NEW ORLEANS — Early results with an investigational new agent suggest it may have disease-modifying activity in myelofibrosis, which would be a first in this condition.
The drug, imetelstat (under development by Geron), has a novel mechanism of action of inhibiting telomerase activity in tumor cells, which leads to tumor cell death. This is a rational target for cancer, says the manufacturer, because most cancer cells have a high level of telomerase activity and relatively short telomeres, compared with normal cells.
The new results in myelofibrosis come from 22 patients treated with imetelstat with a follow-up of at least 6 months, and were reported by Ayalew Tefferi, MD, from the Mayo Clinic in Rochester, Minnesota, here at the American Society of Hematology 55th Annual Meeting.
Four of the 22 patients (18%) had a complete remission, which "has never been seen before with any drug," he said.
As well as complete resolution of symptoms, these 4 patients also showed a complete reversal of bone marrow fibrosis, which is almost unheard of, Dr. Tefferi commented. He showed histology slides from the 4 patients, which showed bone marrow fibrosis before treatment and a complete absence of fibrosis after treatment, so that the bone marrow looked normal.
"These are early results, but they are promising" Dr. Tefferi commented. "Some patients had dramatic responses."
However, one expert not involved with the study said that the responses are in need of qualification.
The bone marrow fibrosis that was reversed was reticulin fibrosis, which is seen in early phases of the disease and is not the striking and severe myelosclerosis and bone marrow scarring that is seen in more advanced disease, said Richard Silver, MD, professor of medicine and director of the Leukemia and Myeloproliferative Center at New York Presbyterian-Weill Cornell Medical Center in New York City. He chaired the session at which these results were presented, and said he found some of the data to be "confounding."
"These were patients in the cellular phase of myelofibrosis," he said. He also noted that 3 of the 4 patients who showed this bone marrow reversal did not have enlarged spleens, so they were relatively early cases, he said. One of the patients had essential thrombocytopenia with a very cellular bone marrow, and was very anemic.
"These are very unusual presenting cases," Dr. Silver commented.
These patients showed clearing of the reticulin bone marrow fibrosis that is seen in earlier stages of myelofibrosis, he continued. This has been seen before with interferon and also with ruxolitinib, but with these drugs, the changes leading to reversal take a long time — several years — to be seen, he said. In contrast, the reversal with imetelstat was seen within 6 months, and as the patients were in the cellular phase of the disease, there is some speculation that the effect seen was some sort of "toxic reaction."
Dr. Silver noted that the drug was toxic, causing severe myelosuppression, and he said that this was a cause for concern. Nevertheless, he said that further clinical investigation of imetelstat in myelofibrosis was warranted.
However, Dr. Tefferi told Medscape Medical News that some of these remarks are "factually inaccurate." He also made the following comments. "First, only 1 of the 5 patients with complete or partial responses [CR, PR] had cellular-phase myelofibrosis, whereas the remaining 4 had overt myelofibrosis that was advanced, and grade 3 in 2 of the patients with CR. Second, 4 of 5 patients with CR or PR had a palpably enlarged spleen, which measured 10 and 8 cm in 2 of them, and all had complete resolution of their spleen. Finally, among over 200 patients treated with a JAK inhibitor at our institution, we have not witnessed a single case of reversal of bone marrow fibrosis. The reports otherwise all come from company-sponsored projects and have not been validated by independent company-independent investigators. Furthermore, bone marrow fibrosis is a package that comes with leukoerythroblastosis and increased lactate dehydrogenase (LDH), and it makes no scientific sense for reversal of bone marrow fibrosis that is not accompanied by complete resolution of leukoerythroblastosis and normalization of serum LDH levels. The latter has thus far been accomplished by imetelstat only."
Myelosuppressive Adverse Events
The 22 evaluable patients (with >6 months follow-up) that Dr. Tefferi reported on at the meeting were participating in an investigator-led trial that had enrolled 33 patients, all treated with imetelstat (9.4 mg/kg), but in 2 different schedules.
One group (n = 19) received the drug once every 3 weeks, while another group (n = 14) received the drug weekly for 4 weeks followed by a dose once every three weeks.
However, this second, more intense dosing schedule was associated with unacceptable myelosuppression, and so this treatment group was discontinued, Dr. Tefferi said. This treatment group (i.e., imetelstat weekly for 4 weeks and then once every 3 weeks) had 14 patients, of whom 3 patients developed grade 4 neutropenia, 4 patients developed grade 4 thrombocytopenia, and 1 patient died after developing grade 5 intracranial bleeding and febrile neutropenia.
In contrast, in the group of 19 patients treated with the less intense dosing regimen (1 dose every 3 weeks), only 1 patient developed grade 4 neutropenia, he noted. In addition, grade 3/4 neutropenia was seen in 2 patients, grade 3/4 thrombocytopenia in 5 patients, and grade 3/4 anemia in 1 patient. Other adverse events included grade 1 nausea and vomiting, grade 1/2 fatigue, and grade 2 liver enzyme disturbances (APTT increase and hyperbilirubinemia).
"The drug's potent anticlonal, on-target activity probably accounts for the severe myelosuppression seen in some patients, and warrants close monitoring of patients, especially in the first few cycles of treatment," Dr. Tefferi commented.
Clinical Activity
Table. Outcomes for the 22 Evaluable Patients
| Outcome | n | % |
| Complete or partial response | 5 | 23 |
| Clinical improvement (in spleen size or anemia) | 4 | 18 |
| Reversal of bone marrow fibrosis | 4 | 18 |
| Megakaryocyte morphologic remission | 2 | 9 |
| Complete molecular remission | 2 | 9 |
Dr. Tefferi noted that patients who were classified as having a complete remission had reversal of bone marrow fibrosis and also had complete resolution of symptoms and palpable splenomegaly, complete disappearance of circulating immature cells, and achievement of hemoglobin 10 g/dL or more without transfusion, platelet count of 100 × 10⁹/L or more, and absolute neutrophil count of 1 × 10⁹/L or more but all below the upper limits of normal.
Partial response had the same characteristics except for the reversal of bone marrow fibrosis, Dr. Tefferi explained.
The effect on symptoms such as spleen size and anemia was similar to what has been seen with ruxolitinib (Jakafi), which is the first new therapy in decades for myelofibrosis. However, Dr. Tefferi noted that ruxolitinib alleviates only the symptoms of the disease; it does not affect the cancer cells. "It is like comparing apples and oranges," he commented to Medscape Medical News. "As a cancer doctor, my mission is to make the cancer go away and not only to make the night sweats go away."
Analysis of gene mutations in the patients treated with imetelstat suggest that the activity of the drug was influenced by the absence or presence of specific mutations, and the data so far show that the complete remissions were seen in patients with spliceosome mutations, Dr. Tefferi commented.
This suggests that the drug may be useful in other cancers, he added, and noted that his team has just started a trial in patients who are in the blastic phase of acute myeloid leukemia.
The manufacturer also has an ongoing clinical trial in patients with essential thrombocythemia, and says that there is evidence that imetelstat has disease-modifying activity in this disorder.
"It's an entirely new concept," commented Eyal Atttar, MD, assistant professor of medicine at Massachusetts General Hospital in Boston. "We know that alterations in telomerase activity are probably important in a variety of different cancers, but there is really no track record of using inhibitors of telomerase to treat diseases...so this is interesting, it's a first demonstration that it has clinical activity in patients, and there may be other applications in other cancers."
The trial was investigator-initiated, but received some support from Geron. Dr. Tefferi has disclosed no relevant financial relationships.
American Society of Hematology (ASH) 55th Annual Meeting: Abstract 662. Presented December 9, 2013.
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