Bortezomib (BTZ) and Panobinostat (PAN) Combination Is Effective in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL) and Maintenance Treatment May Be Essential for Sustained Response

Abstract Abstract 3669 Background: Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. Inhibition of HDAC6 by PAN abrogates BTZ-induced protective aggreosome formation and accentuates BTZ induced endoplasmic reticulum stress, leading to further apoptosis. Primary end point of this ongoing phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. Methods: Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. Preliminary response data were available for all 11 pts recruited for stage 1 of the study. A response rate of >25% will allow the study to proceed to stage 2. Results: Among pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=4, PTCL (unspecified) n=4, ALK+ Anaplastic large cell lymphoma n=1 and NKL, nasal type n=2. The median age was 52 (35–72) years, and 70% were male. The ORR was 54.5% with 18% attaining a complete response. Four pts (36%) had a partial response, and stable disease was noted in 2 (18%). Pts received a median of 2 prior therapies (range 1–3); 27% received an autogous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (36%), neutropenia (27%), diarrhoea (18%) and fatigue (9%). Peripheral neuropathy of any grade was observed in 35%. Among pts who responded or had stable disease, the median PFS was 6 months and disease progression occurred at a median of 2.5 months after stopping trial drugs. Two deaths have occurred: 1 due to progressive disease and 1 associated with an unrelated cardiac event. 3 pts successfully underwent subsequent allogeneic SCT. Conclusions: The study regimen shows activity across T/NK-cell lymphomas and ORR greatly exceeds the predefined threshold of 25% allowing, together with early tolerability data, continuation of study enrolment in stage 2. The early progression of the disease after stopping trial drugs albeit the high initial ORR suggests that the novel combination provides a tonic suppression of tumor proliferation and ongoing treatment will be beneficial for pts without option for subsequent alternative treatment like SCT. An extended phase of maintenance treatment will be incorporated into stage 2 of the study to allow pts to optimally benefit from the combination. Our interim findings may have implications on the design of future studies seeking proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/co-regulators known to be modified by acetylation. Disclosures: Tan: Novartis: Research Funding; Janssen: Equity Ownership, Honoraria, Research Funding. Goh:Novartis: Honoraria, Research Funding; Jansen: Honoraria, Research Funding.

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A Phase 2 Study of Panobinostat (PAN) in Combination with Bortezomib (BTZ) in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL)

Blood ◽

10.1182/blood.v124.21.503.503 ◽

2014 ◽

Vol 124 (21) ◽

pp. 503-503 ◽

Cited By ~ 3

Author(s):

Yeow-Tee Goh ◽

William YK Hwang ◽

Colin Phipps Diong ◽

Yap chun Hsien ◽

Kevin Tay ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Performance Status ◽

Objective Response ◽

T Cell Lymphoma ◽

Conventional Chemotherapy ◽

Advisory Committees

Abstract Background Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. PAN inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by BTZ. Primary end point of this phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (Cheson 2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. We report the final clinical results of our study exploring this novel combination. Methods Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 or more prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. CT scanning and/or FDG-PET were performed after every two cycles. Results: Among 25 pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=8, PTCL (unspecified) n=11, Anaplastic large cell lymphoma, ALK+ and ALK- n=1 and 2 respectively, NKL, nasal type n=2 and subcutaneous panniculitis-like T-cell lymphoma n=1. The median age was 59 (35-79) years, and 64% were male. Outcomes are available on 23 patients as 2 patients withdrew consent before any response assessment could be made. The ORR (CR+PR) was 43% (10/23) with 22% (5/23) attaining a CR. Median time to response was 6 weeks. Five pts (22%) had stable disease while 8 pts developed progressive disease (35%) while on study. Pts received a median of 2 prior therapies (range 1-4); 28% had prior autologous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (68%), neutropenia (36%), diarrhoea (28%) and asthenia/fatigue (16%). Peripheral neuropathy of any grade was observed in 40%. 5 pts successfully underwent subsequent allogeneic SCT. Updated survival analysis will be presented. Conclusions The study regimen is generally well tolerated and shows encouraging activity across different T/NK-cell lymphomas. The novel combination could successfully serve as a bridge to allogeneic SCT for many transplant-eligible patients who have failed conventional chemotherapy. These results form the basis for further validation studies on proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation. Disclosures Goh: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kim:Novartis, Celgene, Takeda: Research Funding. Tan:JANSEN: Honoraria, Research Funding; NOVARTIS: Research Funding.

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Frontline Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin and Prednisone in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression (SGN35-032, Trial in Progress)

Blood ◽

10.1182/blood-2021-151645 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1401-1401

Author(s):

Deepa Jagadeesh ◽

Scott Knowles ◽

Steven M. Horwitz

Keyword(s):

T Cell ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

Efficacy And Safety ◽

Time To Event ◽

Peripheral T Cell Lymphoma ◽

Secondary Endpoints

Abstract Background Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing CD30-targeted cell cycle arrest and apoptosis as well as the bystander effect on adjacent cells (Sutherland 2006, Hansen 2016, Schönberger 2018). In the ECHELON-2 phase 3 clinical trial, BV, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by immunohistochemistry when compared with patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (Advani 2019). It is hypothesized that A+CHP will demonstrate efficacy in PTCL with <10% CD30 expression because i) clinical responses to BV have occurred in patients with PTCL, cutaneous T-cell lymphoma, or B-cell lymphoma with low (<10%) and undetectable CD30 expression (Jagadeesh 2019) and ii) CD30 expression levels were not predictive of A+CHP responses in non-systemic anaplastic large cell lymphoma (sALCL) (Advani 2019). Study Design and Methods SGN35-032 is a dual-cohort, open-label, multicenter, phase 2 clinical trial (NCT04569032) designed to evaluate the efficacy and safety of A+CHP in patients with non-sALCL PTCL and CD30 expression of <10% on tumor cells. Up to approximately 40 patients will be enrolled in each of the CD30-negative (expression <1%) and the CD30-low (expression ≥1% to <10%) cohorts. Patients will be enrolled based on local results but only patients with CD30 expression <10% per central confirmation will be analyzed for the primary and secondary endpoints. Patients will receive 21-day cycles of A+CHP for 6-8 cycles. Key inclusion criteria include adults with newly diagnosed PTCL, excluding sALCL, per the World Health Organization 2016 classification; CD30 expression <10% by local assessment; and fluorodeoxyglucose-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist. Patients with previous exposure to BV or doxorubicin will not be eligible. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR) using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Secondary endpoints include ORR by BICR using the modified Lugano criteria (Cheson 2014), complete response rate, progression-free survival (PFS), and duration of response per BICR using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), overall survival, and safety and tolerability. A PET scan is required at baseline, after Cycle 4, and after the completion of study treatment. Follow-up restaging CT scans will be performed over the next 2 years. In both the CD30-negative and the CD30-low cohorts, efficacy and safety endpoints will be summarized using descriptive statistics to describe continuous variables by cohort. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier (KM) methodology and KM plots will be presented. Medians for time-to-event analyses (e.g., median PFS) will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. Enrollment is planned for 15 US sites and 32 sites across the Czech Republic, France, Italy, and the UK. Disclosures Knowles: Seagen Inc.: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

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Alemtuzumab and DHAP (A-DHAP) Is An Effective Salvage Therapy for Peripheral T-Cell Lymphoma, Unspecified: Interim Results of a Phase II Prospective Multicenter Study

Blood ◽

10.1182/blood.v112.11.5002.5002 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5002-5002

Author(s):

Seok Jin Kim ◽

Kihyun Kim ◽

Byung Soo Kim ◽

Cheolwon Suh ◽

Won Seog Kim

Keyword(s):

Stem Cell ◽

T Cell ◽

Cell Count ◽

Response Rate ◽

Chemotherapy Regimen ◽

Cell Lymphoma ◽

Objective Response ◽

T Cell Lymphoma ◽

Prospective Multicenter Study ◽

Peripheral T Cell Lymphoma

Abstract Purpose: The prognosis for relapsed or refractory peripheral T-cell lymphomas (PTCLs) is extremely poor, and there is still no consensus on the optimal salvage therapy. Alemtuzumab (Campath-1H®, Bayer-Schering, Berlin, Germany) is a humanized immunoglobulin G1 anti-CD52 monoclonal antibody. Considering the expression of CD52 antigen on the surface of T-cell lymphoma cells, alemtuzumab could be a suitable agent for the treatment of PTCLs. A previous pilot study showed the efficacy of alemtuzumab as a single agent for patients with relapsed or refractory PTCLs. Thus, we designed a new chemotherapy regimen, A-DHAP, consisting of alemtuzumab and DHAP (dexamethasone, cisplatin, and cytarabine) to augment the efficacy of alemtuzumab against PTCLs. Herein, we report the interim results of phase II prospective multicenter study using the A-DHAP regimen in patients with relapsed or refractory PTCLs. Patients and Methods: We enrolled 16 patients between the ages of 18 and 65 years who had histologically confirmed PTCLs, excluding ALK-positive anaplastic large cell lymphoma. Patients were required to have failed primary treatments such as anthracycline-containing regimens. Failure was defined as a relapse from previous confirmed complete response (CR) or progress during treatment. Each patient received DHAP plus an escalated dosage of alemtuzumab (10 mg on day -1 and 30 mg on day 1 and 2) every 3 weeks for up to 3 cycles. Responders then received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Results: At relapse or progression after previous therapy, 13 patients presented as stage III or IV (81.3%). However, 11 patients belonged to low or low-intermediate IPI (international prognostic index) risk as they were less than 60 years old, had normal serum LDH and good performance status. Peripheral T-cell lymphoma, unspecified (PTCL-U) and extranodal NK/T cell lymphoma, nasal type (ENKTCL) were the dominant histological subtypes (14/16, 87.6%). The median treatment was 2 cycles (range 1–3 cycles). Seven patients completed the planned 3 cycles of A-DHAP. Eight patients showed an objective response including four CR and four PR, while seven patients showed PD (Progressive disease), and one patient had SD (Stable disease) after the 3rd cycle. Thus, the objective response rate was 50.0% (8 of 16 patients). When we analyzed the response according to the histological type, the objective response rate was much higher for PTCL-U (85.7%: 3 CR, 3 PR) than for ENKTCL (14.3%, 1 PR). Seven patients could receive autologous stem cell transplantation (ASCT); five patients after objective response and two patients after other salvage treatments. The median CD34+ cell count was more than 3.79×106/kg (range, 2.30 – 5.90×106/kg), and there was no engraftment failure. However, one patient could not receive ASCT because the yield of CD34+ cell count was less than the minimal requirement (2.00×106/kg) although his complete blood cell count was within normal range after the completion of three cycles of A-DHAP chemotherapy. The median overall survival (OS) after enrollment in the study was 6.0 months (95% confidence interval 3.51–8.49 months). Responders to A-DHAP showed a better OS than non-responders (P = 0.038). The most frequent side effects were grade 3/4 leukopenia and infectious complications including cytomegalovirus reactivation, hepatitis B virus infection and pneumonia. Conclusions: The combination of alemtuzumab plus DHAP might be an effective salvage chemotherapy regimen for PTCL-U patients. However, careful monitoring and dosage modification are warranted to prevent treatment-related toxicity.

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Histone Deacetylase Inhibitors Downregulate CCR4 Expression and Decrease Mogamulizumab Efficacy in CCR4-Positive Mature T-Cell Lymphomas

Blood ◽

10.1182/blood.v130.suppl_1.720.720 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 720-720

Author(s):

Akihiro Kitadate ◽

Sho Ikeda ◽

Fumito Abe ◽

Naoto Takahashi ◽

Norio Shimizu ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Selective Inhibitor ◽

T Cell Lymphoma ◽

Lymphoma Cell ◽

Class I ◽

T Cell Lymphomas

Abstract Background: Histone deacetylase inhibitors (HDACis) are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and adult T-cell lymphoma/leukemia (ATLL). CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against CTCL, PTCL, and ATLL. However, their combined effects and interactions have not been examined thus far. We previously showed that CCR6, a chemokine receptor, is overexpressed in cutaneous T-cell lymphomas (Ito et al., 2014 Blood). Moreover, we recently demonstrated that HDACis downregulate CCR6 expression in advanced cutaneous T-cell lymphomas (Abe et al., 2017 Oncotarget). These reports lead us to hypothesize that HDACis might also downregulate CCR4 in various T-cell lymphomas. In this study, we clarify the effect of the combined use of mogamulizumab and HDACis on various T-cell and NK-cell lymphomas. Based on our findings, we discuss what benefits or adverse effects might be assumed for patients if these molecular targeting agents are used in clinical practice. Methods: We evaluated changes in CCR4 expression and antibody-dependent cell-mediated cytotoxicity (ADCC) activities against mogamulizumab- and HDACi-treated T-cell and NK-cell lymphoma lines and primary cases. To determine which HDAC mainly regulated CCR4 expression, we used isoform-specific HDACis and induced knockdown of respective HDACs for T-cell lymphoma cell lines. To examine the effect of CCR4 downregulation by HDACis in clinical cases, we examined the CCR4 expression of CTCL skin samples, which were obtained from the same patients before and after HDACi treatment (n = 6). Results: We first examined the expression of CCR4 for 15 T-cell and NK-cell lymphoma cell lines and a peripheral blood mononuclear cell (PBMC) sample derived from healthy donors to investigate the effect of vorinostat, a pan-HDACi, on CCR4 expression. The expression of CCR4 was mostly expressed in the (11 out of 15) cell lines: ATLL (MT-1, MT-2, MT-4, and TL-Su), CTCL (My-La, HH, and MJ), and NK/T-cell lymphoma cell lines (Kai3, SNK6, HANK1, and SNK10). We found that vorinostat decreases mRNA expression and surface expression of CCR4 except for the cell lines without CCR4 expression. Next, we used isoform-specific HDACis to examine which isoform of HDAC is involved in the regulation of CCR4. We used the following class-specific HDACis: romidepsin as a class I selective HDACi, CI-994 as an HDAC1/HDAC2-selective inhibitor, RGFP966 as an HDAC3-selective inhibitor, ricolinostat as an HDAC6-selective inhibitor, and PCI-34051 as an HDAC8-selective inhibitor. When these drugs were exposed to T-cell lymphoma cells, romidepsin and CI-994 strongly suppressed CCR4 expression. These results suggest that class I HDACs might controls CCR4 expression. We further performed knockdown experiments using siRNAs against HDAC1, HDAC2, and HDAC3. When we compared the expression change of CCR4 in HDAC-knockdown cells, HDAC2 knockdown cells showed the most significantly decreased expression of CCR4. These results suggest that class I HDACs, especially HDAC2, might be deeply involved in CCR4 expression regulation. When we examined the CCR4 expression in skin samples from primary CTCL, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after vorinostat treatment. Finally, when we conducted an ADCC assay with mogamulizumab by using various lymphoma cell lines and primary T-cell lymphoma samples, we found that the efficacy of mogamulizumab was significantly reduced by pre-treatment with vorinostat. Conclusion: Our results suggest that the primary use of HDACis before treatment of mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results provide potential implications for optimal therapeutic sequences in various CCR4 positive T-cell and NK-cell lymphomas. Disclosures Kitadate: Kyowa Kirin: Research Funding; Fujimoto: Research Funding; Eisai: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Asahi Kasei: Research Funding; Chugai: Research Funding; Toyama kagaku: Research Funding. Abe: Kyowa Kirin: Research Funding; Fujimoto: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Otsuka: Research Funding; Toyama Kagaku: Research Funding; Chugai: Research Funding; Asahi Kasei: Research Funding; Eisai: Research Funding. Tagawa: TaNeDS (Daiichi Sankyo): Research Funding.

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A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas

Blood ◽

10.1182/blood.v128.22.2991.2991 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2991-2991 ◽

Cited By ~ 13

Author(s):

Neha Mehta-Shah ◽

Alison J Moskowitz ◽

Matthew Lunning ◽

Peggy Lynch ◽

Mark Scheuerman ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Grade 3

Abstract Background:Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide demonstrated a 58% overall response rate, complete response rate of 11% and median event free survival was 16 weeks in patients (pts) with relapsed or refractory T-cell lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study to evaluate the safety and toxicity of romidepsin and lenalidomide in combination with carfilzomib in pts with relapsed or refractory lymphoma. Here we report the safety, toxicity, and maximum tolerated dose (MTD) from the completed phase I portion of the study as well as the efficacy data from the completed T-cell lymphoma phase IIa cohort. Methods: The phase I portion evaluated toxicity and defined MTD. The clinicalactivity of the combination of romidepsin, lenalidomide, and carfilzomib was assessed in the phase I and lineage specific phase IIa cohorts. Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation schema was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity, grade ≥ 3 thrombocytopenia with bleeding, grade 3 hematologic toxicity resulting in a significant delay of treatment or inability to receive day 1 of cycle 2 due to continued drug related toxicity. Tumor response was based on disease-specific criteria.Pts could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation. Results:20 pts were enrolled with 19 evaluable for toxicity (1 patient with T-cell lymphoma progressed prior to receipt of any study drug). 17 pts were treated for T-cell lymphoma (11 in the phase 1 portion and 6 in the phase IIa cohort): peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)-9, angioimmunoblastic T-cell lymphoma (AITL)-4 (one with concurrent diffuse large B-cell lymphoma-DLBCL), mycosis fungoides (MF)-2, transformed MF-1, extra-nodal NK/T-cell lymphoma (ENKTCL)-1. 3 pts in the phase 1 portion were treated for B-cell lymphoma: DLBCL-3. The T-cell lymphoma cohort is complete and efficacy data is reported here. Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 pt with grade 3 thrombocytopenia resulting in treatment delay and 1 pt with grade 4 thrombocytopenia. There were no DLTs among 6 pts treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD. Grade 3-4 toxicities in >10% pts included neutropenia and thrombocytopenia. SAEs included: infection-3, progression of disease resulting in hospitalization-3, fever-2, febrile neutropenia-1, DVT-1, edema-1, dyspnea-1, atrial flutter-1, generalized weakness-1, and vomiting with diarrhea-1. Of the 16 pts with T-cell lymphoma evaluable for response, the overall response rate was 50% (8/16, 95% CI: 25 to 75%). The complete responses rate was 31% (5/16, 95% CI: 11 to 59%) and the partial response rate was 19% (3/16, 95% CI: 4 to 46%). Complete responses were seen in AITL (4/5) and PTCL-NOS (1/8) with 3 pts in CR proceeding to allogeneic stem cell transplantation. Partial responses were seen in PTCL-NOS-1, AITL-1, and transformed MF-1. In T-cell lymphoma, the median event free survival for all pts was 9.7 weeks (95% CI: 6.0 to NR) and for responders was not reached (95% CI: 15.0 to NR). The median time to response was 5.8 weeks. The median duration of response was 9.6 weeks (95% CI: 8.0 to NR). 3 pts underwent allogeneic transplantation following this therapy and another 2 pts with CR remain in continuous remission. Median duration of follow up was 20.4 weeks (range 3.4-40.9 weeks). Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2. No unexpected toxicities have emerged. The preliminary overall and complete response rates of this regimen are promising in T-cell lymphoma, particularly in AITL, and warrants further study. An expansion cohort in B-cell lymphoma cohort is ongoing. Disclosures Moskowitz: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy. Lunning:Gilead: Consultancy; Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Kumar:Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board. Zelenetz:Gilead Sciences: Research Funding. Hamlin:Novartis: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Seattle Genetics: Research Funding; Molecular Templates: Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Palomba:Pharmacyclics: Consultancy. Dogan:Seattle Genetics: Consultancy; Consulting Cancer Panel: Membership on an entity's Board of Directors or advisory committees; Cancer Genetics: Membership on an entity's Board of Directors or advisory committees; Peerview Institute: Consultancy. Horwitz:Bristol-Myers Squibb: Consultancy; Infinity: Consultancy, Research Funding; Celgene: Consultancy; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Huya: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding.

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Salvage Therapy with Brentuximab-Vedotin and Bendamustine for Patients with Relapsed/Refractory T Cell Lymphoma. a Multicenter and Retrospective Study

Blood ◽

10.1182/blood-2021-150953 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 620-620

Author(s):

Krimo Bouabdallah ◽

Raphaëlle Aubrais ◽

Loïc Chartier ◽

Charles Herbaux ◽

Anne Banos ◽

...

Keyword(s):

Retrospective Study ◽

T Cell ◽

Salvage Therapy ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Multivariable Analysis ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

Hematologic Toxicity

Abstract Methods : This multicentric retrospective study aimed to evaluate the efficacy and the safety of the combination of BBV in patients with non-cutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was to evaluate the best overall response rate (ORR) (complete response (CR) and partial response (PR)). Secondary objectives were progression free survival (PFS), overall survival (OS), duration of response (DoR), impact of transplantation on outcome, and safety. Patients treated between January 2013 and October 2020 were reviewed and all the data were collected through an electronic questionnaire sent to all the physicians. Results : Eighty two patients with R/R PTCL (40 angioimmunoblastic lymphoma (AITL), 2 T-cell lymphoma with TFH phenotype ,13 PTCL not otherwise specified (PTCL NOS), 5 Alk+ anaplastic large cell lymphoma (ALCL), 17 Alk- ALCL, , 1 Extranodal NK-/T-cell lymphoma, 3 Enteropathy-associated T-cell lymphoma (EATL), 1 subcutaneous panniculitis) were included. Median age at beginning of BBV was 60 years, most of patients were male (61%), had advanced stage (88%) and an IPI ≥ 2 (79%). Half of patients were refractory to their last treatment. Median number of prior regimens was 1 (range 1 to 6). The best ORR was 71%, with 51% of patients in CR. In multivariable analysis, only the relapse status after the last regimen (relapse vs refractory) was associated with ORR, relapsed patients having a better ORR (83% vs 57% in refractory patients, p=.014, OR=3.70 (95%CI:1.3-10.5)). Median DoR was 15.4 months in patients with CR but differed significantly whether patients were transplanted or not (Not reached vs 8.4 months, p=.0055). Twenty-two patients (30% of patients ≤ 70 years of age) were transplanted (6 autologous and 16 allogenic). With a median follow-up of 9 months, the median PFS and OS were 8.3 and 26.3 months respectively. In multivariable analysis, only 2 factors had a significant impact on PFS and OS: best response (CR/PR vs SD/PD with a median PFS of 17.4 vs 1.9 months, p<.0001, and a median OS Not Reached vs 5,9 months, p<.0001) and transplantation (for patients in CR, median PFS was Not Reached in transplanted patients vs 13.1 months; p=.0410, and median OS was Not Reached vs 34, 6 months; p=.0304) (Fig1). Histological subgroups was also significantly associated with PFS (p=.012) but not with OS (p=.26) in multivariable analysis. Patients with PTCL NOS/Other subtypes had worse PFS than patients with TFH subtypes (HR=2.89 (95%CI: 1.4-5.8), p=.0029). Interestingly the CD30 status (positive vs negative) had no impact on ORR or survival. Fifty-nine percent of patients experienced a grade 3 to 4 adverse event which was mainly hematologic toxicity. Treatment had to be stopped in 11% of patients. Conclusion: To the best of our knowledge, this is the first study reporting on the combination of BBV in the treatment of R/R PTCL in such a large cohort. The results are very encouraging with a high response rate, long DoR in responding patients and a very good outcome. Furthermore, patients in CR who are eligible for transplant have the best outcome, making this combination a good candidate as salvage therapy before transplant consolidation in these high-risk lymphomas with limited treatment options. Figure 1 Figure 1. Disclosures Bouabdallah: Kite/Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Herbaux: Takeda: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Sibon: Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy; iQone: Consultancy; Takeda: Consultancy. Laribi: AstraZeneca: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Jansen: Research Funding. Damaj: roche: Consultancy, Honoraria; takeda: Consultancy, Honoraria. OffLabel Disclosure: Brentuximab Vedotin and Bendamustine

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Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study

Blood ◽

10.1182/blood.v112.11.263.263 ◽

2008 ◽

Vol 112 (11) ◽

pp. 263-263 ◽

Cited By ~ 5

Author(s):

Youn Kim ◽

Sean Whittaker ◽

Marie France Demierre ◽

Alain H Rook ◽

Adam Lerner ◽

...

Keyword(s):

T Cell ◽

Disease Progression ◽

Median Time ◽

Stable Disease ◽

Response Rate ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Cutaneous T Cell Lymphoma ◽

Duration Of Response ◽

Treatment Refractory

Abstract Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell Lymphoma (CTCL). This Phase 2B, singlearm, open-label registration study enrolled pts with CTCL (Stages IB–IVA) at 33 European and US sites. Pts with histologically confirmed CTCL who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease or response). Aim: The primary endpoint was the response rate among evaluable pts, measured by a combination of a weighted scoring instrument to determine skin involvement (SWAT), imaging, and circulating Sézary cells (as applicable). Results: 96 pts were enrolled and received romidepsin (as-treated); 72 (75%) were evaluable (≥2 cycles) for efficacy. Enrollment is complete, 4 pts with confirmed PR continue to receive romidepsin on extended treatment, 5 pts off-treatment are being followed. Mean age of all pts was 57±12 yrs, and median time since diagnosis was 3 yrs (range <1–26). 68 pts (71%) had disease stage ≥IIB. Median number of prior systemic therapies was 2 (range 1–8). Response (assessed by investigators) and pruritus relief (assessed by visual analog scale [VAS]) data are in the table. Objective disease response rate (ORR) was not lower in pts with advanced-stage disease; 23 (47.9%) of 48 pts with stage IIB-IVA and 7 (29%) of 24 pts with stage IB-IIA achieved OR. With a median follow-up of 5.3 months (mo), median duration of response has not been reached. 50% of responders (evaluable pts) have maintained a response for ≥5 mo and 30% for ≥8 mo. The maximum duration of response was 19.8 mo. 24 (80%) of the 30 pts with a response had not progressed as of the last assessment. Most pts (48/52; 92%) with pruritus at baseline (≥30 mm on VAS) had some relief, including most of those with severe pruritus. Adverse events (AEs) occurred in 93 pts (97%). AEs reported in ≥20% of pts were nausea (56%), asthenia (52%), vomiting (29%), anorexia (23%), hypomagnesemia (21%), and pyrexia (20%). AEs ≥ grade 3 occurred in 32 pts (33%), most commonly fatigue (7%), disease progression (4%), and pyrexia (4%). 21 pts (22%) had a serious AE; the most frequently reported serious AEs were disease progression (6%), pyrexia (3%), sepsis (2%), tumor lysis syndrome (2%), and hypotension (2%). 20 pts (21%) withdrew because of AEs, including fatigue (4%), pyrexia (2%), prolonged QT (2%), and CTCL progression (2%). 6 pts (6%) died, 1 possibly related to treatment. Mean QTcF change from baseline to 2 hrs post-dose was 4.6 msec using baseline assessments before any anti-emetics and 1.3 msec using baseline assessment after anti-emetics. No pts had QTcF values >500 msec. Conclusions: This study shows clinical benefit associated with romidepsin use in treatment-refractory CTCL, with pts achieving durable response and relief from pruritus. Toxicities associated with romidepsin were tolerable and manageable. Evaluable Pts N=72 As-treated Pts N=96 a stable disease for ≥90 days b relief = ≥ 30mm decrease on 100mm VAS or score of 0 for 2 consecutive cycles Confirmed ORR 42% 34% PR, n (%) 24 (33%) 27 (28%) CCR, n (%) 6 (8%) 6 (6%) SD90a, n (%) 26 (36%) 28 (29%) Overall disease control (CCR+PR+SD90) 56 (78%) 61 (64%) Median time (mo) to response (range) 1.9 (0.9–4.8) 1.9 (0.9–4.8) Median time (mo) to disease progression (range) 9.0 (2.7–21.7) 8.3 (0–21.7) Confirmed OR in stage ≥ IIB, n (%) 23/48 (48%) 26/68 (38%) Relief of pruritusb, n (%) 25/52 (48%) NA Relief of severe pruritus, n (%) 16/29 (55%) NA

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Pralatrexate Is An Effective Treatment for Heavily Pretreated Patients with Relapsed/Refractory Transformed Mycosis Fungoides (tMF)

Blood ◽

10.1182/blood.v116.21.1762.1762 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1762-1762 ◽

Cited By ~ 5

Author(s):

Francine M Foss ◽

Steven M Horwitz ◽

Lauren Pinter-Brown ◽

Andre Goy ◽

Barbara Pro ◽

...

Keyword(s):

T Cell ◽

Mycosis Fungoides ◽

Research Funding ◽

Response Rate ◽

Cell Transformation ◽

Cell Lymphoma ◽

Large Cell ◽

The United States ◽

T Cell Lymphoma ◽

Large Cell Transformation

Abstract Abstract 1762 Background: Cutaneous T-cell lymphoma, which includes mycosis fungoides (MF) and the Sézary Syndrome, is an indolent T-cell lymphoma. Large-cell transformation (tMF) is a well-defined histopathological disease that is distinguished from primarily cutaneous MF by the presence of large cells that exceed 25% of total lymphoid infiltrate (Barberio et al. Br J Dermatol 2007; 157:284-9) and occurs in 11% to 23% of cases. tMF represents a significantly poorer prognostic subset of MF patients with median overall survival of 12 to 22 months from the time of diagnosis of large-cell transformation (Arulogun et al. Blood 2008; 112:3082-7). There is no standard therapy for tMF and most patients are treated with multiagent systemic chemotherapy regimens. Because of its poor outcome similar to that of aggressive peripheral T-cell lymphomas (PTCLs), tMF patients were included in PROPEL, the pivotal study that led to the accelerated approval of pralatrexate (FOLOTYN®) in the United States for the treatment of relapsed or refractory PTCL. Methods: Of 109 evaluable patients in the PROPEL trial, 12 patients had histologically confirmed tMF. All patients received pralatrexate at a dose of 30 mg/m2 weekly for 6 weeks in a 7 week cycle. Results: Of the 12 patients with tMF, the median age was 56.5 years. The median number of prior therapies was 6.5 (range 1 to 12), and 5 patients (42%) received ≥5 prior systemic regimens. The majority of patients had received prior multiagent chemotherapy, including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP-based therapy in 67% of patients and other multiagent regimens in 17% of patients. Only 1 of 12 patients had a response to their most recent prior chemotherapy regimen. The objective response rate (ORR) to pralatrexate in this group of refractory tMF using International Workshop Criteria based on investigator assessment, was 58%. Consistent with the overall study population, the ORR by independent central review was 25%. The difference in ORR between independent central review and investigator assessment for tMF is mainly due to challenges with photodocumentation of response assessment of cutaneous lesions. The 12 patients with tMF received a median of 10 doses of pralatrexate and remained on treatment for a median of 89 days. The median response duration was 4.4 months and median PFS was 5.3 months, per investigator assessment. The median survival in this group of patients was 13 months. Mucosal inflammation was reported in 7 patients (58%) including 1 patient with grade 3. Grade 4 adverse events (AEs) were fatigue (1 patient) and thrombocytopenia (1 patient). Overall, patients with tMF were able to tolerate full-dose pralatrexate treatment, with no patients discontinuing due to an AE. Conclusions: Pralatrexate demonstrated significant activity in the 12 refractory tMF patients enrolled in the PROPEL trial with an investigator assessed response rate of 58%. Pralatrexate should be considered as a treatment option for patients with tMF. Disclosures: Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc.: Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

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Romidepsin Induces Durable Responses in Patients with Peripheral T-Cell Lymphoma: GPI-06–0002 Study Update

Blood ◽

10.1182/blood.v120.21.3641.3641 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3641-3641 ◽

Cited By ~ 1

Author(s):

Bertrand Coiffier ◽

Barbara Pro ◽

Miles Prince ◽

Francine M. Foss ◽

Lubomir Sokol ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

T Cell Lymphoma ◽

Prior Therapy ◽

Prior Systemic Therapy ◽

Systemic Therapies

Abstract Abstract 3641 Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative disorders, and most subtypes have a poor prognosis even with aggressive chemotherapy. Romidepsin is a potent class 1 histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with PTCL who have received at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. A phase 2, single-arm, open-label registration study (GPI-06–0002) demonstrated the clinical benefit and tolerability of romidepsin in patients with relapsed or refractory PTCL (data cutoff: Oct 2010). Here, we present an update of the efficacy of GPI-06–0002 and characterize patients who achieved long-term responses (≥ 12 months) as of Dec 2011 (median follow-up: 22.3 months). Methods: Patients with histologically confirmed PTCL (N = 130) who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for responding patients. The primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee (IRC) based on the International Workshop Response Criteria. Secondary endpoints included objective response rate (ORR: CR/CRu + partial response), duration of response (DOR), and time to progression. Disease response was assessed every 2 treatment cycles. Baseline patient characteristics by DOR (≥ 12 months vs < 12 months) were examined. Results: The majority of the 130 patients had stage III or IV disease (70%); 28% had bone marrow involvement. PTCL not otherwise specified (53%) and angioimmunoblastic T-cell lymphoma (21%) were the most common subtypes. Patients received a median of 2 prior systemic therapies (range, 1–8); 38% of patients were refractory to their last line of therapy. The ORR was 25% (33 of 130 patients), including CR/CRu in 15% (19 of 130) of patients. The median duration of objective response was 28 months, with the longest response ongoing at 48 months (Figure). Of the 19 patients who achieved CR/CRu, 13 (68%) had not experienced disease progression per the IRC at a median follow-up of 25.8 months. The median duration of CR had not yet been reached (range, 1–48+ months; Figure). Of the 19 patients who achieved CR/CRu, 10 were long-term responders (responses ≥ 12 months). Interestingly, heavy pretreatment (≥ 4 prior systemic therapies) did not preclude patients from achieving long-term CR/CRu: 5 of 10 patients (50%) who maintained CR/CRu for ≥ 12 months were heavily pretreated vs 1 of 9 (11%) patients with CR/CRu maintained for < 12 months. Long-term CR/CRu was achieved regardless of response to last prior therapy; only 2 of 10 (20%) long-term responders had an objective response on their last treatment. In contrast, 6 of 9 (67%) patients with CR/CRu for < 12 months responded to their last prior therapy. Furthermore, advanced disease did not preclude long-term response to romidepsin: all 10 patients (100%) who maintained CR/CRu for ≥ 12 months had stage III/IV disease vs 55.5% of those who maintained CR/CRu for < 12 months. Other characteristics, such as Eastern Cooperative Oncology Group performance status, International Prognostic Index score, age, sex, and race, were similar among patients achieving CR/CRu for ≥ 12 months or < 12 months. Conclusions: Single-agent romidepsin induced durable responses in patients with relapsed/refractory PTCL, with responses ongoing at 48 months. None of the examined patient and disease characteristics predicted failure to achieve long-term remissions. These results support the use of romidepsin in relapsed/refractory PTCL. Disclosures: Coiffier: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pro:Allos: Honoraria; Spectrum : Honoraria; Seattle Genetics : Research Funding; Celgene: Honoraria, Research Funding. Prince:Celgene : Consultancy, Honoraria, Research Funding. Foss:Celgene : Consultancy. Sokol:Celgene : Honoraria, Speakers Bureau. Morschhauser:Celgene : Consultancy, Honoraria. Pinter-Brown:Celgene : Consultancy; Allos : Consultancy. Shustov:Celgene : Honoraria, Research Funding, Speakers Bureau. Nielsen:Celgene: Employment, Equity Ownership. Nichols:Celgene: Consultancy, Employment, Equity Ownership. Horwitz:Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Allos: Consultancy, Research Funding; Genzyme: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding.

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The Use Of GDP (Gemcitabine, Dexamethasone and Cisplatin) in The Primary Therapy Of Peripheral T-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.1804.1804 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1804-1804

Author(s):

Jean-Michel Lavoie ◽

Joseph M. Connors ◽

Diego Villa ◽

Richard Klasa ◽

Tamara Shenkier ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Primary Therapy ◽

Chop Chemotherapy ◽

T Cell Lymphomas ◽

Cancer Agency ◽

Peripheral T Cell Lymphomas

Abstract Introduction The outcome of peripheral T-cell lymphomas (PTCLs) is poor using standard CHOP chemotherapy. Previous studies have shown good single agent activity of gemcitabine in the relapsed/refractory setting. GDP (gemcitabine, dexamethasone and cisplatin) was developed as a secondary chemotherapy regimen in relapsed aggressive lymphomas and in a comparison to DHAP has recently been shown to have equivalent efficacy, a favourable side effect profile, and it can be delivered in the outpatient setting. At the BC Cancer Agency, GDP has recently been integrated into the primary therapy of patients with PTCLs in an attempt to improve outcomes with CHOP chemotherapy in this poor risk population. Methods The BC Cancer Agency Centre for Lymphoid Cancer and pharmacy databases were searched to identify all cases of newly diagnosed PTCLs with diagnoses by the WHO classification, (with the exception of ALK-positive ALCL, extranodal NK/T-cell lymphoma, cutaneous T-cell lymphoma and hepatosplenic t-cell lymphoma) that received at least one cycle of GDP chemotherapy integrated into their primary therapy, typically alternating with CHOP. Results In total, 34 patients received GDP as part of their first-line treatment (PTCL-NOS n=19, ALK-neg ALCL n=10, enteropathy-type TCL n=2, angioimmunoblastic T-cell lymphoma n=3) in addition to CHOP chemotherapy. The median age was 58 years, 65% were male and the majority of patients had high risk features including stage 3 or 4 disease (94%), elevated LDH (62%). high IPI score (>3 65%; >2 82%) and 32% had bone marrow involvement. The median number of cycles of GDP was 3 (1-8). Two patients underwent consolidative treatment with high dose chemotherapy and autologous stem cell transplantation in first remission and two patients received consolidative radiotherapy. The overall response rate at the end of primary chemotherapy was 82% (CR 62%). With a median follow-up in living patients of 2.8 years the 1- and 2-year time to progression (TTP) were 50% and 36%, respectively and the corresponding estimates for OS were 78% and 64%. Interestingly, the IPI was not prognostic (2 y TTP IPI 0,1 42%, 2,3 34%%, 4,5 37.5% p=.87) even if the 2 patients undergoing transplant are excluded. GDP was generally well tolerated and only 2 patients discontinued treatment due to toxicity (renal dysfunction/hearing loss and rash) and there were no treatment-related deaths. Two patients were hospitalized for febrile neutropenia following GDP and 9 patients (26%) required GCSF support through their therapy. Conclusion The use of GDP in the primary treatment of PTCL is associated with a high response rate. Outcomes in high IPI patients compare favourably with historical results using CHOP chemotherapy and suggest that it may be able to overcome disease resistance in this poor risk group, providing rationale to explore it in further in future clinical trials of PTCLs. Disclosures: Connors: F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Savage:Eli-Lilly: Consultancy.

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