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In: Blood, American Society of Hematology, Vol. 135, No. 21 ( 2020-05-21), p. 1859-1869

Abstract: Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019003453

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 580-580

Abstract: Background: High-dose methotrexate (HD-MTX)-based chemotherapy is the conventional approach to primary CNS lymphomas (PCNSL), but superiority of polychemotherapy over HD-MTX alone is unproven. A benefit of adding high-dose cytarabine (araC) to MTX has been suggested by a meta-analysis and a large retrospective series. This is a randomized phase II trial comparing HD-MTX monochemotherapy versus HD-MTX plus HD-araC as primary chemotherapy in immunocompetent patients (pts) with PCNSL. Patients: HIV-negative pts with newly diagnosed PCNSL, age 18–75 ys, ECOG-PS≤3, and measurable disease were randomly assigned to receive 4 courses (interval 3 weeks) of MTX 3.5 g/mq (control arm) or MTX (same dose) + araC 2 g/mq × 2/d, d 2–3 (experimental arm). Chemotherapy was followed by complementary whole-brain irradiation (WBRT). Pts were stratified based on IELSG score and centre WBRT policy for pts & gt;60 ys in complete remission (CR) after chemotherapy. Complete remission rate (CRR) after chemotherapy was the primary endpoint; planned accrual (a=.05 b=.2) for P0 30% and P1 50% was 39 pts/arm. Results: 79 pts (median age 58 ys; range 25–74) were randomly assigned to receive MTX (n=40) or MTX+araC (n=39). IELSG risk was low in 22 (28%) pts, intermediate in 48 (61%) and high in 9; 7 (9%) pts had ocular lesions and 7 (9%) had meningeal disease; no differences in clinical presentation between arms were observed. Two hundred thirty-one (73%) of the 316 planned courses were actually delivered (MTX 71%; MTX+araC 76%). Causes of chemotherapy interruption were: progressive disease (PD) in 20 (50%) MTX and 8 (21%) MTX+araC pts (p & lt;0.001), toxicity in 1 (3%) MTX and 7 (18%) MTX+araC pts (p=0.009) and refusal in 2 MTX+araC pts. Dose reduction ≥25% was indicated in 1 MTX and 17 MTX+araC pts. G4 neutropenia (10% vs. 74%), G4 thrombocytopenia (5% vs. 64%) and infections (3% vs. 23%) were significantly higher in MTX+araC arm. All G3–4 non-hematological toxicities were & lt;5%. One MTX pt (3%, cardiotoxicity) and 3 MTX+araC pts (8%, sepsis - hepatotoxicity) died of toxicity. After chemotherapy, 7 MTX and 18 MTX+araC pts achieved CR (18% vs. 46%; p=0.0002); 9 MTX and 9 MTX+araC pts achieved PR (ORR: 40% vs. 69%; p=0.0002). After conclusion of the whole upfront treatment, 11 MTX and 25 MTX+araC pts achieved CR (28% vs. 64%; p & lt;0.0001). At a median follow-up of 25 months, 31 MTX and 22 MTX+araC pts experienced failure (PD, relapse, death), with a 3-yr event-free survival (EFS) of 20% and 38% (p=0.01), respectively. Relapse/progression involved the brain, alone (n=34) or associated with eyes or meninges (n=8) in 42 (88% of relapses) cases, while it involved meninges, with or without eyes, in 4 (8%) cases; a systemic dissemination was detected in 2 (4%) pts. No differences in relapse sites between treatment arms were observed. Salvage with MTX+araC in 6 pts relapsed after MTX was invariably followed by PD. Conversely, 8 of 12 pts with PD after primary chemotherapy treated with salvage WBRT achieved an objective response, with a median response duration of 10 months (1–51+). Treatment arm and IELSG risk score were the two variables independently associated with EFS. Fifteen MTX and 21 MTX+araC pts are alive, with a 3-yr OS of 34% vs. 47% (p=0.12). Conclusions: This is the first randomized trial on PCNSL with completed accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity. MTX+araC may be the chemotherapy combination used as control arm in future randomized trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.580.580

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1770-1770

Abstract: Abstract 1770 Bronchial-associated lymphoid tissue (BALT) lymphoma is a distinct subgroup of low grade B-cell extranodal lymphoma. The limited clinical information available in the literature makes it difficult to understand if such an indolent lymphoma may have a clinical outcome different from that observed in other extranodal marginal zone lymphomas. The aim of this study is to collect and analyze clinical characteristics of patients with primary marginal zone malignant lymphoma of the lung principally focusing on diagnosis, treatment modality, outcome and finally to evaluate biological and molecular features which may correlate with clinical behaviour. We collected clinical information and histological material on 73 patients diagnosed with marginal zone lymphoma of the lung from February 1990 to August 2008. Central pathology reviewed all histopathological material and the diagnosis was confirmed in 64 (88%) patients. The retrospective analysis has been conducted on this subset of patients. The majority of them (58/64) had limited disease at diagnosis with a good performance status (0-1) and low prognostic index (IPI 0–2). FISH analysis showed a rearrangement on 18q21 in 12 of cases. Median time from diagnosis to any treatment was 30 days (range 0–773). Twenty patients received only local treatment including definitive surgery or radiotherapy. 52 patients needed additional systemic treatment because of advanced stage or incomplete surgical resection. Most of them (26) received an alkylating containing regimen while only 10 patients were treated with an anthracycline containing regimen and 16/52 received monoclonal antibody in combination with chemotherapy. With a median follow up of 54 months, 17/64 patients (27%) relapsed. The median time to relapse was 28 months (range 1–82). No difference in terms of PFS or OS was observed among patients receiving systemic anthracycline or alkylating containing regimens. No significant correlation with MALT 1 aberrations was found. Clinical results observed in such retrospective study seem to suggest as surgery clearly benefits patients with localized disease. Chemotherapy can be reserved for early aggressive relapse. Systemic treatment could be recommended for patients with advanced stage or with incomplete response after the surgical procedure: when chemotherapy must be considered, alkylating containing regimens seem the best option. Considering data of a “pre-rituximab era”, the role of monoclonal antibodies still needs to be clarified and ongoing trials from IELSG could be helpful on this topic. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.1770.1770

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2339-2339

Abstract: Abstract 2339 Poster Board II-316 BACKGROUND: CLL, the most common adult-onset leukemia in the Western world, has a heterogeneous clinical course. Many advances have led to a better understanding of its pathogenesis and to improvements in treatment strategies, but striking solutions are still missing. We conducted a study to evaluate the impact of genomic aberrations on the clinical course. METHODS: From January 1980 to May 2008, 395 frozen samples of CLL patients, were prospectively collected in four centers. Extracted DNA was analyzed with Affymetrix Human Mapping 6.0 arrays. Normal matched DNA was analyzed for one fourth of the cases. Correlations between minimal common regions (MCR) and clinical parameters were evaluated with the Fisherôs-exact test and their impact on OS with the log-rank test. A p-value after Bonferroni multiple test correction (MTC) (p-adj.) 〈 0.05 was considered as statistically significant. Up to now 266 samples have been analyzed. RESULTS: Analysis of the clinical parameters (CPs) and known risk factors (Rai/Binet, age, doubling time, LDH, beta2, IGVH status, p53 mutations, telomere length, CD38, 11q, 17p) was consistent to previous published series. ZAP70 did not affect the clinical course, likely due inter-laboratories variability. After a median follow up of 53 months, 143/239 (60%) of the patients have started therapy and 63/261 (24%) died. 5-yr OS was 82%. Fisher test between the MCRs and CPs revealed an inverse relation between the presence of trisomy 12 by FISH and del13q14.3, an association between del17p and losses of 8p regions and between CD38 and 12q gain. Before MTC, 46 MCRs had a significant impact on OS and 67. After MTC, 3 regions maintained their role: 8p22 loss (38/248, 15%, p-adj.=0.002, median OS: 26 months vs. 48), 17p13.3-11.2 loss (20/248, 8%, p-adj.=0.001; median OS: 10 months vs. 48). In univariate analysis, the log-rank test among pts with 8p-/17p- (8/248, 3%), 8p- (30/248, 12%), 17p- (12/248, 5%), wild type (198/248, 80%) was statistically significant (p 〈 0.001; see figure). Importantly, none of the analyzed clinical and biological parameters was associated with this aberration. CONCLUSIONS: Loss of 8p22 designated a CLL subgroup with a worse outcome among all patients and in the subset with 17p loss. Our data suggested that this aberration might constitute an independent prognostic factor to be evaluated in independent studies. Results, including a Cox regression model, will be presented on all 395 cases. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2339.2339

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 267-267

Abstract: Abstract 267 BACKGROUND: Chlamydophila psittaci (Cp) infection carries a potential pathogenic role in OAMZL and has been detected in tumor tissue of a high proportion of patients (pts), with geographic differences in its prevalence rates. The use of immunohistochemistry, immunofluorescence and electronic microscopy techniques has identified monocyte/macrophage as carriers of Cp in OAMZL, and bacteria eradication with doxycycline (DOXY) has been associated with lymphoma regression in half of pts. Notwithstanding these achievements, clinical and therapeutic knowledge on this association mainly result from retrospective studies or trials including also patients with relapsed disease after wide-ranging follow-up. Prospective studies focusing exclusively on pts with newly diagnosed OAMZL do not exist. Herein, we report the final results of the first international prospective phase II trial aimed to investigate Cp prevalence and DOXY efficacy as first-line therapy in pts with newly diagnosed OAMZL (ClinicalTrial.gov NCT01010295). AIMS: To elucidate prevalence of Chlamydiae infections, and to evaluate the efficacy of DOXY both in terms of bacterial eradication and as upfront anti-lymphoma therapy in pts with newly diagnosed OAMZL. METHODS: This trial included two different parts, named A and B. The part A included pts with newly diagnosed stage-IEA OAMZL and measurable/parametrable disease; these pts were assessed for chlamydial infection and were treated with DOXY 100 mg orally twice daily for 21 days. The part B included pts with lymphoma categories other than MZL, non neoplastic lesions of the ocular adnexae or OAMZL not eligible for part A; these pts were treated following local guidelines. Chlamydial infections were assessed on diagnostic tumor samples, conjunctival swabs and peripheral blood mononuclear cells (PBMC) from A and B pts by three different PCR protocols targeting 16rRNS and intergenic spacer 16S–23S, ompA and hsp60, respectively. Bacterial eradication was tested on conjunctival swabs and PBMC collected at basal time, at 3 and 12 months after DOXY (only part A pts). Clinical and ophthalmologic examination and MRI imaging were performed at the same timepoints, and every six months during follow-up. RESULTS: From August 2006 to November 2010, 54 pts from 6 centers were enrolled; 34 pts with OAMZL entered the part A, while 13 pts with non-parametrable OAMZL and 7 pts with other lymphoproliferative disorders entered the part B. Diagnostic material was available for molecular analysis in 44 cases; Cp was detected in biopsies of 32/37 OAMZL (86%) and in 4/7 non-MZL. All cases were negative for C. pneumoniae and C. trachomatis. Among 36 Cp+ pts, infection was detected in 100% of swabs and in 75% of PBMC; swabs or PBMCs from pts with Cp-negative OAMZL were invariably negative. All pts completed the planned DOXY treatment; no relevant toxicity was reported. Among 34 pts entering the part A, 28 were evaluable for bacteria eradication (Cp detected in swabs in 8 pts, in PBMC in one, in both samples in 19). At 3 months from DOXY, Cp was not detected in swabs and PBMC of 14 evaluable pts, with an eradication rate of 50%; at one year of follow-up, Cp was still detected in three of these apparently eradicated pts. Lymphoma regression after DOXY treatment (part A) was complete in six pts (18%; 95%CI: 5–31%), and partial in 16 (ORR= 65%, 95%CI: 49–81%); 11 had SD and one PD. At a median follow-up of 27 months (range 3–51), 13 pts experienced relapse, with a 2-year PFS of 55±9%. A trend to a higher response rate (82% vs. 53%; p=0.12) and 3-yr PFS (72% vs. 52%; p=0.14) was observed in eradicated pts. No significant association between site of presentation (conjunctiva vs. orbit) and clinical outcome was detected. There was no association between animal exposure and bacteria eradication or lymphoma response. All patients but two (stroke and myocardial infarction) are alive, with a 3-yr OS of 92%. CONCLUSIONS: Cp infection is frequent in newly diagnosed OAMZL, and could be also present in other lymphoproliferative disorders of the ocular adnexae. First-line DOXY is an active, safe and rational strategy in pts with limited-stage OAMZL, with lymphoma regression in 65% of cases. However, DOXY failed to eradicate Cp infection in half of pts, with a negative impact on outcome. Further investigations aimed to identify additional potential infective agents associated with OAMZL and more active antibiotic regimens are warranted. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.267.267

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 927-927

Abstract: The purpose of this study was to evaluate the clinical outcome, prognostic factors and the rate of CNS recurrence in PHNBCL patients. From December 1990 to June 2004, 401 patients, with a median age of 60 years (range, 19–85), were diagnosed as having PHNBCL in 9 IELSG centers. The tumor site was: Waldeyer’s ring (69%), followed by parotid and salivary glands (12%), nasal cavity and paranasal sinuses (8%), thyroid (6%) and palate and oral cavity (5%). Regarding histology 77% of cases had DLBCL,18% indolent lymphomas (MALT=42; FL=29), while only 5% had Burkitt lymphoma or MCL. DLBCL and indolent lymphomas (IL) were selected for the present analysis. Stage II was slightly higher in DLBCL (67% vs 54%; P=0.03), while the rate of other adverse features such as advanced age ( & gt;60 yrs), bulky disease ( & gt;10 cm), B symptoms, ECOG-PS & gt;1, No of extranodal sites & gt;1, elevated LDH, beta 2-microglobulin or ESR, reduced albumin and & gt;1 MIPI risk factors (RF) (50 vs 40%) was not statistically different into 2 groups. One hundred ninety four patients (51%) were treated with single therapy, mostly consinsting in anthracyclin containing chemotherapy (CHT), while 183 patients (49%) were given 3–4 courses of CHT, followed by IF RT. Only 26/250 DLBCL (10%) and 2/35 IL (6%) patients received CNS prophylaxis (Methotrexate 12 mg i.t.; median of cycles 3, range1–6). Two hundred sixty two DLBCL (85%) and 63 IL patients (91%) achieved a complete remission. Sixty DLBCL and 25 IL remitters, eventually relapsed (23 vs 40 %; P=0.007), 40 and 35% in the same site, 53 and 60% in other sites (1/234 patients with DLBCL of Waildeyer’s ring or paranasal sinuses, in CNS, 0.4%) and 7 and 5 in both. After a median follow-up of 42 and 35 months the DFS varied according to histology (DLBCL, 73% vs IL 52%; P=0.005), while OS and EFS were comparable into two groups (OS, 72% vs 74%; EFS, 56% vs 45%). In DLBL patients, the 5-year EFS varied according to MIPI (0–1 RF, 44% vs & gt;1 RF, 69%; P=0.0001), and treatment (CHT, 42% vs CHT+IFRT, 60%; P=0.0001), while in IL patients MIPI and treatment did not influence EFS. Cox multivariate analysis showed that MIPI and treatment were independent prognostic factors for OS in DLBCL. Also in IL patients the MIPI score maitained its independent value for OS. In conclusion, this retrospective analysis shows that MIPI, histology and a combined treatment influence the outcome of patients with PHNBCL. Moreover, in the present series a very low rate of CNS recurrence occurred in high risk patients, who did not receive adequate prophylaxis, suggesting that CNS prophylaxis could not be mandatory in PHNBCL patients. This should be confirmed by prospective studies of clinical outcome.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.927.927

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

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In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1417-1417

Abstract: Background. Literature on the treatment of rrPCNSL is limited to a few retrospective studies and phase II trials addressing new drugs or strategies. Evidence supporting therapeutic choice in patients (pts) with rrPCNSL after modern high-dose-methotrexate (HD-MTX)-based chemotherapy (chemo) followed by consolidative whole-brain irradiation (WBRT) or autologous stem cell transplantation (ASCT) is lacking. We reviewed management and outcome of pts with rrPCNSL in the randomized trials of the IELSG, which included 294 assessable pts, treated with modern approaches, and followed for several years. Herein, we analyse efficacy of salvage options to provide recommendations for routine practice. Methods. Pts enrolled in the IELSG20 or IELSG32 trials who experienced progressive disease (PD) at any time were considered. Pts who died due to toxicity and pts with extra-CNS relapse were excluded. Pts were grouped according to the time to progression after the first-line treatment: refractory (REF; relapse/PD ≤6 months from end of treatment), early relapse (ER; 6-35 months) and late relapse (LR; ≥36 months). Effect of salvage therapy on survival after relapse (SAR) was the primary objective. SAR was estimated from date of PD/relapse to date of death or last visit. Results. 164 pts (median age 58, range: 26-70; 94 males) were considered: 119 (73%) REF, 24 (15%) ER and 21 (13%) LR. First-line chemo included HD-MTX in all pts, alone in 31, +cytarabine in 68, +cytarabine/rituximab in 36, and +cytarabine/rituximab/thiotepa (MATRIX regimen) in 29. Consolidation was part of first-line treatment in 58 (35%) pts: WBRT in 39 and carmustine-thiotepa/conditioned ASCT in 19; 106 pts did not receive consolidation due to PD during first-line chemo (n=96), pt refusal (2), poor conditions (4) or per protocol (4). Treatment of relapsed/PD was WBRT in 47 pts and chemo in 58; 59 pts received only supportive care (BSC) due to rapid neurological impairment or pt refusal. Importantly, except for performance status (ECOG PS 0-1: 49% of BSC pts, 70% of treated pts; p=0.009), pts managed with BSC showed the same characteristics (age, gender, extension of disease, first-line treatment) than pts who received salvage therapy. Salvage chemo consisted of HD-ifosfamide-based chemo (R-IE, RICE, DeVIC) in 20 pts, rechallenging with HD-MTX-based chemo (same regimen or ± other drugs) in 25, direct myeloablative chemo and ASCT in 3, single drugs in 10; 17 pts responsive to salvage chemo received consolidative ASCT (n=12) or WBRT. Pts with LR had a better outcome than REF and ER cohorts, with a 2-year SAR of 64±11%, 11±3% and 13±7% (p= 0.001), respectively. These figures were similar when only treated pts were considered, with 2-year SAR of 80±11%, 17±4% and 23±12% (p= 0.0002), respectively. All untreated pts died of lymphoma within 4 months of progression. Salvage WBRT (n= 45) and chemo (n= 31) were associated with poor outcome in REF pts (2-year SAR 18±5% vs 16±6%; p= 0.76). Salvage treatment after ER or LR consisted of chemo in 27 pts and WBRT in two; HD-MTX retreatment showed a trend to a better outcome with respect to other chemo combinations, with a 2-year SAR of 73±12% and 27±13% (p=0.25), respectively. Importantly, 12 of the 15 pts with a SAR longer than one year were treated with HD-MTX-based chemo, followed by consolidation in 5 of them. A 2-year SAR of 90±9% was observed in the 11 LR pts retreated with HD-MTX-based chemo. At a median follow-up from relapse/PD of 40 (range 3-118) months, 16 (10%) pts are alive and disease-free. Deaths were due to lymphoma in 137 (93%) pts, infections in six (4%), and thromboembolic events in two (1%); cause unknown in two pts. Multivariable analysis showed that ECOG PS 0-1, LR and HD-MTX retreatment were independently associated with better SAR and that outcome was not affected by age, gender, first-line induction and consolidation, and considered trial. Conclusions. Mortality of rrPCNSL is regrettably high (≈90%), even among selected pts enrolled in prospective trials. One-third of pts are considered unsuitable candidates for salvage treatment. WBRT provides a marginal benefit over BSC in REF pts, suggesting that other strategies, including novel agents, should be considered in routine practice. Pts experiencing LR can achieve long-lasting second remission, especially when retreatment with HD-MTX-based chemo is feasible. Efficacy of salvage therapy appears to be independent of the first-line treatment. Disclosures Ferreri: Pfizer: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Genmab: Research Funding; Amgen: Research Funding; Hutchison Medipharma: Research Funding; Beigene: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees; Ospedale San Raffaele srl: Patents & Royalties. Cwynarski: Roche: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Takeda: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Celgene/BMS: Honoraria, Other: Travel / Conference Support; Atara: Honoraria; Gilead, KITE: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Janssen: Honoraria, Other: Travel / Conference Support; Incyte: Honoraria, Speakers Bureau. Pulczynski: Roche: Research Funding. Fox: Abbvie: Honoraria, Research Funding; Astrazeneca: Honoraria; Atarabio: Honoraria; BMS/Celgene: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Incyte: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Beigene: Honoraria, Research Funding. La Rosée: AstraZeneca: Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen-Cilag: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Schorb: Roche: Research Funding; AbbVie: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roeth: Roche: Consultancy, Honoraria, Research Funding; Kira: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. Linton: BeiGene: Research Funding; Celgene: Research Funding; University of Manchester: Current Employment; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hartley Taylor: Honoraria; Aptitude Health: Honoraria. Binder: Deutsche Krebsgellschaft, Medconcept GmbH, event Lab. GmbH: Honoraria, Other: Speaker Activity; Amgen GmbH, Janssen-Cilage GmbH, DGHO, Art tempi, Tumorzentrum Anhalt MD, Uniklinikum Hamburg, Sanofi Aventis: Honoraria, Other: Speaker Activity. Hemmaway: Abbvie: Honoraria. Pinto: Takeda: Consultancy; MSD: Honoraria; Bristol Myers Squibb-CELGENE: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau. Zucca: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147822

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 585-585

Abstract: Introduction. Ibrutinib inhibits the BTK molecule downstream the B-cell receptor (BCR). Though highly active in high risk chronic lymphocytic leukemia (CLL), the most typical response achievable in patients is a minimal residual disease (MRD) positive partial remission (PR) which is maintained until the development of genetically driven resistance caused by the acquisition of mutations in the BTK or PLCG2 genes. The study aims at characterizing the adaptation process allowing residual CLL cells to persist despite BTK inhibition. Methods. The IOSI-EMA-001 study (NCT02827617) is an observational study consisting in the prospective and longitudinal collection of peripheral blood samples and clinical data from high risk CLL patients treated with ibrutinib. Peripheral blood CLL cells longitudinally drawn from patients before treatment start and at fixed timepoints under ibrutinib were monitored by: i) next generation flow cytometry approaches for changes in proliferation rate, surfaceome, and pathway activation; and ii) CAPP-seq targeted deep next generation (sensitivity ~10-3) for clonal evolution. Results. The study cohort comprised 31 high risk CLL patients, including 15 treatment naïve, 16 relapsed, 80% IGHV unmutated, 42% 17p deleted and 55% TP53 mutated. Median duration of ibrutinib treatment was 45 weeks (24-72 weeks). All patients obtained a MRD positive PR that was maintained in all but one who progressed with a PLCG2 mutation (VAF 3%). Compared to baseline, under ibrutinib therapy CLL cells slowed down their proliferation, as suggested by the decreased expression of Ki-67, the reduction of the proliferating fraction (CXCR4dimCD5bright), and the increase of the resting fraction (CXCR4brightCD5dim). Compared to baseline, under ibrutinib therapy CLL cells also upregulated BCR and adhesion/homing proteins, and decreased the expression of BCR inhibitor proteins. Upon stimulation of the BCR with anti-IgM, the downstream path through pBTK and pPLCG2 was inhibited by ibrutinib, while conversely the downstream path through pAKT and pERK was still inducible throughout all the assessed timepoints. The proportion of CLL cells harboring nuclear localization of NF-kB progressively increased over time under ibrutinib. NF-kB nuclear localization was inducible throughout all the assessed timepoints by CD40L stimulation of the non-canonical NF-kB pathway, but not by anti-IgM stimulation of the BCR/canonical NF-kB pathway. Overall, 880 individual mutations were longitudinally discovered and monitored across a total of 121 sequential timepoints collected during ibrutinib treatment. Clonal evolution was observed in (67.7%) cases, a proportion rate previously documented in CLL treated with chemoimmunotherapy. Clonal evolution appeared to be heterogeneous involving different genes without a stereotypic targeting. Consistently, none of the main driver gene mutations was homogeneously selected or suppressed by ibrutinib suggesting that the biological adaptation of CLL cells under ibrutinib is not genetically driven. Clonal evolution propensity was not associated with any of the biomarkers of the disease, and it did not decrease over time under ibrutinib. Conclusions. Taken together these results suggest that residual CLL cells persisting under ibrutinib therapy adapt their phenotype by upregulating adhesion molecules, chemokine receptors and BCR molecules, and by maintaining a competence of BCR signaling through the PI3K/AKT/ERK pathway. The progressive selection of CLL cells having NF-kB in the nucleus, likely due to the BTK independent non-canonical NF-kB pathway, might explain their survival despite ibrutinib therapy. Finally, clonal evolution is not suppressed by ibrutinib chemotherapy, and despite does not seem to be directly involved in such adaptation process, may ultimately favor the acquisition of BTK and PLCG2 ibrutinib resistance mutations. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116739

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. 128, No. 22 ( 2016-12-02), p. 4367-4367

Abstract: Evolution of the chronic lymphocytic leukemia (CLL) clone upon treatment with the BTK-inhibitor ibrutinib has never been systematically assessed in a prospective way, though changes in the tumor genetic composition have been anecdotally reported by retrospective backtracking of mutations acquired in ibrutinib-refractory patients. The IOSI-EMA001 observational study (NCT02827617) enrolls patients treated with ibrutinib in the clinical practice, and aims at prospectively assessing the dynamics of the clonal architecture of high risk CLL upon therapy with ibrutinib by taking advantage of leukemia samples homogeneously collected at pre-specified timepoints during treatment course. Ibrutinib induces a transient lymphocytosis by displacing CLL cells formerly residing in the tissue compartments into the peripheral blood (PB). By analyzing samples collected after two weeks of ibrutinib treatment, here we tracked early genetic changes of the CLL clone occurring at the time of redistribution lymphocytosis. This analysis includes the first 10 patients enrolled in the study (median age=76 years; Binet A=10%, B=60%, C=30%; IGHV unmutated=60%, mutated=20%, NA=20%; 17p deletion=40%). PB samples were collected before ibrutinib treatment start (day -28 to 0) and after two weeks of treatment (week 2, +/-3 days). Tumor genomic DNA was isolated from FACS sorted CLL cells (CD19+/CD5+ elements; 〉 99% purity). T cells were also sorted as source of germline material to confirm the somatic origin of mutations and filter out sequencing noise. The HaloPlex High Sensitivity library preparation protocol and ultra-deep next generation sequencing (coverage ~40.000x) on MiSeq (Illumina) were used to track TP53, BTK and PLCG2 mutations. By uniquely molecular barcoding each DNA library fragment, and by targeting both DNA strands, this approach allowed to reach a sensitivity of 10E-4. The CAPP-seq library preparation protocol and deep next generation sequencing (sensitivity ~5x10E-3) were used to track mutations of a panel of genes known to be recurrently affected in CLL (ASXL1, ATM, BIRC3, BRAF, EGR2, FBXW7, IKZF3, IRF4, KRAS, MAP2K1, MGA, MYD88, NFKBIE, NFKB2, NOTCH1 including 3'UTR, PAX5 enhancer, POT1, RPS15, SAMHD1, SF3B1, TP53, XPO1, ZMYM3). At baseline before treatment start, 33 non-synonymous somatic mutations (allele frequency: 0.65-99%) were identified in 9 of the 10 cases (one patient was devoid of mutations of the above-mentioned genes). The mutational profile was consistent with that expected in a high risk population meeting the current indication for ibrutinib treatment in the clinical practice(TP53=60%; NOTCH1=40%; MGA=30%; ZYMYM3=20%; ATM=10%; BIRC3=10%; EGR2=10%; IRF4=10%; IKZF3=10%; MYD88=10% NFKBIE=10%; SF3B1=10%; XPO1=10%) (Fig. 1A). Before treatment start, high sensitive ultra deep next generation sequencing did not disclose any non-synonymous somatic mutation of BTK and PLCG2 in CLL cells circulating in the blood. The genetic composition of the circulating leukemia clone did not significantly change after two weeks of treatment despite redistribution of CLL cells in the blood compartment (median lymphocyte count at baseline 50.9x10E9/L vs 77.5x10E9/L at week 2) (Fig 1B). Minor genetic changes between baseline and week 2 included the appearance of a small clone mutated in SAMHD1 and the disappearance of a small clone mutated in BIRC3 in 2 different patients. At week 2, no mutations of BTK and PLCG2 became evident in the circulating compartment. With the limitation of the current sample size, these data suggest that redistribution lymphocytosis does not mobilize CLL high risk clones harboring mutations of clinical relevance into the blood compartment. Figure 1 Figure 1. Disclosures Rossi: Gilead: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4367.4367

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 5 ( 2016-08-04), p. 667-679

Abstract: Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression. Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2016-01-690743

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7