% of the 523 pts, respectively) in 271 pts, associated with R in 73%, or a program including autologous HSCT in 151 (29%), or MoAb/radioimmunoconjugate without CHT in 101 (19%). The primary endpoint of the study was time to next treatment (TTNT) after relapse. Progression-free survival after relapse (PFS) and overall survival (OS) were secondary endpoints. Results The median follow-up after first relapse was 41 months (range 1–122) and the median TTNT (50%) was 41 months (CI95% 35–47 months). Among first-line treatments, AC+/−R was associated with a better TTNT after any salvage than AA+/−R or NA+/−R (HR: 0.71, P=0.007; HR: 0.73, P=0.021 after adjustment by age, stage and year of diagnosis). The addition of R to first-line CHT did not adversely impact on the efficacy of salvage treatments (P=0.156). As salvage treatment, auto-HSCT had a significantly better outcome when compared to any other program +/−R (HR ranging from 1.79 to 2.40). Patients receiving auto-HSCT were younger (P 〈 0.001), had a shorter duration of first remission (P=0.012), but the efficacy of HSCT was not affected by these two parameters. ASCT program included R in 63% and was followed by R maintenance in 7% of pts. Considering the combinations of first-line and salvage treatments received, using multiple Cox regression, the TTNT after relapse was significantly better in pts receiving first-line anthracycline CHT +/−R followed by auto-HSCT as salvage (HR ranging from 1.88 to 3.3 compared to any other sequence, including AA/NA CHT followed by auto-HSCT). Other factors independently influencing TTNT after HSCT were R maintenance (HR: 0.66), duration of first remission 〉 12 months (HR: 0.8), and stage III-IV at diagnosis (HR: 1.89). PFS after relapse was 35% at 5 years, superimposable to TTNT (36% at 5 years); in fact treatment sequences had the same effects on PFS as on TTNT. Overall survival from diagnosis was 89% at 5-yr (CI95% 85–91%) and the sequences CHT- 〉 HSCT and CHT- 〉 CHT with R showed a better outcome than CHT - 〉 CHT without R (HR:0.55, P=0.015; HR 0.61, P=0.047 after adjusting by age and stage at diagnosis). Conclusions Auto-HSCT obtained the best TTNT after relapse compared to any other regimen but its efficacy was maximized when anthracycline-containing CHT was used as first-line treatment, compared to other CHT programs. The addition of R to first-line CHT did not adversely impact on the results of any salvage. This study supports the concept that different sequences of active treatments do not necessarily obtain similar long-term results, which is important in the management of indolent diseases like FL and warrants further studies. The sequence of AC-CHT at diagnosis and auto-HSCT at relapse may be tested as the reference sequence of active treatments in FL patients. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.154.154

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. 136, No. Supplement 1 ( 2020-11-5), p. 22-23

Abstract: Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). A number of therapies are used for second- and later-line treatment including Bruton's tyrosine kinase inhibitors (BTKi). However, treatment failure and intolerance are common and alternative therapies are needed. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor that demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for a cohort of BTK inhibitor-naïve pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments. Prior treatment with BTKi and PI3Ki were prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG] ). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 104 pts were treated (WG, n = 31; DG, n = 73). Enrollment was ongoing (target:100 pts). At cut-off, a total of 50 (48%) pts had discontinued treatment, including 31 (30%) pts for disease progression. The median exposure (range) was 4.0 months (0.1-19.1). The median age was 72 years and 80% of pts were men. The median time since initial diagnosis was 3.6 years. The majority of pts (92%) had ECOG PS ≤1, and 57% had high-risk MCL International Prognostic Index. The median number of previous systemic therapies was 1; 31% of pts had prior hematopoietic stem cell transplant, and 44% were refractory to their most recent systemic therapy. At the data cut-off, 92 pts were evaluable for efficacy including 31 in WG and 61 in DG (Table). The median follow-up duration (range) for this population was 11.8 months (1.9-24.0) overall and 9.1 (1.9-24.0) for DG. The ORR (95% confidence interval CI) and CRR were 66.3% (55.7-75.8) and 15.2%, respectively in all evaluable pts, and were 65.6% (52.3-77.3) and 11.5% for DG. The median time to response for pts with a complete or partial response was 7.9 weeks. The median DOR (95% CI) was 11.0 months (6.6-14.7) for all responders and 9.0 months (7.7-14.7) for DG. The median PFS (95% CI) was 11.1 (5.8-16.6) months overall, and 11.1 (5.6-16.6) months for DG. Among 104 safety-evaluable pts, most common treatment-emergent AEs (TEAEs) occurring in & gt;10% of pts were diarrhea (25.0%), pyrexia (16.3%), constipation (11.5%), and neutropenia (10.6%). Most common grade ≥3 TEAEs reported in ≥5% of pts were neutropenia (8.7%) and diarrhea (7.7%). TEAEs leading to dose interruption or dose reduction occurred in 31.7% and 1.9% of pts, respectively. TEAEs leading to discontinuation occurred in 16.3% of pts including diarrhea (5.8%) and colitis (2.9%). Serious TEAEs reported in ≥2 pts included diarrhea (5.8%), colitis (2.9%), pyrexia (2.9%) and cytomegalovirus infection (1.9%). Four pts experienced fatal TEAEs. The fatal TEAEs in one pt (monocytic acute myeloid leukemia, leukocytosis, and acute kidney injury) were considered related to treatment. TEAEs of clinical interest included neutropenia (10.6%), rash (8.7%), colitis (4.8%), pneumonia (1.9%), PJP and pneumonitis (1% each). New or worsening grade ≥3 laboratory test values of clinical interest included decreased neutrophils (8.7%), platelets (7.7%), and hemoglobin (1.9%), and increases in alanine/aspartate aminotransferase (2.9%/1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safely profile and was generally well tolerated. These preliminary results suggest that parsaclisib represents a potentially new drug class and treatment option for BTKi-naïve, R/R MCL. Updated study results will be presented. Disclosures Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, 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; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: 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-2020-134872

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. 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