Radioimmunotherapy involves the binding of a monoclonal antibody to a radioisotope. The antibody binds to the target cell while the radioactive portion of the molecules attacks not only the cells to which the antibody is bound but also the cells that are not accessible to the antibody or those that do not express sufficient antigen for the antibody to bind to them. The two radioimmunotherapy agents currently available for the treatment of leukemia and lymphoma are yttrium-90-ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 tositumomab (Bexxar).
The radioimmunotherapy agent 90Y-ibritumomab is approved for the treatment of relapsed or refractory follicular and low-grade NHL. In a small study of patients with rituximab(Drug information on rituximab)-refractory indolent lymphomas, the ORR with 90Y-ibritumomab tiuxetan was 74%, with a CR rate of 15%. 90Y-ibritumomab tiuxetan has produced a higher ORR (80% vs 56%) and CR (30% vs 16%) when compared with rituximab in rituximab-naive patients with relapsed or refractory follicular or low-grade lymphomas. 90Y-ibritumomab tiuxetan has also been approved as consolidation therapy for patients with follicular lymphoma who have achieved a CR or PR to initial chemotherapy. 90Y-ibritumomab tiuxetan may also have a role in the transplant setting, where it has been used in lieu of total body irradiation.
Toxicity. The most significant toxicity with radioimmunotherapy is delayed myelosuppression, which occurs at approximately 6 to 8 weeks after therapy. Because of the risk of severe myelosuppression, patients who have significant cytopenias (ie, absolute neutrophil count < 1,500/mm3, platelets < 100 × 109/L, hemoglobin < 9 g/dL, > 25% disease involvement of marrow, or prior radiotherapy to > 25% of marrow) are not candidates for these agents. It is not clear if these agents induce secondary acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).
90Y-ibritumomab tiuxetan is given in combination with rituximab, therefore all of the side effects caused by rituximab are also possible with 90Y-ibritumomab tiuxetan, including infusion reactions during the administration of rituximab, reactivation of hepatitis B, tumor lysis syndrome, and myelosuppression. The myelosuppression can be more serious; it usually begins to occur during the first month after treatment, is the most significant during the second month, and resolves during the third month after treatment.
Serious infusion reactions with the 90Y-ibritumomab tiuxetan have been reported, including swelling of the lips, tongue, or face; difficulty in breathing; and hypotension. Lung problems such as shortness of breath, wheezing, sudden difficulty breathing, or increased coughing have also been reported, along with cardiac manifestations such as chest pain and irregular heartbeats. Bruising and unusual bleeding have also been reported.
Tositumomab/131I-tositumomab is approved for the treatment of CD20-positive rituximab- and chemotherapy-refractory lymphomas. It has been reported to induce an ORR of 65% and a CR rate of 20% in patients with NHL who were rituximab-naive and refractory to chemotherapy. It has also been shown to have a 95% ORR, including a 75% CR rate, when given as frontline therapy for follicular lymphoma. In addition, 131I-tositumomab has been used as consolidation following CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) [Adriamycin], vincristine [Oncovin], and prednisone(Drug information on prednisone)) therapy in patients who achieved a CR or PR.
Toxicity of Tositumomab and 90Y-Ibritumomab Tiuxetan
As previously mentioned, the most common toxicity related to radioimmunotherapy is delayed myelosuppression. Both tositumomab and 90Y-ibritumomab tiuxetan share this toxicity with similar rates and degree of toxicity. The majority of patients who receive tositumomab experience severe cytopenia, which can be prolonged. Adverse reactions to tositumomab consist mainly of hypersensitivity reactions such as fever, rigors, chills, sweating, nausea, dypsnea, and bronchospasm, along with anaphylaxis. The hypersensitivity reactions occur in approximately 29% of patients within 14 days of treatment and can be managed by slowing or interrupting the infusion.
Hypothyroidism has been reported in 18% of patients who receive tositumomab. Cases of myelodysplastic syndrome, leukemias, and other malignancies have been reported following treatment with tositumomab; however, development of secondary malignancies has not been established as a risk for patients treated with tositumomab.
Tyrosine Kinase Inhibitors
Three tyrosine kinase inhibitors (TKIs) are currently approved for treatment of chronic myeloid leukemia (CML). Development of the TKIs has changed the prognosis of patients with newly diagnosed CML. Imatinib(Drug information on imatinib) (Gleevec) was the first TKI to be FDA-approved for the management of CML. Imatinib is administered at a dose of 400 mg/day. In IRIS (International Randomized Study of Interferon Versus STI571 [imatinib]), which investigated more than 500 patients with CML, at 84 months reported overall survival with imatinib was 86.4%, and progression-free survival was 81.2%. Imatinib was approved by the FDA for front-line treatment of CML in December 2002. Since then, two other TKIs have been approved for the management of CML, including the imatinib derivative nilotinib(Drug information on nilotinib) (Tasigna) and the dual-specific SRC and BCR-ABL inhibitor dasatinib(Drug information on dasatinib) (Sprycel). Patients who fail to respond to initial treatment with imatinib or who do not tolerate it have a very high rate of response to treatment with one of the second-generation TKIs (nilotinib or dasatinib). Nilotinib and dasatinib are more potent inhibitors of BCR-ABL than imatinib, with approximately 30-fold and 100- to 300-fold greater potency, respectively, shown by in vitro studies.
Nilotinib was tested in a phase III trial, ENESTnd (Evaluating Nilotinib Efficacy and Safety in clinical Trials—newly diagnosed Patients), in which two different doses of nilotinib (300 mg or 400 mg twice daily) were compared with imatinib (at 400 mg daily). The rate of major molecular response by 12 months was 27% with imatinib and 55% or 51% for the 300-mg and 400-mg dosing schedules, respectively. The rates of progression to accelerated phase (AP) or blast crisis (BC) were 3.9% for imatinib and 0.7% and .04% for nilotinib at the 300-mg and 400-mg doses, respectively.
In DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients), dasatinib at 100 mg was compared with 400 mg once-daily imatinib. The 12-month and 18-month data from the DASISION trial demonstrated superior responses with dasatinib, with a major molecular response by 12 months of 28% with imatinib and 46% with dasatinib. In contrast, the rate of progression to AP or BC was 3.5% with imatinib and 1.9% with dasatinib. Both agents are approved not only for second-line therapy but also for front-line therapy. Point mutations can cause a loss of sensitivity to the TKIs. At least 90 mutations have been identified and occur in up to 90% of patients who develop resistance to imatinib. The T315I mutation is resistant to all three of the TKIs.
Toxicity of the TKIs
The side effects of treatment with the TKIs can include cardiac, renal, and dermatologic effects, as well as fluid retention (see Table 2). Some of the side effects are due to drug–drug or food–drug interactions. All three TKIs are metabolized by CYP3A. Inducers of CYP3A4 may decrease the plasma concentration of the TKIs, while inhibitors of CYP3A4 can reduce the rate of TKI metabolism and increase the plasma concentration. In addition, the TKIs can alter the concentration of other common medications such as acetaminophen, alfentanil(Drug information on alfentanil), cyclosporine, diergotamine, dihydropyridine, ergotamine, fentanyl(Drug information on fentanyl), select statins, pimozide, quinidine, simvastatin(Drug information on simvastatin), sirolimus(Drug information on sirolimus), tacrolimus(Drug information on tacrolimus), triazolobenzodiazepines, and warfarin(Drug information on warfarin). Myelosuppression commonly occurs early after the initiation of any of the three of the TKIs. Complete blood counts should be obtained weekly for the first month, biweekly for the second month, and periodically thereafter.
Imatinib toxicities. In patients receiving imatinib, approximately 15% experience liver dysfunction, with 8% experiencing grade 3 or 4 toxicity. While altered liver function tests can occur with imatinib, this effect is reported less commonly than with nilotinib, as reported in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) Trial; however, the incidence of decreased phosphate is higher with imatinib. Mild to moderate edema is not unusual in patients receiving imatinib. The most common site of edema is periorbital edema, but this is rarely severe. Patients should be weighed regularly and unexpected rapid weight gain should be managed with interruption of the imatinib. Treatment for most cases of imatinib-associated edema consists of the administration of diuretics, along with dose reduction of the imatinib.
Early studies suggested that imatinib may be cardiotoxic and lead to severe left ventricular dysfunction and congestive heart failure. In a study by Kerkela et al, only 1.7% of patients receiving imatinib experienced symptoms that could be attributed to systolic heart failure. Therefore, it has been concluded that the risk of heart failure related to imatinib is uncommon and is mainly seen in elderly patients who have pre-existing cardiac conditions. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated as necessary. While routine EKG monitoring is not recommended, monitoring of patients with cardiac disease or signs and symptoms of cardiac dysfunction is recommended.
In addition, nausea, vomiting, diarrhea is common among the TKIs but more common with imatinib.
Cutaneous reactions to imatinib are common and have been reported in 9.5% to 69% of patients in various studies. Rashes are reported in 32% to 39% of patients, with Stevens-Johnson syndrome being reported in a small number of patients receiving imatinib. The majority of dermal reactions from imatinib do not require discontinuance of imatinib and are usually self-limiting.
Nilotinib toxicities. Food can increase blood nilotinib levels, so food should be avoided 2 hours before and 1 hour after a dose of nilotinib. Liver dysfunction has also been reported with nilotinib. The rates of biochemical abnormalities, including altered liver function studies, is higher than that reported with imatinib in the ENESTnd Trial. In addition, serum lipase elevations have been reported with nilotinib.
There is an increased risk of cardiac toxicity with nilotinib. Nilotinib has a black-box warning for QT prolongation and sudden death. Electrocardiograms should be obtained at baseline, at 7 days, and periodically thereafter, as well as following any dose adjustment of nilotinib. Hypokalemia and hypomagnesemia must be corrected prior to starting treatment with nilotinib, and then periodically. Other drugs known to prolong QT interval should be avoided.
While rash can occur from each of the TKIs, the incidence seems to be higher with nilotinib than with imatinib.
Dasatinib toxicities. There also is a warning in the dasatinib package insert regarding QT prolongation with dasatinib, and this agent should be used with caution in patients who have or may develop a prolonged QT interval. While routine EKG monitoring is not recommended, monitoring of patients with cardiac disease or signs and symptoms of cardiac dysfunction is recommended.
Dasatinib has an association with pleural effusions. In the DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP Patients) trial, pleural effusions occurred at a rate of 10% with dasatinib but did not occur in any patient receiving imatinib.
Other nonhematologic toxicities that are similar with the other TKIs include nausea, vomiting myalgias, muscle inflammation, rash and fluid retention can occur with dasatinib but were reported more commonly with imatinib in the DASISION trial than with dasatinib.