Kooperativer Bibliotheksverbund

In: British Journal of Haematology, Wiley, Vol. 91, No. 4 ( 1995-12), p. 865-870

Abstract: Summary. Homozygous deletions of the cyclin‐dependent kinase 4 (CDK4) inhibitor gene CDKN2 (pi6, MTS1) have been demonstrated to occur frequently in human cancer cell lines of different origin. However, in most primary tumours the frequencies of CDKN2 deletions are not well defined. We studied primary samples of 100 patients with lymphoid leukaemias [B‐lineage acute lymphoblastic leukaemia (ALL), n = 23; T‐ALL, n= 7; B‐cell chronic lymphocytic (B‐CLL) or prolymphocytic (B‐PLL) leukaemia, =50; T‐CLL/T‐PLL, n = 20] using fluorescence in situ hybridization (FISH) with eight overlapping cosmid clones covering the region on chromosome band 9p21 containing CDKN2. We did not observe any CDKN2 deletions in the 70 patients with chronic lymphoid leukaemias of B‐ or T‐cell origin. Of the 23 patients with B‐lineage ALL, one (4%) exhibited a CDKN2 deletion: in this patient, two clones were detected, one exhibiting a hemizygous and the other a homozygous deletion. On chromosome banding analysis, four patients with B‐lineage ALL had a 9p aberration, whereas all CDKN2 copies were retained. In contrast, six of the seven (86%) patients with T‐ALL exhibited CDKN2 deletions (homozygous, n = 4; hemizygous, n = 2). We conclude that hemizygous or homozygous deletions of the CDKN2 gene occur at high frequency in T‐ALL and at low frequency in B‐lineage ALL, supporting the role of this gene as a tumour suppressor, especially in T‐ALL. However, from our data there is no evidence that CDKN2 is involved in the pathogenesis of chronic lymphoid leukaemias of B‐ or T‐cell origin.

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.1995.91.issue-4

DOI: 10.1111/j.1365-2141.1995.tb05402.x

Language: English

Publisher: Wiley

Publication Date: 1995

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3700-3700

Abstract: Abstract 3700 Poster Board III-636 Background Indolent lymphoma and mantle cell lymphoma have typically a history of multiple relapses. Especially elderly patients who are not fit enough for intensive treatments may receive various chemotherapies in the course of their disease. Therefore, new cytostatic drugs are needed which are not cross resistant to the common combinations. The aim of the study is to establish a chemotherapy regimen which is non cross resistant to alkylating agents, anthracyclines and purin antimetabolites. Gemcitabine and Oxaliplatin have activity in several lymphoma entities. Different side effects and in vitro synergy make the combination even more attractive. Patients and methods Eligible were patients with age above 18 and relapsed or refractory indolent lymphoma or mantle cell lymphoma, measurable tumour lesion, ECOG performance status 0-2. Patients were excluded if they had a secondary high grade lymphoma or were eligible for high dose therapy. Leukocyte count ≥1.5/nl and platelets ≥100/nl were required unless bone marrow infiltration accounted for blood counts. Study entry required adequate renal (creatinine 〈 2.0 mg/dl) and hepatic function (≥ 3.0x the upper limit of laboratory normal for AST and ALT and ≥2.0 mg/dl for total bilirubin). Patients achieved 2 cycles of R-GO (Rituximab 375 mg/m2 at day 0, Gemcitabine 1,000 mg/m2 and Oxaliplatin at day 1 and 15 [in phase 1 Oxaliplatin was escalated from a dose of 70 mg/m2 in steps of 10 mg/m2, in phase 2 the maximal tolerable dose (MTD) of phase 1 was used] every 28 days for a maximum of 4 cycles. In phase 1 dose limiting toxicity (DLT) was defined as granulocytes 〈 0.5/nl or platelets 〈 25/nl, bleeding due to thrombocytopenia, any non haematological toxicity ≥ WHO grade 3 with exception of alopecia and emesis, granulocytes 〈 1.5/nl or platelets 〈 100/nl at day 29 of cycle 1, persistency of any toxicity ≥ WHO grade 2 until day 29 of cycle 1. Response and progression were based on International Working Group Response Criteria for NHL. The primary end point was the MTD of Oxaliplatin in the phase 1 part and the overall remission rate (ORR) in the phase 2 part of the study. Results The study enrolled 54 patients at 22 sites until June 2009. The median age was 69 years (range 31 – 82). 26 patients were male and 28 female. The median number of prior therapies was 2 (range 1 to 10). Phase 1: 14 patients were treated in the phase 1 part of the study. 7 out of 14 received Gemcitabine and Oxaliplatin only before a protocol amendment added Rituximab to the combination. 6 patients were treated with Oxaliplatin 70 mg/m2 (dose level 1) and 8 patients were treated with Oxaliplatin 80 mg/m2 (dose level 2). At dose level 2 occurred 3 DLT (peripheral neurotoxicity 1, neutropenia 1, thrombocytopenia 1). Therefore, the MTD for Oxaliplatin was 70 mg/m2 in phase 2. 11 patients (dose level 1: 4 without Rituximab, dose level 2: 1 without Rituximab, 6 with Rituximab) were evaluable for response. There were 8 PR, 2 SD and 1 PRO. Phase 2: 40 patients were enrolled and 27 patients had response data after 1 - 4 cycles (median number of cycles: 4). 2 had to be excluded due to false histology. Objective responses were observed in 21 patients (0 CR/19 PR/2 MR), 3 had stable disease and only one patient had progressive disease. Median follow up time was 16 months. Median time to treatment failure was 8 months, median overall survival was about 31 months. 28 patients were evaluable for toxicity. WHO grade 3-4 toxicity was mainly haematological. (11 patients had WHO grade 3-4 thrombocytopenia, 11 leukopenia, 12 neutropenia, 7 anaemia). Non-haematogical toxicity grade 4: 1 patient with constipation, grade 3: 2 infection, 1 fever, 1 nausea and emesis, 1 mucositis, 1 liver toxicity, 1 peripheral neuropathy. Conclusion The combination of Gemcitabine and Oxaliplatin with Rituximab showed encouraging activity in a heavily pretreated, elderly patient population with indolent lymphoma and mantle cell lymphoma. Toxicity was acceptable and mainly haematological. Phase 2 of the trial is ongoing. Disclosures: Hoffmann: Sanofi: Research Funding; Roche: Research Funding; Lilly: Research Funding. Off Label Use: Gemcitabine and Oxaliplatin are not approved for treatment in lymphoma. Dreyling:Lilly: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dührsen:Roche: Honoraria, Research Funding. Unterhalt:Roche: travel support.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3700.3700

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3058-3058

Abstract: Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach. Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes 〉 3 cm, elevated LDH, 〉 20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma. Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%). Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.3058.3058

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. e19554-e19554

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.e19554

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2820-2820

Abstract: On behalf of the Lymphoma Study Association (LYSA) Introduction: Aggressive Mantle Cell Lymphoma variant (A-MCL), including blastic and pleomorphic morphological variants, is a rare subtype of MCL whose frequency varies around 10-15% of all newly-diagnosed MCL patients. According to 2017 World Health Organization (WHO) classification, the diagnosis of A-MCL is based on morphology. A high proliferation rate on Ki-67 staining is not sufficient to be classified as a blastoid or pleomorphic subtype. This might induce diagnostic confusion. The aim of the present retrospective study is to investigate whether or not the CD71, c-Myc, SOX11, P53, ki67 and P16 expressions assessed by immunohistochemistry (IHC) can distinguish A-MCL from classical MCL (C-MCL). We also investigate the prognostic value of these markers in A-MCL patients. Methods: We re-investigated all MCL patients presented with A-MCL (n=110) at diagnosis and who have been enrolled in six prospective clinical trials. At time of inclusion, a centralized pathological review was performed to confirm the diagnosis of MCL. Cases were initially classified according to the 2008 WHO classification (LYMA, MCL-SA, MCL-SJ, RIBVD and RIPAD trials) or according to the 2017 WHO classification (MCLR2-ELDERLY trials). For the present study, we performed a supplemental pathology review by a panel of 5 hematopathologists experts from the LYSA group according to 2017 WHO classification. We identified 75 cases (out of 110) of A-MCL (8 blastic and 67 pleomorphic variants) which represent 15% of all MCL enrolled in these six trials. We have compared A-MCL characteristics to C-MCL who had specimens available for TMA (n=412 C-MCL out of 487 patients enrolled). IHC was performed on TMA, using the six selected antibodies and were scored by quantifying the percentage of cells stained on each spot. Patients available for survival analysis (53 A-MCL and 312 C-MCL) were drawn from all studies (except from the MCLR2-Elderly study that is ongoing). Different cut-offs were considered for progression free survival (PFS) and overall survival (OS) for each variable. The proliferation index was evaluated with Ki67 classical determination eyeballing and Ki67 reading by grid counting. Cut-offs for each of these markers were determined using X-tile software, which determines the optimal value for classifying patients into groups based on overall and progression-free survival. Results: At baseline, the aggressive forms were similar to classical forms in terms of demographic characteristics (age at diagnosis, localization and sex). p53 protein expression was significantly higher in A-MCL patients than in C-MCL (p 〈 0.001) like p16 (p=0.002), c-MYC (p 〈 0.001), CD71 (p 〈 0.001) and Ki67 index (both classical and by grid) (p 〈 0.001). There was no statistically significant difference in SOX11 expression. In univariate analyses, elevated levels of P16 ( 〉 10%), c-MYC ( 〉 30%) Ki67 ( 〉 40%) were associated with poorer OS and PFS in the cohort of A-MCL and C-MCL patients. There was no significant difference in survival both for OS and PFS regarding P53 ( 〉 30%). In multivariate analysis stratified by trial, Ki67 by grid 〉 40% (HR=2.303[1.479-3.585] ; p =0.0002) and c-MYC 〉 30% (HR=1.865 [1.060-3.279] p =0.0305) were predictive for OS whereas only Ki67 by grid 〉 40% (HR=2.055 [1.434, 2.944], p 〈 0.0001) was a significant prognostic factor for PFS. Conclusion: CD71, c-Myc, P53 and P16 expression levels assessed by IHC are higher in A-MCL as compared to C-MCL. These markers could therefore be recommended in routine practice to distinguish between A-MCL and C-MCL. We also found that patients with Ki67 count by grid 〉 40% had significantly shorter PFS and OS and patients with high Myc expression 〉 30% had a significantly poorer OS. Thus, MYC expression and Ki67 by IHC is a suitable test for routine diagnostic practice to assess A-MCL prognosis. Disclosures Le Gouill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dreyling:Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129790

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2449-2449

Abstract: Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach. Treatment: 2 g/m2 Ara-C was applied on day 2 and 3 (1 g/m2 in patients with impaired hematopoiesis or age 〉 60 years) combined with BZ 1.5 mg/m2 iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m2). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles. Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved. Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.2449.2449

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 419-419

Abstract: The anti-CD20 antibody rituximab has dramatically changed the treatment paradigms for advanced stage follicular lymphoma (FL) and has improved overall survival. The question whether myeloablative treatment followed by autologous stem cell transplantation (ASCT) in first remission may add further benefit in the era of initial rituximab-chemotherapy induction remains currently unsolved. Methods We report on the long-term outcome of 940 patients, randomized for treatment with ASCT versus IFN-alpha maintenance in first remission after initial therapy with MCP, CHOP or R-CHOP in two consecutive randomized trials for patients with advanced stage FL of the GLSG . Results A total of 472 patients, (38 with initial MCP therapy, 199 with initial CHOP therapy and 224 with initial R-CHOP therapy, 13 not documented), were randomized to receive ASCT. The remaining 468 patients were randomized for IFN-maintenance (39 with MCP, 201 with CHOP and 219 with R-CHOP, 7 not documented). The patient characteristics, the initial therapy and the quality of remission were well balanced between ASCT and IFN-maintenance. After a median follow up of 8.3 years 454 pts randomized for IFN-maintenance and 445 pts randomized for ASCT were evaluable for treatment failure. The estimated failure free survival at 10 years was 32% (95% CI 0.26-0.37) for IFN-alpha maintenance and 51% (95% CI 0.45-0.57) for ASCT. For patients assigned to CHOP or MCP (no rituximab during induction) the estimated failure free survival after 10 years was 18% for IFN-maintenance and 45% for ASCT (hazard ratio 0.49, 95% CI 0.39-0.61). Among the 423 evaluable patients assigned to R-CHOP the estimated failure free survival at 10 years was 53% for IFN-maintenance and 58% for ASCT (hazard ratio 0.77, 95% CI 0.56-1.07). Conclusions After a median follow up of more than 6 years in 423 patients assigned to R-CHOP, only a small improvement in time to treatment failure could be observed for ASCT compared to IFN-alpha maintenance. This is in strong contrast to patients treated with chemotherapy only (figure 1). The promising results for ASCT observed in the pre-rituximab era cannot be confirmed after initial immuno-chemotherapy. Since the use of ASCT is hampered by relevant toxic side effects, the actual data suggest that ASCT for patients with follicular lymphomas in first line therapy is of questionable benefit. Disclosures: Hiddemann: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hoster:Roche: Honoraria, Travel Support Other. Unterhalt:Roche: Travel Support Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.419.419

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1708-1708

Abstract: Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes double-refractory to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease 〉 7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p 〈 .0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1708.1708

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1589-1589

Abstract: Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%] , FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123637

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 85-85

Abstract: Alkylating agent-rituximab combinations are a current standard of care for patients with iNHL. Most iNHL will eventually become refractory to current therapies. Particularly, once iNHL becomes “double-refractory” to rituximab + alkylating agents, there are few data available on beneficial therapeutic options and development of novel therapies is essential for this patient population. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated considerable activity in recurrent iNHL in a phase 1 trial (Kahl, ICML 2011). We thus evaluated idelalisib in a phase 2 trial for patients with double-refractory iNHL, an area of unmet medical need. We present mature response data and extended follow-up of this study. Methods Eligible iNHL patients (pts) included those with measurable disease who were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to, or progression of lymphoma within 6 months of completion of therapy, documented by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007). The new data cutoff date for this analysis was June 2013, 8 months after the last patient enrolled. Results Enrolled pts (N=125) had a median age of 64 years [range 33-87] and were 64% male. Indolent NHL subtypes included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12] , most common regimens included bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and 14 pts (11%) had a prior autologous transplant. 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. Median time since completion of last regimen was 3.9 months. At baseline, pts had elevated LDH (30%), bulky disease 〉 7 cm (26%), anemia ≥grade 1 (51%), neutropenia ≥ grade 1 (24%), and thrombocytopenia ≥grade 1 (34%). With a median follow up 9.4 months, the overall response rate (ORR) was 57% (95% CI = 47.6, 65.6) with 71 responders, comprising 7 CRs (6%), 63 PRs (50%), and 1 minor response (MR) in a WM pt. There were 42 pts with stable disease (SD) (33%). 90% of pts experienced some decrease in tumor burden (Figure 1). Median time to response was 1.9 months (range 1.6-8.3), median time to CR was 3.7 months (range 1.9-12). ORR for iNHL subtypes was: FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). ORR for bendamustine refractory pts was 59%. ORR for pts with 〈 4 /≥4 prior therapies was 50%/62%, and for bulky disease 〈 7cm/≥7cm was 57/57%. Among responders, median DOR was 12.5 months. Median PFS for all pts was 11.0 months and median overall survival was 20.4 months. The most common adverse events were (total%/≥ grade 3%) diarrhea (43/13), fatigue (30/2), nausea (30/2), cough (29/0), pyrexia (28/2), dyspnea (18/3), rash (13/2), and pneumonia (11/7). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 16 pts (13%). Drug was held for these pts, and 11/14 pts (79%) were re-treated without recurrence of ALT/AST elevation. Grade ≥3 neutropenia occurred in 27%, thrombocytopenia in 6%, and anemia in 2%. 20% of pts have discontinued therapy due to adverse events. Conclusions Idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory iNHL population with an ORR of 57%. The ORR was consistent across all subgroups, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. With continued administration of idelalisib, responses were durable beyond one year, substantially exceeding the median DOR for the last prior therapy. Mature response data demonstrate that idelalisib can provide clinical benefit to patients with the unmet medical need of double-refractory iNHL. Disclosures: Gopal: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Kahl:Gilead Sciences: Advisory Board Other, Research Funding. De Vos:Gilead Sciences: Advisory Board Other, Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment. Li:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Godfrey:Gilead Sciences: Employment. Salles:Gilead Sciences: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.85.85

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7