Hematology highlights:
Making the Philadelphia chromosome disappear

The Philadelphia (Ph) chromosome, which occurs in 95% of cases of chronic myeloid leukemia and sometimes other types of leukemias as well, was discovered in 1960 in Philadelphia, the site of the 2002 American Society of Hematology (ASH) meeting.

The ABL-BCR Ph chromosome consists of a translocation between the long arms of chromosomes 22 and 9, in which the ABL proto-oncogene is transported to the BCR, or breakpoint cluster, on 22q. It has long been the goal of oncologists and others to make the Ph chromosome disappear. And, coming full circle here in Philadelphia decades later, reports indicated that the Ph chromosome can indeed be made to disappear, with what looks like the best treatment yet for this disease, both early on and for the longer term.

The disappearing trick is being performed by the use of imatinib mesylate (Gleevec, Novartis), according to Richard Larson, M.D., of the University of Chicago. He reported on an 18-month follow-up of the 1,106 patients in the IRIS trial. It showed that chronic-phase patients randomized to imatinib 400 mg per day rather than to the standard interferon-alpha and cytosine arabinoside (IFN/Ara-C) showed "a significantly higher response rate and a longer time before the disease progressed."

The target dose for IFN was 5 MU/m²/d and for AraC was 20 mg/m² given for 10 days out of each month.

The hematologic complete response rate was estimated at 97% for imatinib versus 69% for IFN-AraC; the major cytogenetic response rate (defined as no more than 35% Ph+ cells remaining) at 87% versus 45%, respectively, while the complete cytogenetic response (no cells with detectable Ph+ cells) at 76% versus 14%, respectively.

There were also reports at ASH on the drug treatment of many other blood disorders, including new ways to prevent and treat deep vein thrombosis and life-threatening pulmonary embolism, new ways to treat leukemia in adults, as well as multiple myeloma–both of which have a very poor prognosis–and a new type of oral chelation therapy for transfusion overload.

Deep vein thrombosis

Two randomized phase III trials of the investigational oral anticoagulant ximelagatran (Exanta, AstraZeneca) showed high efficacy. Ximelagatran is the first oral direct thrombin inhibitor under phase III investigation and the first oral anticoagulant to reach phase III in more than 50 years.

According to lead investigator Charles Francis, M.D., professor of medicine and pathology and laboratory medicine at the University of Rochester School of Medicine and Dentistry, about two-thirds of patients undergoing total knee replacement would develop deep vein thrombosis without prophylaxis. And, at the moment, warfarin is the only anticoagulant approved for this purpose.

The first trial reported at ASH, called EXULT A (Exanta Used to Lessen Thrombosis), was a multicenter, randomized, double-blind trial that included 2,301 patients undergoing knee replacement surgery at 116 trial sites in five countries. It showed a 26% reduction in the risk of blood clots at a fixed 36-mg b.i.d. after total knee replacement compared with standard warfarin therapy.

Patients were given a fixed dose of either 24 mg or 36 mg b.i.d. at a target INR of 2.5, which was initiated the evening of the day of surgery and continued for seven to 12 days.

The second trial, THRIVE III (Oral Direct Thrombin inhibitor ximelagatran for Venous Thromboembolism), a multicenter trial with 1,233 patients, was to evaluate the efficacy, safety, and tolerability of continuing the drug for an additional 18 months at a 24-mg fixed dose, to prevent recurrence of clotting. This study resulted in about an 84% relative risk reduction in venous thromboembolism compared with placebo in patients who previously had blood clots.

In another study in 772 cancer patients presenting with acute venous thrombosis, the cumulative recurrence rate was reduced from 17.4% in the group receiving standard warfarin therapy to 8.8% in the group receiving the low molecular weight heparin Fragmin (dalteparin, Pharmacia).

Mark Levine, M.D., professor of clinical epidemiology and statistics at McMaster University, commented that "treatment with Fragmin may also simplify the patient management process. Oral anticoagulant therapy can often be difficult to manage in cancer patients because it requires frequent blood testing to maintain the appropriate therapeutic levels of those drugs."

Treatment of difficult adult cancers

Adults with multiple myeloma and acute myeloid leukemia generally have a poor prognosis, but some new approaches may improve their chances of living longer.

Paul Richardson, M.D., and Kenneth Anderson, M.D., of the Dana-Farber Cancer Institute in Boston, are finding promising results so far in a phase II study with an analog of thalidomide (CC-5013, Celgene), which has fewer side effects while being more potent than the parent drug.

Also at Dana-Farber, Daniel DeAngelo, M.D., Ph.D., and other investigators have found that acute myeloid leukemia in adults can be treated with a combination therapy, which has produced the highest remission rate yet. The combination treatment involves adding gemtuzumab ozogamicin for injection (Mylotarg, Wyeth) to the standard agents cytarabine and daunorubicin.

In this phase II study, 15 of 18 patients achieved remissions.

In patients with indolent non-Hodgkin's lymphoma, the use of extended MabThera/rituximab (Rituxan, Genentech, IDEC), given eight times over a nine-month period, reduced the risk of disease progression or relapse by 55% in responding patients and nearly doubled survival when used as front-line therapy.

In this study, 185 of 202 patients were available for evaluation, 57 of whom had received no prior therapy. All patients received an induction course of Rituxan 375 mg/m² weekly for four weeks, resulting in a 67% response rate for the 57 patients who were chemotherapy-naïve.

At week 12, 151 of the 185, or 80%, had either complete or partial responses or stable disease. These patients were then randomized to receive either extended Rituxan therapy (73) or not (78). Treated patients received 375 mg/m² at months three, five, seven, and nine, or were observed and did not receive further treatment.

After a median of 35 months follow-up, event-free survival was a median of 23 months in patients receiving extended Rituxan therapy, compared with 12 months for the nontreated group. Also, adverse events were not clinically significant with the Rituxan therapy.

Larger phase III trials are now under way of extended Rituxan therapy by the U.S. Cooperative Cancer Study Groups.

New oral iron chelator shows promise

For patients who have to undergo multiple transfusions, resulting in iron overload, a new kind of iron chelation drug, the bis-hydroxyphenyl-triazole ICL670, which can be taken by mouth, was found by Italian investigators to be as effective in 71 anemic patients with transfusional iron overload as deferoxamine (Desferal vials, Novartis), which requires hours of daily transfusions.

Lead investigator Antonio Piga, M.D., of Turin University, said, "We desperately need potent oral alternatives to deferoxamine. The early studies of ICL670, though preliminary, look very promising."

Drug may prevent transplant complications

A three-drug regimen, which includes sirolimus (Rapamune, Wyeth) along with methotrexate and tacrolimus (Prograf, Fujisawa), produces a better outcome in patients receiving stem cell transplants for diseases such as leukemia and lymphoma, according to Joseph Antin, M.D., of Dana-Farber. He said only 13% of patients in a study of 41 patients on this regimen developed severe graft-versus-host disease, against an expected 30% in stem cell transplants from unrelated donors. "These are very exciting early data," he said.

Jean McCann

The author is a writer based in Ohio.