scholarly journals A Phase I/II Trial of Vorinostat (SAHA) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0806

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3931-3931 ◽  
Author(s):  
Daniel O. Persky ◽  
Hongli Li ◽  
Lisa M. Rimsza ◽  
Paul M. Barr ◽  
Leslie L. Popplewell ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Loss of major histocompatibility Class II antigens (MHCII) in diffuse large B-cell lymphoma (DLBCL) is associated with a decreased CD8+ tumor-infiltrating T-lymphocyte (TIL) response and poor patient survival. Transcription of the MHCII gene complex is under the control of the master transactivator, CIITA, which in part is regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor vorinostat with standard chemotherapy will enhance MHCII expression and improve patient outcome in DLBCL. Methods: SWOG S0806 was a phase I/II open label trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently reduced to days 1-5) combined with Rituximab-CHOP (R-CHOP) at standard doses, given on day 3 of a 21-day cycle for 8 cycles. Eligibility criteria included having newly diagnosed advanced stage DLBCL, international prognostic index (IPI) of at least 1, and lack of known CNS involvement or HIV. Primary endpoint of phase I was to establish maximum tolerated dose (MTD) of vorinostat with standard R-CHOP. Primary endpoint of phase II was to estimate 2-year progression free survival (PFS). Translational endpoints included correlation of pre-treatment acetylation status of histones, expression of MHCII genes, and percentage of TIL to PFS; and correlation of cytokine profile to response and outcomes. Results: Phase I was open in 5 SWOG institutions and enrolled 11 patients. There were only 2 patients who had dose limiting toxicities in the first cycle - grade 3 febrile neutropenia and grade 4 hypokalemia - allowing phase II to proceed with the original vorinostat dosing of 400 mg daily days 1-9, at all SWOG institutions. However, excess rates of febrile neutropenia and sepsis were seen upon further follow up, and the study was amended to reduce the duration of vorinostat to days 1-5. A total of 72 patients were enrolled in phase II, of which 8 were ineligible and 2 withdrew consent prior to treatment. For the remaining 62 patients, median age was 64 years, 92% had stage III/IV disease, 39% B symptoms, 61% elevated LDH, 39% had more than 1 extranodal site of involvement, with IPI breakdown of 13/26/47/13/2%. Notable grade 3-4 non-hematologic toxicities included febrile neutropenia (39%), sepsis (18%), fatigue (15%), hypokalemia (11%), hyponatremia (10%), and small bowel perforation (3%). Grade 3-4 hematologic toxicities included neutropenia (60%), anemia (35%), and thrombocytopenia (35%). There was one death in phase I from sepsis and multi-organ failure at the end of 8 cycles of treatment, but no deaths from toxicity in phase II. Overall response rate was 81% (95% CI: 69-90%). With median follow-up of 24.3 months, estimate of 2-year PFS is 72% (95% CI: 58%, 81%) and of 2-year OS is 85% (95% CI: 74%, 92%). Analysis of the panel of 30 cytokines performed on matched serum specimens of 40 patients showed correlation of baseline elevated IL-2R levels with worsened PFS and OS, and correlation of decrease in Epidermal Growth Factor level with improved PFS and OS. Results of immunohistochemical stains for expression of MHCII genes and percentage of TIL will be reported at the meeting. Conclusions: The regimen of vorinostat-R-CHOP achieved 2-year PFS estimate of 72%, which is slightly more than 68% expected from R-CHOP alone per IPI adjusted historical rate, but less than an IPI adjusted target of 78% that would be sufficient to warrant further investigation. It also resulted in unexpected excess rates of febrile neutropenia and sepsis. This regimen cannot be recommended for the broad DLBCL population. Current studies are focused on finding biomarkers of response to histone deacetylase inhibitors. Disclosures Persky: Gilead Sciences, Inc: Speakers Bureau. Off Label Use: vorinostat in diffuse large B-cell lymphoma. Barr:Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

scholarly journals A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4162-4162 ◽  
Author(s):  
Tony Reiman ◽  
Kerry J. Savage ◽  
Michael Crump ◽  
Matthew Cheung ◽  
David A. MacDonald ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included. Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting >10 days, grade 4 hematological toxicity lasting >7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans. Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received >90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3). On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia >10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma. The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43% Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. Disclosures Reiman: Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

Long-Term Follow-Up of a Phase II Trial of Six Cycles of Dose-Dense R-CHOP-14 for First-Line Treatment of Diffuse Large B-Cell Lymphoma in Young and Elderly Patients

2016 ◽  
Vol 136 (2) ◽  
pp. 76-84 ◽  
Author(s):  
Eva González-Barca ◽  
Miguel A. Canales ◽  
Antonio Salar ◽  
Secundino Ferrer ◽  
Eva Domingo-Domenech ◽  
...  
Keyword(s):  
Survival Rate ◽  
Elderly Patients ◽  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Background/Aims: Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days. Methods: This is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged ≥65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2). Results: With a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged ≥65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related. Conclusion: In conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients.

Favorable Results of Rituximab in Combination with CHOP in the Front-Line Treatment of Follicular Lymphoma Grade 3.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2770-2770
Author(s):  
Luis Fayad ◽  
Michael Overman ◽  
Barbara Pro ◽  
Peter McLaughlin ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking. Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP. Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was >1 in 2%, and >1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease (>7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values >3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%). Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.

Pegylated Recombinant Human Granulocyte Colony Stimulating Factor (pegfilgrastim) Reduces Hematological Toxicity in Dose-Adjusted (DA) R-EPOCH in the treatment of Diffuse Large B Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4631-4631
Author(s):  
Susanna Hong ◽  
Nouneh J. Gostanian ◽  
Douglas E. Gladstone ◽  
Kenneth W. Zamkoff
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Sale Price ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Hematological toxicity is a significant dose limiting side effect in the aggressive treatment of Diffuse Large B Cell Lymphoma (DLBCL). In the current study, pegfilgrastim was given to patients following each cycle of DA R-EPOCH. ANC and platelet nadirs were then compared to a previous report utilizing filgrastim. Pegfilgrastim is a covalent conjugate form of filgrastim, whereby a molecule is covalently bonded to the N terminal of filgastrim, allowing the molecule to be cleared slower than filgastrim. The prolonged effect on the promotion of granulocyte proliferation allows for pegfilgrastim to be given once every 2 weeks in comparison to filgrastim which is injected daily. In this study, records of 5 patients treated with DA R-EPOCH for DLBCL were examined. There were a total of 20 cycles with 15 cycles qualifying for analysis in regards to hematological toxicity. To qualify each cycle met the following criteria: i) treatment with R-EPOCH at starting dose or dose-escalation; ii) pegfilgrastim was administered 24 to 48 hours after completion of chemotherapy at the standard dose of 6mg sc; iii) follow-up of at least two weeks following each cycle; iv) CBC monitored at least once weekly. Of the cycles excluded, 3 cycle did not have at least 2 weeks of follow-up, 1 cycle was followed by filgrastim and 1 cycle was treated with R-CHO. Nadir was defined as lowest value obtained from initiation of one cycle to initiation of next cycle or to two weeks from last day of all chemotherapy. Hematological toxicities were graded according to WHO criteria. Grade 4 neutropenia (ANC less than 0.5 x 109/L) occurred in 13% (2/15) of cycles. There was no Grade 3 neutropenia (ANC 0.5 – 1.0 x 109/L). Range of ANC nadir was 0.02 – 4.4 x 109/L with mean of 2.4 x 109/L. There was no Grade 3 thrombocytopenia (Platelet 25 – 50 25 x 109/L) nor Grade 4 thrombocytopenia (Platelet &lt; 25 x 109/L). Range of platelet nadir was 53 – 230 x 109/L with mean of 130. Examining treatment records, 13 cycles of 20 were candidates for dose escalation. Each cycle was included if it followed a cycle of R-EPOCH and the patient had received pegfilgrastim for neutropenic support. Excluded cycles included 5 cycles at starting doses, 1 cycle in which filgrastim was administered prior, and 1 cycle in which the R-CHO was given prior. Following the criteria for allowable DA EPOCH according to the paradigm published in Blood Apr 15, 2002, Vo 99, No 8 pp 2685– 2693, dose escalation was allowed for ANC of at least 0.5 x 109/L and platelets of at least 25 x 109/L. 11 of 13 (85%) cycles in this study were eligible for dose escalation based on the above mentioned paradigm. In the previous mentioned publication filgrastim was given after completion of each cycle of EPOCH with 49% of cycles complicated by Grade 4 neutropenia and 7% complicated by Grade 4 thrombocytopenia. 58% of the cycles were dose escalated in the previous study. In conclusion this study indicates that pegfilgrastim results in less hematological toxcity in DA R-EPOCH. This allows for DA in a higher percentage of treatment cycles. In addition, examination of the cost reveals the average whole sale price of a single 6 mg dose of pegfilgrastim is $3127, while the average whole sale price of a daily dose of 480 mcg of filgrastim for 10 days is $3500.

De Novo Treatment of Diffuse Large B-Cell Lymphoma With Rituximab, Cyclophosphamide, Vincristine, Gemcitabine, and Prednisolone in Patients With Cardiac Comorbidity: A United Kingdom National Cancer Research Institute Trial

2014 ◽  
Vol 32 (4) ◽  
pp. 282-287 ◽  
Author(s):  
Paul A. Fields ◽  
William Townsend ◽  
Andrew Webb ◽  
Nicholas Counsell ◽  
Christopher Pocock ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multicenter Trial ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell ◽  
Cardiac Comorbidity

Purpose The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity. Patients and Methods Sixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had borderline ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension. Primary end point was overall response rate at the end of treatment. Results Thirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response [CR], n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population. Conclusion Our phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.

scholarly journals Valproate in Combination with Rituximab and CHOP As First Line Therapy in Diffuse Large B-Cell Lymphoma (VALFRID): Preliminary Results from a Phase I Trial with a Dose Expansion Cohort

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3939-3939
Author(s):  
Kristina Drott ◽  
Hans Hagberg ◽  
Thomas Relander ◽  
Cecilia Graffman ◽  
Johan Drott ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dose Finding ◽  
Large B Cell Lymphoma ◽  
Cd20 Expression ◽  
Expansion Cohort ◽  
Large B Cell

Abstract Rationale: The anticonvulsant valproate is an HDAC inhibitor, which has in vitro been shown to sensitize lymphoma cell lines for CHOP chemotherapy, and to upregulate CD20 expression. Based on these findings, we initiated a dose finding trial of valproate in combination with R-CHOP in primary treatment of diffuse large B-cell lymphoma (DLBCL), including a dose expansion cohort. Methods: Eligibility criteria were: age 18-80 years, histologically confirmed (according to the WHO classification) diffuse large B-cell lymphoma stage II-IV, WHO performance status 0-2. R-CHOP was given at standard dose in 14 or 21 day cycles, 6 cycles. Valproate was given in escalating doses days 1-3, starting at 10 mg/kg every 8 hrs, by a standard 3+3 design. Prednisone was given days 1-5, R-CHOP on day 3. Response was evaluated according to the Lugano criteria. Results: In the phase I portion, the MTD of valproate was established as 20 mg/kg every 8 hrs (total 60 mg/kg). At a dose of 80 mg/kg, 2 of 3 patients experienced tinnitus (grade 1 and 2) during the latter part of the treatment course. At a dose of 100 mg/kg, 1 of 5 patients developed hearing impairment, grade 1, after 3 cycles, which worsened to grade 2 after 4 cycles, leading to omission of valproate. By August 1, 2015, 28 patients have been included, of which 17 in the dose finding portion. The median age is 69 years (range 47-78). According to the IPI, 43, 36 and 21% were low, low-intermediate and high intermediate/high risk, respectively. Apart from the auditory adverse effects presented above, toxicity was comparable to that of standard R-CHOP, without any impact on hematological toxicity. Presently, 17 patients are evaluable for response after 6 cycles VR-CHOP, ORR 17/17 CR 15/17 (88%). After a median time of follow-up of 16 months, median PFS has not been reached, and estimated PFS at 18 months is 77%. One patient has died due to progressive lymphoma, 21 months after inclusion. By flow cytometry of fine needle aspirates from lymphoma lesions before and after 3 days of valproate, we could show significant upregulation of CD20 expression in 3 patients. Conclusions: Sensitization to rituximab and CHOP by pretreatment with an HDAC inhibitor is a novel therapeutic strategy for the treatment of DLBCL. At a dose of 60 mg/kg, divided into 3 doses, the combination of valproate with R-CHOP is feasible in 1st line treatment of DLBCL. Higher doses of valproate was associated with intolerable auditory side effects. Early data show promising efficacy, which may form the basis for a randomized phase III trial. The long-term efficacy of this regimen remains to be established by longer follow-up. Disclosures Drott: Respiratorius: Membership on an entity's Board of Directors or advisory committees. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL. Drott:Respiratorius: Employment. Off Label Use: Valproate for treatment of diffuse large B-cell lymphoma..

scholarly journals Phase I Study Combining Ibrutinib with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients with Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL): NCI-Cancer Therapeutics Evaluation Program (CTEP) #9588

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4198-4198 ◽  
Author(s):  
Craig S. Sauter ◽  
Stephanie L. Verwys ◽  
Susan J. McCall ◽  
Shoshana T. Miller ◽  
Amanda I. Courtien ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Fdg Pet ◽  
Phase I Study ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: In the post-rituximab era, half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response with standard salvage therapy, and are thus ineligible to proceed to consolidative autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, predominately of the non-germinal center B-cell (non-GCB) phenotype, with minimal toxicity. This single center, NCI-CTEP sponsored phase I study is the first to evaluate the combination of ibrutinib with standard salvage therapy of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in transplant-eligible rel/ref DLBCL patients. Methods: Patients with rel/ref DLBCL, including transformed B-cell non-Hodgkin lymphoma, are eligible for study. The phase I study design is a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine safety and the maximum tolerated dose (MTD) of ibrutinib in combination with R-ICE. Secondary objectives include response rate according to computed tomography (CT) and functional imaging (FDG-PET) per Deauville criteria. Results: To date, 16 patients are evaluable for toxicity, and 15 are evaluable for response. The median age of the 16 evaluable patients is 51 years (range 19-75 years). Histologies of the patients evaluable for response are: GCB DLBCL n=3, non-GCB DLBCL n=4, primary mediastinal large B-cell lymphoma n=4, and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (tCLL/SLL) n=4. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n=3), 2 (n=3), or 3 (n=10, currently in expansion). Of the 16 patients evaluable for toxicity, 15 experienced expected and transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number of cumulative platelet transfusions per patient for 3 cycles was 2 (range 0-11). Eleven of the 15 patients evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 106CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV-positive patient at DL #3 in the setting of febrile illness. One patient experienced grade 3 atrial fibrillation/flutter and was subsequently removed from study per treating physician's decision. Per CT criteria, five patients achieved complete remission (CR), eight patients achieved partial remission (PR), and two patients had stable disease for an overall response rate of 87%. All eight patients with non-GCB DLBCL and tCLL/SLL that were evaluable for response achieved chemosensitive remission per CT criteria (CR=4, PR=4). Seven of the 15 total patients (47%) evaluable for response achieved a complete metabolic remission (Deauville 1-3) per FDG-PET, including all 4 patients of non-GCB phenotype. Conclusions: Currently, no DLTs have been observed with ibrutinib at dosing up to 840 mg daily in combination with R-ICE. We are currently expanding DL #3. Manageable and expected hematologic toxicities have been observed. Importantly, hematologic toxicity has not resulted in failure to complete protocol therapy on-schedule or mobilize HPCs. Encouragingly, 87% of patients achieved a CT response (CR/PR) and 47% of patients achieved a complete metabolic remission per FDG-PET, including 100% of patients with non-GCB phenotype. These results compare favorably to historic cohorts. Given the safety and efficacy observed in this phase I, later phase studies for this treatment program are warranted. Disclosures No relevant conflicts of interest to declare.

Interim Report of Phase II Study of Bortezomib Plus CHOP Every 2 Weeks in Patients with Disseminated Stage Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2688-2688
Author(s):  
Jeong Eun Kim ◽  
Dae Ho Lee ◽  
Soon Il Lee ◽  
Jae Hoon Lee ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Large B Cell Lymphoma ◽  
Number Of Patients ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Abstract 2688 Poster Board II-664 Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and dose-dense CHOP therapy has improved the treatment results of diffuse Large B-cell lymphoma (DLBCL) patients. Nevertheless, a substantial number of patients progress or relapse. Bortezomib is a proteasome inhibitor that is widely used in myeloma treatment and was recently approved for use in mantle cell lymphoma treatment. Its antitumor activity in DLBCL patients was reported in several studies, both as a single agent and in combination with chemotherapy. In this study, we tried to add bortezomib to dose-dense CHOP every 2 weeks to evaluate the complete response (CR) rate and safety of the treatment. Patients with previously untreated disseminated stage DLBCL and age 70 years or less were eligible. All patients received CHOP (Cyclophosphamide 750 mg/m2 IV, doxorubicin 50mg/m2 IV, vincristine 1.4mg/m2 IV on day 1, and prednisolone 100mg PO on days 1 to 5) and granulocyte colony-stimulating factor at a dose of 5μg/kg from days 4 to 13 every 2 weeks. Bortezomib, as recommended by the previous phase I trial, was administered at a dose of 1.6mg/m2 on days 1 and 4 of each cycle. Thirty-five patients were enrolled from March, 2007 to March 2009. Total 188 cycles of treatment were done. Twenty-six patients finished planned 6 cycles of treatment, while 9 patients could not continue all planned treatment due to treatment related toxicities and one patient experienced disease progression after 5 cycles of treatment. Twenty-four patients had a CR (92.4%), one patient had a partial response (3.8%), and one patient had a progressive disease (3.8%). Grade 3 hematologic toxicity episodes occurred including 20 anemia (10.7%), 4 neutropenia (2.1%), and 6 thrombocytopenia (3.2%). Grade 4 hematologic toxicity episodes comprised 2 anemia (1.6%), 11 neutropenia (5.9%), and 6 thrombocytopenia (3.2%). One patient died of severe infection with neutropenia. Among 35 patients, grade 3 non-hematologic toxicity occurred with fatigue (11.4%), nausea (2.9%), vomiting (5.7%), diarrhea (8.6%), abdominal pain (8.6%), and sensory neuropathy (20.0%). One patient experienced grade 4 constipation. This interim analysis shows that bortezomib plus dose-dense CHOP every two weeks showed promising activity in disseminated DLBCL patients as the first-line treatment with acceptable toxicity. Further accrual will be continued till the planned patient enrollment goal for phase II results. Disclosures: No relevant conflicts of interest to declare.

Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma or Mantle-Cell Lymphoma: Results From the Phase II GAUGUIN Study

2013 ◽  
Vol 31 (23) ◽  
pp. 2912-2919 ◽  
Author(s):  
Franck Andre Morschhauser ◽  
Guillaume Cartron ◽  
Catherine Thieblemont ◽  
Philippe Solal-Céligny ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Treatment Response ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Purpose Obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In phase I of our study, obinutuzumab (GA101) exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. The efficacy and safety of two doses of obinutuzumab (GA101) were explored in our randomized phase II trial in patients with heavily pretreated DBLCL and MCL. Patients and Methods Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8. Results Forty patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28% (32% and 24% in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates were 37% in the 1,600/800-mg arm and 24% in the 400/400-mg study arm (DLBCL, eight [32%] of 25 patients; MCL, four [27%] of 15 patients). Five (20%) of 25 rituximab-refractory patients exhibited treatment response, including four of 12 in the 1,600/800-mg group. The most common adverse events were infusion-related reactions (IRRs), which were manageable. Three patients had grade 3/4 IRRs. Grade 3/4 neutropenia was seen in only one patient. Conclusion Obinutuzumab (GA101) 1,600/800 mg achieves early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.

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