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Bortezomib denies leukemia stem cell development

Acute myelogenous leukemia (AML), a disease for which treatment has remained relatively unchanged for the past 30 years, is the subject of a new clinical trial featuring a drug aimed at boosting the efficacy of standard induction chemotherapy. Bortezomib (Velcade), a proteosome inhibitor already used in the treatment of myeloma and non-Hodgkin’s lymphoma, inhibits a variety of cellular processes believed to be important in the survival of the very earliest stages of leukemia.

Objectives and importance of this trial

“We need new and better treatments based on the latest science,” says researcher Eyal Attar, MD (MGH). Attar, along with co-PI Philip Amrein, MD (MGH), leads the study of bortezomib in addition to daunorubicin and cytarabine in patients with AML aged 60-75. The main objective behind the study is to see if adding bortezomib improves the remission induction response rate of standard chemotherapy in these patients.

A major challenge of treating patients with leukemia is that they often relapse, especially in adults over the age of 60. Relapse is caused by a small population of leukemia stem cells that are intrinsically resistant to chemotherapy. Leukemia stem cells tend to be quiescent, express high levels of chemotherapy drug export proteins, and have high levels of survival proteins such as nuclear factor-kappa B (NF-kB). These factors make them resistant to standard chemotherapies.

Bortezomib inhibits a number of cellular processes, including the NF-kB master transcription factor, which is regulated by the proteosome. By inhibiting the proteosome with bortezomib, the active form of NF-kB is also inhibited. The importance of this in treating patients with AML is that leukemia stem cells, not normal hematopoietic stem cells, express high levels of active NF-kB and rely on this pathway. “We hope that by inhibiting the proteosome and NF-kB we will improve the ability to kill leukemia stem cells, augment the efficacy of standard chemotherapy, and help patients,” says Attar.   

Bortezomib offers other potential benefits for use in leukemia. For example, leukemia stem cells do not divide very frequently. However, most of the drugs used for treating AML rely on the division cycle to kill the cell. “Bortezomib offers the promise of a cell cytotoxic effect independent of cell cycle,” adds Attar. Preclinical testing in multiple leukemia cancer cell lines has shown that combining bortezomib with other chemotherapy drugs yields synergistic cytotoxicity.  

In the first clinical study of the same three therapies in AML patients, researchers saw a complete response rate of 63 percent, higher than the expected rate of 40-50 percent.  

In this earlier study, Attar and colleagues also identified a molecule — CD74 — that was associated with complete remission in patients with AML treated with the three-drug regimen. Using bone marrow samples from all of the patients, Attar performed a microarray analysis to determine if any molecules could be associated with those patients experiencing remission. “We identified that complete response was indeed associated with CD74 expression,” he says. CD74 was expressed at a six-fold increase in those patients who achieved a complete response.

Paradoxically, CD74 is associated with poor prognosis in patients with AML treated with chemotherapy without bortezomib. “This raises the interesting possibility that while CD74 is a poor prognostic marker for patients with AML, it may also be a marker of response to bortezomib,” says Attar. He adds that CD74 stimulation activates NF-kB, the very target bortezomib appears to inhibit. The study team continues to analyze the prognostic role of CD74 in this study using flow cytometry.

Approximately 75 of a total planned 88 patients have been enrolled and treated in the trial to date. The trial team includes Karen Ballen, MD (MGH), Daniel DeAngelo, MD, PhD (DFCI), Richard Stone, MD (DFCI), and Martha Wadleigh, MD (BWH).

Official title
Dose Escalation and Phase II Study of Bortezomib Added to Standard Daunorubicin and Cytarabine Therapy for Patients with Previously Untreated Acute Myeloid Leukemia (AML) Age 60-75 Years

Principal investigator
Eyal Attar, MD (MGH)

More information
For eligibility criteria, contact information, and sites, go to NCT00742625 on ClinicalTrials.gov.

—Alice McCarthy