Bortezomib Is Not Active in Patients with Relapsed Hodgkin’s Lymphoma: Results of a Prematurely Closed Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2477-2477 ◽  
Author(s):  
Sven Trelle ◽  
Orhan Sezer ◽  
Ralph Naumann ◽  
Mathias Rummel ◽  
Ulrich Keller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Nuclear Factor Kappa B ◽  
Phase Ii Study ◽  
The Other ◽  
Hodgkin's Lymphoma ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Heavily Pretreated ◽  
Pretreated Patients

Abstract Background: Hodgkin’s and Reed-Sternberg cells are known to be resistant to apoptosis due to over-expression of Nuclear Factor kappa-B (NF-κB). Bortezomib increases intracellular levels of Inhibitor of Nuclear Factor kappa-B (I-κB) which inhibits activation of NF-κB. Laboratory studies indicate that bortezomib has a strong antiproliferative activity in Hodgkin’s lymphoma derived cell lines. We aimed to investigate the activity of bortezomib given in combination with dexamethasone in patients with relapsed Hodgkin’s lymphoma (HL). Methods: This was a multicenter, two-stage phase II study. Patients (pts.) with relapsed HL received 1.3 mg/m2 bortezomib plus 20 mg dexamethasone on days 1, 4, 8, and 11 of a 3-weekly cycle for up to 8 cycles. Response and toxicity were evaluated using standard criteria (Cheson 1999, Lister 1989; NCI-CTC v3.0). Circulating proteasome concentration was measured using sandwich enzyme-linked immunosorbent assay. Sample size was calculated according to Simon’s optimal design with 12 pts in the first stage and 25 thereafter. At least one response in the first 12 pts was required to proceed to the second stage. Results: As pre-specified in the protocol twelve pts were entered in the first stage and are assessable for response. All pts were heavily pre-treated with a median of 3 prior therapies and all but one had received high-dose chemotherapy. Two pts prematurely discontinued the study treatment due to toxicities after 2 and 3 cycles respectively. Both had stable disease at their final evaluation. All of the other 10 pts had progressive disease. Nine of these prematurely discontinued the study treatment due to insufficient response after a median of 2 cycles (range: 2–5 cycles) and only 1 received all 8 cycles. Since no response was observed in the first 12 pts, the study was stopped after the first stage. Eleven patients were assessable for toxicity as of August 2006. Two of these experienced no toxicity > °I. The other 9 patients experienced at least 1 episode of a ≥ °II toxicity requiring some dose modifications, treatment delays, or discontinuation and 4 of these experienced °IV toxicity. Reported toxicities included thrombocytopenia (°II: 1 pat; °III: 1 pat; IV: 2 pat); lymphopenia (°III: 1 pat); febrile neutropenia (°IV: 1 pat); infection (°II: 2 pat); herpes zoster (°III: 1 pat); pain (°II: 2 pat); loss of appetite (°IV: 1 pat); cough (°III: 1 pat); epistaxis (°III: 1 pat); paralytic ileus (°IV: 1 pat); diarrhea (°III: 1 pat); and sleep disturbance (°III: 2 pat). Details on treatment administration and proteasome concentration will be presented as well as results of a meta-analysis of all available phase II studies of bortezomib in HL. Interpretation: Bortezomib in combination with dexamethasone is not active in heavily-pretreated patients with relapsed Hodgkin’s lymphoma. Furthermore, this treatment regimen possesses severe toxicities in heavily pre-treated Hodgkin’s patients. The use of bortezomib combined with dexamethasone is therefore discouraging in heavily pre-treated patients with HL. Further studies may only be justified with other combinations or less heavily pretreated patients.

Multicentre phase II study of the baseline BEACOPP regimen for patients with advanced-stage Hodgkin's lymphoma

2006 ◽  
Vol 47 (9) ◽  
pp. 1908-1914 ◽  
Author(s):  
Nozomi Niitsu ◽  
Masataka Okamoto ◽  
Naoto Tomita ◽  
Sadao Aoki ◽  
Jun-ichi Tamaru ◽  
...  
Keyword(s):  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Hodgkin's Lymphoma ◽  
Advanced Stage ◽  
Multicentre Phase

Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4602-4602
Author(s):  
Maria Alma Rodriguez ◽  
Andreas Sarris ◽  
Nam H. Dang ◽  
Luis Fayad ◽  
Andre Goy ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Hodgkin's Lymphoma ◽  
Total N ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
New Treatment

Abstract Sphingosomal vincristine (SV) is a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes’. SV was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst.412, 1999). The addition of rituximab to CHOP improves response in aggressive B-cell lymphomas in the elderly (Coiffier et al., NEJM2002:346; 235–42). Based on these data, a phase II study of RCHOP, substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL (excluding rituximab if T-cell lymphoma). Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH Abst.338, 2002). Results: Of 73 patients enrolled in the study, 68 were evaluable for response. Median age was 63 (range 22–80). IPI score was 0–2 in 44 pts and ≥ 3 in 24 pts. Patients received a median of 6 study treatments (range 1–8). ORR was 93% (63/68 pts) with 62 pts achieving CR and Cru (91%), and 1 PR (2%). 3 pts had PD (4%) and 2 were not assessed for response (3%). The median PFS and OS have not been reached at a median follow up of 29.5 months. Responses according to IPI score were as follows: Results IPI 0–2 (n=44) IPI ≥3 (n=24) Total (n=68) ORR 93% (41) 92% (22) 93% (63) −CR 77% (34) 88% (21) 81% (55) −Cru 14% (6) 4% (1) 10 (7) −PR 2% (1) 0% (0) 2% (1) PD 5% (2) 4% (1) 4% (3) Not Assessed 2% (1) 4% (1) 3% (2) The probability of being progression free at 25 months was 86% (5 relapses and 1 death, reason unknown) for pts with IPI 0–2 and 77% (6 relapses) for pts with IPI ≥3. Overall survival probability was 94% at 28 months (1 death in the group with IPI 0–2 and 2 deaths in the group with IPI ≥3). Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 64% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 14% Gr.3–4 thrombocytopenia. Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine demonstrated promising activity with durable responses similar in both groups of patients with IPI score 0–2 and IPI ≥ 3. The treatment was well tolerated with only mild neurotoxicity.

Interim Analysis of a Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2641-2641 ◽  
Author(s):  
Nam H. Dang ◽  
Barbara Pro ◽  
Fredrick B. Hagemeister ◽  
Dan Jones ◽  
Barry Samuels ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Denileukin Diftitox ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Denileukin diftitox (Ontak) is a fusion protein combining the enzymatically active domain of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor (IL-2R). The drug has established efficacy in cutaneous T-cell lymphoma (CTCL), and we have recently demonstrated its single-agent activity in B-cell non Hodgkin’s lymphoma (NHL) (Dang et al. Journal of Clinical Oncology. In Press). We initiated a phase II study to evaluate its efficacy in relapsed/refractory T-cell NHL, excluding CTCL. Denileukin diftitox was administered at a dose schedule of 18 μg/kg/day by IV infusion once daily for 5 days every three weeks, for up to 8 cycles. Premedications in the form of corticosteroids, antihistamines and fluids were given prior to each drug infusion to reduce the incidence and severity of acute hypersensitivity. 14 patients are currently evaluable for response. Median age was 57 (range 26–80), and mean number of previous treatments was 2.2 (range 1–4). Tumor CD25 status was determined by immunohistochemistry and/or flow cytometry, with CD25-positivity being defined as 10% or more of tumor cells expressing detectable CD25. Of the 7 patients with CD25+ T-NHL, there were 2 CR (1 case of Alk-1 negative ALCL and 1 case of PTCL), 3 PR (1 case of PTCL and 2 cases of angioimmunoblastic lymphoma), 1 SD (1 case of PTCL) and 1 PD (1 case of PTCL). Of the 7 patients with CD25− T-NHL, there were 2 PR (1 case of PTCL and 1 case of T/NK-lymphoma), 4 SD (3 cases of PTCL and 1 case of Sezary syndrome), and 1 PD (1 case of angioimmunoblastic lymphoma). Overall response rate (CR+ PR) was 50%, with 2 of 14 patients having CR (14%) and 5 of 14 patients having PR (36%). One patient with Alk-1negative ALCL still has an ongoing CR at 15+ months. Treatment was well-tolerated, with the majority of toxicity being grade 1 or 2 and transient. Denileukin diftitox appears to have activity in relapsed/refractory T-cell NHL, and is well-tolerated at the dosing schedule tested. Additional patients are being studied to further evaluate the relationship between detectable CD25 expression and tumor response to denileukin diftitox.

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