Zosia Chustecka

December 01, 2009

December 1, 2009 — This year's American Society of Hematology (ASH) 51st Annual Meeting, being held in New Orleans, Louisiana, looks like it will be even bigger than the 50th anniversary meeting last year; registrations are already at an all time high. To whet the appetite of our readers, Medscape Oncology asked the cochairs of the scientific program to highlight presentations that they feel are particularly noteworthy or potentially practice-changing.

Dr. Richard Van Etten

Richard Van Etten, MD, PhD, chief of hematology/oncology and director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts, highlighted hot topics within the hematological malignancies field, and Joel Anne Chasis, MD, associate professor of hematology/oncology at the University of California, San Francisco and a staff scientist at the Lawrence Berkeley National Laboratory, discussed hot topics related to nonmalignant hematology.

Progress in Lymphoma

In the lymphoma field, new data on bendamustine will attract a lot of attention, Dr. Van Etten predicted. Results from a phase 3 study (abstract 405) show that when bendamustine was used with rituximab in the first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas, it "beat the standard in the field," he said, which is rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin] and prednisolone).

Bendamustine is an old drug that was used more than 30 years ago in Germany, but it got a new lease on life last year when it was approved (as Treanda, Cephalon) by the US Food and Drug Administration for first-line use in chronic lymphocytic leukemia (CLL), Dr. Van Etten explained in an interview. The new study used first-line bendamustine in B-cell non-Hodgkin's lymphoma, and the results showed improved progression-free survival and tolerability. These new data for bendamustine are potentially practice-changing, he said.

A new standard of care in early-stage Hodgkin's lymphoma has been established by the final analysis of the German Hodgkin Study Group, say the researchers (abstract 716). The best results were seen with a combination of chemotherapy with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) followed by 20 Gy involved-field radiotherapy. There has been an ongoing debate about whether using chemotherapy or radiotherapy, or both, is the best approach, Dr. Van Etten explained. These new results show that a combination of the 2 is the best option in patients with early-phase disease with a favorable prognosis, and "it looks as if it will become a standard," he told Medscape Oncology.

There will be several important updates to immunotherapy for lymphoma with monoclonal antibodies presented at the meeting. The standard therapy in the field is the anti-CD20 monoclonal rituximab (Rituxan, Genentech/Roche). A new agent that works in a similar manner, also an anti-CD20 monoclonal antibody, is ofatumumab (GlaxoSmithKline). This drug has just been approved for use in relapsed or refractory CLL, and is now being investigated in a more up-front setting, Dr. Van Etten explained. Phase 2 data from a trial in previously untreated CLL patients show that ofatumumab given in combination with fludarabine and cyclophosphamide is "highly active" (abstract 207).

Another agent, GA101 (also know as RO5072759), from the same manufacturer, Genentech, is being billed as "son of rituximab." It is being investigated in relapsed/refractory CLL (abstract 884). "These are early days," Dr. Van Etten said, "but it will be interesting to follow this one."

New Treatment Approaches in Myeloma

A new approach to initial therapy for myeloma in elderly patients comes from an Italian study in which researchers used a 4-drug combination of bortezomib (Velcade, Millennium Pharmaceuticals), melphalan, prednisone, and thalidomide (VMPT). Up to now, the most recent standard for initial therapy has been the 3-drug regimen of bortezomib, melphalan, and prednisone (VMP). This is the first report to show superiority with a 4-drug combination, say the researchers (abstract 128). Dr. Van Etten pointed out that this is unique to elderly patients with myeloma; "you would tend not to give melphalan to a younger patient because it might compromise your ability to harvest stem cells." But in elderly patients with myeloma, these new data will lead to a change in initial therapy, he predicted.

An interesting new product on the horizon is pomalidomide, the newest immunomodulatory agent to have shown activity in multiple myeloma. Data from a small trial show that it is active and well tolerated in multiple myeloma patients who are refractory to lenalidomide (abstract 429).

Developments in Leukemia

Two conclusions from a trial in childhood acute lymphoblastic leukemia (abstract 321) are potentially practice-changing, Dr. Van Etten noted. Individualizing the dose of asparaginase on the basis of pharmacokinetic measurements produced superior results to those seen with a fixed-dose regimen, and "everybody should now start doing this," he said. The same trial also showed superior results with dexamethasone, compared with prednisone, when added to asparaginase.

In the treatment of acute myeloid leukemia (AML), several new compounds with activity against FLT3 mutations are piquing the interest of researchers. These FLT3 mutations occur in about a third of patients with AML, are associated with a poor prognosis, and represent a new therapeutic target, Dr. Van Etten explained. "We haven't had a new target in AML for 30 years, so there are a lot of eyes on this," he added.

One of these products is lestaurtinib (under development by Cephalon), a multitargeted kinase inhibitor with potent activity against FLT3, which was tested as a salvage treatment for patients with FLT3-mutant AML in first relapse (abstract 788). The results are negative, but Dr. Van Etten said they beg the question: "Is it the therapeutic approach that has failed, or is it rather this particular drug at this dose?"

A similar product is midostaurin (under development by Novartis), which is currently in a large phase 3 clinical trial. Results from a preliminary phase 2b study with follow-up of more than 1000 days suggest that this product, together with chemotherapy, "might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3-mutant AML patients in first complete remission," say the researchers (abstract 634).

Further back in development is AC220 (under development by Ambit Biosciences), which is described as a second-generation FLT3 receptor tyrosine kinase inhibitor. It might be more potent and specific; the data to be presented are the first results in humans (abstract 636).

In chronic myeloid leukemia (CML), the introduction of imatinib (Gleevec, Novartis) has revolutionized treatment, but "we are now realizing that it is probably not curing most patients," Dr. Van Etten noted.

New data from the Stop Imatinib (STIM) study show that when CML patients who had achieved a molecular response on imatinib stopped taking the drug, nearly 60% relapsed. The relapse came quickly — within 6 months, Dr. Van Etten said, although the remainder of patients remained in remission (abstract 859).

Long-term data on imatinib from the IRIS trial now go out to 8 years, and show that 45% of patients are no longer taking the drug, for a variety of reasons, including adverse effects, unsatisfactory therapeutic outcome (which can include developing resistance to the drug), changing to another drug, and death (abstract 1126).

As a result, there is a lot of interest in the follow-on compounds — nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb), Dr. Van Etten explained. Both of these are currently approved for use in second-line therapy for CML in patients who have been treated with other therapies, including imatinib, but both drugs are now being investigated in the first-line treatment of CML.

New data for first-line nilotinib treatment come from the ENESTnd trial (abstract LBA-1). This trial showed that a complete cytogenic response at 1 year was achieved by 78% patients receiving nilotinib and by 65% receiving imatinib, and that the rate of progression to the accelerated phase or blast crisis was significantly lower with nilotinib (<1% for nilotinib vs 4% for imatinib). These data will be used to argue that nilotinib is a better choice for first-line CML therapy, which would be "paradigm-shifting," Dr. Van Etten said, pointing out that "the devil is always in the details." For instance, the 4% rate of progression seen with imatinib in this trial is quite different from the 1.5% that was reported with the drug in the IRIS trial.

Another approach in the treatment of CML is the addition of interferon therapy to imatinib, Dr. Van Etten noted. Interferon was the treatment of choice before imatinib arrived, and there is interest in combing the 2 products. However, the data on this so far are conflicting, and updates from 2 ongoing studies are showing opposite results. A French group has reported achieving a higher rate of complete molecular response in patients who received both interferon and imatinib as initial treatment (abstract 340), but a German study did not see this (abstract 862). "This raises the question of whether this is a real effect or not," Dr. Van Etten noted. He mentioned that there is a difference in the type of interferon product — the French group used pegylated interferon alpha-2a (Pegasys) but the German group did not — which could have affected both disease response and patient compliance.

New Anticoagulant Might Replace Older Products

Data on a new anticoagulant have the potential to be practice-changing, Dr. Chasis said in an interview; they suggest that dabigatran (Pradaxa, Boehringer Ingelheim) could offer a replacement for older products.

Selected for presentation at the plenary session is a large trial that shows that, in the treatment of acute venous thromboembolism, fixed-dose dabigatran is similar in efficacy and safety, including bleeding, to the older product, warfarin (abstract 1). "This suggests that dabigatran could offer a potential replacement for warfarin, which would be welcome news for both patients and physicians," Dr. Chasis said, because warfarin requires regular monitoring, but dabigatran does not. "It would ease the burden on the physicians," she added.

Improvements in Transfusions?

A practical clinical message comes from the FOCUS trial (abstract LBA-6), which investigated the use of blood transfusions in cardiovascular patients who had undergone hip-fracture repair. "These cardiovascular patients are particularly vulnerable to anemia, so they are given blood transfusions, with the trigger being a set hemoglobin level," Dr. Chasis explained. She added, however, that this indication for transfusion has been controversial. "In a surprise to us all, the results from the new trial show that there are no adverse effects to waiting until a patient becomes symptomatic before transfusing," she told Medscape Oncology.

Also concerning blood transfusions is translational research that could eventually lead to a reduction of transfusion-related acute lung injury (TRALI), which is the single most important cause of transfusion-related mortality. TRALI is known to be caused by HNA-3a-specific antibodies, and about 4% to 5% of the general population is at risk because they are HNA-3a-negative. The new research comes from a genome-wide survey that found a single-nucleotide polymorphism, which correlates with the HNS-3a-negative phenotype (abstract LBA-4). The hope is that this research will eventually lead to strategies to screen individuals for the HNA-3a-negative phenotype and to screen donated blood for the presence of HNA-3a-specific antibodies, which are capable of causing TRALI, Dr. Chasis explained.

Progress in Platelet Disorders

Treatment of chronic immune thrombocytopenia has been improved with the recent introduction of 2 agents, romiplostim (Nplate, Amgen) and eltrombopag (Revolade, GlaxoSmithKline). Long-term data for these agents going out to 5 years for romiplostim (abstract 681) and out to 2 years for eltrombopag (abstract 682) will be presented. "These longer-term data have not shown any new safety issues, which is reassuring," Dr. Chasis said. In addition, data from a year-long study with a 6-month extension follow-up show that romiplostim significantly reduces the incidence of splenectomy and treatment failure, compared with the standard of care (abstract 679).

Essential thrombocythemia gets a boost with a new mouse model of the disease (abstract 226). "These patients are at an increased risk of thrombosis because they have dysfunctional platelets," Dr. Chasis explained. "This research may help us to understand why the platelets are dysfunctional," she continued, and unraveling the mechanism involved might lead, in the future, to new therapeutic approaches to this disease.

Dr. Van Etten and Dr. Chasis have disclosed no relevant financial relationships.


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