Not all cases of myelofibrosis respond well to ruxolitinib, the only drug approved for this disease. However, early studies indicate that a new class of drugs, Smac mimetics, can achieve a response in some patients with myelofibrosis.
These drugs imitate an endogenous protein called second mitochondria-derived activator of caspases (Smac), which induces cell death. A clinical trial of one such drug is now enrolling patients who cannot receive or whose disease is resistant to standard treatment for myelofibrosis.
Many patients with myelofibrosis are in their 60s or 70s, have abnormal blood counts, or have other comorbid health conditions—all of which can preclude the use of ruxolitinib and other drugs. “There is an urgent, unmet clinical need for treatment options for these patients,” said Naveen Pemmaraju, M.D., an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Clinical trials, if available, are often the best and sometimes the only option for this group of patients.
One potential treatment for these patients is Smac mimetics. These drugs target a natural mechanism that inhibits programmed cell death, or apoptosis, by mimicking a protein that cells normally release to promote apoptosis in a stressful environment. “Smac mimetics take away the apoptosis-blocking mechanism to promote cell death,” Dr. Pemmaraju said. “Because this blocking of apoptosis is upregulated in cancer cells, we hypothesize that this class of drugs should preferentially hit the cancer cells over the healthy cells.”
There is a strong rationale for pursuing the use of Smac mimetics in hematological cancers specifically. Researchers have observed that blood and tissue samples from patients with myeloproliferative neoplasms, including myelofibrosis (see “Myeloproliferative Neoplasms,” below), have elevated levels of pro-inflammatory cytokines, particularly tumor necrosis factor α. Additionally, Bing Carter, Ph.D., a professor in the Department of Leukemia, has found that tumor necrosis factor α or related cytokines are required for the activity of Smac mimetics in acute myelogenous leukemia cells. These findings, along with the results of a recent dose-escalation trial that showed activity of the Smac mimetic LCL-161 in patients with various advanced solid tumors, gave MD Anderson investigators the impetus needed to undertake trials of Smac mimetics in myelofibrosis and other hematological cancers.
Dr. Pemmaraju, Dr. Carter, and Srdan Verstovsek, M.D., a professor in the Department of Leukemia, are performing a single-institution phase II trial (No. 2013-0612) at MD Anderson to test LCL-161 for adult patients with intermediate- to high-risk myeloproliferative neoplasms, including myelofibrosis, who are ineligible for or in tolerant to ruxolitinib or other JAK inhibitors. An unusual aspect of the trial is its inclusion of patients with characteristics that often disqualify patients from other trials or treatments. Specifically, there are no limits on spleen size, platelet count, or prior therapies such as stem cell transplants.
“Our thinking was to offer a different mechanism of action from that of the approved drugs that are available,” said Dr. Pemmaraju. “LCL-161 targets a completely different pathway, and this is the first LCL-161 study in patients with a myeloproliferative neoplasm.”
The trial follows a Simon optimal two-stage design, which means that LCL-161 must meet predefined efficacy and safety requirements in the first 13 patients before the trial can be expanded to include the planned 40 patients.
The drug is given orally once per week in 4-week cycles. The patients undergo blood tests and physical examinations after every three cycles and bone marrow biopsies after the third cycle and then every six cycles. Objective responses are stringently defined: they must last more than 12 weeks and consist of a change in hemoglobin level, in symptoms as scored by a validated survey done over time, or in spleen size.
The patients enrolled so far are a heavily pretreated group with a median age in the 70s, with mostly high-risk myelofibrosis, and with a median platelet count of around 50,000/mL, whereas the normal range is 140,000–440,000/mL. Four of the first 13 patients had objective responses: two had increased hemoglobin levels, two had decreased symptoms, and one had a decreased spleen size (one patient responded according to two measures).
Importantly, none of the patients has experienced cytokine release syndrome, a dysregulation of the immune system that harms healthy cells. The investigators were on the lookout for cytokine release syndrome in these patients because Smac mimetics have the potential to intolerably increase cytokine levels, which are already elevated in myelofibrosis patients. To avoid this effect, patients received a conservative dose at first and did not at any point exceed the dose recommended by the investigators who carried out the dose-escalation trial of LCL-161 in patients with solid tumors. A small dose of steroids also may have helped prevent cytokine release syndrome in the current study. The most common side effects in the myelofibrosis patients have been fatigue, nausea, and vomiting. No major hematological toxic effects have been seen.
Analyses of blood samples collected before, during, and at the end of treatment from the patients who responded to LCL-161 supported the hypothesized mechanism of the drug. “We measured whether cIAP1, the anti-apoptotic protein targeted by the drug, was indeed inhibited after treatment. The lab results reflected the clinical results,” Dr. Carter said. “Of the 13 patients analyzed so far, eight have had reductions in cIAP1 protein levels. Four of these patients had minor reductions, and their disease did not respond to the drug. The other four had strong reductions, and their disease responded clinically.”
Dr. Pemmaraju remarked that this type of correlative analysis, done in real time, extends the insights to be gained from a trial. “Whether the trial has positive, negative, or in-between results, this type of multifaceted collaboration between our patients, doctors, investigators, and scientists creates a loop of information that benefits the entire patient community.”
On the whole, the first stage of the trial demonstrated that LCL-161 can feasibly be administered to patients with myelofibrosis who are ineligible for or intolerant of the approved JAK inhibitor therapy. Over the next year, the trial will continue enrolling patients.
If LCL-161 continues to show activity in patients with myelofibrosis, the next steps would include testing the drug in combination with other agents, both novel and standard. LCL-161 also could potentially be tested in other hematological cancers, including acute myelogenous leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Like myelofibrosis, these three cancers have few standard therapies.
Through clinical trials of Smac mimetics and other therapies, Dr. Pemmaraju said that MD Anderson researchers hope to increase the treatment options for patients with hematological cancers. “It’s not just about the latest therapy, it’s the availability of a personalized clinical trial that may be right for a particular patient at a particular time in their disease course,” he said.
“Furthermore, if patients can participate in clinical trials with correlative laboratory studies, that helps not only the patients but potentially every other patient with that disease to come.”
For more information, contact Dr. Bing Carter at 713-794-4014 or Dr. Naveen Pemmaraju at 713-792-4956.
OncoLog, November-December 2016, Volume 61, Issue 11-12
Primary myelofibrosis, the most aggressive myeloproliferative neoplasm, is characterized by uncontrolled growth of bone marrow cells, reactive bone marrow fibrosis, and a subsequent lack of red blood cells. Symptoms of myelofibrosis include anemia and enlargement of the spleen or liver.
Polycythemia vera and essential thrombocythemia typically are not life threatening, although both disorders carry an increased risk of thrombosis. Polycythemia vera is characterized by uncontrolled growth of bone marrow cells that increases the total blood volume and essential thrombocythemia by an overproduction of platelets.
Primary myelofibrosis, polycythemia vera, and essential thrombocythemia are considered the three classic myeloproliferative neoplasms. Although some myeloproliferative neoplasms were once considered clinically benign, all are now classified as cancers by the World Health Organization.