Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 8029-8029

Abstract: 8029 Background: Hodgkin Lymphoma (HL) treatment in the elderly is a challenge, as standard ABVD is able to cure no more than 60% of the patients (p.). Bendamustine (Be), and Brentuximab Vedotin (BV), are well-tolerated and effective drugs in relapsing HL, but only preliminary data exist in 1st line treatment of the elderly (Evens AM 2018). Methods: HALO is a prospective international multicenter open-label phase I/II study (NCT02467946) to assess the safety and efficacy of Be-BV in advanced-stage elderly HL p. Briefly, BV 1.2 mg/kg on D1, and Be 90 mg/m2 on D1-2 were administered Q3W for 6 cycles. The primary endpoint was the feasibility and the efficacy of Be-BV. Results: Between July 2015 and February 2019, 59/60 p. consecutive enrolled received at least 1 Be-BV cycle, and are valuable for primary endpoint. One p. was excluded because a histological review showing angioimmunoblastic T-Cell Lymphoma. The mean age was 70.32 (62-79), and M/F ratio 41/18. The Ann-Arbor stage was IIB in 12, III in 14 and IV in 33 patients, B-symptoms (y/n) 40/19. IPS was 0-2 in 19 and ≥ 3 in 40 p., P.S. (ECOG) was 0-1 in 53, 2 in 6 p., nonetheless most of them were frail, as ADL was ≥ 6 in 47 (79%) and IADL was ≥ 8 in 42 (71%) p. Most frequent co-morbidities were cardio-vascular disease (45) metabolism disorders (31) prostatic adenoma (11). 163 treatment-related adverse events (WHO 3-4) were recorded: neutropenia and lymphopenia, (134), infections (7), cutaneous reactions (5), liver toxicity (2). No case of grade 〉 2 peripheral neuropathy was recorded. Out of 59 p., 41 concluded and 18 interrupted the treatment for toxicity (8), progression (5), treatment failure (2), CMV reactivation (3). The latter was recorded in 17 p., 12/17 received valgancyclovir. 4 p. died with CMV viremia. After a mean follow-up of 20.6 (0.3-46.5) months, 37/59 (63%) were in CR, while 22 (37%) have progressed (5) or relapsed (17). The 2-y OS and PFS in ITT analysis were 83% (95% CI 71-96) and 54% (95% CI 41-72) and in PP 89% (95%CI 75-100) and 78% (95%CI 64-96), respectively. 22 p. had a PFS event: 5 progression (2 deaths), 17 relapse (8 deaths). 10 p. died for recurrent HL (5), sepsis (1), secondary malignancy (2), respiratory insufficiency (1) and unknown (1). Conclusions: The Be-BV combination, a novel anthracycline-free regiment for first line treatment of HL in elderly, proved effective in unselected, frail, poor-risk, HL p. aged more than 60 in daily hospital real life. The CMV reactivation is frequent and should be treated with preemptive antiviral therapy upon detection of CMV DNA in plasma. Clinical trial information: NCT02467946 .

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2020.38.15_suppl.8029

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2020

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 25-26

Abstract: Background Ixazomib (IXA) is an orally-administered proteasome inhibitor approved in Europe in November 2016 for relapsed and/or refractory multiple myeloma (RRMM). It became available in France in May 2017 via a compassionate use program (CUP) and from October 2018 via the classical market access (non-CUP). In addition to pivotal clinical trials, real-world evidence (RWE) is required to evaluate effectiveness and safety in clinical routine practices. A non-interventional study, has been conducting in France to evaluate IXA use in combination with lenalidomide and dexamethasone (IRD) in real life. Methods REMIX is a non-interventional, multicentric study to assess IRD effectiveness and safety, conducted in 59 sites (public and private) in patients with RRMM. IRD was initiated in second line or more during the CUP and afterwards. After inclusion, patients were assessed every 3 months (mo) during 24 mo then every 6 mo as per standard practice. This interim analysis assessed IRD effectiveness (median Progression Free Survival (mPFS), 12 and 24-mo overall survival (OS) rates and tolerance in the CUP patients initiating IXA concomitantly to RD (patients who started lenalidomide more than 6 weeks before IXA were excluded). The analysis was conducted globally and per subgroups (age, number of lines of treatment, frailty as defined by Facon T & al.in Leukemia 2020). The CUP-patient median study follow-up was 17.4 mo for this interim analysis. Results The 198 eligible CUP patients were 47% of males, with a median age of 69 years (26% ≥75y). Out of them, 45% were frail and 7% had renal failure (CrCl ≤30 ml/min). Comorbidities were reported in 64% of patients including diabetes (9%), renal disease (10%), solid tumor (9%). At diagnosis, the cytogenetic risk was standard, high or unknown in respectively 46%, 13% and 41% of patients; 11% presented a plasmacytoma. 41% had multiple or severe bone lesions and 25% peripheral neuropathy. MM was diagnosed at a median of 4 years before IRD initiation. IXA was initiated after one (L2) / two (L3) / three or more lines of treatment (L4+) in respectively 58%, 18% and 24% of patients. Of them, 38% had received lenalidomide during prior line(s), mainly in patients with L3 and L4+ (78%, 65/84) vs L2 (8%, 9/114). The median washout period between lenalidomide discontinuation and IRD start was 18 mo 95%CI [17.6 - 29.6]. The mPFS was 19.2 mo 95%CI [13.3; 21.9] for the CUP cohort. mPFS was 21.5 mo 95%CI [13.3; 21.9] for L2 (104 patients), 17,8 mo 95%CI [12.2; 26.7] for L3 (29 patients) and 5.6 mo 95%CI [4.1; 8.8] for L4+ (38 patients) (c.f. Figure1). mPFS was similar in & lt;75 YO (19.2, mo 95%CI [12.3; 24.8]) and in ≥75 YO patients (19.2 mo, 95%CI [1.7; 21.5] ). In the subgroup with available frailty score (n= 124), mPFS was 21.5 mo 95%CI [12.5; -] in non-frail and 13.3 mo 95%CI [5.6 ; 19.8] ) in frail patients. 12mo and 24mo-OS rates were 84% 95%CI [78%; 89%] and 73% 95%CI [65%; 80%] for the global group. Among the 166 patients with available response according to investigators, overall response rate (ORR) was 68% (66% in & lt;75 YO and 71% in ≥75 YO patients) and very good partial response (VGPR) 35% (38% in & lt;75 YO and 27% in ≥75 YO patients). The 187 followed-up CUP patients received a median of 14 IRD cycles. IXA discontinuation was reported in 50% of patients (n=92), related to AE in 13% of cases (n= 24). Serious adverse events were reported in 34% (n=69), including 14 (7%) patients with SAE considered related to IXA. Most frequent ( & gt;10%) AE were thrombocytopenia (30%), diarrhoea (28%), asthenia (20%), anaemia (18%), neutropenia (15%), nausea (14%) and peripheral neuropathy (10%). Conclusion Few RWE data have been published for IXA use in Europe. In this first interim analysis, estimated mPFS is consistent with MM1 results or data reported in MM1 study (19,2 mo vs 20.6 mo) even though CUP patients in REMIX were globally elder, frailer and more frequently treated in advanced lines (24% of L4+ in REMIX vs 11% of L4 in MM1). Reported adverse events were in line with known safety IXA profile. Figure 1 Disclosures Laribi: abbvie: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; takeda: Research Funding. Vincent:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Macro:sanofi: Honoraria; gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Texier:Kappa Santé: Other: employee of the CRO in charge of REMIX. Chouaid:pfizer: Honoraria, Research Funding; GSK: Honoraria, Research Funding; novartis: Honoraria, Research Funding; pfizer: Honoraria, Research Funding; takeda: Honoraria, Research Funding; bms: Honoraria, Research Funding; msd: Honoraria, Research Funding; astra zeneca: Consultancy, Honoraria, Research Funding; amgen: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding. Leleu:GSK: Honoraria; Amgen: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptide: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Karyopharm: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-133807

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. 140, No. Supplement 1 ( 2022-11-15), p. 4312-4314

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157942

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 108, No. 1 ( 2022-06-16), p. 181-195

Abstract: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%] ) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.

Type of Medium: Online Resource

ISSN: 1592-8721 , 0390-6078

URL: Article

DOI: 10.3324/haematol.2022.281226

Language: Unknown

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2022

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 20-21

Abstract: Background : AETHERA randomized controlled study (Moskowitz, Lancet 2015) showed that the administration of Brentuximab Vedotin (BV) maintenance after autologous stem cell transplantation (ASCT) improved progression free survival (PFS) in BV-naive refractory/relapsed (R/R) Hodgkin lymphoma (HL) patients. However, since BV approval for R/R HL in 2012, many patients are receiving salvage BV before ASCT, alone or combined with chemotherapy. In the AMAHRELIS retrospective nationwide French study, we investigated the real-life outcome of patients with R/R HL mostly treated with BV-based salvage therapies and who received post-ASCT BV maintenance. Objectives : As primary 0objective, we assessed 2 years-PFS of patients treated with post-ASCT BV maintenance from 2012 to 2017 in France. As secondary objectives, we correlated variables (such as use of salvage BV before ASCT, centrally reviewed TEP-assessed response) with survival, and evaluated reported tolerance of BV using the CTCAE v4.0 criteria. Methods : We conducted this observational retrospective study in 58 national centers. Inclusion criteria were R/R HL patients who received at least two infusions of BV after ASCT, at the exclusion of patients in progression after transplant. Among 1134 patients who underwent ASCT for R/R HL between 2012 and 2017 in France based on the French society of bone marrow transplantation database, 835 (74%) patients were screened and data were available for 794 (70%) patients. FDG-PET scan at relapse and before transplantation were recorded and centrally reviewed (still ongoing). FDG-PET scan were reported using the Deauville score (DS), and complete remission was defined by a DS & lt; 4. Post-transplant status was evaluated based on CT-scan or on FDG-PET scan results. This study was approved by the SFGMTC and the LYSA. Results : Fifteen percent (115/794) of patients met eligibility criteria, and were enrolled in this study. Among them, 95% met inclusion criteria for BV maintenance according to the AETHERA study as primary refractory disease (43%), early relapse (27%) or extranodal disease (49%). The mean number of BV injections after ASCT was 11 (3-18). Patients characteristics were : mean age was 34 y (range between 16-70y), 54% were male, and 57% of patients were stage III or IV at relapse. Notably, 70% of patients received BV as salvage therapy and 81% achieved a complete remission before ASCT. The median follow-up period was 35 months. The 2 years survival for the whole cohort was 75,3% for PFS (95% CI : 68,4-84,3) and 96,4% for overall survival (95% CI : 94,2-100) (Figure 1). The use of BV as part of salvage therapy before transplant had no impact on PFS. We observed a trend to an increased occurrence of neuropathy in patients receiving BV before transplant without impact on early treatment discontinuation. We tested several variables for correlation with survival using a univariate Cox model including high risk patients defined as primary refractory disease or early relapse and disseminated disease, extranodal relapse, use of BV before transplant, number of salvage lines, remission status before and after transplant (complete response versus partial response or stable disease), time between ASCT and BV onset and number of BV cycles after transplant. Among these variables, high risk status, less than 10 post transplant BV cycles and absence of post transplant complete remission significantly correlated with a reduced survival probability, and remained significant after analysis using a multivariate Cox model (Table 1). Conclusion : From the real-life AMAHRELIS study, we confirmed the very good outcome of R/R HL patients in the era of post-transplant BV maintenance, with a 2y-PFS of 75% similar to the results of the AETHERA landmark study (2y-PFS of 63%). The results of current strategies with pre- and post-transplant BV outperformed historical series based on high dose therapies, including those of tandem transplant for high risk patients. Future studies incorporating BV strategies with immune checkpoint inhibitors might improve outcome in R/R HL patients. Disclosures Meignan: ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Fornecker:Takeda: Consultancy; Roche: Consultancy. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cartron:Gilead: Honoraria; Jansen: Honoraria; Abbvie: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Ghesquieres:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Brice:Takeda: Consultancy; Roche: Consultancy. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Roche: Consultancy; Novartis: Research Funding; Alexion: Research Funding. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding. Deau Fischer:Takeda: Consultancy; Roche: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138666

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. 39-39

Abstract: Introduction The IFM 2009 study prospectively evaluated the combination of 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) versus (vs) 3 cycles of RVd plus high dose (HD) melphalan with autologous stem cell transplantation (ASCT) plus 2 consolidation RVd cycles, followed by lenalidomide maintenance for 12 months (mo) in newly diagnosed multiple myeloma (NDMM) patients (Attal M et al, NEJM 2017). RVd with transplant was associated with significantly longer progression-free survival (PFS) (primary endpoint) compared to RVd alone. Overall survival (OS) at 4 years was similar in both groups. In order to evaluate the long-term outcome in the 2 arms and the impact of 2nd line treatments on PFS2 and OS, we performed an extension of patient follow-up (FU) of the IFM 2009 study over a period of 4 years (DB-FU-IFM 2009 / NCT03679351). Methods 700 NDMM patients (pts) (median age 59 years [range, 28.0-65.0]) were randomized between the 2 arms after stratification by ISS stage and FISH analysis. Patient characteristics were well-balanced, notably age, gender, ISS3, and high risk cytogenetics (defined by t(4;14), t(14;16), del(17p)). 100 patients (50 from each arm) who experienced 1st progression were included in the IFM 2009-02 PCD trial (NCT02244125, Garderet L et al, Blood 2018). The choice of 2nd line treatment and decision to perform an ASCT at relapse was based on investigator's discretion. PFS2 was defined as the time from randomization to progression on next line therapy or death from any cause; second PFS as the time from date of 1st progression to progression on next line therapy or death. This trial was previously reported with a median FU of 44 mo (Attal M et al, NEJM 2017). Results As of March 2020, median FU was 93 mo [range, 88-98]. As previously reported, median PFS was significantly longer in the transplant group (TG), at 47.3 mo compared to 35.0 mo in the RVd alone group (RG) (HR (95CI) 0.70 [0.59-0.83] p & lt;0.001). 497/700 pts experienced disease progression, 270 (77.1%) pts in the RG and 227 (64.9%) pts in the TG; 262 and 217 of them respectively initiated a 2nd line. Among these pts, 76.7% (201/262) in RG and 22.6% (49/217) in TG received an ASCT at 1st relapse; 40.1% (105/262) and 46.5% (101/217) respectively received a pomalidomide-based 2nd line. Only 14 and 12 pts received carfilzomib- and daratumumab-based 2nd line regimens. Median PFS2 was similar in both groups, at 95 mo in the RG and not reached (NR) in the TG (HR [95CI] 0.96 [0.76-1.21] p=0.76). This estimate was homogeneous across ISS stage (p-value for interaction 0.26) and cytogenetic group (p-value for interaction 0.90). Median PFS2 in ISS3 and high-risk cytogenetic pts was 73 and 75 mo, and 48 and 47 mo, in the RG and TG, respectively. Second PFS was significantly increased in the RG, at 36 vs 25 mo in TG (HR [95CI] 1.41 [1.11-1.79] p=0.003). Median OS was NR in either group. At 8 years, the OS rate was 60.2% in the RG and 62.2% in the TG (HR [95CI] 1.03 [0.80-1.32] p=0.81). Minimal residual disease (MRD) was a strong predictor of outcome: PFS (HR [95CI] 0.28 [0.22-0.36] p & lt;0.001), PFS2 (HR [95CI] 0.27 [0.20-0.37] p & lt;0.001) and OS (HR [95CI] 0.35 [0.25-0.49] p & lt;0.001) were longer in pts achieving MRD negativity, in comparison with those who did not. The incidence of invasive 2nd primary cancer was not significantly different between the 2 groups (p=0.38); of note, 2nd hematological malignancies were reported in 5/350 and 7/350 pts in RG and TG respectively. Conclusion RVd before and after HD melphalan and ASCT followed by one-year of lenalidomide maintenance is associated with a significantly longer PFS than RVd alone, without a significant increase of 2nd primary malignancy. At 1st relapse, before the systematic use of daratumumab- or carfilzomib-based combinations, almost half of the pts received pomalidomide-based treatment and about 3 quarters of pts who had not received frontline ASCT underwent delayed transplant. With a FU of almost 8 years, median OS was NR and there was no difference between the 2 strategies with respect to PFS2 and OS. MRD appears to predict outcome and might be used after induction to identify those pts who probably do not require a transplant. Quadruplets with anti-CD38 monoclonal antibodies combined with the selective use of HD therapy and transplant, followed by extended maintenance, should be considered in the future to further improve outcome. Such an approach could potentially provide a functional cure for a significant proportion of NDMM pts. Disclosures Perrot: Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clement-Filliatre:BMS/Celgene: Honoraria. Macro:gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; sanofi: Honoraria; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Leleu:AbbVie: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Oncopeptide: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; BMS-celgene: Honoraria. Munshi:C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Anderson:Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Moreau:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Attal:BMS/Celgene, Sanofi: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134538

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. 28-30

Abstract: Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 and is approved for intravenous (IV) infusion across lines of therapy for MM. In phase 3 clinical studies, DARA IV plus Rd for RRMM (POLLUX) and DARA IV plus VMP for transplant-ineligible (TIE) NDMM (ALCYONE) led to deep and durable responses and reduced the risk of disease progression or death by ≥56% (Kaufman J, Blood 2019. 134[Suppl 1]:1866; Mateos M, Lancet 2020). In the phase 1b MMY1001 study of DARA IV plus carfilzomib/dexamethasone (Kd) in RRMM, DARA IV plus Kd was well tolerated and demonstrated deep responses, regardless of prior lenalidomide treatment (Chari A, Blood 2019.134[Suppl 1] :1876). In the phase 3 CANDOR study, DARA IV plus Kd reduced the risk of disease progression or death by 37% in pts with RRMM (Dimopoulos M, Lancet 2020). A formulation of DARA for subcutaneous administration (DARA SC) was developed (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.). Advantages of DARA SC include reduced administration time (3-5 minutes) and lower rates of infusion-related reactions (IRRs). The phase 2 PLEIADES study is evaluating the safety and efficacy of DARA SC combined with SoC for MM, including D-Kd for RRMM, D-Rd for RRMM, and D-VMP for TIE NDMM. In the primary analysis of the D-Rd and D-VMP cohorts in PLEIADES, D-Rd and D-VMP demonstrated clinical activity and safety comparable to corresponding DARA IV regimens, with low rates of IRRs, leading to approval in the United States (Chari A, Clin Lymphoma Myeloma Leuk 2019.19[10] :e16-e17). Here, we present the primary analysis of the D-Kd cohort and updated data for the D-Rd and D-VMP cohorts of PLEIADES. Methods: RRMM pts with 1 prior line of therapy (including 2 consecutive cycles of lenalidomide therapy) received 28-day cycles of Kd (K: 20 mg/m2 IV Cycle 1 Day 1, escalated to 70 mg/m2 on Cycle 1 Days 8 and 15, then 70 mg/m2 on Days 1, 8 and 15 of each cycle thereafter; d: 40 mg IV or PO QW) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). RRMM pts with ≥1 prior line received 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg IV or PO QW for each cycle) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). TIE NDMM pts received 9, 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly in Cycle 1 and QW in Cycles 2-9; M [9 mg/m2] and P [60 mg/m2] PO on Days 1-4 of Cycles 1-9) with DARA SC (QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ in 28-day cycles). All pts were treated until disease progression/unacceptable toxicity. Overall response rate (ORR) was the primary endpoint for each cohort. Additional outcomes were VGPR or better rate, CR or better rate, duration of response, minimal residual disease (MRD)-negativity rate, DARA serum concentrations, and safety. Results: At the time of the clinical cutoff for the D-Kd cohort, 66 pts were treated and the median duration of follow-up was 8.7 months. The ORR for D-Kd was 84.8% (90% CI, 75.7-91.5; Table) and response rates were consistent with DARA IV plus Kd in CANDOR (Dimopoulos M, Lancet 2020). For the updated analysis of the D-Rd cohort (n=65), median follow-up was 23.1 months, and the ORR was 93.8% (90% CI, 86.5-97.9; Table). Response rates for D-Rd were consistent with DARA IV plus Rd in POLLUX (Kaufman J, Blood 2019. 134[Suppl 1]:1866). For the updated analysis of the D-VMP cohort (n=67), median follow-up was 22.6 months. The ORR for D-VMP was 89.6% (90% CI, 81.3-95.0; Table), and response rates were consistent with DARA IV plus VMP in ALCYONE (Mateos M, Lancet 2020). The median duration of DARA SC administration was 5 minutes for all D-Kd injections. The safety profile of D-Kd was consistent with DARA IV as combination therapy with SoC regimens. The rates of IRRs and injection-site reactions were comparable to those observed with DARA SC monotherapy in the COLUMBA study (Mateos M, Lancet Haematol 2020). Additional data will be presented including MRD-negativity rates for all cohorts and updated safety data for the D-Rd and D-VMP cohorts. Conclusions: The primary analysis of the D-Kd cohort demonstrated comparable clinical activity and safety to DARA IV plus Kd. With extended follow-up in the D-Rd and D-VMP cohorts, clinical activity was comparable to corresponding DARA IV-containing regimens (DARA IV plus Rd [POLLUX]; DARA IV plus VMP [ALCYONE] ). A low incidence of IRRs and a short duration of administration were reported in the D-Kd cohort in PLEIADES. Table 1 Disclosures Moreau: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Chari:Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding; Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Kite: Consultancy, Honoraria. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Sureda Balari:BMS: Speakers Bureau; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Magen:AbbVie: Research Funding; Merck Sharpe and Dohme: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sano: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding. Iida:Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck Sharpe Dohme: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene: Other: Personal fees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Yang:Janssen: Current Employment. Kosh:Janssen: Current Employment. Delioukina:Maria Delioukina: Current Employment. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Goldschmidt:GlaxoSmithKline (GSK): Honoraria; Merck Sharp and Dohme (MSD): Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Incyte: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding. OffLabel Disclosure: This abstract includes discussion of a combination therapy with subcutaneous daratumumab plus carfilzomib and dexamethasone, which is currently under investigation in clinical trials, but has not yet been approved. Subcutaneous daratumumab is approved as monotherapy and in combination with other standard-of-care regimens for the treatment of multiple myeloma.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134935

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 137, No. 9 ( 2021-03-4), p. 1192-1195

Abstract: Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called “double-hit” population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in & gt; 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the “double hit” situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying “double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020008346

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. 134, No. Supplement_1 ( 2019-11-13), p. 132-132

Abstract: Introduction: About 10-15% of patients with localized and 25-30% with disseminated classical HL failed to respond or relapse after primary conventional treatment. For the youngest, autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy leading to an increased disease free survival (DFS). With this strategy 50 to 70% of patients with chemo sensitive disease become eligible for ASCT. As the disease status before ASCT appears to be the most important factor predicting outcome, second line chemotherapy has to be more efficient. Brentuximab-Vedotin (BV) has shown significant activity (SG035-0003) in patients with relapsed or refractory HL. Therefore, it seems logical to use BV in patients treated with ICE before ASCT in order to induce a better Complete Metabolic Response (CMR) rate evaluated by FDG-PET (Deauville score 1-3). Methods: BV was added to ICE in a phase I/II trial chemotherapy trial sponsored by LYSARC with a financial support by Millenium. The optimal dose of BV (1.8 mg/kg) with ICE (3 cycles) was established in the phase I of the study (10 patients). In the second part of the study (phase II), efficacy and toxicity of the Recommended Phase II Dose (RP2D) was assessed. Patients received 2 cycles of BV ICE before evaluation and only CMR received the third course, than an injection of brentuximab alone before ASCT. Primary endpoint was CMR after 2 cycles of treatment. Results: Final analysis was performed in 42 patients for toxicity and 39 patients for the efficacy set. Baseline characteristics were median age: 30 years (range: 18-65), Sex ratio (M/F): 27/15, nodular sclerosis histology in 83%, stage III/IV in 67 % and status of the disease: 12 refractory patients and 30 relapsed patients with a median time to first relapse of 19 months (9-159). First-line treatment was escBEACOPP (n =21) ABVD (n= 17) OEPA/copdac (n= 2) PVAB (n=1) CHOP (n =1). All patients received the two first cycles, 78.6 % the third cycle and 71 % the brentuximab alone without modification of doses but with delay of at least one cycle in 45 %. Grade 3-4 adverse events were encountered in 35 patients (83%) mainly due to hematologic toxicity (71%) followed by infection (21%) and gastro-intestinal disorders (10%). No neuropathy and no toxic death were observed. Most patients (69.2%, n=27) had CMR, followed by PMR (25.6%, n=10). Among the 39 patients, three patients (7.7%) had progressive disease during treatment phase. Leukaphereses were performed in 31 patients (79%) median collected D34+ cells was 7.2 (106/kg) and 20 patients out of the 25 with CMR underwent ASCT. Thirteen patients relapsed mainly during follow-up (10) and no death was observed without progression. The median PFS was not reach and the one-year-PFS was 69% [95% CI: 53%-81%]. Conclusion: Two cycles of BV in R/R HL patients who are treated by ICE chemotherapy allows a CMR in 69.2 % of evaluable patients with sufficient harvest for an ASCT. These results are comparable to other salvage chemotherapies only after two cycles with acceptable toxicities. Disclosures Stamatoullas: Takeda: Consultancy; Celgene: Honoraria. Quittet:Novartis: Honoraria, Speakers Bureau. Morschhauser:F. Hoffmann-La Roche Ltd: Consultancy, 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; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Ribrag:Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses . Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123925

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 12 ( 2021-12), p. 3600-3603

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-021-01250-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2