Ros

The BCR/ABL oncoprotein activates—directly or indirectly—many downstream signal transduction pathways, for example, RAS, P13K, JAK-STAT, Bcl-2, BCLx, and ROS, which induce transformation, proliferation, inhibition of apoptosis, and oxida-tive damage to DNA. Additionally, cytoskeletal proteins are tyrosine phosphorylated and this results in alteration of cytoskeletal function. CML cells are less adherent and egress from the marrow into circulating blood prematurely. Figure 13-3 also depicts various cellular effects of BCR/ABL oncoprotein through downstream transduction pathways.

Several mechanisms play roles in disease progression, which lead eventually to blast crisis of CML. They include:

• Drug resistance: The mechanisms of drug resistance include (1) BCR/ABL gene amplification, (2) overexpression of BCR/ABL transcripts, (3) mutations in the ABL tyrosine kinase domain at the ATP binding site, (4) clonal evolution, and (5) drug efflux.

• Genomic instability.

• Impaired DNA repair.

• Tumor suppressor gene inactivation.

• Differentiation block.

• BCR/ABL-independent activation of more oncogenes and, thus, participation of more oncoproteins resulting in redundant pathways for proliferation, decreased apoptosis, and differentiation block.

Treatment

Treatment of Chronic Phase of CML

Supportive measures at diagnosis Metabolic problems:

Tumor lysis syndrome: Hydration, alkalinization, and allopurinol are employed (see Chapter 26).

Hyperleukocytosis: Marked hyperleukocytosis (leukocyte count >200,000/mm3 or blast count >50,000/mm3) or, if patient is symptomatic, leukapheresis is performed and hydroxyurea (50-75 mg/kg/day) is started. Imatinib is started after the diagnosis of Ph-positive CML is established. If there is an unsatisfactory response to imatinib then IFN-a or IFN-a and Ara-C may be employed. Hydroxyurea may then be gradually tapered and discontinued. Thrombocytosis: Anagrelide is used.

Priapism: Leukapheresis, analgesics, hydration, and cytoreductive therapy; hydroxy-

urea or imatinib should be used. Cytoreduction in chronic phase: Cytoreduction is achieved with the use of imatinib.

Imatinib

Imatinib mesylate (Gleevec, Glivec, ST1571) treatment has ushered in a new era in the treatment of CML. However, imatinib is not curative and allogeneic HSCT is still the treatment of choice, aimed at cure in children and young adult patients.

Mechanism of action

Imatinib inhibits ABL-tyrosine kinase by occupying the adenosine triphosphate (ATP)-binding site in the kinase domain of the ABL component of the BCR/ABL oncoprotein (see Figure 13-3). As a result of this, phosphorylation of ABL-tyrosine kinase-substrates fails to occur, and activation of downstream leukemogenic signal transduction is prevented.

Dose

• In adults: Chronic phase of CML 400 mg/day orally Accelerated phase of CML 600 mg/day orally Blastic transformation of CML 600 mg/day orally

• In children: Chronic phase of CML 340 mg/m2/day orally.

Management of side effects

Myelosuppression. Monitor complete blood counts (CBC) weekly during the first month of therapy. If absolute neutrophil count (ANC) remains greater than 1500/mm3 and platelet count greater than 100,000/mm3, then CBC can be obtained every 2 weeks until 12 weeks of therapy. Thereafter, it may be obtained once a month.

If ANC <1000/mm3 and platelet count <50,000/mm3, imatinib should be withheld until the ANC >1500/mm3 and platelet count >100,000/mm3. If recovery occurs in <4 weeks, imatinib is resumed at 400 mg/day. If recovery takes more than 4 weeks, imatinib is resumed at 300 mg/day and then increased to 400 mg/day if myelosup-pression does not occur for more than 4 weeks.

Gastrointestinal toxicity. Nausea and vomiting can be avoided if imatinib is taken with food. If it persists, antiemetics such as ondansetron or prochlorperazine can be given. Use of antidiarrheal drug may be indicated.

Edema and fluid retention. Use of diuretics may be necessary. If water retention is severe, imatinib should be discontinued until edema is controlled.

Muscle cramps, bone pain, and arthralgia. Calcium and magnesium supplements are effective in controlling muscle cramps, in spite of normal serum levels of ionized calcium and magnesium. Use of nonsteroidal anti-inflammatory drugs is effective in controlling bone pain and arthralgia. They should be given only if the platelet count is greater than 100,000/mm3. For patients with platelet counts of less than 100,000/mm3, acetaminophen may be tried cautiously or a mild narcotic could be used. A patient taking imatinib and high doses of acetaminophen has been reported to die of hepatic failure.

Skin rashes. Use of antihistamines and/or topical steroids may control rashes. Occasionally, Stevens-Johnson syndrome may develop. In that case, imatinib should be discontinued and systemic steroids started.

Hepatotoxicity. If transaminases are greater than five times the upper limit of normal (grade 3 toxicity), discontinue imatinib. It could be restarted at a reduced dose when transaminases are less than 2.5 times the upper limit of normal or bilirubin less than 1.5 times the upper limit of normal.

With recurrent grade 3 hepatotoxicity, imatinib should be permanently discontinued. If there is persistent grade 2 hepatotoxicity, screening for viral hepatitis, ferritin levels, aj-antitrypsin levels, and sonogram of liver should be performed. A liver biopsy may be indicated in some patients.

Drug interactions

Imatinib is metabolized in the liver by the CYP3A4/5 cytochrome P450 enzyme system. Main inducers of CYP3A4/5 activity, which causes a decrease in the level of imatinib, include carbamazepine, dexamethasone, phenytoin, phenobarbital, progesterone, rifampin, and St. John's wort. Drugs that inhibit CYP3A4/5 activity, which causes an increased level of imatinib, include cimetidine, erythromycin, fluoxetine, ketoconazole, ritonavir, itraconazole, verapamil, cyclosporine, clotrimazole, clar-ithromycin, azithromycin, isoniazid, and metronidazole. Grapefruit juice should also be avoided.

Imatinib is an inhibitor of CY2D6 and CYP2C9 isoenzymes. Warfarin is a substrate for these two enzymes. Therefore, when anticoagulation is needed, low-molecular-weight heparin (LMWH) should be used instead of warfarin. A physician should consult a pharmacist for drug interactions with other drugs as needed.

Hydroxyurea, busulfan, IFN-a, and IFN-a with Ara-C have been previously used for the treatment of CML, but at present imatinib is preferred for the treatment of a newly diagnosed patient in the chronic phase of CML.

Figure 13-4 shows an algorithm for the management of CML in the chronic phase in children, based on the guidelines for young adults with CML in the chronic phase, since no evidence-based guidelines are yet available for children with CML.

If IFN-a or IFN-a with Ara-C therapy is used in place of imatinib, because of unsatisfactory response to imatinib or as a matter of choice, the following guidelines are suggested.

Treatment with IFN-a

Timing of initiation of therapy: at the start of treatment. Hydroxyurea is used to reduce the WBC count to 10,000-20,000/mm3. Then IFN-a is started, following which hydroxyurea is tapered and discontinued. Dose of IFN-a: 5 x 106 (5 million) units/m2 per day subcutaneously or intramuscularly. Given daily as long as it is effective. Note: Early flulike side effects (fever, chills, postnasal drip, anorexia) are minimized by starting IFN-a at 50% of dose for the first week of treatment.

The IFN-a dose is reduced to 50% if any of the following indications of toxicity are observed:

• Development of neurologic symptoms of parkinsonism, memory change, reduced attention span

• Increase in liver enzymes more than five times the upper limit of normal

• Increase in serum creatinine to 2.5 mg/dL or more

• Decline in performance status to 80% or less on the Karnofsky scale.

Fig. 13-4. Algorithm for management of chronic-phase CML in pediatric patients.

IFN-a is discontinued when the ANC is less than 750/mm3 or the platelet count is less than 50,000/mm3 or the WBC count is less than 2000/mm3, or serious systemic toxicity develops.

Treatment with IFN-a and Ara-C

Dose of interferon-a: 5 x 106 units/m2 per day. Dose of IFN-a is modified, as per above-

mentioned guidelines. Dose of Ara-C: 20 mg/m2 per day for 10 days per month. Ara-C is discontinued when

ANC is less than 1000/mm3 or platelet count is below 60,000/mm3. Combination therapy with IFN-a and Ara-C is superior to IFN-a alone because it induces higher major cytogenetic responses (35% versus 21% at 12 months) and higher 8-year survival (56% versus 45%).

Monitoring Response to Therapy

Hematologic criteria:

Complete response: WBC less than 9000/mm3

Morphology normal Splenomegaly absent Partial response WBC less than 20,000/mm3

Splenomegaly present Failure WBC greater than 20,000/mm3

Splenomegaly present.

Cytogenetic criteria:

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