Month: April 2013

Platelet Transfusion for Patients With Cancer (Part One)

April 27, 2013 Chemotherapy, Hematology, Therapeutics 3 comments , , , ,

Intensive therapies producing severe and sustained thrombocytopenia are used routinely in patients with hematologic malignancies and are being applied to many patients with solid tumors as well.

Platelet Products

Platelets for transfusion can be prepared either by separation of units of platelet concentrates (PCs) from whole blood, which are pooled before administration, or by apheresis from single donors. Comparative studies have shown that the posttransfusion increments, hemostatic benefit, and side effects are similar with either product. Thus, in routine circumstances, they can be used interchangeably.

Both preparations can be store for up 5 days after collection at 20℃ to 24℃ with good maintenance of platelet viability.

PCs, which can also be called random donor platelets, are prepared by centrifugation of standard units of whole blood. With the separate technology, PCs contain approximately 0.5 to 0.75 × 1011 platelets/unit or approximately 60% to 75% of the platelets from the original unit of whole blood. However, PCs also contain 108 to 109 WBCs or approximately 50% or more of the leukocytes from original unit of whole blood. Because the PCs are centrifuged from whole blood, the volume of plasma in might be too large for pediatric patients or recipients require severe volume restriction.

Single-donor platelets are produced by apheresis. Donor usually undergo two venipunctures. Blood pumped from one vein passes through a blood-cell separator centrifugation system with removal of the platelets or other cellular components and return of the plasma and RBCs to the donor's other arm.

Plateletpheresis usually requires approximately 11/2 to 2 hours and involves processing 4,000 to 5,000 mL of the donor's blood. This results in a plateletpheresis product that contains the number of platelets equivalent to six to nine units of PC prepared from whole blood. Some centers have recently begun to split their apheresis collections into two products so that the dose may actually be more equivalent to four to five units of PC.

Single-donor platelets contain at least 3 × 1011 platelets in each bag of apheresis. Each apheresis product has a volume of approximately 200 mL and contains few red cells, so that red cell crossmatching is not necessary. The WBC content varies, but most plateletpheresis products now contain less than 5 × 106 leukocytes and can be considered to be leukocyte reduced.

Prophylactic VS Therapeutic Platelet Transfusion

It is recommended that prophylactic platelet transfusion be administered to patients with thrombocytopenia resulting from impaired bone marrow function to reduce the risk of hemorrhage when the platelet count falls below a predefined threshold level. This threshold level for transfusion varies according to the patient's diagnosis, clinical condition, and treatment modality. For example, if the patient has a clinical condition believed to be associated with increased risks of bleeding, it should be provisioned that the threshold might be set greater.

Why prophylactic transfusion? In 1966, Han et al reported that the 63% incidence of hemorrhagic deaths occurring in leukemia patients in the yeaer before the implementation of a prophylactic platelet transfusion policy decreased to 15% in the following year. A similar reduction was observed in a small double-blinded randomized clinical trial performed by Higby et al in 21 patients with acute leukemia.

Prevention of Alloimmunization to RhD Antigens

Platelets do not express Rh antigens on their surface, but the quantity of RBCs in platelet preparations is sufficient to induce Rh sensitization, even in immunosuppressed cancer patients. Different studies have documented that anti-D antibodies can be detected in 7.8% to 19% of heterogeneous groups of RhD-negative cancer patients exposed to RhD antigens via transfusion. Two small studies have demonstrated that RhD immunoprophylaxis can prevent the development of anti-D in this setting.

Thus, if platelets from an Rh-positive donor or platelets from a donor of unknown Rh phenotype are given to an Rh-negative recipient, administration of Rh immunoprophylaxis should be considered, especially for younger female patients who might become pregnant after successful treatment.

The amount of anti-D immunoglobulin necessary to prevent sensitization depends on the number of contaminating RBCs in the PCs. Extrapolating from guidelines used to prevent maternal sensitization after fetal-maternal hemorrhage, a dose of 25 mcg (125 IU) of anti-D immunoglobulin will protect aganist 1mL of RBCs. If possible, the immunoglobulin should be given before or immediately after the transfusion, although, as in the obstetrical setting, it may still be efficacious if given within 72 hours of exposure to the RhD-positive RBCs.

Prevention of Alloimmunization Using Leukoreduced Blood Products

Alloimmunization against histocompatibility antigens occurs in many recipients of multiple random donor platelet transfusions and is the most important long-term complication of platelet transfusion. Recent experience suggests that between 25% and 35% of newly diagnosed patients with AML will produce lymphocytotoxic antibody and become alloimmunized and refractory to nonhistocompatible platelet transfusion. There is evidence from murine and canine models that the leukocytes contaminating platelet preparations are the primary stimulus for alloimmunization and the alloimmunization due to leukocytes will mediate refractoriness to platelet transfusion.

The methods to remove leukocytes include filtration or modification of the antigen presenting capacity of the leukocyte. It has been shown that ultraviolet B irradiation can abolish reactivity in mixed lymphocyte reactions and do not affect platelet function in vitro.

Despite greater understanding of factors that influence the results of transfusion from HLA-selected donors, as many as 40% to 60% of apparently histocompatible platelet transfusions administered to alloimmunized patients are unsuccessful. So the elimination of alloimmunization would greatly simplify platelet transfusion therapy and increase the safety of intensive postremission therapy administered to patients with leukemia.

The incidence of alloantibody mediated refractoriness to platelet transfusion can be decreased in patients with acute myeloid leukemia receiving induction chemotherapy when both platelet and RBC products are leukoreduced by filtration before transfusion. Although randomized trials have not been conducted in other patients groups, it is likely that alloimmunization can also be decreased in patients with other types of leukemia and in other cancer patients receiving chemotherapy. But there are no data in patients who are not receiving chemotherapy in the same time periods that the transfusion are being administered (e.g., aplastic anemia, myelodysplasia), however, the consensus of opinion of American Society of Clinical Oncology (ASCO) would favor its use in these patients as well.

Because leukoreduction ads appreciably to the costs of transfusion, it should be used only for patients expected to require multiple or long-term platelet transfusions during their treatment courses and is not indicated for patients with cancer receiving RBCs or therapies that do not produce significant and sustained thrombocytopenia. However, because the antibodies often developed after 3 to 4 weeks, at a time when the patients may no longer have require platelet transfusion during induction, the major impact of prevention of alloimmunization may be noted in patients receiving intensive consolidation.


Update on Oct 9th 2016

From the perspective of critical care medicine.

There are two main indications for platelet transfusion: to promote hemostasis in bleeding patients with thrombocytopenia or functional platelet disorders and to prevent bleeding in patients with profound thrombocytopenia. Indications for platelet transfusion are related to 1) the underlying disease, 2) presence or absence of active bleeding, 3) anticipation of invasive procedures, and 4) platelet count. In general, patients with active life-threatening bleeding, intracranial hemorrhage, or undergoing neurological or vascular surgery should receive platelet transfusion to maintain concentrations over 100 x 109/L. For most bleeding situations, general surgical procedures, and routine endoscopies with biopsies; however, lower thresholds (50 x 109/L) are adequate; 20 x 109/L is an adequate platelet threshold for most bedside, needle-based procedures including central venous catheterization and lumbar puncture. While the role of prophylactic platelet transfusion in patients with hematologic malignancy has been debated, there appears to be some benefit when a transfusion threshold of 10 x 109/L is used.

In clinical practice, each unit of pooled, random donor platelets increases the circulating platelet count by 5 to 10 x 109/L in patients with average body size. For this reason, random donor platelets are pooled and typically given as a "six pack". By comparsion, one single-donor pheresis platelet unit may increase the platelet count by 30 to 60 x 109/L and these are administered singly. Routine monitoring of platelet transfusion should include posttransfusion platelet count to determine transfusion responsiveness. Failure of the circulating platelet count to increase may result from destruction of the transfused platelets or consumption of the platelets at sites of injury or clot activation. Risks for ineffective platelet transfusion include ITP, presence of antiplatelet antibodies, DIC, drug-induced thrombocytopenia, and sepsis. In general, platelet transfusions are ineffective if the cause of thrombocytopenia is enhanced destruction, since the transfused platelets are destroyed through the same mechanism.

Myelofibrosis (Part One)

April 23, 2013 Cytogenetics, Hematology, Pharmacotherapy, Therapeutics 1 comment , , , ,

Definition

Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1Age > 65 yrs
2Presence of constitutional Symptoms
3Anemia (Hemoglobin < 10 g/dL)
4Leukocytosis (White blood cell count > 25 x 103/mm3)
5Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.

Biology

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).

(more…)

Pharmacoeconomic Evaluating Methods

April 14, 2013 Pharmacoeconomics 1 comment , , , ,

The pharmacoeconomic methods of evaluation are listed in Figure 1. These methods or tools can be separated into two distinct categories: economic and humanistic evaluation techniques.

Economic Evaluation

Figure 1 Components of pharmacoeconomics.

 

The basic task of economic evaluation is to identify, measure, value, and compare the costs and consequences of the alternatives being considered.

Basic concepts

Costs: Cost is defined as the value of the resources consumed by a program or drug therapy of interest. Example of healthcare cost include direct medical costs, direct nonmedical costs, indirect costs, intangible costs, opportunity costs, and incremental costs.

Consequence (or outcome): Consequence is defined as the effects, outputs, or outcomes of the program or drug therapy of interest.

Consequences can be categorized as positive or negative.

Consequences also can be discussed in terms of intermediate and final outcomes.

Outcomes can be separate into three categories: economic, clinical, and humanistic. Economic outcomes are the direct, indirect, and intangible costs compared with the consequences of medical treatment alternatives. Clinical outcomes are the medical events that occur as a result of disease or treatment. Humanistic outcomes are the consequences of disease or treatment on patient functional status or quality of life along several dimensions.

Economic Evaluation Methods

There are four types of economic evaluation methods shown in Table 1.

Table 1 Summary of Pharmacoeconomic Methodologies

Table 1-2 Summary of Pharmacoeconomic Methodologies
MethodDescriptionApplicationCost UnitOutcome Unit
COIEstimates the cost of a disease on a defined populationUse to provide baseline to compare prevention/treatment options against$$$NA
CMAFinds the least expensive cost alternativeUse when benefits are the same$$$Assume to be equivalent
CBAMeasures benefit in monetary units and computes a net gainCan compare programs with different objectives$$$$$$
CEACompares alternatives with therapeutic effects measured in physical units; computes a cost-effectiveness ratioCan compare drugs/programs that differ inclinical outcomes and use the same unit of benefit$$$Natural units
CUAMeasures therapeutic consequences in utility units rather than physical units; computes a cost-utility ratioUse to compare drugs/programs that are life extending with serious side effects or those producing reductions in morbidity$$$QALYs
QOLPhysical, social, and emotional aspects of patient’s well-being that are relevant and important to the patientExamines drug effects in areas not covered by laboratory or physiologic measurementsNAQOL score

 

Humanistic Evaluation

Methods for humanistic evaluation including the assessment for QoL (quality of life), patient preferences, and patient satisfaction.

Basic concepts

Humanistic Outcomes: Humanistic outcomes are the consequences of the disease and/or its treatment as perceived and reported by the patient.

Health-Related Quality of Life (HRQoL): HRQoL is defined as the subjective assessment of the impact of a disease and treatment across the physical, psychological, social, and somatic domains of functioning and well-being. HRQoL include three domains which are (1) physical health and functioning;(2) mental/emotional health and functioning;(3) social and role functioning.

Humanistic Evaluation Methods (Quality of Life)

Table 2 provides a taxonomy of the different types of instrument of HRQoL.

Table 2 Taxonomy of Health-Related Quality of Life Instruments

TABLE 2-1 Taxonomy of Health-Related Quality of Life Instruments
Generic instruments
Health profiles
Preference-based measures
Specific instruments
Disease specific (e.g., diabetes)
Population specific (e.g., frail older adults)
Function specific (e.g., sexual functioning)
Condition or problem specific (e.g., pain)

 

Here three methods are used to measure health state preferences directly. They are (1) Visual Analog Scales;(2) Standard Gamble;and (3) Time Trade-Off.

Visual Analog Scales (VAS)

The VAS is a line, typically 10 to 20 cm in length, with the end points well-defined (e.g., 0 = worst imaginable heath state and 100 = best imaginable heath state). The respondent is asked to mark the line where he or she would place a real or hypothetical health state in relation to the two end points. In addition, because death may not always be considered the worst possible health state, the subject’s placement of death on the scale in relation to the other health states must be explicitly elicited. If a subject has placed death at 0 and rates a health state at the midpoint between 0 and 100 on the scale, that subject’s preference for that health state is 0.5.

Standard Gamble

The standard gamble offers a choice between two alternatives: choice A, living in health state i with certainty, or choice B, taking a gamble on a new treatment for which the outcome is uncertain.

Figure 2 shows this gamble. The subject is told that hypothetical treatment will lead to perfect health, for a defined remaining lifetime, with a probability of P or immediate death with a probability of 1 – P. The subject can choose between remaining, for the same defined lifetime, in state i, which is intermediate between healthy and dead, or taking the gamble and trying the new treatment. The probability P is varied until the subject is indifferent between choices A and B. For example, if a subject is indifferent between the choices A and B when P = 0.75, the preference of state i is 0.75.

Figure 2 The Standard Gamble

 

Time Trade-Off

Figure 3 represents the time trade-off (TTO) technique for a chronic disease state. Here, the subject is offered a choice living for a variable amount of time x in perfect health or a defined amount of time t in a health state i that is less desirable. By reducing the time x of being healthy (at 1.0) and leaving the time t in the suboptimal health state fixed, an indifference point can be determined (hi = x/t). For example, a subject may indicate that undergoing chronic hemodialysis for 2 years is equivalent to perfect health for 1 year. Therefore, the value of that health state would be 0.5.

Figure 3 Time Trade-Off