Month: January 2013

Quizartinib: Surprising, Unprecedented Activity in Relapsed AML

January 29, 2013 Chemotherapy, Drug Informatics, Hematology, Pharmacotherapy, Therapeutics No comments , , , ,

ATLANTA, Georgia — The investigational agent quizartinib (Astellas/Ambit) has shown unprecedented activity in patients with relapsed and refractory acute myeloid leukemia (AML) in a phase 2 clinical trial.

On the basis of these results, larger phase 3 clinical trials with the drug are being planned, according to Astellas/Ambit.

Patients with AML can develop many different genetic mutations, but one of the most threatening is FLT3 internal tandem duplications (ITD), which makes the leukemia even more aggressive and typically leads to resistance to standard chemotherapy. This mutation develops in 34% of AML patients and is associated with more rapid relapse and reduced overall survival, explained lead author Mark Levis, MD, PhD, associate professor of oncology, pharmacology, and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland.

“Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy,” he said. “It caught us by surprise how well it worked.”

Dr. Levis presented results from a large phase 2 study of patients with relapsed or refractory AML here at the American Society of Hematology (ASH) 54th Annual Meeting. Many patients achieved a complete response to quizartinib, and one third were stabilized with quizartinib for long enough to undergo potentially life-saving hematopoietic stem cell transplantation (HSCT).

“The number of patients bridged to a transplant was very significant,” Dr. Levis said in a statement. “We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible for patients who previously had no hope for a cure,” he added.

“I am desperate to get this drug in the clinic…. I treat mainly a refractory patient population, and this is the drug that I want to use in them,” he explained.

Patients with a FLT3 mutation present a “major management problem,” said ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada. “You can put them in remission, but then they relapse…and the disease progresses so quickly that they don’t get a chance for transplant and for cure,” he said.

“This study is important because it shows that quizartinib can stabilize these patients for long enough to do a transplant. It shows that this is possible in about a third of patients,” Dr. Keating reported. It is another example of a new drug offering fresh hope for a hard-to-heal patient population, he said at a premeeting press briefing.

Mutation Is Like a Power Switch

“The FTL3 mutation is essentially a power switch that leukemia cells use to spread more aggressively and helps them to grow back immediately after chemotherapy,” Dr. Levis explained. “The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long.”

Quizartinib appears to do just that. It was designed to “turn off” the mutated FLT3 enzyme, which forces the immature cancer cells to die immediately or to undergo maturation and then die. This eliminates enough cancer cells to stabilize the patient for long enough to offer them another treatment, including transplantation.

The phase 2 study of quizartinib was conducted in AML patients who had relapsed, did not respond to second-line therapy, or had relapsed after HSCT. The patients were divided into 2 groups: 133 were older than 60 years, and 137 were 18 to 60 years.

Dr. Levis presented data from the younger cohort. Of the 137 patients, 99 had the FLT3 mutation and 38 did not.

Oral quizartinib was used alone at a starting dose of 135 mg/day for men and 90 mg/day for women, and was given continuously in 28-day cycles. The difference in the dose between the sexes relates to an adverse cardiac effect of the drug; quizartinib can cause a prolongation of the QT interval on electrocardiogram, and women are more sensitive to this effect than men, Dr. Levis explained.

The drug elicited responses in patients with and without the mutation, but the responses were better in those with the mutation. The primary end point was a composite complete remission rate (CR), which included complete remission with no active disease, complete remission with incomplete platelet recovery (so no active disease but an incomplete platelet count), and complete remission with incomplete hematologic recovery (no active disease but abnormal red and white blood cells counts).

For the 99 patients who had the FLT3 mutation, the composite CR was 44% (4% with CR, 0% with incomplete platelet recovery, and 40% with incomplete hematologic recovery). The median duration of response was 11.3 weeks and median overall survival was 23.1 weeks.

For the 38 patients without the mutation, the composite CR was 34% (3% with CR, 3% with incomplete platelet recovery, and 29% with incomplete hematologic recovery). The median duration of response was 5.0 weeks and median overall survival 25.6 weeks.

Of the 137 patients 18 to 60 years of age, 47 (34%) underwent HSCT after responding to quizartinib. Some of these patients have survived more than 2 years without any disease recurrence, Dr. Levis said.

Adverse events included nausea (reported by 38% of patients), anemia (29%), QT prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). Adverse events led to discontinuation of treatment in 10% of patients.

Quizartinib was “extremely well tolerated,” Dr. Levis noted. The main adverse events are the QT prolongation and myelosuppression, but these are “manageable,” he said.
“We are still playing around with the dose,” he explained. A future trial will look at using lower doses of the drug, and a randomized trial of 30 mg vs 60 mg is planned.

The findings from this phase 2 trial of quizartinib in patients with relapsed and refractory AML are “especially encouraging,” said Jorge Cortes, MD, deputy chair in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, in a statement. “In the patients with the FLT3-ITD mutation, quizartinib represents the most active single agent we have observed with any class of investigational drugs in this challenging patient population,” he added.

The study was funded by Astellas/Ambit, the developers of quizartinib. Dr. Levis reports consultancy for Ambit Biosciences. Several of his coauthors are company employees. Dr. Keating reports serving on the data safety monitoring board for Clavis, Novartis, and Pfizer.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 673. Presented December 10, 2012.

The Management of Waldenstrom Macroglobulinemia

January 7, 2013 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics 1 comment ,

Definition

Waldenstrom macroglobulinemia (WM) is a distinct B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells, which secrete a monoclonal IgM protein. The paramters predicting prognosis of WM are list below:

Table 1 International Prognostic Scoring System for WM.

Factor associated with WM prognosisValue
Age, yr>65
Hemoglobin, g/dL≤11.5
Platelet count, No./mcL≤100,000
β2-Microglobulin, mg/L>3
Monoclonal IgM, g/dL>7

Risk stratum and survival

Risk categoryScoreMedian survival, mon
Low0 or 1 (except age)142.5
Intermediate2 or age >65 yr98.6
High>243.5

What can WM result in?

  1. Hyperviscosity syndrome. The symptoms of hyperviscosity are due primarily to shear forces that rupture unsupported venous channels. The presentation generally includes epistaxis, gingival bleeding, and visual changes due to retinal hemorrhages.
  2. Peripheral neuropathy. Autoantibody activity to myelin-associated glycoprotein, ganglioside M1, sulfatide moieties on peripheral nerve sheaths can result in peripheral neuropathy.
  3. Hemolytic anemia. Cold or warm antibodies in WM patients can result in autoimmune hemolytic anemia.
  4. Immune complex vasculitis.

Management of WM

The identification of the asymptomatic patient is important because this group of patients do not need therapy. What this group need is closely observation. For patients with symptoms of WM, therapy should be initiated. Frontline treatment options for WM include oral alkylators, nucleoside analogs, rituximab, or the combinations of these three. Other durgs to be considered includes bortezomib and thalidomide. The goal is to reduce the paraprotein level. (more…)

A Whole New Pharmacy Profession Forum

January 3, 2013 Pharmacy Education, Social Network 2 comments

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