Month: July 2013

Use of White Blood Cell Growth Factors in Cancer Patients with Neutropenia

July 31, 2013 Infectious Diseases, Pharmacotherapy, Therapeutics 1 comment , ,

This post is based on the guideline of American Society of Clinical Oncology and Infectious Diseases Society of America.

Prophylactic CSF Administration

Prophylacitc CSF is recommended for the prevention of FN in patients who have a high risk of FN based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. New clinical trial data support the use of CSF when the risk of FN is in the range of approximately 20% or higher. The use of regimens, if available, that do not require CSFs because of equal efficacy and low risk of FN remains standard medical practice.

Factors predispose to increased complications from prolonged neutropenia include:

  • Patient age greater than 65 years;
  • Poor performace status;previous episodes of FN;
  • Extensive prior treatment including large radiation ports;administration of combined chemoradiotherapy;
  • Cytopenias due to bone marrow involvement by tumor;
  • Poor nutritional status;the presence of open wounds or active infections;more advanced cancer, as well as other serious comorbidities.

In such situations, prophylaxis with CSF is often appropriate even with regimens with FN rates less than 20%.

Therapeutic CSF Administration

CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. CSFs should be considered in patients with FN who are at high-risk for infection-associated complications, or who have prognostic factors that are predictive of poor clinical outcomes.

Risk Factors for Infection-Associated Complications

Clinical prediction models have been developed to help prospectively identify patients with cancer who are at higher risk of complications as a result of FN. Reported risk factors for serious medical complications in patients with established FN include:

  • The development of FN as an inpateint;
  • Hypothension;
  • Sepsis;
  • Various comorbidities, including cardiovascular and pulmonary disease;
  • Leukemia or lymphoma diagnosis;
  • Age greater than 65 years;
  • Prior fungal infection;
  • Visceral organ involvement;
  • Organ dysfunction;
  • Uncontrolled malignancy;
  • The severity and duration of neutropenia (>10 days or/and ANC<0.1 × 109/L)

Prognostic Factors for Poor Clinical Outcomes

While a number of clinical characteristics may provide prognostic information regarding the outcomes of hospitalized patients with FN, predictive models are needed to better identify high-risk patients who may benefit from the additon of adjunctive CSFs. In a multivariate model, several independent risk factors for inpatient mortality among hospitalized patients with FN have been idenfitied including:

  • Age ≥65
  • Cancer type (leukemia, lung cancer)
  • Comorbidities (CHF, PE, lung, renal, liver, and cerebrovascular disease)
  • Infectious complications (hypotension, pneumonia, bacteremia, and fungal infection)

CSF Initiation, Duration, Dosing, and Administration

CSF should be given 24 to 72 hours after administration of myelotoxic chemotherapy and should be continued until reaching an ANC of at least 2 to 3 ×109/L. In adults, the recommended CSF doses are 5 µg/kg/d for G-CSF and 250 µg/m2/d for granulocyte macrophage colony stimulating factor (GM-CSF) for all clinical settings other than PBPC (Peripheral-Blood Progenitor Cell) mobilization.

The Management of Acute Lymphoblastic Leukemia in Adults (Stratetgies)

July 22, 2013 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments ,

Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is a heterogeneous disease, both in terms of its pathology and the populations that it affects.

Prognostic Factors and Risk Categories

Several factors determine the prognosis of ALL in adults. These most important variables include initial white blood cell count, age at diagnosis, immunophenotype, genetic subset, extramedullary disease, and early treatment response/minimal residual disease.

35 years appears to be a clear prognostic cut-off. Age older than 35 years decreases the chance of remission as well as increases the risk of relapse in patients given conventional chemotherapy. Presenting white cell count (>30 × 109/L for B-cell disease and >100 × 109/L for T-cell disease) is a poor prognostic factor. Immunophenotype: T-cell disease has a better outcome than B-cell disease in adults.

Ph chromosome, t(4;11), t(8:14), complex karyotype (defined as 5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy are also poor prognostic factors too. The presence of the Ph chromosome affects the chance of remission after induction, as well as the risk of relapse, when using conventional chemotherapy.

Minimal residual disease (MRD) in adult ALL could be detected by both molecular and immunophenotypic methods, which can reliably detect the presence of residual ALL at levels of less than 0.01%. The presence of detectable MRD by molecular methods after completion of both phases of induction predicts for a poor prognosis even in patients with standard-risk group. One study reported that patients with standard-risk ALL who had a rapid decline in MRD within the first month of therapy had a 0% 3-year relapse rate while those with molecular persistence of ALL by week 16 of therapy had a 94% 3-year relapse rate. Another study showed that > 8 weeks to CR1 was associated with a poor survival. In the MRC-ECOG UKALLXII/EC2993 trial time to attain CR > 4 weeks is defined as a high risk criteria.

However, the significance of many prognostic factors changes with improvements in treatment. For example, the outcome for both children and adults with Ph+ ALL has improved substantially with the addition of tyrosine kinase inhibitors to the treatment. Recently, children with Ph+ genotyp treated with chemotherapy and imatinib (without allo-SCT) had a 3-year event-free survival (EFS) of over 80%. If the favorable outcome is confirmed with longer follow-up, the Ph chromosome may join a long list of other factors such as male sex and African-American ethnicity that have lost adverse prognostic impact with improved treatment in childhood ALL.

More recently, the application of microarray-based, genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, re-sequencing and epigenetic approaches, has identified specific genetic alterations with biologic and therapeutic implication.

Table 1 Prognostic Factors Used in Pediatric and Adult Clinical Trials

Of note that there are no “low risk” group in ALL. Instead, there are standard risk group and adverse risk group.

Molecular Monitoring For MRD

Several investigators have introduced more sensitive molecular techniques such as clonal immunoglobulin or T-cell receptor gene rearrangements to detect MRD that can accurately predict relapse in patients with ALL. Pediatricians have recognized that molecular persistence of residual ALL at the end of induction chemotherapy or afterward effectively predicted relapse independent of other risk factors.

Molecular marker monitoring has been used less extensively in adult ALL but appears to be an extremely powerful tool that has yet to be exploited.

Update from Medscape on Sep 19th 2013

Multiparameter flow cytometry and real-time quantitative polymerase chain reaction (qPCR) are two coming techniques that might make routinely monitoring for MRD possible. (Original from http://www.medscape.com/viewarticle/808782?nlid=32288_330&src=wnl_edit_medn_honc&uac=180112PN&spon=7)

Treatment Strategies for ALL

Contrary to the excellent results achieved in pediatric patients, the outcomes for ALL in adult patients are disappointing. While in recent multicenter trials more than 90% of adult patients with ALL younger than 60 years attain CR, conventional chemotherapy is a long arduous process and will result in long-term survival in only one-third of patients.

Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Induction chemotherapy is used first to reduce the burden of lymphoblasts in the bone marrow and to restore normal hematopoietic funtion. Consolidation therapy (also termed intensification) is used with the intention of clearing any drug-resistant leukemia cells that have survived induction therapy and to eliminate minimal residual disease (MRD). Maintenance chemotherapy consists of 2 to 3 years of low-dose antineoplastic drugs designed to prevent leukemia relapse during the crucial few years after remission induction and consolidation. Finally, central nervous system (CNS) prophylaxis is necessary to treat sanctuary sites that are shielded from systemic thearpy by the blood-brain barrier.

Induction Therapy

The induction chemotherapy is determined according to Ph status. For Ph-negative ALL patients, regimens comprise steroid, vincristine, and L-asparaginase, usually with anthracycline (up to 2 to 3 times the dose given in pediatric protocols) and often with the addition of cyclophosphamide and cyarabine. Comparable rates of complete remission (CR) of approximately 85% to 95% and treatment-related mortality (TRM) are seen in all published regimens, which is between 5% and 10% —— much higher than the <1% in children.

25% of all adults are Ph+ chromosome ALL. For Ph-positive patients with ALL, the induction therapy dose not differ from that for Ph-negative patients, except the addition of tyrosine kinase inhibitor (TKIs) imatinib. Studies show imatinib has improved the CR rate to >90% and makes more patients eligible for transplant. One studieMust to mention that in the latest NCCN guideline for ALL, the addition of one of TKIs to induction therapy, consolidation therapy, and maintenance therapy, respectively, has been the standard of care.

An alternative induction therapy is the hyper-CVAD regimen comprising hyper-fractionated cyclophosphamide, vincristine, doxorubicin (that is adriamycin), and dexamethasone, which reported a CR rate in excess of 90%.

Table 3 Common Chemotherapy Regimen for ALL

Regimen
BFM/COGvincristine, anthracycline, corticosteroid, L-asparaginase
CALGBvincristine, anthracycline, corticosteroid, L-asparaginase+cyclophosphamide
hyper-CVAD Ahyper-fractionated cyclophosphamide, vincristine, dexorubicin, dexamethasone
hyper-CVAD Bhigh-dose methotrexate, cytarabine

For adolescents young adults (AYA) with ALL, there are increasing data that suggests that this group of patients treated with adult ALL protocols have a worse outcome than similar patients treated on pediatric protocols (two studies, the age of enrolled patients are 15-21, 16-20, respectively). A “pediatric” approach to therapy gives superior survival than an adult approach in adolescents with ALL. According to a study published in the May issue of the American Journal of Hematology, Ron Ram et al. found that adolescent and young adult patients with acute lymphoblastic leukemia (ALL) who were treated with pediatric-inspired regimens exhibit lower all-cause mortality, higher complete remission and event-free survival rates, and lower relapse rates compared with those treated with conventional adult-chemotherapy regimens. Some results of certain trials are listed in Table 2.

However, definition of the age range that encompasses the AYA patient is itself controversial, because the age range described in the literature for this population varies depending on the study. In recent studies, the age range was set up to 30 yrs or even up to 40 yrs. Of note, the latest NCCN guideline for ALL suggests that the age of 40 is the cut-off between AYA and “older” adults.

Postremission Therapy

Consolidation/maintenance therapy for adults is based on that used in pediatric regimens. No randomized studies usefully address the benefits of the number or composition of consolidation cycles in adult ALL. Consolidation/intensification with high-dose methotrexate 1.5 to 3 g/m2, somethimes in conjunction with L-asp (L-asparaginase), is commonly used and is an important component of central nervous system (CNS)-directed therapy.

Maintenance therapy remains obligatory in those not undergoing allo-SCT. Daily mercaptopurine, weekly methotrexate and pluses of monthly vincristine and steroids for 18 to 24 months after consolidation is standard.

CNS-Directed Therapy

CNS involvement occurs in 5% of adults at diagnosis and although it impacts on survival (29% vs 38%; P = .03), it is unclear how much prophylactic CNS-directed therapy is required. Most protocols do not now give CNS irradiation, and 4 to 6 intrathecal doses of chemotherapy and high-dose methotrexate seem to be adequate to prevent CNS relapse. However, there are no data on the most efficacious drug or drug combination in adults to CNS-directed therapy. For patients proceeding to TBI-containing allograft regimens, intrathecal chemotherapy alone is sufficient. More prophylaxis may be required with RIC regimens, but this remains untested. CNS involvement is more common with high WBCs, T-cell disease, and a mediastinal mass.

The role of cranial irradiation in providing CNS-directed prophylaxis in adults is difficult to gauge. In the pediatric group, cranial irradiation is now used very infrequently. CNS relapse is now sufficiently infrequent as to render the numbers of patients required to evaluate this in a randomized manner pragmatically impossible.

Hematopoietic Stem Cell Transplantation

The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia is not clear-cut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in CR. Those considered to be at high risk for relapse often are considered for HSCT in CR1 while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor.

During the past 14 years the MRC/ECOG study has assigned allo-SCT to all adult patients, including those with standard-risk ALL, who had an HLA-compatible sibling. The final data were recently reported and showed an unequivocal benefit for HLA-compatible sibling transplantation for patients with standard-risk ALL over other forms of conventional therapy, whether this is consolidation or maintenance therapy or an auto-SCT. The transplantation was performed as soon as possible after successful induction.

Table 4 Recommedations for HSCT of ALL Patients

However, there is a consideration that all standard-risk patients in MRC/ECOG trial were treated with a typical adult regimen rather than a pediatric-like regimen, so the benefit of allo-SCT for AYA group after indcution therapy of a pediatric-like regimen remains open. However, the data recently reported by Dana-Farber Cancer Institute in Boston, Massachusetts, for 51 adolescent patients aged 15 to 18 years showed a remarkable event-free survival of 78% in this population. This is clearly better than anything else that has been reported to date, and, if such data are confirmed in an unselected population, there clearly will be no role for an allogeneic transplantation in this age group.

Impact of Age to allo-HSCT

Although the risk of relapse decreases with allo-SCT, the concomitant treatment-related mortality (TRM) might eliminate the potential survival benefit under some conditions. TRM among “high-risk” patients was sufficient in magnitude to abrogate a survival advantage in this group despite the evident anti-leukemia activity of the procedure indicated by the reduction in relapse risk.

The UKALLXII/ECOG2993 study found that patients with sibling donors who were Ph-negative had an 8% higher chance of survival at 5 years, irrespective of risk status, but the benefit of allo-HSCT was apparently confined to those with “standard risk” disease. The reason for this might be that since one of the criteria for “high-risk” is age greater than 35 years and given that advancing age also confers the highest risk of TRM, this is probably the main reason for lack of survival advantage in the “high-risk” group. To date, the threshold at which TRM exceeds reduction in relapse risk may be as low as 35 to 40 years of age.

For high-risk Ph patients (age < 35 to 40) without sibling donor, whether the benefits of using a sibling-matched allogeneic HSCT can be extended to un-related donor allogeneic HSCT is still open and need more investigation.

Table 5 MRC-ECOG Trial: Outcome after allo-HSCT in Ph Patients

Allo-HSCT: Matched Unrelated Donor

Allo-HSCT is particularly effective in Ph+ patients.

Accumulated evidence of the very poor results of treating this disease with chemotherapy alone, accompanied by reports from retrospective series of allo-HSCT suggest that myeloablative therapy, with a TBI-based conditioning regimen followed by sibling allo-HSCT, represents the current best available treatment option for appropriately aged patients with Ph+ ALL in CR1. The MRC-ECOG UKALLXII/EC2993 trial for Ph-positive ALL patients undergoing URD allo-HSCT showed that  at 5 years there was no statistically significant difference in OS or in cause of death between those receiving sibling allo-HSCT and those receiving matched unrelated donor allo-HSCT.

Reduced-intensity Conditioned allo-HSCT

There are few publish large-scale data about the efficacy of reduced-intensity allografting for older patients with ALL. The success of RIC allo-HSCT is likely to be disease burden dependent; absence of MRD at the time of transplant may be of crucial importance although this has not been formally studied. Preliminary, retrospective data do not provide sufficient basis for recommending RIC allografts in older or more infirm patients with ALL in CR1. This approach merits consideration, but careful prospective study is still requried to define its role.

Autologous HSCT

The MRC-ECOG UKALLXII/E2993 trial compared 446 CR1 patients randomized to undergo either an autologous HSCT (N = 233) or 2.5 years of maintenance therapy (N = 223). EFS was statistically superior for the chemotherapy-treated patients, 42% versus 33% (P = .02). While OS also was improved in the chemotherapy group (47% versus 37%), in which the evidence showed that autografting in CR1 is inferior to continuous maintenance chemotherapy. An analysis of > 300 patients in three French trials also found no advantage for autografting. Therefore, routine use of autologous HSCT in adult patients with ALL is not recommended.

Table 5 Response Criteria for Acute Lymphoblastic Leukemia

Antimicrobial Therapy in Neutropenic and Fever Patients With Cancer (Risk Evaluation and Initial Therapy)

July 16, 2013 Infectious Diseases, Therapeutics 4 comments

This thread is based on the guideline from IDSA (Infectious Diseases Society of America) and ASCO (American Society of Clinical Oncology), which provides a general approach to the management of patients with cancer who have neutropenia and present with fever, and it gives special attention to antimicrobial management.

Fever occurs frequently during chemotherapy-induced neutropenia: 10%-50% of patients with solid tumors and >80% of those with hematologic malignancies will develop fever during ≥1 chemotherapy cycle associated with neutropenia. Most patients will have no infectious etiology documented. Clinically documented infections occur in 20%-30% of febrile episodes;common sites of tissue-based infection include the intestinal tract, lung, and skin. Bacteremia occurs in 10%-25% of all patients, with most episodes occurring in the setting of prolonged or profound neutropenia.

Table 1 Common Bacterial Pathogens in Neutropenic Patients

Drug-resistant gram-negative bacteria species are causing an increasing number of infections in febrile neutropenic patients. ESBL genes, acquired primarily among Klebsiella species and E. coli strains, confer a broad range of β-lactam antibiotic resistance. The ESBL pathogens are often only susceptible to carbapenems, such as imipenem or meropenem. Carbapenemase-producing isolates of Klebsiella species and P. aeruginosa have been reported to cause infections that are resistant to carbapenems.

In addition, resistant gram-positive pathogens, such as MRSA and VRE, have become more common and are the most prevalent resistant isolates in some centers, accounting for 20% and slightly >50% of episodes, respectively. Penicillin-resistant strains of S. pneumoniae and of viridans group streptococci are less common but may cause severe infections.

Fungi are rarely identified as the cause of first fever early in the course of neutropenia; rather, they are encountered after the first week of prolonged neutropenia and empirical antibiotic therapy. Yeasts may cause superficial infections of mucosal surfaces; chemotherapy-induced mucositis, in turn, may disrupt this barrier, allowing yeasts to enter the bloodstream. Molds, such as aspergillus, are most likely to cause life-threatening infection of the sinuses and lungs, typically after≥2 weeks of neutropenia.

Definitions

Fever is defined as a single oral temperature measurement of ≥38.3℃ (101℉) or a temperature of  ≥38.0℃ (100.4℉) sustained over a 1-h period. Neutropenia is defined as an ANC of <500 cells/mm3 or an ANC that is expected to decrease to <500 cells/mm3 during the next 48 h. “Profound” is used to describe neutropenia in which the ANC is <100 cells/mm3.

During fever and neutropenia, no specific drug or combination of drugs and no specific period of treatment can be unequivocally recommended for all patients. Rather, the recommendations outlined in these guidelines are generally applicable in most clinical situations but, in some instances, will require modifications according to circumstances and local epidemiologic data.

The Management of Fever with Neutropenia

Risk assessing

To assess the risk of patients with  FN, a serial specific tests and cultures should be performed.

Patients with respiratory signs and symptoms should have a chest radiograph to rule out pneumonia. Pneumonia during neutropenia can progress rapidly to respiratory compromise and therefore should be managed in the inpatient setting. CT of other areas should be performed as clinically indicated.

Laboratory tests should include a CBC count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin.

Blood culture. At least 2 sets of blood cultures are recommended. Because the total volume of blood cultured is a crucial determinant of detecting a bloodstream infection, each set of blood culture should consist 20 mL of blood, which is divided into 1 aerobic and 1 anaerobic blood culture bottle. If a CVC exist, a set of bllod culture should be obtain from the catheter in order to diagnose catheter-related infection. Without CVC, 2 blood culture should be obtained from separate venipunctures. Of note that a single blood culture positive for coagulase-negative staphylococci should generally be dismissed as attributable to a contaminant, assuming that a second set of blood specimens have been drawn that have negative culture results. Culture of other sites including stool, urine, CSF, skin, and/or respiratory specimens should be guided by clinical signs and symptoms but should not be performed routinely.

Generally, cancer patients with FN can be categorized into high-risk group and low-risk group. The risk evaluation is according to the patient’s degree (druation and severity) of neutropenia, clinical stability, medical co-morbidities, age, underlying cancer, and/or the intensity of chemotherapy.

Patients with any of the following criteria are considered to be at high risk for serious complications during FN.

  • Profound neutropenia (ANC ≤100 cells/mm3) anticipated to extend >7 days
  • Presence of any co-morbid problems including but not limited to:
  1. Hemodynamic instability;
  2. Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea;
  3. Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea;
  4. Neurologic or mental-status changes of new onset; Intravascular catheter infection, especially catheter tunnel infection;
  5. New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease.
  • Evidence of hepatic insufficiency (defined as aminotransferase levels >5 × normal values) or renal insufficiency (defined as a creatinine clearance of <30 mL/min)

Also, MASCC scoring system could be the alternative way to evaluate the risk, which is a summation of weighted risk factors. High risk patients have a MASCC sore <21.

Table 2 The Multinational Association for Supportive Care in Cancer Risk-Index Score

Patients are considered to low-risk when neutropenia is expected to resolve within 7 days and no active medical co-morbidity, as well as stable and adequate hepatic function and renal function. In general, any patient who dose not strictly fulfill criteria for being at low risk should be treated according to guidelines for high-risk patients. Patients who are at low risk by MASCC criteria should have a MASCC score ≥ 21.

Initial Therapy

The goal of initial empirical antibiotic therapy is to prevent serious morbidity and mortality due to bacterial pathogens, until the results of blood cultures are available to guide more precise antibiotic choices. However, recent studies showed that only 23% of FNE are associated with bacteremia. Frequencies of gram-positive, gram-negative, and polymicrobial bacteremia were approximately 57%, 34%, and 9%, respectively.

Despite decades of well-performed clinical trials, no single empirical therapeutic regimen for the initial treatment of febrile patients with neutropenia has emerged as clearly superior to others. All effective empirical antibiotic regimens share certain essential features, including bactericidal activity in the absence of white blood cells, anti-pseudomonal activity, and minimal toxicity.

Routine empirical coverage of this broad range of bacteria is not possible. Rather, the aim is to cover the most likely and most virulent pathogens that may rapidly cause serious or life-threatening infections in a given patient. Once blood culture results and organism suscepibilities are available, usually within several days after blood samples are drawn, they may direct a more specific choice of antibiotics. However, in a majority of cases blood culture results are negative and in these cases empirical antibiotics are generally continued until ANC recovery is imminent or until an infection requiring alternative antimicrobial coverage is identified.

High Risk

High-risk patients requrie inpatient management with IV broad-spectrum antibiotic therapy that covers P. aeruginosa and other serious gram-negative pathogens. Monotherapy with an anti-pseudomonal β-lactam agent, such as cefepime, a carbapenem, or piperacillin-tazobactam are each as effective as multidrug combinations and are recommended as first-line therapy.

      Table 3 Indication for Additon of Antibiotics Active Against

Gram-Positive Organisms to the Empirical Regimen for FN

Vancomycin is not a standard part of empirical antibiotic therapy for FN, since studies show that initial regimen with vancomycin has no significant reduction in either duration of fever or overall mortality compared with control. And due to the epidemiological link between overuse of vancomycin and the development of drug resistance in Enterococcus species and S. aureus. However, there are specific circumstances that warrant the addition of vancomycin (or another antibiotic with enhanced gram-positive coverage) to the initial empirical regimen for FN, which is listed in table 3.

Other newer gram-positive agents have no proven role in routine empirical coverage too. Accordingly, they should be used only for target thearpy of specific pathogens.

If vancomycin or another gram-positive active agent is added to the initial regimen for clinical reasons, it should be discontinued 2 or 3 days later if susceptible bacteria are not recovered from the patient.

Modification to initial empirical thearpy may be considered for patients at risk for infection with the following antibiotic resistant organisms including:

MRSA: Consider early addition of vancomycin, linezold, or daptomycin

VRE: Consider early additon of linezolid or daptomycin

ESBLs: Consider early use of a carbapenem

KPCs (Klebsiella pneumoniae carbapenemases): Consider early use of polymyxin-colistin or tigecycline

Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-tupe hypersensitivity reaction should be treated with a combination that avoids β-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin.

Low Risk

These patients can be treated with oral broad-spectrum antibiotics. In general, the use of oral antibiotics may be considered only for patients who fulfill clear criteria for being at low-risk for complications during neutropenia. Those with MASCC score ≥ 21 with no other risk factors in Table 4 could be managed as outpatient, however, inpatient treatment is the standard approach for managing an FNE.

Table 4 Additional Specific Clinical Criteria That Exclude Oncology Patients With FN From Initial Outpatient Care Even With a MASCC Score ≥ 21

If outpatient management is prescribed, then vigilant observation and prompt access to appropriate medical care must also be ensured 24 h a day, 7 days a week. Preferably, patients whose clinical conditions worsen should be able to reach their local medical facility within 1 h.

Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. However, patients receiving fluoroquinolone prophylaxis and become febrile later should not receive oral empirical therapy with a fluoroquinolone.

Anti-infection Prophylaxis in Cancer Patients With Neutropenia (Drug Selection)

July 12, 2013 Chemotherapy, Hematology, Infectious Diseases, Pharmacotherapy, Therapeutics, Transplantation 19 comments , , ,

Because evidence was unavailable from trials limited to outpatients, the ASCO Panel considered evidence from studies on inpatients or mixed populations, and the recommendatons are based on the summarized evidence and Panel members’ expert opinion.

Antibacterial Prophylaxis

Majority of randomly assigned patients in studies were hospitalized and treated for hematolgic malignancies. Taken together, evidence shows that systemically absorbed fluoroquinolones are more tolerable than other antibacterials investigated for prophylaxis in neutropenic oncology patients and are as efficisous yet more tolerable when used alone as when combined with other antibacterials active against Gram-positive organisms. Of note, use of a nonabsorbable antibacterial also significantly increased the number of microbiologically documented infections, Gram-negative infections, Gram-positive infections, bactermia, and overall adverse effects.

The Panel recommends use of an orally administered, systemically absorbed fluoroquinolone for antibacterial prophylaxis. Prophylaxis should be administered from the first day of the cytotoxic antineoplastic regimen unitl myeloid reconstitution. However, routine antibacterial prophylaxis should be avoided when expected duration of neutropenia is < 7 days, the severity is less than profound, and none of the risk factors list in table 1 in the post of risk evaluation and patient selection are present.

Also if antibacterial prophylaxis is given, a strategy to systematically monitor for fluoroquinolone resistance among Gram-negative bacilli in environments where fluoroquinolones are being deployed.

Antifungal Prophylaxis

Results from clinical trial show that a majority of patients benefit from antifungal prophylaxis with orally absorbable or parenteral drugs versus controls receiving placebo, no treatment, or nonabsorbable oral drugs. These patients were at high risk for invasive Candida infection or aspergillosis resulting from long periods (≥ 7 days) of severe to profound neutropenia as a consequence of induction therapy for acute leukemia or HSCT.

The Panel recommends an orally administered triazole (fluconazole, itraconazole, posaconazole, or voriconazole) or an echinocandin administered parenterally (micafungin or caspofungin) for antifungal prophylaxis. Note that more trials of antifungal prophylaxis with more randomly assigned oncology patients at risk for IFIs have investigated fluconazole than any other orally absorbed or parenterally administered antifungal drug.

PCP Prophylaxis

Meta-analysis found that TMP-SMX decreased the incidence of documented PCP, and PCP-related mortality versus controls receiving placebo, no treatment, or an antibacterial drug inactive against Pneumocystis. Also, additional meta-analyses showed no statistically significant differences between those randomly assigned to TMP-SMX and those randomly assigned to placebo or no treatment with respect to any adverse events or adverse event causing patients to discontinue treatment.

The Panel recommends using any of the published daily, twice per week, or three times per week schedules of TMP-SMX during the period of immunodeficiency: from engraftment until day 180 for those undergoing allogeneic HSCT, from initiation of induction therapy in acute lymphoblastic leukemia until completion of all antileukemic therapy. For patients who may be hypersensitive or unable to tolerate TMP-SMX for any reasons, alternatives may include dapsone, aerosolized pentamidine, or atovaquone.

Virus Reactivation Prophylaxis

HBV

It is recommended that an antiviral nucleoside analog with demonstrated activity against HBV as prophylaxis for those at substantial risk for reactivation of HBV infection. Studies reported statistically significant decreases in HBV reactivation and HBV-related hepatitis with lamivudine prophylaxis in patients at risk. The approach is to start therapy 1 week before chemotherapy begins and continuing for at least 6 months after chemotherapy ends.

HSV and VZV

It is recommend to use a nucleoside analog to prevent herpesvirus infection in those at risk from the initiation of cytotoxic therapy until myeloid reconstitution.

Finally, influenza immunization is recommended for all patients undergoing treatment for malignancy and for all family and household contacts. Trivalent inactivated vaccine should be used. In select circumstances after proven exposure of a susceptible patient with cancer, a neuraminidase inhibitor may be offered.

The Management of Therapy-related Acute Meyloid Leukemia

July 1, 2013 Chemotherapy, Cytogenetics, Hematology, Transplantation No comments

Until recently, the term “secondary leukemia” broadly included any AML with a history of prior malignancy as well as patients with any antecedent hematologic disorder and, in some series, any patient who presented with unfavorable cytogenetics.

Among therapy-related AML patients, 70% present with abnormalities of chromosome 5 or 7, which is the most typical presentation after the exposure to alkylating agents and/or ionizing radiation; 30% are those that arise after treatment with topoisomerase-2 inhibitors.

In general, the management of therapy-related AML is fraught with uncertainty because, among other reasons, most early studies included small numbers of patients and were retrospective. There have been no prospective randomized studies specifically directed at the treatment of therapy-related leukemias. Furthermore, the published data often included patients with myelodysplastic syndromes.

Induction Therapy

Hisytorically, it was presumed that every patient with therapy-related leukemia had an adverse prognosis and that standard induction therapy was inappropriated. However, there is no evidence that any induction therapy is superior to the standard 3+7 regimen. Among young adults, quite remarkably, prospective studies report an almost identical CR rate of 55% to 60% for patients treated with recognized unfavorable cytogenetics, and there are no reports that anything is better than this. Standard induction should remain the induction therapy regimen.

Postremission Therapy

Figure 1 AML in Patients Less Than 60 Years of Age.

It is still somewhat controversial whether thearpy-related AML has a prognosis that is intrinsically worse that de novo AML, independent of cytogenetics. In a very large database, the National Cancer Research Institute in Great Britain reported a significantly worse outcome for therapy-related AML than de novo AML, within each cytogenetic risk group (favourable, intermediate, and adverse). But, still, the management of patients with therapy-related AML should be guided by the cytogenetic and molecular features, which is the same as de novo AML.

Although there is a perception that any patient with therapy-related AML should be considered at high risk and referred to an allogeneic transplantation, there is no evidence that the long-term outcome for patients who present with a favorable karotype, with no adverse molecular features, is different from patients with the de novo AML. Thus, such patients with favorable category should not be referred to an allogeneic transplantation in CR1.