Myelosuppressive therapy

Additional myelosuppressive therapy is required in most patients. This is indicated if frequent vene-... 

Blumenthal RD, Lew W, Juweid M, Alisauskas R, Ying Z, Goldenberg DM. Plasma FLT3-L levels predict bone marrow recovery from myelosuppressive therapy. Cancer... 

The treatment of patients with AIDS-associated lymphomas is difficult because the immunocompromised state of these patients increases their risk of significant toxicity due to myelosuppressive therapy. Except for primary CNS lymphoma, AIDS-related lymphoma is never considered truly localized, and systemic chemotherapy is indicated. For patients with adequate immune function and without a history of an opportunistic infection, chemotherapy regimens similar to those used for aggressive lymphomas may be used. " However, many patients with AIDS-related lymphoma are treated with less intensive regimens because of the increased risk of treatment-related toxicity. In the era of highly active antiretroviral therapy (HAART), however, some clinicians believe that standard doses of chemotherapy can be safely administered to patients who achieve a virologic response to HAART. 

Bendamustine is a useful antineoplastic drug for the treatment of non-Hodgkin s lymphomas, multiple myeloma and as a partner drug in the combination therapy of some solid tumors. The cross-resistance with other alkylating drugs is not complete. Myelosuppression and lymphocytopenia is its main dose-limiting toxicity. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Linezolid Myelosuppression monitor CBC once weekly if more than 2 weeks of therapy Peripheral and/or optic neuropathy has been reported with long-term therapy Mild MAO inhibitor evaluate for potential drug-drug or drug-food interactions... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Myelosuppression is the major side effect. Nausea, vomiting, and a flulike syndrome occur initially with therapy. Patients must be counseled to avoid tyramine-rich foods because procarbazine is a monoamine oxidase inhibitor. Patients should be provided a list of foods and beverages to avoid to prevent a hypertensive crisis. A disulhramlike reaction can occur with the ingestion of alcohol. 

Myelosuppression mild, anorexia, low emetoginic potential dry skin rash, photosensivity hepatotoxicity jaundice and hyperbilirubinemia occur after 1-2 months of therapy and may be dose-limiting... 

The therapy far AML is extremely myelosuppressive. Children with AML have a 10% to 20% induction mortality rate secondary to infection and bleeding complications. Therefore, patients receiving induction therapy usually are hospitalized for the first 4 to 6 weeks of therapy. The induction therapy for ALL is less myelosuppressive therefore, these patients recover their counts quicker and usually do not require prolonged hospitalizations.6... 

The most commonly used dose for fludarabine is 20 mg/m2 intravenously daily for 5 consecutive days, whereas chlorambucil can be taken daily as an oral tablet with the dose ranging from 4 to 10 mg/day.21 Fludarabine is associated with more toxicities than chlorambucil, including myelosuppression and prolonged immunosuppression.19 Resulting infectious complications may occur during the periods of prolonged immunosuppression. The ease of administration and limited side effects make chlorambucil a practical option for symptomatic elderly patients who require palliative therapy... 

Hydroxychloroquine lacks the myelosuppressive, hepatic, and renal tox-icities seen with some other DMARDs, which simplifies monitoring. Its onset may be delayed for up to 6 weeks, but the drug should not be considered a therapeutic failure until after 6 months of therapy with no... 

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

Tests for the TPMT genotype and phenotype are commercially available. Attention should be paid for those patients who test negative for TPMT status. Patients with poor or intermediate TPMT activity may tolerate only 1/10 to 1/2 of the average 6-MP dose. A pharmacoeconomic model has been developed to analyze the potential cost of screening to prevent azathioprine toxicity. In this model, it was assumed that TPMT deficiency is present in 0.3% of the population, that intermediate activity is present in 11%, and that both groups have an increased risk of developing myelosuppression. Under these circumstances, the model predicted that the costs per Caucasian patient for the first 6 mo of therapy with screening are lower... 

Fig. 13.2 Thiopurine methyl transferase (TPMT) methylator genotypes in Crohn s disease during azathioprine/6-mercaptopurine (AZA/6-MP) treatment influences the time in months to development of severe myelosuppression. However, only 27% of patients with Crohn s disease and myelo-suppression during AZA therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with AZA. (Reproduced from ref 35.)...

Colombel, J. F., Ferrari, N., Debuysere, H., et al. (2000) Genotypic analysis of thiopuiine S-methyltransferase in patients with Crohn s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 118, 1025-1030. 

Myelosuppression Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. Monitor complete blood counts weekly in patients who receive linezolid, particularly in those who receive linezolid for more than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. 

Weekly therapy may be instituted with the Rheumatrex Dose Packs, which are designed to provide doses over a range of 5 to 15 mg administered as a single weekly dose. The dose packs are not recommended for weekly doses greater than 15 mg. Tailor schedules to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Maximal myelosuppression usually occurs in 7 to 10 days. 

Myelosuppression When mitoxantrone is used in high doses (more than 14 mg/m /day for 3 days), severe myelosuppression will occur. Assure full hematologic recovery before undertaking consolidation therapy and monitor patients closely during this phase. 

Patients with preexisting myelosuppression as the result of prior drug therapy should not receive mitoxantrone unless the possible benefit warrants the risk of further suppression. 

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