A Phase II Study of Temsirolimus (CCI-779) in Combination with Rituximab in Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1665-1665 ◽  
Author(s):  
Stephen M Ansell ◽  
Hui Tang ◽  
Paul Kurtin ◽  
Patricia Koenig ◽  
David J Inwards ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Signal Transduction Pathway ◽  
Antitumor Agent ◽  
Cell Transplant ◽  
Mantle Cell

Abstract Abstract 1665 Poster Board I-691 Mantle cell lymphoma (MCL) is an aggressive, incurable B-cell malignancy that represents approximately 6% of lymphoma cases. Patients with MCL who relapse after conventional therapy or stem cell transplantation have a poor prognosis and are candidates for treatment with novel agents. The characteristic feature of MCL is overexpression of cyclin D1. Cyclin D1 is under the control of the phosphatidylinositol-3 kinase signal-transduction pathway and is downstream of the mammalian target of rapamycin kinase (mTOR). We have previously shown that temsirolimus (CCI-779), a dihydroester of the selective mTOR inhibitor rapamycin, is an active antitumor agent in MCL. In previous phase 2 trials of temsirolimus as a single agent, we observed a 40% overall response rate (ORR) with a median duration of response (DR) of 6 months in patients with relapsed or refractory disease (J Clin Oncol 23:5347-56, 2005; Cancer 113:508-514, 2008). Due to the fact that rituximab has improved the response rate and overall outcome of lymphoma patients when combined with chemotherapy, we tested the efficacy and toxicity of temsirolimus in combination with rituximab in patients with MCL. Eligible patients with confirmed relapsed or refractory MCL based on morphologic and phenotypic features received temsirolimus 25 mg intravenously every week and four weekly doses of rituximab with the first cycle and then one dose of rituximab every other cycle. Patients with a tumor response after six cycles were eligible to continue treatment for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance. Seventy-one patients were enrolled between May 2005 and March 2009. The median age was 67 years (range, 44 to 86 years), with 51 males and 20 females enrolled. Patients had received a median of two prior therapies (range, 1-9), 31% had received a prior stem cell transplant and 28% were rituximab refractory. The ORR was 48% (34/71 patients) with 20% (14/71) complete responses and 28% (20/71) partial responses. The median DR was 9.5 months (95% CI, 4.5 to 11.3 months). The median DR in the rituximab sensitive patients was 9.5 months (CI: 4.5-11.6) and 7.15 months (CI: 4.1-11.3) in the rituximab refractory patients (p= 0.73). While the combination was generally well tolerated, 12 patients experienced grade 4 toxicity and 2 patients died while on therapy – both from progressive disease. Hematologic toxicities were the most common, with 5 patients having grade 4 thrombocytopenia and 3 having grade 4 neutropenia. This study demonstrates that temsirolimus in combination with rituximab is well tolerated and has substantial antitumor activity in relapsed MCL. Further comparative studies of this combination in MCL are therefore warranted. Disclosures Witzig: Wyeth: Patents & Royalties.

Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 129-129 ◽  
Author(s):  
Thomas Witzig ◽  
Susan Geyer ◽  
Irene Ghobrial ◽  
David Inwards ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Median Time ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Pi3k Pathway ◽  
Mantle Cell ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7532-7532 ◽  
Author(s):  
S. M. Ansell ◽  
S. M. Geyer ◽  
P. J. Kurtin ◽  
D. J. Inwards ◽  
S. H. Kaufmann ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Early Evaluation ◽  
Overall Response ◽  
Mantle Cell ◽  
Anti Tumor Activity

7532 Background: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. Temsirolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly temsirolimus at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (JCO 23 (23); 5347–56, 2005). Thrombocytopenia was frequently observed and was dose limiting. The current study tested whether low-doses (25mg) of temsirolimus could produce a similar overall response rate (ORR) with less toxicity. Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received temsirolimus 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. The goal was to achieve an ORR of at least 20%. Results: Twenty-nine patients were enrolled between March and August 2005. Twenty-two patients have completed therapy. One patient with a major protocol violation on cycle-1 and one ineligible patient were excluded, leaving 27 evaluable patients. The ORR was 41% (11/27), with 1 CR and 10 PRs. Early evaluation of TTP showed a median of 5.5 months (95% CI: 3.3–7.7) and the duration of response for the 11 responders was 6.2 months (95% CI: 3.6 to not yet reached). These results compare favorably with the 6.5 months and 6.9 months, respectively, found in previous trials that used 250 mg. The median dose delivered per month was 80 mg (range, 10–100 mg). Sixteen (59%) of patients required a dose reduction. The median time on treatment was 4.4 months (95% CI, 3.3–7.7). The incidence of grade 3 and 4 thrombocytopenia was 12% and 0%, respectively. One patient experienced grade 5 infection without neutropenia, which was considered unrelated to CCI-779. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL similar to the 250 mg dose. This study indicates that combinations of temsirolimus with other agents should be feasible. [Table: see text]

A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2803-2803 ◽  
Author(s):  
Christoph Renner ◽  
Pier Luigi Zinzani ◽  
Remy Gressin ◽  
Dirk Klingbiel ◽  
Laurence Favet ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Objective Response ◽  
Response Duration ◽  
Molecular Response ◽  
Hematopoietic Stem ◽  
Mantle Cell

Abstract Abstract 2803 Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 – 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8–37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8–8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL. Disclosures: Off Label Use: everolimus for the treatment of mantle cell lymphoma.

scholarly journals Outcomes in Mantle Cell Lymphoma for Elderly Patients Undergoing Autologous Stem Cell Transplant in CR1

2017 ◽  
Vol 23 (3) ◽  
pp. S265-S266
Author(s):  
Irl Brian Greenwell ◽  
Kelly Valla ◽  
Sarah Caulfield ◽  
Jeffrey M. Switchenko ◽  
Ashley Staton ◽  
...  
Keyword(s):  
Stem Cell ◽  
Elderly Patients ◽  
Mantle Cell Lymphoma ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Mantle Cell

Effectiveness and tolerability of first-line autologous stem cell transplant and maintenance rituximab for mantle cell lymphoma

2017 ◽  
Vol 53 (3) ◽  
pp. 347-351
Author(s):  
Umberto Falcone ◽  
Haiyan Jiang ◽  
Shaheena Bashir ◽  
Richard Tsang ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mantle Cell Lymphoma ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
First Line ◽  
Mantle Cell

scholarly journals Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Marco Gunnellini ◽  
Lorenzo Falchi
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Response Rates ◽  
Prognostic Scores ◽  
Cell Transplant ◽  
Survival Times ◽  
Phase Ii Studies ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

scholarly journals T-Cell Replete Allogeneic Stem Cell Transplant Is an Effective Treatment Option for Patients with TP53 mutated Mantle Cell Lymphoma

2021 ◽  
Vol 27 (3) ◽  
pp. S421-S422
Author(s):  
Edward Robert Scheffer Cliff ◽  
Thomas Eliot Lew ◽  
Piers Blombery ◽  
Michael Dickinson ◽  
Constantine S. Tam ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Effective Treatment ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Effective Treatment Option ◽  
Mantle Cell

Comparison of Survival Outcomes of Patients with Mantle Cell Lymphoma (MCL) Treated with Autologous Stem Cell Transplant (ASCT) and Conventional Chemotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4491-4491
Author(s):  
Daniel C McFarland ◽  
Parameswaran Venugopal ◽  
Yan Li ◽  
Youping Deng ◽  
Stephanie A. Gregory
Keyword(s):  
Stem Cell ◽  
Treatment Group ◽  
Mantle Cell Lymphoma ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Initial Therapy ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Chemotherapy Group ◽  
Mantle Cell

Abstract Abstract 4491 Background: Mantle cell lymphoma is typically considered to be aggressive and incurable. About 15% of these patients have an indolent course. MCL demonstrates the aggressive features of a rapidly progressive neoplasm but with the negative consequences of an indolent lymphoma, namely incurability and frequent relapses. The median overall survival (OS) was reported at 3–4 years when MCL was first described in the 1990's. OS has since increased substantially and this is thought to be secondary to more aggressive initial therapy and improvement in supportive care. In many parts of the world, autologous stem cell transplant (ASCT) is incorporated in the front line therapy for MCL patients with good performance status. However, improvement in survival has not deemed MCL a curable disease. Concern for treatment-related morbidity seen with aggressive therapy in an incurable disease has led some centers to practice a more conservative approach. The purpose of our study was to compare patient characteristics and the overall survival of patients treated aggressively with ASCT versus conservatively with either conventional chemotherapy or no treatment at a single institution. Methods: 52 cases of confirmed mantle cell lymphoma diagnosed at Rush University Medical Center between January 2000 and November 2010 were studied. Demographic, clinical and treatment data were collected and reviewed. The Social Security Death Index and hospital records were used to assess survival. Comparative survival analysis was performed based on treatment strategies including the following: no treatment (watch and wait), chemotherapy, ASCT at any time during course of treatment. None of these patients had an allogeneic stem cell transplant. Results: 43 of the 52 cases met all inclusion criteria and had complete diagnostic and treatment data. The no-treatment group consisted of 5 cases with a median age of 59 years. The chemotherapy group included 23 cases with a median age of 68 years. The most common initial therapy was RCHOP in 14 cases, followed by various other regimens (i.e. bortezomib + rituximab, bendamustine + rituximab) in 7 cases and HyperCVAD in 2 cases. The ASCT group included 15 cases with a median age of 61 years. Pre-transplant chemotherapy was RCHOP in 4 cases, HyperCVAD in 5 cases and other regimens in 6 cases. The comparative survival analysis for the three treatment groups was not statistically significant (p=0.496) and the estimated 3 year OS was 100% for the no treatment group, 74% for the chemotherapy group and 85% for the ASCT group. The estimated 5 year OS was 100% for the no treatment group, 66% for the chemotherapy group and 68% for the ASCT group. There were no cases of allogeneic stem cell transplants. Conclusions: Our review of MCL cases treated at a single institution supports a role for conservative treatment approaches to this disease entity. This can avoid the potential long term morbidity from ASCT in a subgroup of patients while still keeping the modality of therapy as an option for them at relapse. The incidence of indolent MCL requiring no treatment was 12% which is consistent with those seen in other studies. Further research is necessary to guide treatment decisions for MCL patients whose disease characteristics are intermediate between aggressive and indolent. Disclosures: Gregory: Genentech:.

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