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, may benefit patients with various forms of thrombocytopenia.
Thrombocytopenia is a group of bleeding disorders characterized by a low number of platelets in the blood. Failed platelet production, increased splenic sequestration of platelets with normal platelet survival, increased platelet destruction or consumption, dilution of platelets, or a combination of these are the main causes of this condition.
Four studies presented during the during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA (December 6 - 9) on Saturday, highlighted significant advances in treatment and survival outcomes for patients with various forms of
thrombocytopenia.
“We have some very exciting data on novel therapeutic approaches to minimize bleeding episodes in patients with platelet disorders,” explained 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 or (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 (the spleen breaks down blood cells such as platelets), and platelet transfusions.
Rituximab and Dexamethasone vs Dexamethasone Alone in Idiopathic thrombocytopenic purpura
Results from a multicenter phase III study conducted by a team of researchers from Clinica Ematologica DIRM AOUD, Udine, Italy, were presented by Francesco Zaja, MD.
This study is the first trial to prospectively determine that adding the immunotherapy drug
rituximab, an anti-CD20 monoclonal antibody, to
dexamethasone, a steroid that is a standard therapy for idiopathic thrombocytopenic purpura (ITP), is safe and effective in adult patients with previously untreated ITP, an autoimmune disorder characterized by low platelet counts. Primary ITP, which typically occurs in an otherwise healthy individuals, has an unknown etiology.
After analyzing the data, the researchers concluded 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.
While were no clinical or laboratory factors predictive of a sustained response identified in the study, the researchers did report 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).
For more infromation, read:
Francesco Zaja, Michele Baccarani, Patrizio Mazza, Nicola Vianelli, et al.
A Prospective Randomized Study Comparing Rituximab and Dexamethasone Vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up. (Plenary Session), Blood (ASH Annual Meeting Abstracts) 2008 112:
Abstract #1Click
here for an educational resource (The ITP Paradox).
Also read Pubmed abstracts:
- Medeot M, Zaja F, Vianelli N, Battista M, et al. Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results. Eur J Haematol. 2008 Sep;81(3):165-9. Epub 2008 May 27.
- Toffoletti E, Zaja F, Chiarvesio A, Michelutti A, et al. No evidences for B-cell clonality by spectratyping analysis in patients with idiopathic thrombocytopenic purpura undergoing rituximab therapy. Haematologica. 2008 May;93(5):795-6.
- Stasi R, Cooper N, Del Poeta G, Stipa E, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008 Aug 15;112(4):1147-50. Epub 2008 Mar 28.
Effects of Prophylactic Platelet Dose on Transfusion Outcomes (PLADO Trial)
Patients with hypoproliferative thrombocytopenia 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. This is the conclusion of Sherrill J. Slichter, MD and her team of researchers at Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network, Seattle, WA, analyzing the data of the first large-scale clinical trial comparing the effects of different platelet-transfusion dosing regimens on hemostatic outcomes.
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.
Participating 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.
For more information, please read:
Sherrill J. Slichter, MD, Richard M. Kaufman, MD, Susan F Assmann, PhD, Mark E. Brecher, MD, BC.
Effects of Prophylactic Platelet (Plt) Dose on Transfusion (Tx) Outcomes (PLADO Trial) Blood (ASH Annual Meeting Abstracts) 2008 112:
Abstract #285Also read PubMed abstracts:
Therapeutic platelet transfusion without prophylactic transfusion may significantly reduces platelet transfusion needs.
This study is the first worldwide randomized trial 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. MD, at the Klinikum Nuremberg Nord, Nuremberg, Germany.
In this multicenter, randomized trial, the researchers 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. The experimental strategy in this trial 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, including 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.
For more information, please read:
Hannes Wandt, MD, Knut Wendelin, MD, Kerstin Schaefer-Eckart, MD, Markus Thalheimer, MD. 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. Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #286.
Also read PubMed abstracts:
Wandt H, Schaefer-Eckart K, Frank M. et al. A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006 Feb;37(4):387-92.
Oral Eltrombopag for the treatment of chronic Idiopathic Thrombocytopenic Purpura (ITP)
This double-blind, multicenter, phase III study found that long-term therapy with eltrombopag, a thrombopoietin-receptor agonist, 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.
In this study Gregory Cheng, MD and his team of researchers at the Chinese University of Hong Kong, Hong Kong, China, stratified 197 patients with platelet counts less than 30,000 microliters by splenectomy status, use of baseline ITP medication, and platelets of less than or equal to 15,000 microliters. Patients 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.
More information, please read:
Gregory Cheng, Mansoor N Saleh, James B Bussel, Claus Marcher.
Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #400
Also read PubMed abstracts:
Also read NEJM article (full article):
McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M.
Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N Engl J Med. 2007 Nov 29;357(22):2227-36. Clieck
here for the PubMed abstract.
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