Month: May 2013

Platelet transfusion for patients with cancer (part two)

May 31, 2013 Hematology, Therapeutics 2 comments , ,

In our last discussion about platelet transfusion for patients with cancer 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.

Today we will talk about the specific cases to implement the rule above. There are total 5 specific cases which consist of acute leukemia, hematopoietic cell transplantation, chronic stable severe thrombocytopenia, solid tumors, and surgical or invasive procedures.

Acute Leukemia

We recommend a threshold of 10 × 109/L for prophylactic platelet transfusion in adult patients receiving therapy for acute leukemia, on the basis of the results of multiple randomized trials that demonstrate that this approach is equivalent to the use of 20 × 109/L threshold. Transfusion at higher levels may be necessary in newborns or in patients with signs of hemorrhage, high fever, hyperleukocytosis, rapid fall of platelet count, or coagulation abnormalities and in those undergoing invasive procedures or in circumstances in which platelet transfusions may not be readily available in case of emergencies.

For children and older infants it is reasonable to use similar recommendation.

Hematopoietic Cell Transplantation

Fewer studies have been performed in recipients of high-dose therapy with stem-cell support. Although such patients may experience more mucosal injury than patients receiving conventional antileukemic chemotherapy, clinical experience and the available data suggest that guidelines for prophylactic tranfusion similar to those for patients with acute leukemia can be used in transplant recipients, with similar caveats about transfusion at higher counts in patients with complicating clinical conditions.

Chronic, Stable, Severe Thrombocytopenia

No randomized studies have been performed in patients with sustained, severe thrombocytopenia such as can be seen in individuals with myelodysplasia and aplastic anemia. Many such patients have minimal or no significant bleeding for long periods of time despite low platelet counts. On the basis of clinical experience and limited retrospective studies, we suggest that many of these patients can be observed without prophylactic transfusion, reserving platelet transfusion for episodes of hemmorrhage or during times of active treatment.

Solid Tumors

The risk of bleeding in patients with solid tumors during chemotherapy-induced thrombocytopenia is related to the depth of the platelet nadir, although other factors contribute as well. Evidence obtained from observational studies supports the clinical benefit of prophylactic transfusion at a threshold of 10 × 109/L platelets or less. However, for bladder tumors as well as those with demonstrated necrotic tumors, based on the experts’ option guideline suggest that prophylactic transfusion threshold should be 20 × 109/L , if patients are receiving aggressive therapy.

Surgical or Invasive Procedures in Thrombocytopenia

Thrombocytopenic patients frequently require invasive diagnostic or therapeutic procedures. Common procedures include placement of permanent or temporary central venous catheters, transbronchial and esophageal endoscopic biopsies, paranasal sinus aspirations, bone marrow biopsies, and occasionally even major surgery. We suggest, on the basis of accumulated clinical experience, that a platelet count of 40 × 109/L to 50 × 109/L is sufficient to perform major invasive procedures with safety, but in the absence of associated coagulation abnormalities. If platelet transfusions are administered before a procedure, it is critical that a posttransfusion platelet count be obtained to prove that the desired platelet count level has been reached. Platelet transfusions should also be available on short notice, in case intraoperative or postoperative bleeding occurs. For alloimmunized patients, histocompatible platelets must be available in these circumstances.

How I treat acute myeloid leukemia in adults (strategies)

May 31, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments , , , , ,

More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Few diseases other than acute myeloid leukemia (AML) engender so much personal and institutional passion regarding treatment strategies. The median age of AML is 72 years of age, as reported by the Swedish Acute Leukemia Registry, a model for collection of real world data.

Although some improvement during the last 4 decades is apparent among younger patients, still only approximately 35% of such patients entered on clinical trials are cured of their disease. However, little progress occurred among older patients and indeed only those with acute promyelocytic leukemia (APL) which is a rare subgroup enjoy the excellent outcome and likelihood of cure we all desire.

Management of AML in Adults

To some extent, the management of adults with AML appears to be standardized. However, much of the so-called conventional therapy has been established with a lack of data or without rigorous review of the existing evidence; and so, considerable uncertainty remains. Such uncertainty is reflected in the significant diversity in the management of patients with AML, both in induction of older patients and postremission therapy of all patients.

Generally, the management of AML can be divided into three parts including the induction therapy, the postremission therapy, and the hematological emergent management. The induction therapy regimen now is standarized. The choice of induction and postremission thearpy is primarily and solely determined and based on the cytogenetic and molecular determinants at diagnosis. However, possibly minimal residual disease (MRD) after induction therapy, as determined by refined molecular or immunophenotypic analyses, plays a role in deciding the choice of postremission therapy.

When a patient is newly diagnosed with AML, the first thing to do is to evaluate the cytogenetics and karyotype of the patient,since that the two is important in the determining of the risk status, the prognosis, and then the treatment strategy of AML. According to the cytogenetics and karyotype the risk status of AML can be divided into three categories consisting of better-risk (favorable), intermediate-risk, and poor-risk (unfavorable).

Table 1. Risk Status of AML Based on Cytogenetics and Molecular Abnormalities

Table 2. Standardized Reporting for Correlation of Cytogenetic and Molecular Genetic Data in AML with Clinical Data

Induction Therapy

Although in the early 1990s several randomized studies of induction therapy suggested that using idarubicin, mitoxantrone, aclarubicin, or amsacrine demonstrated superior results compared with daunorubicin, there is no evidence that these studies reflected a true biologic advantage rather than a lack of dose equivalence. So the standard induction therapy regimen remains the “3+7”. It has now been established that the traditional approved dose of daunorubicin (45 mg/mfor 3 days) is no longer appropriate as induction therapy for AML. A recent randomized trial for younger patients under age 60 years reported a significantly higher complete remission (CR) rate for patients receiving 90 mg/m2 of daunorbuicin compared with 45 mg/m2. The overall survival was also improved with the higher dose of daunorubicin.

The E1900 trial, which was undertaken by the Eastern Cooperative Oncology Group (ECOG) in 657 younger patients, compared a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 in a 3+7 schedule for the first induction course. The higher dose achieved a significantly higher overall remission rate, with more patiens in CR after the first course and a better overall survival (23.7 vs 15.7 months). However, a study by Dutch-Belgian Hemato-Oncology Cooperative Group showed that with the similar approach in older patients with AML the overall remission rate was similarly improved, but overall survival was not, except in the case of patients in the 60- to 65-year subgroup.

So the induction therapy regimen is 3+7 that daunorubicin 90 mg/m2 for 3 days together with cytarabine 100 mg/m2 for 7 days.

Postremission Therapy

Once the patient get CR after induction therapy postremission therapy need consideration. The choice of postremission therapy could be allogeneic hematopoietic cell transplantation (allo-HSCT), autologous transplantation (auto-HSCT), and consolidation chemotherapy. The decision for postremission therapy should be based on cytogenetic and molecular determinants, regardless of other factors.

Allo-HCT provides the most potent antileukemic effect of any postremission strategy in AML, as demonstrated by the lowest rates of relapse in all clinical studies. The donor categories of allo-HCT consist of HLA-identical sibling donor, matched unrelated donor (MUD), genetically haploidentical donor, and umbilical cord donor. Probably the HLA-identical sibling donor is the first-line and preferred choice, because other three choices might have higher rates of mortality and morbidity associated with GVHD (graft-versus-host disease). Although there is a substantial transplantation-related mortality of 15% to 20% with allo-HCT, the reduction in the relapse rate significantly outweighs the transplantation-associated risk.

In AML patients, it is clear that fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. So to obtain CR before transplantation in AML is a rule (see post “The Management of Myelodysplastic Syndromes”). However, in relapsed AML, patients with CR1 less than 6 months have less than 20% of likelihood to achieve CR2, where we would elect to proceed to an transplantation in an untreated first relapse. But there is a expection, it is older individuals with relapsed AML, more than or equal to 60 to 65 years. In these patients a RIC often is the preferred conditioning regimen before transplantation, but the likelihood of a cure when transplantation a patient with elevated blasts with RIC is low, where our own preference in this case would be to administer one cycle of induction therapy in an attempt to obtain a better control of the disease before transplantaion.

However, not all patients with AML should undergo hematopoietic cell transplantation. Patients whose leukemia cells expressing more favorable mutations with normal karyotype at diagnosis such as mutation of NPM1 or CEBPA have a more favorable outcome and may not benefit from an allo-HCT. These patients should not undergo allo-HCT.

Table 3. Suggested indications for allo-HSCT

If there is no HLA-identical sibling donor, MUD donor, genetically haploidentical donor, or umbilical cord donor could be the alternative approach. But, a recent study showed that there was an increased replase rate in MUD transplantation for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation.

There was an increased relapse rate in MUD transplantations for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation. Although the presence of GVHD is associated with reduced relapse of AML, it dose not appear that such an effect is dependent on the degree of genetic disparity and the best donor remains the most closely matched donor.

If allo-HCT is chosen, a fully myeloablative conditioning regimen is appropriate and the reduced-intensity conditioning (RIC) regimen should be reserved for older patients or those with significant comorbidities. The transplantion should be underwent immediately after the CR1 without any consolidation chemotherapy. 2 retrospective analyses from large international registries suggest that there is no benefit to adding any consolidation therapy before an allo-HCT. Also the allo-HCT transplantation should not be delayed or reserved until the patient has a event of relapse. Delaying transplantation until after relapse is a misleading strategy.

In the majority of major prospective studies published over the past decade, a lower relapse rate was reported for patients undergoing an autologous transplantation compared with chemotherapy. If autologous transplantation is chosen, the patient should receive 2 cycles of consolidation therapy with high-dose cytarabine (3g/m2 given every 12 hours on days 1, 3, and 5) followed by the transplantation. The rationale for using an autologous transplantation is based on the fundamental concept that the optimal approach to postremission therapy is based on the regimens with the most potent antileukemic activity, provided this effect is not abrogated by unacceptably high mortality. Currently, the mortality rate associated with an autologous transplantation is less than 2%, which results from the technology that collecting hematopoietic cells from the peripheral blood. Of note, if the patient is in the poor-risk group, autologous transplantation should be avoided. I think the reason is associated the unfavorable cytogenetic mutations or karyotype.

One point must be emphasized that if the patient dosen’t achieve CR after the first induction course (i.e., the patient dosen’t clear his/her blasts in bone marrow by day 14 after the first induction therapy) but subsequently achieve CR after the second induction therapy, the prognosis is similar to those achieving CR with one cycle of induction. Thus, the postremission strategy should not be altered if the patient eventually responds successfully to the induction therapy.

Table 4. Response Criteria in AML

Blood 2009; 115: 453-574

Hematological Emergencies

Patients with initial AML may experience hyperleukocytosis which could result in leukostasis (when the WBC > 200 × 109/L) and therefore potentially lethal central nervous system and pulmonary complications. The optimal emergent management is uncertain, and one approach is to initiate immediate induction thearpy. An alternative strategy consists of daily leukapheresis with the concurrent administration of hydroxyurea at doses of 2 to 6 g/day. Generally, some experts suggest this alternative approach and wait for the initiation of induction therapy until the WBC has fallen below 40 × 109/L to 50 × 109/L, they think that this approach would increase the likelihood of achieving CR with a single cycle of chemotherapy.

The issue of prophylaxis for the central nervous system is controversial in any patients with AML and is often considered in a patient who presents initially with a high WBC. The experts don’t recommend the prophylaxis routinely if in the absence of any symptoms related to the central nervous system.

Table 5. Outcome Measures in AML

Outcome Measures in AML

The Rh Blood System – Basic and Clinical Senses

May 26, 2013 Hematology, Physiology and Pathophysiology No comments ,

Basic information

As we all know blood system are firstly be discovered by Landsteiner from University of Vienna, which consists of type A, type B, and type O. However, 60 years ago a woman had a severe transfusion reaction when she was transfused with blood from the donor despite the ABO blood system was compatible. After research about this case, finally it was found that besides ABO blood system there was another blood system which was called the Rh blood system later.

The Rh blood group system is the most polymorphic of the human blood groups, consisting of at least 45 independent antigens and, next to ABO, is the most clinically significant in transfusion medicine.

Several nomenclatures have been used to describe antigens, proteins, and in the Rh system. RH is used to describe genes encoding either the RhD protein or the RhCcEe (also known as RhCE) protein and RHAG for the genes encoding the Rh-associated glycoprotein (RhAG).

The common Rh five antigens are D, C or c, and E or e. And c, e describes antithetical to C, or E antigens. Note that d antigen does not exist and d indicates the D-negative phenotype. So the most frequently occurring forms of RHCE and RHD encode 8 haplotypes: Dce, dce, DCe, dCe, DcE, dcE, DCE, and dCE, known in short, respectively, as R0, r, R1, r’, R2, r”, Rz, and ry. The uppercase “R” is used when the D antigen is expressed, lowercase “r” when it is not. Rare deletion phentoypes use dashes in the notation to indicate a lack of antithetical antigens: eg, Dc- RBCs lack E and e antigens, and D– RBCs lack C, c, E, and e antigens. RBCs with the Rhnull phenotype do not express any of the Rh antigens.

The Rh proteins carry Rh antigens but are only expressed on the erythrocyte surface if RhAG is also present. The complex of the Rh protein family is estimated by density ultracentrifugation to be 170,000 daltons and consist of a tetramer with 2 RhAG molecules and 2 RhCE or RhD protein molecules stabilized by both N-terminal and C-terminal domain associations.

The RhD protein expresses the D antigen, while the RhCE protein carries either C or c antigens together with E or e antigens on the same protein. The RhAG is not known to possess a protein-based blood group polymorphism. Base on the predicted amino acid sequence, RhAG shares 39.2% and 38.5% amino acid sequence identity with, respectively, the RhCE and RhD proteins.

Expression of Rh proteins and RhAG during erythropoiesis

Rh antigen appear early during erythropoietic differentiation. Anti-D binds to approximately 3% of BFU-E (burst-forming unit, erythroid), 68% of CFU-E (colony-forming unit, erythrocyte), and to all of the more mature erythroid cells. However, the binding of anti-D to proerythroblasts, basophilic erythroblasts, polychromatophilic erythroblasts, and normoblasts was, respectively, 25%, 50%, 66%, and 75% compared with mature RBCs. RhAG protein is detectable on CD34 progenitors isolated from cord blood, after culture for 3 to 5 days, while RhCE appears after 5 to 7 days, and RhD appears after 9 to 11 days of culture. In the fetus, Rh antigens are expressed on RBCs from the 6-week conceptus.

Functions

The function of Rh complex remains unclear. Rh proteins have approximately 20% homology to the methylamine permease transporters and ammonium transporters in yeast, bacteria, and simple plants. This family of transporters are uniporters that have evolved to concentrate ammonium salts from the surrounding environment. The role of the Rh complex as a dedicated ammonium transporter is unlikely, but the complex could cotransport ammonium with other cations. However, further study is needed.

Clinical Senses

People whose RBCs have a rare deleted Rh phenotype readily make alloantibodies. People with the Rhnull phenotype of amorph or regulator type can make anti-Rh29 antibody which binds to all Rh antigens, anti-Rh17 which binds to RhCE antigens, anti-D, anti-C, or a mixture of them. Transfusion of a patient with anti-Rh29 is a problem because only Rhnull RBCs will be compatible. However, people with the Rhnull phenotype are not only rare but also have a compensated hemolytic anemia, therefore they are unlikely to meet predonation criteria. People with anti-Rh17 also represent a transfusion problem because only RBCs with a deleted phenotype will be compatible.

Patients with autoimmune hemolytic anemia have autoantibody which reacts with an antigen on the antibody maker’s own RBCs. Many of these antibodies have specificity to Rh antigen, notably to e. The antoantibody commonly reacts more weakly with antigen-negative RBCs than with antigen-negative RBCs;however, in these cases, transfused antigen-negative RBCs only rarely survive better than antigen-positive RBCs. Autoantibodies in serum from patients with warm autoimmune hemolytic anemia may be nonreactive only with Rhnull and D– RBCs (autoanti-Rh17), or only with Rhnull RBCs (autoanti-Rh29). In such cases, antigen-negative blood will not be available, and transfusion with antigen-positive RBCs should not be withheld if the patient has life-threatening anemia.

There is the possibility that the patient has a weak D phenotype or partial D phenotypes. People with a weak D phenotype do not make anti-D, whereas people with a partial D phenotype can make alloanti-D. This presents a different problem depending on whether the person is a donor or a patient. For donors, detection of weak and partial D antigens would eliminate the possibility of immunization should such blood be transfused to a true D-negative patient. However, historical data show that weekly expressed D antigents are most unlikely to be immunogenic. For transfusion recipients and pregnant women, it is common practice to use a procedure that will classify RBCs with a weak D antigen or some partial D antigens as D-negative. Thus, blood donated from such a person should be labeled as D-positive, but the same person should be labeled as D-negative when they are recipients in need of transfusion.

The antithyroid drug approach for the management of hyperthyroidism caused by GD

May 17, 2013 Pharmacotherapy, Therapeutics 1 comment , ,

Introduction

Hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid. The most common causes of hyperthyroidism include Graves’ disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA). Several varieties of thyroiditis can present with thyrotoxicosis, including postpartum thyroiditis, painless thyroiditis, drug-induced thyroiditis, subacute thyroiditis, traumatic thyroiditis, and acute thyroiditis.

GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAbs) stimulate the TSH receptor, increasing thyroid hormone production. TMNG is disease status in which there is excess production of thyroid hormones from functionally autonomous thyroid nodules, which do not require stimulation from thyroid stimulating hormone (TSH). In TAs, autonomous hormone production can be caused by somatic activating mutation of genes regulating thyroid hormone systhesis.

A thyroid adenoma (TA) is distinguished from a multinodular goiter (TMNG) of the thyroid in that an adenoma is typically solitary, and is a neoplasm resulting from a genetic mutation(or other genetic abnormality) in a single precursor cell.

Table 1 Causes of Thyrotoxicosis

Before initiating therapy, the disease should be evaluated including assessment of disease severity, biochemical evaluation, and the etiology of hyperthyroidism should be determined.

The assessment of disease severity comprises of thyrotoxic manifestations, cardiovascular complications, and neuromuscular complications. Goiter size, obstructive symptoms, and the severity of Graves’ ophthalmopathy (GO; the inflammatory disease that develops in the orbit in association with autoimmune thyroid disorders).

Serum TSH, free T4 and total T3 should be used for biochemical evaluation. Serum TSH should be used as an initial screening test. The relationship between free T4 and TSH (when the pituitary-thyroid axis is intact) is an inverse log-linear relationship;therefore, small changes in free T4 result in large changes in serum TSH concentrations.

In overt hyperthyroidism, usually both serum free T4 and T3 estimates are elevated, and serum TSH is undetectable. However, in milder hyperthyroidism, serum T4 and free T4 estimates can be normal, only serum T3 may be elevated, and serum TSH will be <0.01 mU/L (or undectable). These laboratory findings have been called “T3-toxicosis” and may represent the earliest stages of disease or that caused by an autonomously functioning thyroid nodule.

Subclincial hyperthyroidism is defined as a normal serum free T4 estimate and normal total T3 or free T3 estimate, with subnormal srum TSH concentration.

In the absence of a TSH-producing pituitary adenoma or thyroid hormone resistance, if the serum TSH is normal, the patient is almost never hyperthyroid. Euthyroid hyperthyroxinemia has been used to describe a disease status that total serum T4 level is elevated (and usually elevated total serum T3 level) in the absence of hyperthyroidism. Euthyroid hyperthyroxinemia usually is caused by thyroid hormone-binding protein disorders, or some specific drugs.

When free thyroid hormone concentrations are elevated and TSH is normal or elevated, further evaluation is necessary. After excluding euthyroid hyperthyroxinemia, TSH-producing pituitary adenoma or thyroid hormone resistance caused by genetic mutation may be the reason.

To determination the etiology of hyperthyroidism, a radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD, a thyroid scan should be added in the presence of thyroid nodularity.

Symptomatic management

Thyroid hormone influences almost every tissue and organ system in the body. It increases tissue thermogenesis and basal metabolic rate (BMR) and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels are on the cardiovascular system.

The signs and symptoms of overt and mild, or subclinical thyrotoxicosis are similar, but differ in magnitude. Overt thyrotoxicosis, whether endogenous or exogenous, is characterized by excess thyroid hormones in serum and suppressed TSH (<0.01 mU/L). There are also measureable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function. Symptoms and signs that result from increased adrenergic stimulation inculde tachycardia and anxiety.

Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease.

Thyroid Storm Management

Life-threatening thyrotoxicosis or thyroid storm is a rare, occasionally iatrogenic disorder characterized by multisystem involvement and a high mortality rate if not immediately recognized and treated aggressively. Precise criteria for thyroid storm have been defined and include tachycardia, arrhythmias, congestive heart failure, hypotension, hyperpyrexia, agitation, delirium, psychosis, stupor and coma, as well as nausea, vomiting, diarrhea, and hepatic failure.

Table 2 Point Scale for the Diagnosis of Thyroid Storm

Precipitants of thyroid storm in a patient with previously compensated thyrotoxicosis include abrupt cessation of antithyroid drugs, thyroid or nonthyroidal surgery in a patient with unrecognized or inadequately treated thyrotoxicosis, and a number of acute illnesses unrelated to thyroid disease. Thyroid storm also occurs rarely following radioactive iodine therapy.

Each pharmacologically accessible step in thyroid hormone production and action is targeted in the treatment of patients with thyroid storm, which includes beta-adrenergic blockade, antithyroid drug therapy, inorganic iodide, corticosteroid therapy, aggressive cooling with acetaminophen and cooling blankets, volume resuscitation, respiratory support and monitoring in an intensive care unit.

Management of Hyperthyroidism due to GD

There are three approaches to management hyperthyroidism due to GD. They are 131I therapy, antithyroid drugs (ATD) therapy, and thyroidectomy. Each approach has it benefits and disadvantages. In this post we discuss the antithyroid drugs approach.

Factors that favor antithyroid drug thearpy include patients with high likelihood of remission (patients, especially females, with mild disease, small goiters, and negative or low-titer TRAb);the elderly or others with comorbidities increasing surgical risk or with limited life expectancy;individuals in nursing homes or other facilities who may have limited longevity and are unable to follow radiation safety regulations;patients with previously operated or irradiated necks;patients with lack of access to a high-volume thyroid surgeon;and patients with moderate to severe active GO (Graves’ ophthalmopathy).

But if patients have definite contraindications to long-term ATD thearpy including previous known major adverse reactions to ATDs, this approach should be avoided. A baseline absolute neutrophil count <500/mm3 (0.5 ×109/L) or liver transaminase enzyme levels elevated more than fivefold the upper limit of normal are contraindications to initiating ATD therapy. With this approach, the possibility of disease recurrence exists and patients need continued monitoring. Although the possibility of remission is high, there might be the possibility of un-remission with this approach.

The goal of ATD therapy is to render the patient euthyroid as quickly and safely as possible. These medications do not cure Graves’ hyperthyroidism but if given in adequate doses, they are very effective in controlling the hyperthyroidism;when they fail to achieve euthyroidism the usual cause is nonadherence. The treatment might have a beneficial immunosuppressive role, but the major effect is to reduce the production of thyroid hormones and maintain a euthyroid state while awaiting a spontaneous remission.

Before initiating ATD therapy, baseline blood test including CBC, liver funtion, thyroid biochemical evaluation etc should be considered to aid in the interpretation of future laboratory values. Why? Because low white cell counts are common in patients with autoimmune diseases and abnormal liver enzymes are frequently seen in patients with thyrotoxicosis, and ATDs can cause agranulocytosis and hepatotoxicity, to distinguish whether these phenomenons is due to ATDs or the disease itself, baseline blood test is useful. In addition, a baseline blood test is useful to determined whether ATD therapy is contraindicated.

In China, there are only two antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU). MMI should be used in virtually every patient who choose antithyroid drug theapy for GD, except during the first trimester of pregnancy when PTU is preferred, in the treatment of thyroid storm, and in patients with minor reaction to MMI who refuse radioactive iodine therapy or surgery. However, the pregnancy category of both MMI and PTU are D and MMI is able to cross the blood-placenta barrier.

At the start of MMI therapy, higher initial doses are advised, usually 10-20 mg daily, to restore euthyroidism, following which the dose can be titrated to maintenance level (generally 5-10 mg daily). The ATA and AACE guideline recommended once daily administration of MMI, however the latest FDA label of MMI recommend higher initial doses and to divide the total drug dosage into three doses at 8-hour  intervals. PTU should be started with 50-150 mg three times daily, depending on the severity of the hyperthyroidism.

Monitor

There is a need for periodic clinical and biochemical evaluation of thyroid status in patients taking ATDs, if needed blood tests such as CBC and liver function should be monitored. An assessment of serum free T4 should be obtained about 4 weeks after initiation of thearpy, and the dose of medication adjusted accordingly. Serum T3 also may be monitored, since the estimated serum free T4 levels may normalize with persistent elevation of serum T(See “T3-toxicosis” aforementioned). Appropriate monitoring intervals are every 4-8 weeks until euthyroid levels are achieved with the minimal dose of medication. Once the patient is euthyroid, biochemical testing and clinical evaluation can be undertaken at intervals of 2-3 months.

Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter to monitor therapy early in the course. This may be confounded with subclinical hyperthyroidism, which the level of T3 and T4 are normal but serum TSH is suppressed or subnormal.

A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking ATDs. Routine monitoring of white blood counts is not recommended. I had met a case of severe agranulocytosis, in which the patient had both febrile and pharyngitis. Routine monitoring of white blood cell counts is not likely to identify cases, as the frequency is quite low (0.2%-0.5%) and the condition sudden in onset. Because patients are typically symptomatic, measuring white blood cell counts during febrile illness and at the onset of pharyngitis has been the standard approach to monitoring. If patients develop agranulocytosis due to ATDs, the ATD therapy is contraindicated.

Liver functnion and hepatocellular integrity should be assessed in patients taking PTU who experience pruritic rash, jaundice, light-colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. Hyperthyroidism can itself cause mildly abnormal liver function tests, and PTU may cause transient elevations of serum transaminases in up to one-third of patients. Significant elevations to threefold above the upper limit of normal are seen in up to 4% of patients taking PTU.

In patients with improving thyrotoxicosis, a rising alkaline phosphatase with normalization of other liver function does not indicate worsening hepatic toxicity. The onset of PTU-induced hepatotoxicity may be acute, difficult to appreciate clinically, and rapidly progressive. If not recognized, it can lead to liver failure and death. Routine monitoring of liver function in all patients taking ATDs has not been found to prevent severe hepatotoxicity. PTU should be discontinued if transaminase levels (either elevated at onset of therapy, found incidentally or measured as clinically indicated) reach 2-3 times the upper limit of normal and fail to improve within 1 week with repeat testing. After discontinuing the drug, liver function tests should be monitored weekly until there is evidence of resolution.

When ATDs are discontinued, thyroid function testing should continude to be monitored at 1-3 month intervals for 6-12 months to diagnose relapse early.

Duration of antithyroid drug therapy for GD

If MMI is chosen as the primary therapy for GD, the medication should be continued for approximately 12-18 months, then tapered or discontinued if the TSH is normal at that time. A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after discontinuation of ATD therapy. Pay attention that a meta-analysis shows the remission rate in adults is not improved by a course of ATDs longer than 18 months.

Measurement of TRAb levels prior to stopping ATD therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission. Persistently high levels of TRAb and high thyroid blood flow identified by color Doppler ultrasound are also associated with higher relapse rates, and these patients should be assessed more frequently and at shorter intervals after ATDs are discontinued.

If a patient with GD becomes hyperthyroid after completing a course of methimazole, consideration should be given to treatment with radioactive iodine or thyroidectomy. However, low-dose of methimazole treatment for longer than 12-18 months may be considered in patients not in remission who prefer the ATD approach.

Myelofibrosis (Part Two)

May 7, 2013 Hematology, Pharmacotherapy, Therapeutics No comments , ,

In last blog we discussed the definition, the clinical manifestations, the biology, and the first part of the management of myelofibrosis.

Let’s review the risk evaluation of myelofibrosis. According the Dynamic International Prognostic Scoring System (DIPSS) the risk grade can be divided into 5 groups.

  • 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.

For low- or intermediate 1-risk patients without symptoms, the strategy of “watch and wait” is preferred. For low- and intermediate 1-risk patients with symptoms, if clinical needed, it is reasonable to start with conventional drug therapy.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug thearpy. We have talked about these approaches (except experimental drug therapy) in the first part. Today we focus on the experimental drug therapy or novel therapies.

Novel therapies

Pomalidomide

Pomalidomide is a thalidomide derivative classified with lenalidomide as an immunomodulatory drug. In vitro, immunomodulatory drugs antagonize angiogenesis and expression of tumor necrosis factor α and IL-6 while they facilitate production of IL-2 and interferon IFN-γ and enhance T-cell and nature killer-cell proliferation and activity;the precise mechanism of their action is not known but might include down-regulation cytokine signaling.

Due to the peripheral neuropathy or severe myelosuppression of thalidomide and lenalidomide, there was a room for improvement in both therapeutic activity and side effect profile. So pomalidomide was here.

In a phase 2 randomized study, ~ 25% of patients with anemia responded to pomalidomide alone (2mg/d) or pomalidomide (0.5 or 2 mg/d) combined with prednisone. In a subsequent phase 2 study of single-agent pomalidomide (0.5 mg/d), anemia response was documented only in the  presence of JAK2V617F (24% vs 0%) and predicted by the presence of pomalidomide-induced basophilia (38% vs 6%) or the absence of marked splenomegaly (38% vs 11%). Platelet response was seen in 58% of patients with baseline platelet count of 50-100 ×109/L, but the drug had limited activity in reducing spleen size. Unlike the case with thalidomide or lenalidomide, drug-associated neuropathy or myelosuppression was infrequent. However, higher doses of pomalidomide (> 2 mg/d) were myelosuppressive and not necessarily better in terms of efficacy.

JAK inhibitors

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).

On November 16, 2011 FDA approve ruxolitinib, a small-molecule inhibitor of JAK1 and JAK2, which is the first drug approved for the treatment of symptomatic intermediate- or high-risk myelofibrosis. For patient with symptomatic intermediate- or high-risk myelofibrosis who are not candidates for allogeneic hematopoietic stem cell transplantation, ruxolitinib is the first drug to demonstrate a significant and sustained improvement in splenomegaly and various other myelofibrosis-related symptoms. Quality-of-life measures are significantly improved with this agent, which may be its most dramatic benefit.

The recommended starting dose of ruxolitinib is based on platelet count. For patients with a platelet count of greater than 200 × 109/L, the recommended starting dose is 20 mg orally twice/day. For patients with a platelet count of 100-200 × 109/L, the recommended starting dose is 15 mg twice/day. Due to its hematologic adverse effects, interruption of treatment is warranted for patients with a platelet count less than 50 × 109/L. Once the platelet count has recovered, ruxolitinib should be restarted at the dosages in Table 1.

Table 1 Recommended Dosages for Restarting Ruxolitinib After Interruption of Therapy Due to Decreased Platelet Count

Platelet Count (× 109/L)Restarted Ruxolitinib Dosea
≥ 12520 mg twice/day
100-12415 mg twice/day
75-9910 mg twice/day
50-745 mg twice/day
< 50Withhold therapy

aRestart dose at least 5 mg twice/day less than dose before interruption.