Do Blood Cancers Need Prophylactic Platelet Transfusions?

Nick Mulcahy

May 08, 2013

Prophylactic platelet transfusions reduced rates of clinically significant bleeding events in patients with hematologic cancers, according to the results of a major new study.

The proportion of patients who had bleeding events of World Health Organization (WHO) grade 2, 3, or 4 was reduced by 7% in the group that received prophylactic platelet transfusions, compared with the group that didn't, report Simon Stanworth, MD, from the Oxford University Hospitals NHS Trust in the United Kingdom, and colleagues.

Results from the Trial of Prophylactic Platelets (TOPPS) appear in the May 9 issue of the New England Journal of Medicine.

TOPPS reinforces prophylaxis as the standard of care for adults who are either receiving chemotherapy or undergoing stem-cell transplantation and, consequently, are expected to have thrombocytopenia, Sherrill Slichter, MD, from the University of Washington in Seattle, writes in an accompanying editorial.

Thrombocytopenia requires platelet transfusions to stave off potentially dangerous internal bleeding, including cranial bleeding.

Dr. Slichter notes that the results have considerable clinical relevance because other research has "clearly shown" that the threshold for prophylactic platelet transfusions could be reduced to 10,000/mm³ and that the standard transfusion dose could be reduced by half. As a result, there have been questions about the procedure: Are prophylactic platelet transfusions really necessary in these blood cancer patients? Can such patients be effectively supported with therapeutic transfusions once the bleeding begins?

The TOPPS results suggest that prophylaxis is needed.

Dr. Slichter believes that a "therapeutic-only" platelet-transfusion strategy is a not good idea. She argues that both this study and a 2012 study that examined this strategy (Lancet. 2012;380:1309-1316) were performed in "academic medical centers with highly trained staff who were assessing the patients daily for bleeding and using well-defined platelet-transfusion protocols." In short, there is too much to risk in other settings, which will, by definition, have less intense monitoring and less trained staff, she suggests.

TOPPS was undertaken because the effectiveness of platelet transfusions in preventing bleeding in these blood cancer patients has been "unclear," the study authors write.

There is more clarity now. "The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding," the authors write.

However, other experts are not convinced, and voiced concerns when the TOPPS results were presented at the annual meeting of the American Society of Hematology in December 2012.

"The results raise a lot of questions about whether prophylactic platelet transfusions are necessary, but don't answer the question of whether they prevent the rare adverse events of death or major bleeding, which are of most concern to clinicians and to patients," said David Kuter, MD, DPhil, director of the Center for Hematology, Massachusetts General Hospital, and professor of medicine at Harvard Medical School in Boston. As a result, he suggested that this trial will not change clinical practice.

"With half the no-prophylaxis group experiencing no significant bleeding, it is clear that we transfuse many patients unnecessarily," said another expert, Andrew Leavitt, MD, from the University of California, San Francisco. Yet this practice is increasing, he noted. "It is estimated that about two thirds of the platelet transfusions are for prophylactic use, while approximately one third are administered to treat bleeding."

Data from a US National Blood Collection and Utilization Survey Report show that there were just over 2 million platelet transfusions in the United States in 2008. At an estimated average total cost of $1000 per platelet transfusion, Dr. Leavitt calculated that "the healthcare system spent more than $1.3 billion on prophylactic platelet transfusions in 2008, yet we lack good evidence that prophylactic platelet transfusions provide clinical benefit."

Autologous Stem-cell Transplantation Patients: An Exception?

In TOPPS, 600 blood cancer patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) from 14 centers in the United Kingdom and Australia were enrolled from 2006 to 2011. The patients, who had acute myeloid leukemia, lymphoma, myeloma, or chronic myeloid leukemia, underwent randomization when morning platelet counts were less than 10 × 10^(9)/L.

Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients in the no-prophylaxis group and in 128 of 299 in the prophylaxis group (50% vs 43%; adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 - 15.2; P = .06 for noninferiority).

Despite the clear benefit of prophylaxis, it is troubling that a lot of bleeding still goes on in patients who get prophylaxis, the authors acknowledge.

Most of the bleeding was of grade 2 (moderate). There was more bleeding of grade 3 or 4, which is severe and can be life-threatening, in the no-prophylaxis group than in the prophylaxis group (2% vs 1%).

On average, there were also more days with bleeding in the no-prophylaxis group than in the prophylaxis group (1.7 vs 1.2; P for superiority = .004) and a shorter time to the first bleeding episode (19.5 vs 17.2 days; for superiority = .02).

As would be expected, platelet use was markedly reduced in the no-prophylaxis group.

A prespecified subgroup analysis identified similar rates of bleeding in the 2 study groups for patients undergoing autologous stem-cell transplantation. The TOPPS authors therefore left the door open for this subgroup, for whom prophylaxis might work acceptably.

For these patients, the rates of bleeding events of WHO grade 2, 3, or 4 were similar in the 2 groups (about 45%).

However, TOPPS was not powered to address whether the strategy of not giving prophylactic platelet transfusions in patients undergoing autologous stem-cell transplantation is effective and safe. "Such a strategy requires further research," the authors write.

The study was supported by grants from the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service. Some of the study authors report financial relationships with Celgene, Chugai Pharmaceutical, Therakos, and Roche, as detailed in the paper.

N Engl J Med. 2013; 368:1771-1780 and 1837-1838. Abstract, Editorial

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