Novel therapeutic approaches for various forms of thrombocytopenia

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Four studies that highlight significant advances in treatment and survival outcomes for patients with various forms of thrombocytopenia, a group of bleeding disorders characterized by a low number of platelets in the blood, were presented December 6 during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA.

The studies featured in the press conference will report on a new combination therapy for previously untreated idiopathic thrombocytopenic purpura (ITP), an investigational oral treatment for chronic ITP, a low-dose platelet transfusion strategy for patients with hypoproliferative thrombocytopenia, and a new therapeutic platelet transfusion approach following high-dose chemotherapy and autologous stem cell transplantation.

"We have some very exciting data on novel therapeutic approaches to minimize bleeding episodes in patients with platelet disorders," said press conference moderator Kenneth Kaushansky, MD, 2008 President of the American Society of Hematology and Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego School of Medicine. "The results of these studies will likely transform the way hematologists treat and manage these conditions, ultimately resulting in improvements in overall patient outcomes such as reducing bruising and unnecessary bleeding that can result if left untreated."

Types of thrombocytopenia, a blood disorder with 50 to 150 new cases per 1 million people each year, are typically classified by one of three causes: low production of platelets in the bone marrow, increased breakdown of platelets in the bloodstream, or increased breakdown of platelets in the spleen or liver, which can be induced by certain anemias, cancers, infections, or medications. Symptoms can include bruising, nose bleeds, bleeding in the mouth, and rash-like spots on the skin.

If left untreated, thrombocytopenia can become a life-threatening condition when blood platelet counts fall below 5,000 microliters because the risk of serious hemorrhaging (excessive bleeding) increases. Normal blood platelet counts are typically between 150,000 to 450,000 microliters in adults. Treatment for thrombocytopenia is dependent on the cause and severity of the condition and can include drug therapy, splenectomy (removal of spleen, whose function is to breakdown blood cells such as platelets), and platelet transfusions.

A Prospective Randomized Study Comparing Rituximab and Dexamethasone Versus Dexamethasone Alone in ITP: Results of Final Analysis and Long-Term Follow-Up [Abstract #1]
Francesco Zaja, MD, Clinica Ematologica DIRM AOUD, Udine, Italy

This multicenter phase III study is the first to prospectively determine that adding the immunotherapy drug rituximab to dexamethasone (a steroid that is a standard therapy for ITP) is safe and effective in adult patients with previously untreated idiopathic thrombocytopenic purpura (ITP). The results of this study indicate that this treatment regimen could be an effective option prior to splenectomy for some patients as well as a possible cure for others.

In this study, patients were randomized to one of two treatment regimens: oral dexamethasone alone (40 mg) given on the first four days of treatment or the same regimen of dexamethasone plus rituximab given as an intravenous infusion (375 mg/m2) once a week for four weeks. Some patients in the dexamethasone-only arm who failed to achieve a sustained response and had platelet counts of less than or equal to 20 x 109/L following 30 days of therapy up to the end of six months received a salvage (rescue) treatment of rituximab plus dexamethasone.

The primary objective of the study was to compare the sustained response (platelet counts greater than or equal to 50 x 109/L from one month to six months from the beginning of therapy) between the two treatment groups. Secondary objectives included overall safety, initial response (platelet count of 50 x 109/L after 30 days of treatment), activity of the salvage therapy (dexamethasone/rituximab) in patients not responding to dexamethasone alone, the identification of clinical and laboratory factors predictive of response, and the pharmacokinetic parameters of rituximab (the level of ritixumab circulating in the blood of patients during the study period) and their potential relation to response.

The researchers examined the results for all enrolled patients, regardless of whether or not they completed the study (intention-to-treat basis, ITT), and on a per-protocol (PP) basis, examining those who had completed the treatment regimen. The ITT group included 52 patients treated with dexamethasone alone and 49 treated with rituximab/dexamethasone. The PP group included 38 patients treated with dexamethasone alone and 26 treated with rituximab/dexamethasone. ITT and PP sustained response rates were 63 percent and 85 percent in the rituximab/dexamethasone combination arm as compared with 36 percent and 39 percent in the dexamethasone-alone arm.

A total of 27 patients who failed to achieve an initial or sustained response in the dexamethasone-alone arm received the salvage treatment. In this group, ITT and PP sustained response rates were 56 percent and 59 percent, respectively.

No clinical or laboratory factors predictive of a sustained response were identified in the study. There was a mild increase in the incidence of severe adverse events in the dexamethasone-plus-rituximab arm (2 percent in dexamethasone arm versus 6 percent in dexamethasone-plus-rituximab arm).

Effects of Prophylactic Platelet Dose on Transfusion Outcomes (PLADO Trial) [Abstract #285]
Sherrill J. Slichter, MD, Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network, Seattle, WA

This study, the first large-scale clinical trial to compare the effects of different platelet-transfusion dosing regimens on hemostatic outcomes in patients with hypoproliferative thrombocytopenia, found that patients can be safely and effectively transfused with a low dose of platelets, a strategy that can reduce costs and help prevent shortages in the blood supply.

A total of 1,272 patients with hypoproliferative thrombocytopenia (which is caused by failure of the marrow to produce platelets) who were expected to be hospitalized with platelet counts of less than or equal to 10,000 microliters for more than five days were enrolled in the study and received at least one platelet transfusion. Patients were randomized to receive one of three platelet-transfusion dosing regimens: a low dose (1.1 x 1011 platelets/m2), a medium dose (2.2 x 1011 platelets/m2), or a high dose (4.4 x 1011 platelets/m2). An acceptable dose of platelets could be within 25 percent (lower or higher) of the target dose. Patients were stratified into four groups based on the cause of thrombocytopenia: those who had received chemotherapy for a hematologic malignancy (313 patients), chemotherapy for a solid tumor (seven patients), autologous stem cell transplant (429 patients), or an allogeneic stem cell transplant (523 patients). Patients were prophylactically transfused on days when platelet counts were less than or equal to 10,000 microliters.

The primary endpoint of the study was the percentage of patients with Grade 2 or higher bleeding, calculated using the WHO Bleeding Scale. Grade 2 bleeding is clinically significant bleeding that does not require a red blood cell transfusion. Grade 2 or higher bleeding occurred in 71 percent of patients in the low-dose arm, 69 percent in the medium-dose arm, and 70 percent in the high-dose arm. Grade 3 or higher bleeding, which generally does require treatment by red blood cell transfusion, was seen in 12 percent of patients in the low-dose arm, 9 percent in the medium-dose arm, and 10 percent in the high-dose arm. Grade 4 bleeding, the most serious, was seen in 3 percent, 2 percent, and 2 percent of patients in the low-dose, medium-dose, and high-dose arms, respectively. The median number of red blood cell transfusions (usually given for anemia) was four in each treatment arm. Treatment dose did not affect the frequency of any bleeding grade in any of the four patient groups.

A Therapeutic Platelet Transfusion Strategy Without Routine Prophylactic Transfusion is Feasible and Safe and Reduces Platelet Transfusion Numbers Significantly: Preliminary Analysis of a Randomized Study in Patients After High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation [Abstract #286]
Hannes Wandt, MD, Klinikum Nuremberg Nord, Nuremberg, Germany

This is the first worldwide randomized study showing that one-quarter to one-third of all platelet transfusions were given unnecessarily in the past and can be reduced in the future without any harm to patients following high-dose chemotherapy and autologous stem cell transplantation, according to Dr. Wandt.

This multicenter, randomized trial found that the development of major bleeding following high-dose chemotherapy and autologous stem cell transplant can be prevented through an experimental therapeutic strategy in which patients receive platelet transfusions only if they have experienced clinically relevant bleeding. In this study, the experimental strategy was compared with a traditional preventive transfusion strategy in which patients received a transfusion if platelet counts were less than or equal to 10/nL. The researchers concluded that the experimental strategy was both cost effective and safe in this patient population.

A total of 171 patients who had recently received high-dose chemotherapy or autologous stem cell transplant for the treatment of various hematologic cancers (multiple myeloma, non-Hodgkin lymphoma, Hodgkin disease, and acute leukemia) were randomized to one of two treatment arms: a traditional arm that received preventive platelet transfusions or an experimental arm that was treated only if the patient had experienced signs of clinically relevant bleeding. The primary objective of the study was the reduction of platelet transfusions by 15 to 25 percent. Secondary objectives included safety, duration of leukopenia and thrombocytopenia, and the number of red blood cell transfusions.

Platelet transfusions were significantly reduced by 27 percent in the experimental arm as compared with the traditional arm. In the experimental arm, 46 percent of patients did not need any platelet transfusions, compared with 22 percent of patients in the traditional arm. Using clinically relevant bleeding as the trigger for platelet transfusions rather than using platelet counts of less than or equal to 10/nL as the trigger resulted in more minor hemorrhages occurring in the experimental arm as compared with the traditional arm (28.7 percent versus 9.5 percent); however, no life-threatening or fatal bleeding was reported. The duration of leukopenia and the need for red blood cell transfusions were the same in both arms.

Oral Eltrombopag for the Long-Term Treatment of Patients With Chronic Idiopathic Thrombocytopenic Purpura (ITP): Results of a Phase III, Double-Blind, Placebo-Controlled Study [Abstract #400]
Gregory Cheng, Chinese University of Hong Kong, Hong Kong, China

This double-blind, multicenter, phase III study found that long-term eltrombopag therapy compared with placebo treatment significantly increased platelet counts, decreased bleeding symptoms, allowed for a reduction of baseline ITP therapy, and reduced the use of rescue medications in previously treated patients with chronic ITP. In chronic ITP, low blood platelet counts persist unless treated and can last for an indefinite amount of time.

A total of 197 patients with platelet counts less than 30,000 microliters were stratified by splenectomy status, use of baseline ITP medication, and platelets of less than or equal to 15,000 microliters. They were randomized to receive either eltrombopag at a starting dose of 50 mg once daily (135 patients) or placebo once daily (62 patients). Depending on individual platelet response, the dose of eltrombopag could be titrated within a range from 25 mg once daily to a maximum dose of 75 mg once daily.

The primary endpoint of the study was the odds of achieving platelet counts between 50,000 and 400,000 microliters in patients receiving eltrombopag as compared with placebo. To measure the drug's safety, bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale.

Patients who received eltrombopag were eight times more likely to achieve platelet counts of 50,000 to 400,000 microliters during the six-month treatment period as compared with those in the placebo arm. While baseline median platelet counts were 16,000 microliters in both groups, platelet counts never exceeded 30,000 microliters in the placebo group. This is in contrast to median platelet counts rising to 36,000 microliters in the eltrombopag group after one week of treatment and ranging from 52,000 to 91,000 microliters for the remainder of the study. Median platelet counts returned to baseline levels two weeks after stopping eltrombopag.

Significantly fewer patients treated with eltrombopag experienced any bleeding or clinically significant bleeding throughout the study as compared with those in the placebo arm. Additionally, more patients in the eltrombopag arm were able to stop or reduce other ITP medication and required less rescue therapy compared with those in the placebo group. Overall incidence of adverse events was similar in both treatment groups and was mostly mild to moderate.


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