Concurrent Chemo-Radiotherapy Followed by VIDL (Etoposide, Ifosfamide, Dexamethasone, L-asparaginase) Chemotherapy In Stage I/II Extranodal NK/T-Cell Lymphoma of Nasal Cavity/Nasopharynx

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1765-1765
Author(s):  
Seok Jin Kim ◽  
Hyeon-Seok Eom ◽  
Jin Seok Kim ◽  
Jae-Yong Kwak ◽  
Deok-Hwan Yang ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Major Toxicity ◽  
Nk T Cell ◽  
Grade 3

Abstract Abstract 1765 Background Localized extranodal NK/T-cell lymphoma (ENKTL) mainly occurs in nasal and/or nasopharynx. Thus, ENKTL shows a poor response to anthracycline-based chemotherapy because of the frequent expression of a multidrug-resistant p-glycoprotein, radiotherapy for localized disease produces a higher complete response rate than chemotherapy. However, when ENKTL is treated with radiation alone, local and systemic failures are frequently observed. Therefore, our group previously reported the improved outcome of concurrent chemo-radiotherapy (CCRT) with weekly administration of cisplatin followed by systemic chemotherapy VIPD (etoposide, ifosfamide, cisplatin and dexamethasone). However, the grade 3/4 hematologic toxicity was the major toxicity of VIPD. Thus, in consideration of the risk of toxicity of VIPD, we designed VIDL (etoposide, ifosfamide, dexamethasone, and L-asparaginase) as adjuvant to CCRT. Because etoposide and ifosfamide are less affected by p-glycoprotein, and NK lymphoma cells are known as being sensitive to L-asparaginase, we expected VIDL regimen could be more effective and less toxic than VIPD. Methods Thirty-one newly diagnosed stage IE/IIE nasal/nasopharynx ENKTL patients received CCRT (radiation 40–50.4 Gy and cisplatin 30 mg/m2 weekly). Two cycles of VIDL (etoposide 100 mg/m2 D1–D3, ifosfamide 1200 mg/m2 D1–D3, dexamethasone 40 mg D1–D3, and L-asparaginase 4000IU/m2) were scheduled after CCRT. All patients provided informed written consents and this trial was registered at www.ClinicalTrials.gov (NCT01007526). Results The median age was 46.5 years (range, 22–71 years); 78.1% of all patients were younger than 60 years of age, and male (n = 21) to female (n = 11) was 2:1. Twenty-two patients were stage IE and nine were IIE. The majority of patients were in the low (n = 24) or low–intermediate (n = 6) risk categories of the International Prognostic Index. However, when we grouped patients based on the NK/T cell lymphoma prognostic index (NKPI) proposed previously for ENKTL, which includes the presence of B cell symptoms, lesions at stage III or IV, elevated serum LDH concentration, and lymph node involvement, 25 patients belonged to group I or II and 7 patients were group III or IV (those with more than two risk factors). All patients completed CCRT, which resulted in 90.3% overall response rate including 22 complete response (CR) and 6 partial response (PR). Twenty-seven patients completed the planned two cycles of VIDL while four patients did not because three patients progressed during or after CCRT, and one patient is ongoing. The overall response rate of 27 patients completed VIDL was 92.6%, and two patients relapsed after the completion of VIDL chemotherapy. The major toxicity of VIDL was grade 3/4 leucopenia (85.1%), but there was no treatment-related mortality. The non-hematologic toxicity was tolerable, and the hepatic toxicity-associated with the use of L-asparaginase was frequent (55.5%). However, the majority of the hepatic toxicities were grade 1 or 2. Conclusion Concurrent chemo-radiotherapy followed by VIDL chemotherapy can be an effective treatment strategy with acceptable toxicity in stage I/II extranodal NK/T-Cell lymphoma of nasal cavity/nasopharynx. Disclosures: No relevant conflicts of interest to declare.

Phase II Trial Of L-Asparaginase Plus Concurrent Chemoradiotherapy Followed By Midle (methotrexate, ifosfamide, etoposide, dexamethasone, and L-asparaginase) Chemotherapy For Patients With Newly Diagnosed Stage I/II Extranodal NK/T-Cell Lymphoma, Nasal Type

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3037-3037 ◽  
Author(s):  
Seok Jin Kim ◽  
Dok Hyun Yoon ◽  
Seong Hyun Jeong ◽  
Dong-Yeop Shin ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
T Cell ◽  
Concurrent Chemoradiotherapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Nasal Type ◽  
Nk T Cell ◽  
Grade 3

Abstract Background The treatment of localized extranodal NK/T-cell lymphoma (ENKTL), nasal type has shifted to non-anthracycline-based intensive chemotherapy with radiotherapy since the poor response of ENKTL to anthracycline due to the expression of a multidrug-resistant (MDR) p-glycoprotein was proven. We previously proposed concurrent chemoradiotherapy (CCRT) followed by chemotherapy which is not affected by MDR and reported a significant improvement of outcomes of localized ENKTL. Based on our accumulated data, we designed a new treatment protocol. First, we added tri-weekly administration of L-asparaginase to reduce the probability of systemic progression during CCRT. Second, we designed MIDLE (methotrexate, ifosfamide, etoposide, dexamethasone, and L-asparaginase) according to previous excellent outcomes of methotrexate-containing regimens such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) and MLD (methotrexate, L-asparaginase, dexamethasone). Methods The treatment scheme of CCRT consisted of radiation 40 Gy and weekly administration of cisplatin 30 mg/m2 (total: 4 doses). During the CCRT, tri-weekly intravenous (IV) administration of 4,000 IU of Escherichia coli L-asparaginase was done. The chemotherapy, MIDLE (methotrexate 3g/m2 on day 1, etoposide 100mg/m2, Ifosfamide 1000mg/m2 on day 2-3, dexamethasone 40mg on day 1-4, and L-asparaginase 6000IU/m2 IV on day 4, 6, 8, 10) was repeated every 28 days up to 2 cycles. All patients provided informed written consents and this trial was registered at www.ClinicalTrials.gov(NCT01238159). Results Twenty-eight patients with stage IE/IIE ENKTL were enrolled, and the median age was 51 years (range, 30–77 years). 24 patients were male while only four patients were female. Twenty-two patients were stage IE and six were IIE. All patients completed CCRT, which resulted in 92.9% of overall response rate including 20 complete responses and 6 partial responses. One patient showed stable disease after CCRT whereas the other patient progressed. No grade 3 or 4 hematologic toxicity was found during CCRT. However, grade 3 non-hematologic toxicities included bilirubin elevation (n = 4), mucositis (n = 1), and nausea/vomiting (n = 6). After the completion of CCRT, 23 patients entered the MIDLE chemotherapy as five patients including one disease progression and four cases of withdrawal could not receive MIDLE. All patients achieved complete response after they completed the planned two cycles of MIDLE chemotherapy whereas two patients dropped out after their first cycle due to non-hematologic toxicity. The final complete response rate of patients enrolled was 92.9% (26/28). The major toxicity of MIDLE was grade 3/4 leucopenia, and the non-hematologic toxicity included mucositis and nausea/vomiting. The hepatic toxicity-associated with L-asparaginase was frequent. However, the majority of the hepatic toxicities were grade 1 or 2. With the median potential follow-up of 25 months (95% confidence interval: 19 – 31 months), four patients relapsed. Conclusion L-asparaginase plus concurrent chemoradiotherapy followed by MIDLE chemotherapy can be an effective treatment strategy with acceptable toxicity in stage I/II extranodal NK/T-Cell lymphoma, nasal type. Disclosures: Kwak: celgene: Research Funding.

scholarly journals Final Report on Phase II Trial of L-Asparaginase Plus Concurrent Chemoradiotherapy Followed By Midle (Methotrexate, Ifosfamide, Etoposide, Dexamethasone, and L-asparaginase) Chemotherapy for Patients with Newly Diagnosed Stage I/II Extranodal NK/T-Cell Lymphoma, Nasal Type

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3942-3942
Author(s):  
Dok Hyun Yoon ◽  
Seok Jin Kim ◽  
Seong Hyun Jeong ◽  
Dong-Yeop Shin ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
T Cell ◽  
Concurrent Chemoradiotherapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Stage I ◽  
Nasal Type ◽  
Nk T Cell ◽  
Grade 3

Abstract Background We previously have shown that concurrent chemoradiotherapy (CCRT) followed by chemotherapy such as VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) or VIDL (etoposide, ifosfamide, dexamethasone and L-asparaginase) is an effective treatment for the management of localized extranodal NK/T-cell lymphoma (ENKTL), nasal type. To further improve efficacy, we designed a new treatment protocol, MIDLE (methotrexate, ifosfamide, dexamethasone, L-asparaginase and etoposide), which incorporates tri-weekly administration of L-asparaginase during CCRT to reduce the probability of systemic progression and high dose methotrexate to intensify chemotherapy based on previous excellent outcomes of methotrexate-containing regimens such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) and MLD (methotrexate, L-asparaginase, dexamethasone). Methods The treatment scheme of CCRT consisted of radiation 36-45 Gy and weekly administration of cisplatin 30 mg/m2 (total: 4 doses). During the CCRT, tri-weekly 4,000 IU of Escherichia coli L-asparaginase was administered intravenously (IV). The chemotherapy, MIDLE (methotrexate 3 g/m2 on day 1, etoposide 100 mg/m2, Ifosfamide 1000 mg/m2 on day 2-3, dexamethasone 40mg on day 1-4, and L-asparaginase 6000 IU/m2 IV on day 4, 6, 8, 10) was repeated every 28 days for two cycles. All patients provided informed written consents and this trial was registered at www.ClinicalTrials.gov(NCT01238159). Results Twenty-eight patients with stage IE/IIE ENKTL were enrolled, and the median age was 51 years (range, 30-77 years). Twenty four patients were male while only four patients were female. Twenty-two patients had stage IE and six IIE disease. Twenty four were classified as low risk group and the other four intermediate group according to PINK-E (Kim SJ et al., EHA 2015 S110). All but two patients completed CCRT, which resulted in 85.7% of overall response rate including 16 complete responses (57.1%) and 8 partial responses (28.6%). One showed stable disease (SD) and the other one showed progressive disease (PD) with development of new distant lymph node involvement after CCRT. Grade 3 or 4 hematologic toxicity was not common. Only two patients experienced G3 neutropenia during or after CCRT. However, grade 3 non-hematologic toxicities were noted including bilirubin elevation (n = 3), mucositis (n = 1), anorexia (n=5) and nausea/vomiting (n = 11) Two could not complete CCRT according to the protocol due to G3 allergic reaction to L-asparaginase (n=1) and prolonged G3 mucositis (n=1). After the completion of CCRT, 23 out of 28 patients entered the MIDLE chemotherapy as five patients including one disease progression and four withdrawal during (n=2) or after (n=2) CCRT due to toxicities. All those who completed the planned two cycles of MIDLE chemotherapy achieved complete response after chemotherapy including those with PR (n=6) and SD (n=1) after CCRT. Three patients dropped out during or after their first cycle of MIDLE due to non-hematologic toxicities (recurrent G3 bilirubinemia (n=1), G3 increased creatinine (n=1), G5 infection (n=1)). The final complete response rate was 82% (23/28). It was associated with a significant rate of grade 3/4 neutropenia (n=21) and febrile neutropenia (n=10). Two patients experienced acute kidney injury (AKI) during the first cycle of MIDLE and one of them died of pneumonia complicated by sepsis. With a median follow-up of 46 months (95% confidence interval: 39 - 47 months), four patients progressed and five patients died with the estimated 3-year progression-free survival rate of 74.1% and overall survival rate of 81.5%. PINK-E could successfully stratify both time-to-progression (p=003) and overall survival (p=0.006) in this study. Conclusion L-asparaginase plus concurrent chemoradiotherapy followed by MIDLE chemotherapy may be an effective treatment strategy for stage I/II extranodal NK/T-Cell lymphoma, nasal type. However, higher numbers of patients were withdrawn during or after CCRT due to toxicity or poor tolerance than previous study. MIDLE chemotherapy was associated with high rate of G3 or 4 hematologic toxicities. Thus, this approach should be reserved for selected patients such as young fit but high risk of relapse. PINK-E can be a useful prognostic index for stage I/II extranodal NK/T-Cell lymphoma, nasal type. Disclosures No relevant conflicts of interest to declare.

The Efficacy of Bortezomib-CHOP In Patients with Advanced Stage T or NK/T Cell Lymphomas: The Results of Multicenter Phase II Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1791-1791 ◽  
Author(s):  
Seok Jin Kim ◽  
Hyeon-Seok Eom ◽  
Jin Seok Kim ◽  
Hye Jin Kang ◽  
Hyo Jung Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Advanced Stage ◽  
Chop Regimen ◽  
T Cell Lymphomas ◽  
Nk T Cell

Abstract Abstract 1791 Background Advanced stage T-cell or NK/T-cell lymphomas usually show aggressive clinical course and their treatment outcomes are worse than B-cell non-Hodgkin lymphoma. Furthermore, the optimal treatment regimen is not still established for these disease entities. At present, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen is still used as a primary treatment for advanced stage T or NK/T cell lymphomas although its efficacy is not satisfactory. Thus, more effective treatment regimen is required to improve treatment outcome. The incorporation of new targeted agents into CHOP regimen has been a widely used strategy to develop new regimen for the treatment of lymphoma. Bortezomib, a proteasome inhibitor approved for the use of treatment of multiple myeloma has been tried in many B-cell non-Hodgkin lymphomas. A recent in vitro study results showed that proteasome inhibitor could inhibit the growth of NK/T lymphoma cells. Based on these results, we designed a regimen combining CHOP with. Our previous phase I study determined the maximum tolerated dose of bortezomib as 1.6mg/m2 for combination with CHOP. Thus, we performed the phase II study to evaluate the efficacy of bortezomib plus CHOP chemotherapy. Methods We enrolled patients with newly diagnosed T or NK/T cell lymphoma. All patients were Ann Arbor stage III/IV and had adequate organ function. Patients received bortezomib on days 1 and 8 (weekly schedule, 1.6 mg/m2 per dose) in addition to 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT00374699). Results 46 patients were enrolled between April 2007 and August 2009. Peripheral T-cell lymphoma, unspecified (n=16) and extranodal NK/T cell lymphoma (n=10) were dominant subtypes while angioimmunoblastic T-cell lymphoma (n=8) and ALK-negative anaplastic large cell lymphoma (n=6) account for 30.4% of all patients. Five patients with cutaneous T-cell lymphoma and one hepatosplenic T-cell lymphoma were also recruited. The median age at diagnosis was 52 years (range 21 – 66 years). Serum LDH elevation (n = 28, 60.9%) and stage IV patients were dominant (n = 32, 69.6%). Thus, the International Prognostic Index risk was dominantly high or high-intermediate (n = 26, 56.5%). Complete response was achieved in 30 patients (65.2%) and partial response was 5 patients (10.9%). As a result, the overall response rate was 76.1%. The comparison of complete response rate based on the subtype demonstrated that the complete response rate of peripheral T-cell lymphoma, unspecified (12/19, 63.2%), angioimmunoblastic T-cell lymphoma (6/8, 75%), anaplastic large cell lymphoma (4/6, 66.7%) and cutaneous T-cell lymphoma (5/5, 100.0%) was better than extranodal NK/T cell lymphoma (3/10, 30.0%). Five patients with extranodal NK/T cell lymphoma progressed during the treatment with bortezomib and CHOP. The hematologic toxicity was the major toxicity of this regimen, thus, grade 3/4 leucopenia and febrile neutropenia were the most frequent toxicity. However, there was no treatment-related mortality. In addition, neurotoxicity was tolerable, so the majority of peripheral neurotoxicity was grade 1 or 2. Conclusion The combined treatment of bortezomib with CHOP is an effective regimen for advanced stage T-cell lymphomas with acceptable toxicity. However, it may not be efficient for advanced stage extranodal NK/T-cell lymphomas. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2991-2991 ◽  
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.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

2012 ◽  
Vol 30 (6) ◽  
pp. 631-636 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
H. Miles Prince ◽  
Francine Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Prior Systemic Therapy

Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Conclusion Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

Low Absolute Lymphocyte Count Predicts Chemotherapy Response and Survival In Peripheral T-Cell Lymphoma, NOS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3135-3135
Author(s):  
Yu Ri Kim ◽  
yun Deok Kim ◽  
Jin Seok Kim ◽  
June-Won Cheong ◽  
soo Jeong Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Prognostic Factor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
Independent Prognostic Factor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Overall Response

Abstract Abstract 3135 Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) is heterogenous groups of aggressive T-cell lymphoma and treatment outcome is dismal. Lymphopenia is an independent prognostic factor for survival for B-cell lymphoma. The ALC at diagnosis on survival in T-cell lymphoma has not been studied. Thus, we studied the role of ALC at diagnosis on clinical outcome in patients with PTCL, NOS. Between 2001 and 2009, 32 patients with PTCL, NOS reviewed for the study. Median patient age was 57 (range 34–78) years. Median ALC at the time of diagnosis was 1.54 (range 0.41–12.64×109/L). Patients were divided two groups according to ALC count 1.0 ×109/L. Ten patients (31%) had lower ALC at diagnosis. Median follow up duration was 299 days (range 11–2164 days). Overall response rate was 61.5% (16 of 26 patients) and complete response (CR) rate was 42% (11 of 26 patients). Only two patients reached CR in low ALC group.There was no significant difference in overall response rate because of small number of patients. Superior overall survival was observed with an ALC 1.0 × 109/L (N = 22) versus an ALC < 1.0 × 109/L (N=10) (median OS: not reached vs 242 days, OS rates at 5 years, 57% vs 0%, p =0.016, respectively). Multivariate analysis demonstrated ALC to be an independent prognostic indicator for OS (Hazard Ratio 3.5, 95% confidence intervals 1.2–10.2; p<0.019) when compared to the International prognostic index (IPI) and Prognostic Index for PTCLU (PIT). This study suggested that low ALC is an independent prognostic factor for survival in patients with PTCL, NOS. Disclosures: No relevant conflicts of interest to declare.

Safe and Effective Treatment of Patients with Peripheral T-Cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 253-253 ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Anaplastic Lymphoma ◽  
Not Otherwise Specified ◽  
Baseline Characteristics ◽  
Grade 3

Abstract Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of the cell cycle with different mechanisms of action, there is potential for a synergistic effect of a Bel-CHOP combination treatment regimen for patients with PTCL. Methods: Patients with PTCL received CHOP in association with 1000 mg/m2 of belinostat on various schedules, repeated every 21-days for up to 6 cycles. The cohort schema followed a traditional "3+3" dose escalation design. The objective of Part A of the study was to determine the Maximum Tolerated Dose (MTD) of the Bel-CHOP combination. Once the MTD was determined, at least 10 more patients were to be treated in the Expansion Phase (Part B). Belinostat was to be administered as a 1000 mg/m2 IV infusion once daily for up to 5 days, depending on the assigned cohort (Fig 1). The starting cohort was Cohort 3 (CHOP + 1000 mg/m2 of daily belinostat on Days 1-3). Patients received primary prophylaxis with growth factor (G-CSF) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: non-hematological toxicity Grades 3-4, platelet count &lt; 25 X 109/L at any time or ANC &lt; 0.5 X 109/L lasting more than 7 days despite G-CSF administration. The primary endpoint of the study was the determination of the MTD of the Bel-CHOP combination. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Results: A total of 23 patients were enrolled in the study, 11 of which were treated in Part A. One patient in Part A was deemed inevaluable because the patient died due to disease progression before completing Cycle 1. The MTD was determined to be 1000 mg/m2 on Days 1-5 (Cohort 5); 12 more patients were then treated at this dose level (Part B). The only DLT experienced in the study was in Cohort 3 (Grade 3 Nausea and Vomiting). At the time of this abstract, 18/23 patients (78%) have completed all 6 cycles of Bel-CHOP, with 87% completing at least 4 cycles. Ten patients (43%) had at least one serious adverse event (SAE) and 18 (78%) had at least one Grade 3 or 4 adverse event (AE). The most frequent Grade 3/4 AEs were hematological in nature: neutrophil count decreased (26%), anemia (22%), neutropenia (17%) and white blood cell count decreased (17%). The ORR for the18 patients that have completed an End of Study Visit is 89% (16/18), with the vast majority achieving a CR [72% (n=13)], and 17% (n=3) a PR. Progressive disease was reported in 2 patients. Conclusions: These results demonstrate that the combination of belinostat with CHOP (Bel-CHOP) is well tolerated, with all components of CHOP and belinostat being given at their standard therapeutic doses. The rates of AEs were consistent with those typically reported with CHOP alone, and clinical activity was demonstrated with a response rate of 89% based on 18 evaluable patients. Thus, Bel-CHOP is a promising new regimen in PTCL that will be further tested in a Phase 3 randomized trial. Table. Table. Figure 1. Summary of Demographic and Baseline Characteristics AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Figure 1. Summary of Demographic and Baseline Characteristics. / AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Disclosures Barta: Seattle Genetics: Research Funding. Bhat:Spectrum Pharmaceuticals, Inc: Employment. Song:Spectrum Pharmaceutical, Inc: Employment. Choi:Apectrum Pharmaceuticals, Inc: Employment. Allen:Spectrum Pharmaceuticals, Inc: Employment. Foss:Spectrum Pharmaceuticals; Celgene: Seattle Genetics: Infinity; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Prognostic Value of 25‑Hydroxy Vitamin D in Extranodal NK/T Cell Lymphoma

2020 ◽  
Author(s):  
Jin Mao ◽  
Hua Yin ◽  
Li Wang ◽  
Jia-Zhu Wu ◽  
Yi Xia ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
Vitamin D Deficiency ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
T Cell Lymphoma ◽  
25 Hydroxy Vitamin D ◽  
Nk T Cell

Abstract Background 25-hydroxy vitamin D [25-(OH)D] is widely used to determine vitamin D status in clinic. The aim of our study was to evaluate the prognostic value of 25-(OH)D in extranodal NK/T cell lymphoma (ENKTL). Materials and Methods Ninety-three ENKTL patients with available serum 25-(OH)D values were enrolled in our study. Vitamin D deficiency is defined as a 25-(OH)D below 50 nmol/L. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed to determine the applicable subgroups. Receiver operator characteristic (ROC) curves were plotted to estimate the accuracy of PINK-E (prognostic index of natural killer lymphoma added with Epstein-Barr virus-DNA status) and 25-(OH)D deficiency in ENKTL risk-stratification. Results Our results suggested that vitamin D deficiency was an independent inferior prognostic factor for both PFS [hazard ratio (HR), 2.869; 95% confidence interval (CI), 1.540 to 5.346; P = 0.003] and OS (HR, 3.204; 95%CI, 1.559 to 6.583; P = 0.006) in ENKTL patients with age ≤ 60, ECOG PS ≤ 1, stage III‒IV and PINK-E score ≥ 3. Additionally, we demonstrated that adding 25-(OH)D deficiency to PINK-E score system indeed has a superior prognostic significance than PINK-E alone for PFS [AUC: 0.796 (95% CI: 0.699 to 0.872) vs. 0.759 (95% CI: 0.659 to 0.841), P = 0.020] and OS [AUC: 0.755 (95% CI: 0.655 to 0.838) vs. 0.721 (95% CI: 0.618 to 0.809), P = 0.040]. Conclusion In conclusion, our study proved that 25-(OH)D deficiency was associated with inferior survival outcomes of ENKTL patients.

Multicenter, phase II study of bendamustine in refractory or relapsed T-cell lymphoma: The BENTLY trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8026-8026 ◽  
Author(s):  
Remy Gressin ◽  
Gandhi Laurent Damaj ◽  
Kamal Bouabdallah ◽  
Guillaume Cartron ◽  
B Choufi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Previous Response ◽  
T Cell Lymphomas

8026 Background: T-cell lymphomas have a poor prognosis with few options of effective treatment. This study determined the efficacy and safety of bendamustine as a single agent in the treatment of refractory or relapsed T-cell lymphomas. Methods: Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL), who had previously received at least one line of chemotherapy were selected. Bendamustine was administered IV at the dosage of 120 mg/m2 on days 1 and 2 every 3 weeks, for 6 cycles. Treatment response was assessed using the IWC for non-Hodgkin's lymphoma. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DoR), progression-free survival (PFS), and overall survival (OS), NCT00959686. Results: Twenty two female and 38 male were included. The median age was 66 years with more 1/4 of them > 75. Histology was predominantly angio-immunoblastic lymphadenopathy (n=32) and PTCL-nos (n=23). The median previous line of chemotherapy was 1 (1-3). Nearly one half (45%) of the patients was refractory to the last previous chemotherapy and the median duration of the best previous response was 6.6 (1.5-67) months. The disease was disseminated in the majority of case (87%) and the international prognostic index (IPI) was high (3–5) in 68% of the patients. Twenty patients (33%) received less than 3 cycles of bendamustine. The major reason for early discontinuation was disease progression. In the Intent-To-Treat (ITT) population, the best ORR was 50%, including complete response (CR) in 28% and partial response (PR) in 22 %. Bendamustine showed a consistency in the efficacy as a function of major disease characteristics. The median values for DoR, PFS and OS were 3.5, 4 and 6 months respectively. The most frequent grade 3/4 AEs were neutropenia (30%), thrombocytopenia (24%) and infections (20%). Conclusions: Bendamustine is active in high risk refractory and relapsed T-cell lymphoma with manageable toxicity.

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