scholarly journals 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 733-738 ◽  
Author(s):  
S O'Brien ◽  
R Kurzrock ◽  
M Duvic ◽  
H Kantarjian ◽  
S Stass ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Median Number ◽  
Lymphoproliferative Disorders ◽  
Lymphoproliferative Diseases ◽  
Prior Therapy ◽  
Heterogenous Group ◽  
Daily Dose ◽  
T Cell Malignancies

Abstract Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

scholarly journals 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 733-738 ◽  
Author(s):  
S O'Brien ◽  
R Kurzrock ◽  
M Duvic ◽  
H Kantarjian ◽  
S Stass ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Median Number ◽  
Lymphoproliferative Disorders ◽  
Lymphoproliferative Diseases ◽  
Prior Therapy ◽  
Heterogenous Group ◽  
Daily Dose ◽  
T Cell Malignancies

Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

Impact Of Epstein-Barr Viral Infection In The Regression Of Methotrexate-Induced Lymphoproliferative Diseases In Patients With Rheumatoid Arthritis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3006-3006 ◽  
Author(s):  
Tokuhira Michihide ◽  
Kimura Yuhta ◽  
Takahashi Yasuyuki ◽  
Tomikawa Tatsuki ◽  
Morihiko Sagawa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoproliferative Diseases ◽  
Ebv Infection ◽  
Epstein Barr

Abstract Background Recent studies have investigated the pathogenesis of the class of conditions known as “other iatrogenic immunodeficiency-associated lymphoproliferative diseases” (OIIA-LPDs), particularly in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is a potent cause of LPDs, and withdrawal of MTX can result in spontaneous regression of LPD, which suggests that this drug plays an important role in the tumorigenesis of LPDs. In addition, an impaired immunity against Epstein-Barr virus (EBV) has been obserbed in RA patients. A number of reports describe LPD regression in patients with OIIA-LPDs-RA, but its precise etiology and pathogenesis remain unclear. Furthermore, the phenomenon of relapse/regrowth of LPDs after initial regression has not been well documented. This study retrospectively analyzed the clinicopathological features of OIIA-LPDs-RA patients to determine the influence of EBV infection on regression/relapse of the disease. Methods & Results Data were collected from 35 patients with RA who developed LPD and who were treated at our institute between 1998 and 2013. All patients had received treatment with MTX. The diagnosis of RA was made according to the American College of Rheumatology criteria. Based on immunohistochemistry performed on paraffin-embedded tissue sections, diagnoses were as follows: diffuse large B cell lymphoma (DLBCL; n=14), Hodgkin lymphoma (HL; n=7), follicular lymphoma (FL; n=4), mucosal-associated lymphoid tissue (MALT; n=3), Hodgkin-like lymphoma (HL-like; n=3), T-cell lymphoma (n=3), polymorphic LPD (P-LPD; n=2) according to the 4th WHO classification. Regarding EBV infection, 16 patients (44%) were positive. Patients with FL, MALT, and T-cell lymphoma were negative for EBV, except for one patient with T-cell lymphoma. In contrast, EBV infection positivity was prevalent in patients with DLBCL, HL, HL-like and P-LPD (46%, 100%, 100%, and 50%, respectively). Although HL indicated a specific phenotype, such as positivity for CD15 and CD30 (83%, and 100%, respectively), and rarely expressed CD20, OCT2 or BOB1 (0%, 14%, 14%, respectively), the phenotypes of HL-like and P-LPD were supposedly intermediate between DLBCL and HL. The phenotypes of FL, MALT, and T-cell lymphoma were the same as those of de novo cases. LPD regression was observed in 23 (66%) of 35 patients, which is more common than that seen in previous reports. Although LPD regression was not documented in patients with T-cell lymphoma, it did occur in all patients with HL, HL-like and P-LPD. In addition, the incidence of regression among patients with DLBCL, FL and MALT was 46%, 75% and 33%, respectively. The relationship between EBV infection and LPD regression among patients with HL, DLBCL, HL-like and P-LPD was statistically significant (p=0.048, Fisher's exact test). Of 23 patients with regression, 13 patients (56%) subsequently showed relapse/regrowth, and the incidence of this phenomenon was relatively high in patients with HL, HL-like and P-LPD (100%, 67%, and 50%, respectively), whereas a lower incidence was seen in patients with DLBCL, FL, and MALT (7%, 33%, and 0%, respectively). Summary/Conclusions LPD regression was relatively common (66%) in patients with OIIA-LPDs-RA, particularly in patients with B cell phenotypes. There was a significant relationship between LPDs and EBV infection in patients with HL, DLBCL and HL-like, suggesting that underlying EBV infection might influence the immunosuppressant effect of MTX against EBV in those phenotypes. Further, LPD relapse/regrowth was common in patients with HL, HL-like and P-LPD and was unlikely in patients with DLBCL. Further studies would be of benefit to investigate the underlying molecular mechanism of regression/relapse of LPD after withdrawal of MTX. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study

2011 ◽  
Vol 29 (9) ◽  
pp. 1182-1189 ◽  
Author(s):  
Owen A. O'Connor ◽  
Barbara Pro ◽  
Lauren Pinter-Brown ◽  
Nancy Bartlett ◽  
Leslie Popplewell ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
International Workshop ◽  
Progression Free Survival ◽  
Median Number ◽  
T Cell Lymphoma ◽  
Cell Transplant ◽  
Peripheral T Cell Lymphoma ◽  
Prior Therapy

Purpose Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. Patients and Methods Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received pralatrexate intravenously at 30 mg/m2/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). Results Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%). Conclusion To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.

Prolonged Lymphocytepenia after Bendamustine with or without Rituximab Treatment in Patients with Relapsed or Refractory Indolent B-Cell and Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3066-3066 ◽  
Author(s):  
Hideaki Saito ◽  
Dai Maruyama ◽  
Akiko Miyagi Maeshima ◽  
Shin-ichi Makita ◽  
Hideaki Kitahara ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Median Number ◽  
Marginal Zone Lymphoma ◽  
Cell Counts ◽  
Mantle Cell

Abstract Introduction: Although bendamustine with or without rituximab has demonstrated remarkable efficacy in patients with relapsed or refractory indolent B-cell lymphoma (B-NHL) and mantle cell lymphoma (MCL), previous reports showed that the incidence of lymphocytopenia was higher in patients receiving bendamustine with or without rituximab than in those receiving other conventional cytotoxic chemotherapies such as R-CHOP regimen. However, the length of time until recovery of the decreased lymphocytes and CD4-positive T cells to the baseline upon bendamustine treatment is still unclear. Patients and Methods: We retrospectively analyzed 56 consecutive patients with relapsed or refractory B-NHL and MCL who received bendamustine with or without rituximab at our institution between 2011 and 2014. We analyzed their peripheral blood lymphocytes and CD4-positive T-cell counts at baseline, during, and after bendamustine treatment, the details of infectious events, and their correlations. Results: Thirty-one (55%) patients were male and 25 (45%) female, with a median age of 63 years (range: 36-86). Twenty (35%) patients had follicular lymphoma, 14 (25%) MCL, nine (16%) transformed lymphoma, five (9%) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, four (7%) small lymphocytic lymphoma, two (4%) nodal marginal zone lymphoma, and one (2%) each had lymphoplasmacytic lymphoma and low-grade B-NHL, unclassifiable. The median number of prior regimens administered was two (range: 1-9). Twenty-three (41%) of the 56 patients received rituximab in combination with bendamustine. The median number of bendamustine cycles was four (range: 1-6). The median follow-up period was nine months (range: 0-33 months). At baseline, median lymphocyte and CD4-positive T-cell counts were 1,025/µL (range: 270-3,420/µL) and 282/µL (range: 83-645/µL), respectively. After the first cycle, they immediately decreased to 545/µL (range: 60-2,900/µL) and 190/µL (range: 116-635/µL), respectively. The median lymphocyte and CD4-positive T-cell count nadirs during observation were 365/µL (range: 20-1,310/µL) and 93/µL (range: 7-178/µL), respectively. Significantly decreased lymphocyte counts (median: 260 vs. 410/µL) were detected in the patients who received bendamustine with rituximab compared with those who received bendamustine alone (p=0.03). Recovery of lymphocyte and CD4-positive T-cell counts to those at baseline was observed at 7-9 months after the completion of bendamustine with or without rituximab, and median lymphocyte and CD4-positive T-cell counts were 1,045/µL (range: 170-2,580/µL) and 223/µL (range: 47-709/µL), respectively (Figures A, B). The numbers of patients who received prophylaxis against pneumocystis pneumonia (PCP), varicella zoster virus (VZV), and fungal infection were 44 (78%), 37 (66%), and four (7%), respectively, at the physician's discretion. Infectious events were observed in 32 (57%) patients during follow-up. Cytomegalovirus antigenemia was detected in 15 (27%) patients, VZV infection in two (3%), cytomegalovirus colitis in one (2%), and other infectious complications such as sepsis or febrile neutropenia in 20 (35%) patients. Interestingly, all infectious events occurred within nine months after the completion of bendamustine with or without rituximab in patients who received no treatment after bendamustine during follow-up. Conclusion: The results of this analysis revealed that the majority of relapsed or refractory patients with indolent B-NHL and MCL showed prolonged lymphocytopenia and low CD4-positive T-cell counts, for at least 7-9 months, after the completion of bendamustine with or without rituximab. Because lymphocytopenia, especially low CD4-positive T-cell counts, may increase the risk of opportunistic infections, the prophylaxis against PCP and VZV deserves consideration for at least 7-9 months after bendamustine treatment. Further investigations, especially a prospective study, are needed to confirm our results. Figure A: Figure A:. Figure B: Figure B:. Box plots of lymphocyte counts (Figure A) and CD4-positive T-cell counts (Figure B) among patients who were treated with bendamustine with or without rituximab. Disclosures Maruyama: Eisai Co., Ltd: Honoraria. Kobayashi:Boehringer Ingelheim GmbH: Research Funding; ARIAD Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Tobinai:Eisai Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding.

ACTR087, Autologous T Lymphocytes Expressing Antibody Coupled T-Cell Receptors (ACTR), Induces Complete Responses in Patients with Relapsed or Refractory CD20-Positive B-Cell Lymphoma, in Combination with Rituximab

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 580-580 ◽  
Author(s):  
Luke Paul Akard ◽  
Samantha Jaglowski ◽  
Steven M. Devine ◽  
Matthew S. McKinney ◽  
Michael Vasconcelles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Prior Therapy

Abstract Background: Autologous T cells engineered to express the universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res. 2014]. Preclinical findings with ACTR+ T cells, which bind immunoglobulin Fc via CD16V158 and signal via CD3ζ and 4-1BB (ACTR087), demonstrate markedly enhanced target- and antibody-specific tumor cell cytotoxicity, as evidenced by CD20+ B cell lymphoma killing in combination with rituximab, compared with rituximab alone. Preclinical data also demonstrate rituximab dose-dependent effects in combination with ACTR087, suggesting that the therapeutic index of ACTR087 in combination with rituximab may be affected by rituximab dose or schedule and present an advantage over chimeric antigen receptor (CAR) T cell therapies [Huet H, Blood 2016]. Study UT-201501 (ATTCK-20-2) is the first clinical trial of ACTR087 in combination with rituximab in patients with relapsed or refractory CD20+ B cell lymphoma previously treated with rituximab (NCT02776813). We report data from the 7 patients treated with ACTR087 in the first dose level of the ATTCK-20-2 study. Methods: This is a multicenter Phase 1 dose escalation study. The primary objective is to evaluate the safety of the combination of ACTR087 and rituximab, and the key secondary objective is to evaluate antitumor efficacy. Exploratory objectives include measurement of ACTR T cell persistence, cytokines, and rituximab pharmacokinetics. Eligible patients must have histologically confirmed relapsed/refractory aggressive CD20+ B cell lymphoma of DLBCL, MCL, PBMCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb in combination with anthracycline-containing chemotherapy. In the first dose level, patients received lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR087 (0.5x106 ACTR+ T cells/kg). Up to 7 additional doses of rituximab are then administered, one dose every 3 weeks in the absence of disease progression. Results: Seven patients received ACTR087 in combination with rituximab at the first dose level. Median age was 64 years (range: 36-71), 57.1% were male, all had ECOG PS 1, 86% were treated with ≥ 3 lines of prior therapy, and 86% were refractory to the immediate prior therapy. ACTR087 was successfully manufactured for all subjects. ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. One patient had a dose-limiting toxicity of grade 4 thrombocytopenia for > 14 days that later resolved. At the first dose level, there were no SAEs or deaths related to ACTR087 and no AEs of special interest, including cytokine-release syndrome, neurotoxicity, or autoimmune events. Cytopenias were the most common ≥ grade 3 AEs (neutropenia n=7, leukopenia n=5). Rituximab pharmacokinetics were not affected by ACTR087 administration. Independently-confirmed objective responses were observed in patients evaluable for response (n=6), including 2 ongoing complete responses (CR) and 1 partial response (PR). One of the CRs continues 6+ months after a single dose of ACTR087. Conclusions:In the first dose level studied in patients with relapsed/refractory aggressive CD20+ B cell lymphoma, ACTR087 in combination with rituximab induced complete responses with no serious AEs, AEs leading to treatment discontinuation, cytokine-release syndrome, or neurotoxicity. ACTR+ T cells were detectable in all patients and ACTR+ T cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR087 in combination with rituximab; dose level 2 enrollment is ongoing and updated data, including correlative biomarkers, will be presented. Disclosures Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. McKinney: Kite Pharma: Other: advisory comittee. Vasconcelles: Unum Therapeutics Inc: Employment. Huet: Unum Therapeutics Inc: Employment. Ettenberg: Unum Therapeutics Inc.: Employment. Ranger: Unum Therapeutics Inc: Employment. Abramson: Seattle Genetics: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Kite Pharma: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; LAM Therapeutics: Research Funding; Novartis: Consultancy.

scholarly journals Anti-CD19 CAR T-Cell (CNCT19) Infusion Following HDT/ASCT Is Safe and Effective in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Wei Liu ◽  
Wenyang Huang ◽  
Ryu Lv ◽  
Shuhui Deng ◽  
Shuhua Yi ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cellular Immunotherapy ◽  
Prior Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61st ASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. All patients must have received rituximab and anthracycline-containing treatment during their prior therapy. Conditioning regimen included GBC/M (gemcitabine, busulfan, and cyclophosphamide/melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan, administered in one patient), and CNCT19 was infused on day +2, +3 or +4 following autologous stem-cell infusion. Results: Between January 2018 and May 2020, 13 patients were enrolled. The median age was 48 years (range, 29~ 64 years), and there were 7 males. Diagnosis of lymphoma subtypes included diffuse large B-cell lymphoma (n=10), high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangement (n=1), primary mediastinal large B-cell lymphoma (n=1) and transformed follicular lymphoma (n=1). The patients received a median of 3 (range, 2~4) lines of prior therapy and 76.9% had disease that was resistant to last-line therapy. The median dose of infused stem cells was 2.54×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused CNCT19 cells was 2×106 per kilogram of body weight (range, 1.7~4×106). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT criteria. After CNCT19 infusion, 92.3% of patients experienced grade 1 CRS, and no one experienced grade 2 or higher CRS. The median time after CNCT19 infusion until the onset of CRS was 1.5 days (range, 0~3), and the median time until resolution was 8 days (range, 6~10). Seven patients (53.8%) received tocilizumab and two patients (15.3%) received glucocorticoids for the management of CRS. ICANS occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved after glucocorticoids treatment. The median times to neutrophil and platelet engraftment were 11 days (range, 8~32) and 17 days (range, 8~265), respectively. Ten patients were followed up for 3 or more months and evaluable for response. Eight of 10 patients achieved complete remission (CR), and the best overall response rate (ORR) and CR rate were both 80%. With a median follow-up of 11 months (range, 3~31) after CNCT19 infusion, the CR rate at 3 months and 6 months were 70% and 62.5%, respectively. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated proportion of PFS and OS at 12 months was 66.7% and 77.1%, respectively. Conclusion: CNCT19 infusion following HDT/ASCT could be safely administered in R/R large B-cell lymphoma patients. More patients achieved sustained remission compared with those who received anti-CD19 CAR T-cell therapy alone. The preliminary results of this pilot study support further investigation of the combination of CAR T cellular immunotherapy with HDT/ASCT. Disclosures Lv: Juventas Cell Therapy Ltd.: Current Employment.

scholarly journals A Phase I Trial of Alisertib Plus Romidepsin for Relapsed/Refractory Aggressive B- and T-Cell Lymphomas

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1744-1744 ◽  
Author(s):  
Michelle A. Fanale ◽  
Fredrick B. Hagemeister ◽  
Luis Fayad ◽  
Yasuhiro Oki ◽  
Nathan Fowler ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Aurora A Kinase ◽  
Aurora A ◽  
T Cell Lymphomas

Abstract Background: The histone deacetylase inhibitor (HDACi) romidepsin, while a clear advance for relapsed peripheral and cutaneous T cell lymphomas (CTCL and PTCL), induces short durations of remission at 9 to 10 months (Piekarz et al., 2011 and Coiffier et al., 2011). Other HDACi have been evaluated in other lymphoma types including Hodgkin lymphoma (HL) with panobinostat having a 27% ORR in patients with post-ASCT relapsed disease (Younes et al., 2012). The aurora A kinase inhibitor alisertib has shown promising results to date including in a phase II sponsored trial (Friedberg et al., 2011) in which the ORR was 32% with responses of 100% in Burkitt lymphoma (BL), 20% in diffuse large B cell lymphoma (DLBCL), and 57% in PTCL. Recent data from a SWOG further showed an ORR of 20% in all TCL and 50% in PTCL (Barr et al., 2014), and a registration trial is ongoing in relapsed PTCL. Preclinical data supports the combination of an aurora A kinase inhibitor plus a HDACi. The pan-aurora kinsase inhibitor MK-0457 in combination with the HDACi vorinostat enhanced lymphoma cell death through repression of C-Myc and C-Myc responsive micro RNAs (Kretzner et al., 2008). Also alisertib plus romidepsin exhibit highly synergistic effects in lymphoma cell lines (O’Connor, 2012). Thus, this collective data supports the rationale for the evaluation of the combination of romidepsin plus alisertib in patients with multiple lymphoma subtypes. Methods: Eligible histologies included Hodgkin lymphoma (HL), Burkitt lymphoma (BL), double-hit lymphoma (DHL), other c-Myc positive B-cell lymphomas, diffuse large-B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or peripheral T-cell lymphoma (PTCL). Patients were treated with alisertib orally on days 1 to 7 and romidepsin IV on days 1 and 8. There are 5 planned escalation dose levels with respective dosing of alisertib plus romidespin of 20 mg BID and 8 mg/m2, 20 mg BID and 10 mg/m2, 40 mg BID and 10 mg/m2, 40 mg BID and 12 mg/m2, and 40 mg BID and 14 mg/m2. Next cycle is given if ANC ≥ 1000 and platelets ≥ 50,000 and maximum cycles is 8. Restaging is done after every 2 cycles with revised response criteria (Cheson et al., 2007). DLT is defined as: 1) grade 4 neutropenia or thrombocytopenia ≥ 14 days and/or 2) grade 3 or 4 non-hematological toxicity attributed to study drugs that could not be controlled by supportive care. Patients with an ANC < 1000 received growth factor support. A lymph node core biopsy is conducted at baseline and at the end of 1 cycle of therapy, and whole peripheral blood is also collected. Evaluation of intensity of immnohistochemistry (IHC) expression of aurora A kinase will be performed and will be correlated with response, 2. Gene expression profiling (GEP) will be performed and assessments of markers of apoptosis and mitotic catastrophe, 3. GEP of whole peripheral blood will be performed to assess changes beyond those limited to within the tumor that can contribute towards response to therapy. Results: 9 patients were enrolled and 8 are evaluable for response. The median age was 60 years and histologies were 3 PTCL, 3 DHL defined by FISH, 1 DLBCL with c-Myc translocation by FISH, 1 high-grade (HG) DLBCL, and 1 transformed DLBCL. Median number of prior therapies was 4 (2 to 7) and no patients underwent prior transplant given refractory disease. 3 patients have been enrolled to each of the dose levels 1, 2, and 3. Median number of cycles is 1.5 (1 to 8) with median time for retreatment of 28.5 days (22 to 40). Grade 3/4 toxicities were neutropenia, thrombocytopenia, and anemia in respectively 45%, 45%, and 20% of the cycles. Responses to date are CR (PTCL, dose level 1), SD (PTCL, dose level 3), PD (3 DHL, 1 HG DLBCL, 1 DLBCL with c-Myc, 1 PTCL). 4 of the patients with PD have died from continued refractory disease and 1 has been transitioned to hospice. The CR patient received 7 prior lines of treatment and remains in remission at 5 months in follow-up and declined transplant. The SD patient is now 1 month out from a matched unrelated donor transplant. Conclusions: Enrollment continues. Based on preclinical data, clinical data for both agents, and responses thus far we plan to consider a dose expansion PTCL patient cohort at the MTD. Reversible cytopenias are the main toxicity to date. We anticipate the correlative studies will allow us to further define the patients with the higher likelihood of having disease response to this targeted therapeutic combination. Disclosures Fanale: Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium/Takeda: Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; Roche: Research Funding; Amgen : DMC, DMC Other. Off Label Use: Will discuss off label use of alisertib plus romidepsin in a phase I trial.. Fowler:Gilead Sciences: Research Funding.

scholarly journals Comparative Outcomes for Mature T and NK/T-cell Lymphomas in People with and without HIV and to AIDS-Defining Lymphomas

2022 ◽  
Author(s):  
Min Jung Koh ◽  
Mwanasha H Merrill ◽  
Min Ji Koh ◽  
Robert Stuver ◽  
Carolyn D Alonso ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Survival Probability ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphomas ◽  
Histological Confirmation ◽  
Improvement In Survival ◽  
T Cell Malignancies

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with human immunodeficiency virus (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCL) in the modern antiretroviral therapy (ART) era. NA-ACCORD and COMPLETE are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study 52, 64, 101, 500 and 246 PWH with histological confirmation of TCL, primary CNS, Burkitt's, diffuse large B-cell lymphoma (DLBCL) and Hodgkin's lymphoma (HL) respectively and 450 TCL without HIV were eligible for analysis. At the time of TCL diagnosis, Anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. While PWH with TCL diagnosed between 1996-2009, experienced a low 5-year survival probability at 0.23 (95% CI: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010-2016 (0.69; 95% CI: 0.48, 1; p=0.04) in contrast to TCL among PWoH (0.45; 95% CI: 0.41, 0.51; p=0.53). Similarly, PWH with ALCL diagnosed between 1996-2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; p=0.09) and DLBCL (0.17; 95% CI: 0.06, 0.46; p=0.11) and behind HL (0.57; 95% CI: 0.50, 0.65; p &lt;0.0001). Despite a small number, those diagnosed between 2010-2016, experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison to PWoH (0.76; 95% CI: 0.66, 0.87; p=0.58). Thus, our analysis confirms improved overall survival for aggressive B and T-cell malignancies among PWH in the last decade.

Human BCL11B Is Expressed in Normal T Cells and Differentially Expressed in T-Cell Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4393-4393
Author(s):  
Karen Pulford ◽  
Linden Lyne ◽  
Giovanna Roncador ◽  
Ryo Kominami ◽  
Alison H. Banham
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Zinc Finger ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expression Data ◽  
Wide Range ◽  
T Cell Malignancies

Abstract B-cell lymphomaleukaemia 11B (BCL11B), the human homologue of murine Bcl11b/Rit-1/CTIP2, was originally identified as a novel tumor suppressor gene in a study of gamma-radiation induced thymic lymphomas in mice. Later studies, however, showed Bcl11b to have a vital role in T cell development and survival, with BCL11B translocations involving a variety of partner genes being reported in both T-cell and myeloid leukemias. The human BCL11B gene, located at 14q32.2, encodes an 832aa Kruppel C2H2 zinc finger protein that is functionally uncharacterized but likely to act as a transcriptional regulator. Analysis of publically available normal tissue Affymetrix microarray expression data indicates an expression pattern restricted to hematopoietic cells, with high levels of BCL11B transcripts being present only in peripheral blood T cells, NK cells, thymus and tonsil. We have used two rabbit polyclonal anti-BCL11B antibodies to study the distribution of BCL11B protein in both normal and neoplastic human cells. These reagents, raised against two distinct regions of the murine Bcl11b protein (zinc finger and C-terminus), recognized the human BCL11B protein. While neither antibody stained B-cells in tonsil, one was crossreactive with the highly homologous BCL11AXL protein by Western blotting. In normal tissues, BCL11B protein expression was confined to the nuclei of the vast majority of T cells in thymus (foetal and adult) and tonsil. High levels of BCL11B were detected in T-cell lines, including the Molt-4, CCRF-CEM and Jurkat T-cell acute lymphoblastic leukaemia (T-ALL) derived cell lines. No expression was detected in any B-cell derived (pre-B to plasma cell stage) or myeloid cell lines studied. These results are consistent with the microarray gene expression data. In T-cell malignancies, BCL11B protein was only detected in a proportion of tumors, including 5/6 T-ALLs (one being weakly stained) and 2/8 peripheral T-cell lymphomas (weak cytoplasmic staining only). Interestingly, no expression was detected in ALK-positive anaplastic large cell lymphoma lines or tumors. Further studies of a larger series of T-cell malignancies are in progress. All other tumors studied, including B-ALL, chronic lymphocytic leukaemia, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, myeloma and Hodgkin’s lymphoma, were unlabelled. In conclusion, the distribution pattern of the BCL11B protein in a wide range of both normal and neoplastic tissues is described for the first time. The study of BCL11B expression is an invaluable first step towards elucidating the role of this protein in T-cell biology and the significance of its differential expression in T-cell malignancies.

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