A Novel Combination of the mTORC1 Inhibitor Everolimus and the Immunomodulatory Drug Lenalidomide Produces Durable Responses in Patients With Heavily Pretreated Relapsed Lymphoma

Leslie Padrnos, Brenda Ernst, Amylou Dueck, Heidi E. Kosiorek, Brenda F. Ginos, Angela Toro, Patrick Bruce Johnston, Thomas Matthew Habermann, Jose F. Leis, Joseph R Mikhael, Grzegorz S Nowakowski, Joseph Colgan, Luis Porrata, Stephen Maxted Ansell, Thomas Elmer Witzig, Craig Reeder

Research output: Contribution to journalArticle

Abstract

Relapsed and refractory lymphoproliferative neoplasms have a significant need for novel therapeutic options. A phase I/II trial using a combination therapy of everolimus and lenalidomide in 58 patients with relapsed or refractory Hodgkin and non-Hodgkin lymphomas demonstrated a modest overall response of 27% and tolerability in a heavily pretreated patient population. Background: Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. Patients and Methods: The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49%), 63% had stage IV disease, and ≥ 3 previous therapies had failed in 78%. Results: Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56%), leukopenia (38%), and thrombocytopenia (33%). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27% (15 of 55), with 38% (21 of 55) having stable disease. Conclusion: The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.

Original languageEnglish (US)
JournalClinical Lymphoma, Myeloma and Leukemia
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Lymphoma
Pharmaceutical Preparations
Maximum Tolerated Dose
Neutropenia
Hodgkin Disease
Non-Hodgkin's Lymphoma
lenalidomide
Everolimus
mechanistic target of rapamycin complex 1
Neoplasms
Leukopenia
Stem Cell Transplantation
Proxy
Thrombocytopenia
Disease Progression
Therapeutics
Recurrence
Population

Keywords

  • Combination Therapy
  • Overall response rate
  • Phase I
  • Phase II
  • Relapsed and refractory lymphoma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

@article{ccc3a057b3f94dc680c9b81e69b98a95,
title = "A Novel Combination of the mTORC1 Inhibitor Everolimus and the Immunomodulatory Drug Lenalidomide Produces Durable Responses in Patients With Heavily Pretreated Relapsed Lymphoma",
abstract = "Relapsed and refractory lymphoproliferative neoplasms have a significant need for novel therapeutic options. A phase I/II trial using a combination therapy of everolimus and lenalidomide in 58 patients with relapsed or refractory Hodgkin and non-Hodgkin lymphomas demonstrated a modest overall response of 27{\%} and tolerability in a heavily pretreated patient population. Background: Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. Patients and Methods: The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49{\%}), 63{\%} had stage IV disease, and ≥ 3 previous therapies had failed in 78{\%}. Results: Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56{\%}), leukopenia (38{\%}), and thrombocytopenia (33{\%}). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27{\%} (15 of 55), with 38{\%} (21 of 55) having stable disease. Conclusion: The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.",
keywords = "Combination Therapy, Overall response rate, Phase I, Phase II, Relapsed and refractory lymphoma",
author = "Leslie Padrnos and Brenda Ernst and Amylou Dueck and Kosiorek, {Heidi E.} and Ginos, {Brenda F.} and Angela Toro and Johnston, {Patrick Bruce} and Habermann, {Thomas Matthew} and Leis, {Jose F.} and Mikhael, {Joseph R} and Nowakowski, {Grzegorz S} and Joseph Colgan and Luis Porrata and Ansell, {Stephen Maxted} and Witzig, {Thomas Elmer} and Craig Reeder",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.clml.2018.06.013",
language = "English (US)",
journal = "Clinical Lymphoma, Myeloma and Leukemia",
issn = "2152-2669",
publisher = "Cancer Media Group",

}

TY - JOUR

T1 - A Novel Combination of the mTORC1 Inhibitor Everolimus and the Immunomodulatory Drug Lenalidomide Produces Durable Responses in Patients With Heavily Pretreated Relapsed Lymphoma

AU - Padrnos, Leslie

AU - Ernst, Brenda

AU - Dueck, Amylou

AU - Kosiorek, Heidi E.

AU - Ginos, Brenda F.

AU - Toro, Angela

AU - Johnston, Patrick Bruce

AU - Habermann, Thomas Matthew

AU - Leis, Jose F.

AU - Mikhael, Joseph R

AU - Nowakowski, Grzegorz S

AU - Colgan, Joseph

AU - Porrata, Luis

AU - Ansell, Stephen Maxted

AU - Witzig, Thomas Elmer

AU - Reeder, Craig

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Relapsed and refractory lymphoproliferative neoplasms have a significant need for novel therapeutic options. A phase I/II trial using a combination therapy of everolimus and lenalidomide in 58 patients with relapsed or refractory Hodgkin and non-Hodgkin lymphomas demonstrated a modest overall response of 27% and tolerability in a heavily pretreated patient population. Background: Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. Patients and Methods: The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49%), 63% had stage IV disease, and ≥ 3 previous therapies had failed in 78%. Results: Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56%), leukopenia (38%), and thrombocytopenia (33%). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27% (15 of 55), with 38% (21 of 55) having stable disease. Conclusion: The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.

AB - Relapsed and refractory lymphoproliferative neoplasms have a significant need for novel therapeutic options. A phase I/II trial using a combination therapy of everolimus and lenalidomide in 58 patients with relapsed or refractory Hodgkin and non-Hodgkin lymphomas demonstrated a modest overall response of 27% and tolerability in a heavily pretreated patient population. Background: Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. Patients and Methods: The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49%), 63% had stage IV disease, and ≥ 3 previous therapies had failed in 78%. Results: Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56%), leukopenia (38%), and thrombocytopenia (33%). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27% (15 of 55), with 38% (21 of 55) having stable disease. Conclusion: The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.

KW - Combination Therapy

KW - Overall response rate

KW - Phase I

KW - Phase II

KW - Relapsed and refractory lymphoma

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