Zosia Chustecka

December 03, 2012

"Doing more with less" is one of the main themes of the American Society of Hematology (ASH) 54th Annual Meeting, which opens December 7 in Atlanta, Georgia.

Several presentations will describe innovative ways to achieve better outcomes with lower doses of drugs, said ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada. He was speaking at a press briefing held in advance of the meeting.

One example is "ground-breaking" research that shows that chemotherapy can be omitted from the front-line treatment of newly diagnosed acute promyelocytic leukemia (APL) (abstract 6).

Until about 35 to 40 years ago, APL was a devastating disease, probably the worst hematologic malignancy; mortality was 100% and most patients died within weeks, Dr. Keating explained. "But we have made tremendous progress," he said.

APL is now treated with a combination of all-trans retinoic acid (ATRA) plus chemotherapy, a gold-standard therapy that achieves 80% cure rates; arsenic trioxide (ATO) is the treatment of choice for relapsed patients.

However, the new study shows that in newly diagnosed APL patients, comparable results can be obtained with a combination of ATRA plus ATO, without any cytotoxic chemotherapy. This is "really quite impressive," Dr. Keating said.

"I found this study amazing," said ASH Secretary Charles Abrams, MD, at the briefing. Dr. Abrams is professor of medicine and associate chief of the hematology/oncology division at the University of Pennsylvania in Philadelphia.

"This used to be the worst of the worse" hematologic malignancies, he noted. "Now we see, for the first time, that it can be treated [without] chemotherapy," he added.

The 2 drugs in this novel combination, ATRA and ATO, originally came from traditional Chinese medicine, he explained. ATO has also been used in traditional Indian medicine, and its mechanism of action is now starting to be understood, Dr. Keating said.

"It turns out that these therapies are in fact targeted," he said; specific targets for both ATRA and ATO have been found in APL cells.

 
It is a shift in the way we think of treating potentially fatal diseases. Dr. Armand Keating
 

"This is an exciting development, because it is a shift in the way we think of treating potentially fatal diseases," he added.

On the same theme — using less therapy to achieve similar outcomes — is a study of childhood acute lymphoblastic leukemia (ALL). It shows that the cardiotoxic anthracycline daunorubicin can be omitted from induction chemotherapy (abstract 135).

"ALL was the first malignancy where we really made a major impact," Dr. Keating said, noting that with chemotherapy, cure rates are now estimated to be 85% to 90% and above.

However, the standard induction chemotherapy regimen includes daunorubicin, which can cause cardiomyopathy. This can lead to the "tragic situation where the patient is cured of a very serious malignancy, but then develops an equally serious complication as a result of that treatment," he explained.

"We are talking about a minority of patients, but nonetheless, the complication is devastating.... Some of those patients eventually succumb to heart failure, and may even become candidates for a heart transplant," he added.

In this study, patients were randomized to receive induction chemotherapy with or without daunorubicin. The outcomes were similar in the 2 groups.

This prospective randomized trial is a "very important study," said Dr. Keating. Although further down the line, these patients will require more chemotherapy that will include another anthracycline, this study shows that it can be omitted upfront for induction therapy, he said. It will be important to document the expected reduction in heart complications in the children treated with induction therapy without daunorubicin, he explained.

This study fits well with the idea that "less is probably okay," and suggests that "less may be better, we think, because it is going to avoid some of the longer-term adverse effects," noted Dr. Abrams.

Both APL and ALL represent real success stories. Both were very deadly diseases, and "the idea that we can now cure them is a triumph," Dr. Abrams said.

 
What we are learning now is that we probably swung a little too far. Dr. Charles Abrams
 

"What we are learning now is that we probably swung a little too far," he noted. Faced with such deadly diseases, the treatment devised was very aggressive; it now appears that it might be more toxic than it needs to be. "The way of the future, as we are doing so much better with these diseases, is to see how much less we can give.... I find that very exciting," Dr. Abrams noted.

Dr. Keating agrees. "Maybe we were a bit awed by the seriousness of some of these diseases, so we went in very aggressively. We were successful, but I agree maybe now its time to re-evaluate and recalibrate."

Innovative Solutions for "Hard-to-Heal" Patients

Another theme at the meeting will be innovative solutions for "hard-to-heal" patients — those who do not respond to conventional therapeutic approaches, so are "particularly challenging" to manage, Dr. Keating said.

One example of this occurs in chronic myeloid leukemia (CML), where the novel agent ponatinib now offers hope for patients who have a variant of the disease that is resistant to all currently available agents (abstract 163).

CML is an amazing success story. "It's not that long ago that chronic myeloid leukemia was basically a death sentence," Dr. Abrams said. However, it has been transformed by a molecular understanding that led to targeted therapy. The first of these was imatinib (Gleevec), but in recent years, several other tyrosine kinase inhibitors have become available: dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif). These drugs have transformed the lives of many patients with CML, he added.

"Although we have turned a disease that was a death sentence into a disease that is pretty treatable for most patients, not everyone is so lucky," Dr. Abrams said.

In particular, patients with CML who carry the T3151 mutation are resistant to tyrosine kinase inhibitors. In the past, "these patients would eventually develop a blast crisis and then die," Dr. Keating said, but ponatinib offers hope of a rescue medication for these patients.

"This another major advance," Dr. Abrams noted.

Clinical results from a phase 2 trial of 449 patients treated with ponatinib will be presented at the meeting. They show that the agent works in patients who are resistant to or who cannot tolerate other therapies. This is a follow-on of a recently published phase 1 clinical trial with ponatinib (N Engl J Med. 2012;367:2075-2088), which was reported by Medscape Medical News.

Another study offers hope for hard-to-treat patients with acute myeloid leukemia (AML). It shows successful treatment with the novel agent quizartinib (abstract 673).

AML is one of the more common types of acute leukemia that affects adults, Dr. Abrams explained, and about one third of AML patients have a mutation in the FLT3 gene. This mutation is associated with early relapse after chemotherapy and poor survival.

Over the years, various drugs have been used in this patient population, with limited success, although none of the drugs tried could be used on their own, Dr. Abrams noted. This new study suggests that quizartinib can be used alone, and that it is effective in patients who are resistant to other therapies.

"This is very exciting," he said. It raises the possibility that "we can use quizartinib as a safe option to get patients under control, and then do something more definitive, such as a transplant.... Again, it gives hope to patients who had little hope before," he noted.

Patients with this FLT3 mutation present a "major management problem," Dr. Keating added. "You can put them in remission, but then they relapse.... The disease progresses so quickly that they don't get a chance for transplant or cure," he said. "This study...shows that quizartinib can stabilize these patients for long enough to do a transplant."

Another new compound offers hope for hard-to-manage patients with chronic lymphocytic leukemia (CLL). Ibrutinib is a targeted compound that acts as an inhibitor of Bruton's tyrosine kinases.

Ibrutinib appears to be highly selective for transformed B cells, "so the results are really quite gratifying," Dr. Keating said. It also appears to have low toxicity. Toxicity is a problem in the treatment of CLL, where the standard therapy is a combination of fludarabine, cyclophosphamide, and rituximab. This improves outcomes, but is reasonably toxic for older patients, and it is mainly older patients who develop CLL. "There is a pretty large cohort of patients for whom it is really a challenge to provide effective treatment," he said.

Preliminary results with ibrutinib generated excitement among researchers when they were reported earlier this year.

New data will be presented on the use of ibrutinib in CLL alone (abstract 189) and in combination with rituximab (abstract 187), which could offer an alternative to the standard chemotherapy combination of fludarabine, cyclophosphamide, and rituximab, Dr. Keating explained.

Two other new drugs that the experts highlighted during the briefing are novel approaches to the treatment of multiple myeloma — MLN9708 (abstract 332) and pomalidomide, which will be discussed in a late-breaking abstract.

Dr. Keating has served on the data safety monitoring board for Clavis, Novartis, and Pfizer. Dr. Abrams has disclosed no relevant financial relationships.

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