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The best of 2009: Progress made in rare diseases
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Each December, Joe Bertino and I canvass the members of the HemOnc Today Editorial Board for their suggestions as to the most important developments in the fields of hematology and oncology. The following is my distillation of that canvass along with some personal comments. In the hematology arena, four hemostasis articles and two describing advances in the lymphatic leukemias — both acute and chronic — have been chosen.
At the 50th Annual Meeting of ASH last December, an Italian, multi-institution study compared rituximab (Rituxan, Genentech) plus dexamethasone with “traditional” dexamethasone alone in previously untreated idiopathic thrombocytopenic purpura patients. Their plenary session report demonstrated a more than twofold excellent and sustained response to the combination regimen. Kenneth Kaushansky, MD, last year’s ASH president, commented in HemOnc Today that this “represents an important advance and is likely to change the way we treat patients with ITP.” Moreover, Koneti Rao, MD, a HemOnc Today Editorial Board member, reminded us that the use of this combination plus new thrombopoiesis-stimulating agents will likely be examined in upcoming clinical trials in this disorder. I look forward to that.
In a paper published in The New England Journal of Medicine, Viel and colleagues provided insights into a previously unexplained clinical dilemma in hemophilia. It has been a longstanding observation that black patients with hemophilia are more likely to produce Factor VIII inhibitors and, thus, become harder to treat for than whites. Katherine High, MD, another
HemOnc Today Editorial Board member, provided the needed perspective to understand the Viel results. At least six different haplotypes have been found through genomic studies of hemophiliac Factor VIII genes.
Approximately 25% of blacks have mutations that are different than whites, presumably rendering them more likely to produce antibodies to currently marketed replacement products. High suggested that inhibitor generation might be reduced in the future by matching the haplotype of a recipient with that of the infused product. If so, an enormous cost-saving will be attained in this already very expensive disease.
FDA activity
Based mainly on studies also presented at the last ASH annual meeting, the FDA Cardiovascular and Renal Drugs Advisory Committee voted earlier in the year to recommend the approval of the oral Factor Xa inhibitor rivaroxaban as a deep vein thrombosis prophylactic in patients undergoing knee or hip replacement surgery. The results from four major clinical trials (RECORD) that included nearly 13,000 patients demonstrated a better than 50% improved outcome (assessing DVT, pulmonary embolism, and all-cause mortality) with the oral drug compared with enoxaparin given perioperatively and postoperatively for 12 to 35 days.
A slight increase in the risk of major bleeding (0.4% vs. 0.2%) was not statistically significant and evidently did not dissuade the FDA committee, who did, however, indicate that a slight suggestion of liver toxicity warranted continued vigilance. Kenneth Bauer, MD, a HemOnc Today Editorial Board member, called the FDA decision “a milestone for antithrombotic therapy.” Both he and Stephan Moll, MD, provided perspectives that predicted that rivaroxaban or other oral Factor Xa inhibitors — as well as oral direct thrombin inhibitors — in the pipeline will likely replace vitamin K antagonists in common chronic conditions such as atrial fibrillation and recurrent thromboembolism. Ongoing trials to validate these predictions are eagerly awaited by all of us.
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Another FDA announcement merits attention. Earlier this year, the FDA approved the platelet-inhibitor prasugrel (Effient, Eli Lilly) for prevention of thrombotic cardiovascular events attending percutaneous coronary interventions.
In TRITON-TIMI trials that followed more than 13,000 patients, prasugrel plus aspirin was approximately 20% more efficacious than clopridogrel plus aspirin in preventing cardiovascular death, non-fatal MI and stent thrombosis. Bleeding risk with prasugrel was slightly higher (2.2% vs. 1.7%), as were new strokes (in patients with prior CVAs), especially in patients older than 75. Thus, the drug is not recommended for the elderly. In our July article relaying this approval, I reminded readers of recent studies demonstrating that ubiquitously prescribed proton pump inhibitors interfere with clopidogrel’s metabolism to an active platelet inhibitor. Therefore, it seems likely that prasugrel (whose activity is unaffected by any known medications) will likely supplant clopridogrel, at least in cardiology practice.
Leukemia treatment
We have reviewed two items related to lymphatic leukemia treatment. Results of three studies published in October indicate significant advances in ALL treatment. First, the Children’s Oncology Group concluded that imatinib (Gleevec, Novartis) plus intensive chemotherapy dramatically improved three-year event-free survival without increasing toxicity for patients with Philadelphia chromosome-positive ALL. Next, James Nachman, MD, and colleagues reported that young adult ALL patients who manifest a rapid response to induction chemotherapy benefit so well from intensive post-induction therapy that allogeneic stem cell transplantation in first remission, a previous “traditional” (and risky) modality, may no longer be necessary.
Finally, Italian investigators studied 633 ALL patients in 39 centers using flow cytometry to measure minimal residual disease at day 15 of induction therapy. Separation of patients into “standard-,” “intermediate-” and “high-risk” categories (less than 0.1%, 0.1%-10%, and more 10% blast cells, respectively) provided major prognostic guidelines. Five-year relapse rates were 7.5%, 17.5%, and 47.2%, respectively. These results were virtually identical to those that used parallel assays performed with far more-expensive polymerase chain reaction. The researchers noted that flow cytometry is available even in developing countries and believe their results will “usher in a new era of more effective and less toxic therapy” for ALL patients.
Just a month ago, the FDA approved a new CD-20 targeting antibody, ofatumumab (Arzerra, GlaxoSmithKline; analogous to rituximab), for the treatment of CLL refractory to fludarabine and alemtuzimab. The overall response rate was 58% in patients doubly refractory to both fludarabine and alemtuzimab. In responding patients, B symptoms and thrombocytopenia disappeared for several months.
Because the drug underwent an accelerated approval process, clinical trials are ongoing to confirm, or not, if the addition of the drug to standard chemotherapy delays progression of the disease. Morton Coleman, MD, a HemOnc Today Editorial Board member, questions whether ofatumumab offers any true clinical advantage over rituximab. I suppose a head-to-head comparison of the two will be forthcoming (yawn).
Although not truly a hematology issue, I commend another FDA approval reported last month — that of the HPV vaccine for boys.
Peculiarly, the approval is for the prevention of genital warts! The fact that, until now, pre-adolescent boys have not been sanctioned for vaccination to prevent cervical cancer in their future sexual partners is a travesty. So, the FDA finally got it right, but for the wrong reasons — a gift horse whose mouth will not be further examined.