Patients with leukemia, lymphoma, or myeloma who have undergone stem cell transplantation as well as those undergoing intensive induction and consolidation regimens often experience a large decline in platelet counts, leaving them vulnerable to severe bleeding. Current standard practice is to give such patients prophylactic platelet transfusions when their counts drop below 10,000/uL to protect against bleeding.
However, there has been ongoing debate as to the value of these prophylactic platelet transfusions, and the latest clinical trial examining this issue, presented here at a plenary session of the American Society of Hematology (ASH) 54th Annual Meeting, leaves that question unanswered.
The new results come from the TOPPS trial, presented by Simon Stanworth, MRCP, FRCPath, DPhil, from the John Radcliffe Hospital, Oxford University Hospital National Health Service Trust, United Kingdom. The study was conducted in a cohort of 600 patients with hematologic malignancies and severe thrombocytopenia. Patients were randomly assigned either to receive prophylactic platelet infusions or to not receive such prophylaxis.
The results show that both the strategies had similar outcomes.
"This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis," Dr. Stanworth concluded. There was no significant difference between the treatment groups in the period of thromocytopenia, number of days in hospital, or the number of serious adverse events experienced, he said.
Overall, bleeding classified as World Health Organization grades 2 to 4 was seen in 43% (128/298 patients) in the group receiving prophylaxis and in 50% (151/300 patients) in the no-prophylaxis group.
However, patients in the no-prophylaxis group had more days with bleeding (1.7 days vs 1.2 days; P = .004) and had a shorter time to bleeding, he noted.
Rates of bleeding were high, even in patients with prophylactic platelet infusions, and Dr. Stanworth suggested that other approaches to treatment, including the use of antifibrinolytic agents, should be explored.
There Was a Difference
Approached by Medscape Medical News for comments on this study, David Kuter, MD, DPhil, director of the Center for Hematology, Massachusetts General Hospital, and professor of medicine at Harvard Medical School, Boston, said that the study has not answered many questions, and he predicted that it will not change clinical practice.
Although the differences between the 2 strategies were not statistically significant, he emphasized that "there was a difference."
In particular, Dr. Kuter drew attention to the rate of severe bleeding (grades 3 and 4) — there was only 1 of these events among 298 patients (0.3%) receiving prophylactic platelet transfusions, compared with 6 events among 300 patients (2%) not receiving prophylaxis (P = .13).
That is a 6-fold difference in major bleeding events, and if the trial had been larger, then this difference would have been significant, he suggested, noting that a grade 3 bleed would necessitate red blood cell transfusions, whereas a grade 4 bleed could result in a major impairment, such as a stroke, or even death.
The study was underpowered to show a significant difference in these major bleeding events, he said.
"The results raise a lot of questions about whether prophylactic platelet transfusions are necessary but doesn'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," Dr. Kuter told Medscape Medical News.
Dr. Kuter noted that there are many other factors that can raise the risk of bleeding in these patients, including indwelling catheters, fever, and antibiotics, among others. The fall in platelet counts is not the only risk factor for bleeding. But platelet transfusions are relatively inexpensive, there is no shortage of platelets, and there are few complications, so giving prophylactic platelet transfusions is not a problem. "I won't be changing my practice," he said.
Subgroup of AML Patients Particularly Vulnerable?
In his presentation, Dr. Stanworth noted that the one of the grade 3 to 4 bleeding events involved intracranial bleeding (in a patient in the no-prophylaxis group), and that of the 7 patients who had severe bleeding, only 2 had platelet counts that had fallen below 10,000/uL at the onset of bleeding. Both of these patients were undergoing induction chemotherapy for acute myeloid leukemia (AML).
In the discussion period, an expert in the audience suggested that AML patients may be particularly susceptible to bleeding, because the disease and the intense chemotherapy they are receiving both can cause endothelial damage.
This would make the blood vessels more leaky and more prone to bleeding, Dr. Kuter explained. It may be possible to stratify patients for risk and to separate out those who receive transplants from patients with AML who are receiving induction chemotherapy, he said.
Indeed, Dr. Stanworth reported results from a predefined subgroup analysis, which separated out patients who had received an autologous stem cell transplant from the "others."
This "other" group was composed mainly of AML patients, although it also included a few patients who received allogeneic stem cell transplants, and in this group there was a large difference in the overall bleeding rates. In this subgroup, among patients receiving prophylaxis, grade 2 to 4 bleeding was seen in 38% (33/90 patients) compared with 58% (52/90 patients) in the no-prophylaxis group.
No such difference was seen in the remaining majority of patients who had undergone autologous stem cell transplantation, mainly for the treatment of lymphoma or myeloma. In this subgroup, grade 2 to 4 bleeding was seen in 45% (95/210 patients) who received prophylaxis vs 47% (99/210 patients) who did not receive prophylaxis.
Many Transfusions Unnecessary
A different take on the results of this study was taken by another commentator, Andrew Leavitt, MD, from the University of California, San Francisco. "With half of the no-prophylaxis group experiencing no significant bleeding, it is clear that we transfuse many patients unnecessarily," he wrote in ASH Daily News. And yet the practice is increasing, he noted.
The latest US National Blood Collection and Utilization Survey Report shows that there were just over 2 million platelet transfusions in the United States in 2008, an increase from approximately 1.5 million in 1999, he notes. "It is estimated that about two thirds of the platelet transfusions are for prophylactic use, while approximately one third are administered to treat bleeding," he adds.
"While product acquisition and infusion costs vary regionally and are difficult to determine, an average total cost of $1000 per platelet transfusion is a reasonable estimate," Dr. Leavitt continues. "The US health care system therefore spent more than $1.3 billion on prophylactic platelet transfusions in 2008, yet we lack good evidence that prophylactic platelet transfusions provide clinical benefit."
Dr. Stanworth, Dr. Kuter, and Dr. Leavitt have disclosed no relevant financial relationships.
American Society of Hematology (ASH) 54th Annual Meeting. Abstract 1. Presented December 9, 2012.
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