Targeted Therapies in the Management of Leukemia and Lymphoma

May 9, 2012

The management of leukemias and lymphomas now includes the use of many targeted therapies. Nurses need to have an understanding of the targeted therapies and their side effects so they can appropriately manage the side effects that their patients with leukemias and lymphomas may experience.

ABSTRACT: Click here to link to the CME post-test for this article.

ABSTRACT: The treatment of malignancies now includes therapies that target various components of the malignant cells. The targeted therapies used to treat leukemias and lymphomas include monoclonal antibodies, tyrosine kinase inhibitors, histone deacetylase inhibitors, hypermethylation inhibitors, and proteasome inhibitors. While each of the drugs in each class of agents has similar toxicities, some of the agents within the classes may have unique side effects. For example, the monoclonal antibodies can each cause an infusion reaction, but rarely, rituximab (Rituxan) can reactivate hepatitis B, an effect that has not been noted with other monoclonal antibodies. Nurses need to be aware of the potential side effects of each of the agents in order to manage the toxicities and educate patients about actions they can take to minimize their risk of the side effects.

The treatment of leukemias and lymphomas has evolved significantly over the last few decades. Previously, treatment for these diseases consisted of a variety of chemotherapy agents, given alone or in combination. More recently, new drugs with specific targets in or on the surface of cancer cells have been identified. These “targeted therapies” are now a mainstay of treatment for leukemias and lymphomas. Targeted cancer therapies are agents that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and division. Targeted therapies can cause cancer cell death directly by inducing apoptosis, or indirectly by stimulating the immune system to recognize and kill cancer cells. In addition, targeted therapies can be conjugated so they can deliver toxic substances to the cancer cell. Some of these new targeted therapies include monoclonal antibodies, and other major categories of agents that impede cell growth: inhibitors of tyrosine kinase, of histone deacetylase (HDAC), of proteasomes, and of hypermethylation.

Monoclonal Antibodies 101

Antibodies are proteins that are produced by B lymphocytes in response to foreign proteins, called antigens. They are Y-shaped, with two main portions: the Fab region and the Fc region. The Fab region is the segment that binds to the antigen. The Fc region is a constant component of the antibody. Antibodies function as a marker that binds to the antigen so that the antigen molecules can be recognized and destroyed by phagocytes. Initially, monoclonal antibodies (MoAbs) were murine, indicating that they only contained mouse components. Newer MoAbs contain various components of humans and an animal component, which is often mouse. The amount of each component varies. Chimeric antibodies have a structure that is least 50% human, while the remainder is mouse DNA encoding the binding portion of a monoclonal antibody. Humanized antibodies are antibodies from nonhuman species whose protein sequence has been modified to increase its similarity to an antibody produced naturally in humans. More than 90% of a humanized antibody is human.[1] Human antibodies are fully human. MoAbs are made by identical immune cells which are clones of a parent cell. It is possible to produce MoAbs that specifically bind to any substance (antigen). For an antibody to be effective, it needs to target an antigen that is abundantly expressed on the malignant cell. Once it binds to the cell, the antibody induces cell death through a variety of mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and apoptosis. Multiple monoclonal antibodies have been developed for the treatment of lymphomas and leukemias.

Monoclonal Antibody Agents Used in Treatment of Leukemia and Lymphoma

Rituximab

CD20 is a cell-surface glycoprotein that is highly expressed on B cells. Elevated levels of freely circulating CD20 have been reported in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that was approved by the US Food and Drug Administration (FDA) in 1997. It was the first monoclonal antibody for the treatment of human malignancy to be approved by the FDA. Its initial approval was as a single agent administered at a dose of 375 mg/m2 on a weekly times 4 schedule for relapsed or refractory, follicular or low-grade NHL.[2] The reported response rate was 48%, with 6% complete responses (CRs) and a median duration of response of about 1 year. Subsequent studies confirmed its effectiveness as a single agent in both the upfront and refractory disease settings. Its addition to standard chemotherapy regimens has prolonged the survival of patients with diffuse large B cell NHL and follicular NHL.[3–6] Response rates with use of rituximab in CLL have only been modest, at about 12%. The potential reason for the lower response rates in CLL seems to relate primarily to a lower level of CD20 expression in CLL compared with that in other lymphomas. Alternate dosing schedules have been investigated in CLL, including a three-times-weekly schedule or higher doses administered with each infusion (ie, 500 mg/m2).

Attempts to improve the efficacy of rituximab have included strategies to alter the dosing schedule of rituximab, administering rituximab on a maintenance schedule, and the development of other agents that target CD20. Methods to intensify the dose or schedule of rituximab include administration of treatment combinations more frequently, as in an every-2-week schedule. While the responses were higher, so were the toxicities seen with these schedules.[7,8]

Maintenance therapy is another method to enhance the benefit of rituximab following induction therapy. Administration of rituximab-either following treatment with rituximab as a single agent or after chemotherapy that is given along with rituximab-has been shown to improve overall response rates and the rate of CRs.[9,10] In patients with diffuse large B cell NHL, however, maintenance rituximab given after initial treatment including rituximab has not been shown to be beneficial.[11] In patients with low-grade lymphomas, two schedules for maintenance rituximab that have been demonstrated to be useful include a weekly times 4 course of rituximab every 6 months for 2 years or a single dose of rituximab given every 2 months. The optimal schedule has not been identified.

TABLE 1


Management of Infusion Reactions Caused by Monoclonal Antibodies

Toxicity. Mild to moderate infusion reactions occur in the majority of patients during the first rituximab infusion. Cytokine release is believed to be at least partially responsible for most of the infusion reactions precipitated by rituximab. Levels of inflammatory cytokines have been shown to increase significantly during the administration of rituximab.[1] Symptoms of the infusion-associated reaction to rituximab can include fever, chills, and rigors. Other symptoms associated with rituximab infusion reactions include nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. These reactions generally occur within 30 to 120 minutes from the beginning of the first infusion. The reaction resolves with slowing or interruption of the rituximab infusion and with supportive care such as administration of diphenhydramine, acetaminophen, and IV saline. The incidence of infusion reactions is highest with the first infusion and decreases with each subsequent infusion. The rate of infusion reactions with the first infusion is 77% and is 30% with the fourth infusion. (See Table 1 for nursing management strategies of infusion reactions from monoclonal antibodies.) Pain at the injection site has been reported in less than 5% of patients receiving rituximab.[1]

Tumor lysis has been reported following treatment with rituximab. The risk of tumor lysis seems to be greater in patients with high levels of circulating malignant cells or high tumor burden. Myelosuppression due to rituximab alone is infrequent (2% to 4%) and reversible. It is increased in frequency when rituximab is combined with chemotherapy; however, a higher rate of neutropenia is not noted when rituximab is combined with chemotherapy. Lymphocyte depletion occurs in 70% to 80% of patients, and may be responsible for an increased rate of infection in which no specific organism can be identified.[12] The median duration of lymphopenia is approximately 14 days, and the median duration of neutropenia of 13 days. Bacterial, viral, and fungal infections have been reported following rituximab therapy; however, serious infections have been reported to occur in only 2% of patients.[13,14]

Hepatitis B virus reactivation, with hepatic failure and death, has been reported with rituximab. The median time to the diagnosis of hepatitis was about 4 months after the initiation of rituximab. Cardiac toxicity, with chest pain and arrhythmias, has been reported rarely, especially in patients with cardiac comorbidities. The relationship between cardiac toxicity and rituximab therapy has been difficult to establish.[12]

Ofatumumab

Ofatumumab (Arzerra) is a fully human anti-CD20 monoclonal antibody. It has a stronger complement-dependent cytotoxicity, a slower disassociation rate, and more stability in binding to B cells than rituximab in vitro.[15] Ofatumumab was approved by the FDA in 2009 for patients with CLL who are refractory to both fludarabine (Fludara) and alemtuzumab (Campath). In patients with CLL that was refractory to fludarabine, the overall response rate (ORR) was 47%, with a response rate of 43% in patients who had previously received rituximab and 53% in those who were rituximab-naive.[16] Additional studies are ongoing with the use of ofatumumab in combination with chemotherapeutic regimens.

Toxicity. The most common adverse reactions from ofatumumab are infusion reactions and infections that are primarily grade 1 or 2. Infusion reactions are relatively common with early doses but subside with subsequent infusions.[17] Additional side effects include neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious toxicities are infections, neutropenia, and pyrexia, with infection being the most common cause for discontinuation of the drug.[18]

Brentuximab Vedotin

Brentuximab vedotin (Adcetris) is a novel antibody–drug conjugate consisting of an anti-CD30 antibody conjugated to a potent antimicrotubule agent. It is administered as a 30-minute infusion every 3 weeks.[19] An ORR of 75% with brentuximab vedotin has been reported in Hodgkin lymphoma, with a 34% CR rate.[20] An ORR of 86% has been reported in patients with anaplastic large cell lymphoma, with 57% CRs.[21]

Toxicity. In a phase I study of brentuximab vedotin, the most common reported side effects included fatigue (36%); pyrexia (33%); and diarrhea, nausea, neutropenia, and peripheral neuropathy (22% each). Patients with peripheral neuropathy typically presented with grade 1 or 2 sensory findings, such as numbness or tingling of the hands or feet. The median time to onset of symptoms was 9 weeks. Resolution of neuropathy symptoms was noted in 63% of the patients who developed peripheral neuropathy.[19]

Alemtuzumab

Alemtuzumab (Campath) is a humanized monoclonal antibody against CD52, which is a marker on both normal and malignant B and T cells and on the majority of monocytes, macrophages, and natural killer cells.[14] It was approved in 2001 for relapsed and refractory CLL/small lymphocytic lymphoma (SLL), and for previously untreated CLL patients in 2007. The dosing schedule starts at 3 mg on day 1, then increased to 10 mg on day 2 and 30 mg three times per week for a total of 8 to 12 weeks. Alemtuzumab can be given either by the IV or subcutaneous route. The majority of patients treated via the IV route experience infusion reactions. Alemtuzumab administered subcutaneously has shown biologic activity comparable to that seen with the IV route. While some have reported diminished infusion reactions with the subcutaneous route, others have reported similar infusion reaction rates except for fewer reports of chills when alemtuzumab was given subcutaneously, as compared with IV administration.[22,23] Prophylactic antibacterial and antiviral antibiotics need to be given along with alemtuzumab therapy. In a large international study of patients who had failed to respond to fludarabine, the ORR in CLL patients following treatment with alemtuzumab was 33%, with 2% of patients achieving a CR. Median time to progression for patients who responded to treatment was 9.5 months. The median peripheral blood lymphocyte count decreased by more than 99.9%, but alemtuzumab has been found to be less effective in patients with bulky lymph nodes that are more than 5 cm in diameter. The authors noted that, in prior studies, patients with poor performance status did markedly worse than they observed in their study, with increased hematologic and infectious toxicity.[24] Alemtuzumab is being investigated in combination with other agents.

Toxicity. The most common adverse events with alemtuzumab are cytopenia and infection, as a consequence of profound cellular immune suppression. Profound lymphopenia occurs by 2 to 4 weeks following initiation of treatment, and it may persist for more than a year. Severe neutropenia occurs in about one-third of patients, typically between weeks 4 and 8, and usually resolves in 2 to 3 weeks. Reactivation of herpes virus infections, including cytomegalovirus (CMV), represents the most common opportunistic infection in patients receiving alemtuzumab. Patients should receive prophylaxis against opportunistic infections and be monitored for CMV reactivation. Septicemia has been reported in about 15% of patients.[24]

Notably, in the study by Keating et al, nonresponders to alemtuzumab had an increased risk of severe infection. Infusion reactions in that study resulted in discontinuation of alemtuzumab in 6% of patients. The most common infusion-related reactions with alemtuzumab were rigors in 89% of patients, fever in 83%, nausea in 47%, vomiting in 33%, and hypotension in 15%.[24] Other frequently reported symptoms of infusion reactions include rash, fatigue, urticaria, dyspnea, pruritus, headache, and diarrhea.

Radioimmunotherapy

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).

90Y-Ibritumomab Tiuxetan

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-refractory indolent lymphomas, the ORR with 90Y-ibritumomab tiuxetan was 74%, with a CR rate of 15%.[25] 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.[26]

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

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.[25]

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.[12] Bruising and unusual bleeding have also been reported.

Tositumomab/131I-Tositumomab

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.[27] It has also been shown to have a 95% ORR, including a 75% CR rate, when given as frontline therapy for follicular lymphoma.[28] In addition, 131I-tositumomab has been used as consolidation following CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone) therapy in patients who achieved a CR or PR.[29]

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.[12]

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 (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%.[30] 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 (Tasigna) and the dual-specific SRC and BCR-ABL inhibitor 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.[31]

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.[32] 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.[33]

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, cyclosporine, diergotamine, dihydropyridine, ergotamine, fentanyl, select statins, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, triazolobenzodiazepines, and warfarin.[34] 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.[35] 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.[36]

TABLE 2


Side Effects (all grades) of Tyrosine Kinase Inhibitors in the Management of CML

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.[36] 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.[37]

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.[35] 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.[35]

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.[38]

Histone Deacetylase Inhibitors

Epigenetics refers to changes in genetic expression and cellular phenotype without specific alterations in the DNA sequence. Changes in the cellular epigenetic environment play an important role in tumor formation, progression, and treatment resistance. Modulation of histone aceylation has been shown to be important in the treatment of certain cancers. Two histone deacetylase (HDAC) inhibitors, vorinostat (Zolinza) and romidepsin (Istodax), have been approved for use in patients with cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors cause DNA damage within the cell nucleus via an alteration of DNA structure (by loosening the structure of the chromatin proteins surrounding the DNA) and activation and/or repression of key genes in the cell cycle and apoptotic cycle.

Vorinostat

Vorinostat was approved in 2006 for cutaneous manifestations of CTCL in patients who have progressive, persistent, or recurrent disease while on treatment, or following treatment, with two systemic therapies. The ORR was 32% in patients who had received at least two prior therapies, and was 30% for patients with advanced CTCL.[39] Approximately 32% of the patients treated experienced relief of pruritus.

Toxicity. The most common side effects of vorinostat were diarrhea, fatigue, nausea, and anorexia. Most of the adverse events were grade 2 or lower. The most common grade 3/4 side effects were fatigue, pulmonary embolism, thrombocytopenia, and nausea. Vorinostat is not immunosuppressive; however, some degree of bone marrow suppression can occur with its use.[40]

Romidepsin

Romidepsin was approved in 2009 and also is indicated for the treatment of patients with CTCL. In prior clinical trials, median time to response was 2 months among patients achieving a major response (CR or PR). The median duration of response was 13.7 months.[41]

Toxicity. Side effects of romidepsin include nausea, fatigue, vomiting, and anorexia. Reported hematologic toxicity includes leukopenia, granulocytopenia, lymphopenia, thrombocytopenia, and anemia.

Transient elevation of liver function tests has also been noted, as well as hyperuricemia and hypophosphatemia. EKG changes, consisting of T-wave flattening or ST segment depression, have been reported. Infections, including bacterial infections of the skin; upper respiratory, gastrointestinal, and urinary tracts; and lung were reported, but they were not related to neutropenia.[41]

Hypermethylation Inhibitors

Besides histone modifications, DNA methylation is another primary epigenetic modification, and it is also potentially reversible. Hypermethylation of various genes is relatively common in MDS and AML. Therefore, inhibition of hypermethylation is an interesting target for the management of MDS and AML.

Azacitidine

Azacitidine (Vidaza) was approved by the FDA in 2004 for the management of MDS. It also has been used in AML, especially in the elderly. Azacitidine can be administered either intravenously or subcutaneously, with similar bioavailability. It is rapidly absorbed when given subcutaneously. Prior studies with azacitidine included not only patients with MDS but also some with AML. In an international, open-label randomized phase III study, patients treated with azacitidine had an improved survival compared with those who received conventional therapy (24.5 months vs 15 months, respectively).[42] In a separate randomized controlled phase III study of adult patients with low marrow blast count (20%–30%) WHO-defined AML, the median survival of patients with AML treated with azacitidine was 24.5 months, compared with 16 months for the conventional treatment group.[43] In prior studies, a median of 3.8 cycles of treatment was necessary before a response was seen. This finding has been confirmed in additional studies of azacitidine, and therefore treatment with at least 4 cycles of therapy is recommended before deeming the treatment unsuccessful in its ability to achieve a response.[44]

Toxicity. Myelosuppression is the most common toxicity with azacitidine; however, it is difficult to attribute the level of myelosuppression, since most patients with MDS will have myelosuppression as a component of their disease before starting therapy. Nausea and vomiting also occur in a small number of patients. Constipation occurs in approximately 31% of patients receiving azacitidine, and abdominal pain has been reported also. Fatigue is noted during the days of treatment with azacitidine. Injection site erythema is common. Rarely, gout and acute renal failure may occur. Serum sickness is rare. Abnormal liver function tests can occur in approximately 7% of patients receiving azacitidine, and generalized weakness, muscle tenderness, and lethargy are also uncommon.[45]

Decitabine

Decitabine (Dacogen) is approved for the treatment of adults with MDS, at a dose of 15 mg/m2 every 8 hours for 3 days.[46] An alternate schedule has also been studied in which patients were treated with decitabine at a dose of 20 mg/m2 IV administered over a 1-hour period daily for 5 consecutive days. Cycles were repeated every 28 days. The ORR was 25%, with a 24% CR rate. The median time from first dose to achieve a CR was 126 days. The median survival was 7.7 months from the start of treatment with decitabine. This dosing schedule is now commonly used in the treatment of AML.[46]

TABLE 3


Indications and Nursing Management of Targeted Therapies for Hematologic Malignancies

Toxicity. Myelosuppression is very common with decitabine. Other common side effects include febrile neutropenia and fatigue. Additional side effects include thrombocytopenia, anemia, dyspnea, bacteremia, and pneumonia.[46] Nausea and vomiting can occur, but are usually mild to moderate. Stomatitis can occur in a small number of patients. Pyrexia, along with rigors, occurs in more than half of patients treated with decitabine. Peripheral edema affects about 25% of patients, and patients may experience arthralgias .[47]

Proteasome Inhibitors

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins. It is through this process that protein levels are regulated within the cell. Proteasome inhibitors have been shown to be effective in the management of multiple myeloma and mantle cell lymphoma. Bortezomib is currently the only proteasome inhibitor approved by the FDA. It is administered at a dose of 1.3 mg/m2 either via the IV route or subcutaneously on days 1, 4, 8, and 11 in 21-day cycles. The largest trial investigating the use of bortezomib in mantle cell lymphoma reported a response rate of 33% with an 8% CR rate.[48]

Toxicities

The most common grade 3 or higher adverse events with bortezomib in the trial by Fisher et al were peripheral neuropathy, fatigue, and thrombocytopenia.[48] About one-quarter of patients discontinued their therapy due to toxicity. Other common toxicities occurring in more than 20% of cases include: rash, constipation, diarrhea, nausea, vomiting, decreased appetite, anemia, asthenia, dizziness, headache, insomnia, mental or mood changes, cough, dyspnea, and fever.[49]

Conclusion

The management of leukemias and lymphomas now includes the use of many targeted therapies. More targets are being discovered and therapies developed to better manage these hematologic malignancies. Nurses need to have an understanding of the targeted therapies and their side effects so they can appropriately manage the side effects that their patients with leukemias and lymphomas may experience (see Table 3).

The nonprofit Leukemia & Lymphoma Society (www.lls.org), the world’s largest voluntary organization dedicated to blood cancers, provides support for patients and educational materials about a variety of leukemia and lymphoma types and their treatment, to share and discuss with patients and their families. The Lymphoma Research Foundation (www.lymphoma.org) also provides support to patients with lymphoma including the distribution of educational materials. The Cutaneous Lymphoma Foundation (www.clfoundation.org) is a nonprofit patient advocacy organization that provides information on the various cutaneous lymphomas and their treatment.

In addition, the Cancer.Net website of the American Society of Clinical Oncology (ASCO; www.cancer.net) and the website of the National Cancer Institute (www.cancer.gov) are good sources of patient information.

Barbara Rogers serves on speakers bureaus for Celgene, Millennium, Teva/Cephalon, Allos, and Seattle Genetics.

This article contains reference to drugs approved by the US Food and Drug Administration (FDA) that are used in off-label situations in the management of leukemias and lymphomas. No non–FDA-approved investigational agents are mentioned in the context of management of lymphomas and leukemias.

References:

References

1. Vogel W: Infusion reactions: Diagnosis, assessment, and management. Clin J Oncol Nurs 14(2):E10–E21, 2010.

2. McLaughlin P, Grillo-López A, Link B, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy of relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16(8):2825–2833, 1998.

3. Hainsworth JD, Litchy S, Barton JH, et al: Singe-agent rituximab as front-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21(9):1746–1751, 2003.

4. Marcus R, Imrie K, Solal-Celigny P, et al: Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26(28):4579–4586, 2008.

5. van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/refractory follicular non-Hodgkin’s lymphoma in patients with and without rituximab during induction: Results of a prospective randomized phase III intergroup trial. Blood 108(10):3295–3301, 2006.

6. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 346(4):235–242, 2002.

7. Pfreundschuh M, Schubert J, Ziepert M, et al: Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: A randomized controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116, 2008.

8. Poeschel V, Nickelsen M, Hanel M, et al: Dose-dense rituximab in combination with biweekly CHOP-14 for elderly patients with diffuse large B-cell lymphoma: Results of a phase I/II and pharmacokinetic study of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 108: abstr 2738, 2006.

9. Hainsworth J: First-line and maintenance treatment with rituximab for patients with indolent non-Hodgkin’s lymphoma. Semin Oncol 30(1 Suppl 2):9–15, 2003.

10. Forstpointer R, Unterhalt M, Dreyling M, et al: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108(13):4003–4008, 2006.

11. Habermann TM, Weller EA, Morrison VA, et al: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24(19):3121–3127, 2006.

12. Klastersky J: Adverse effects of the humanized antibodies used as cancer therapeutics. Curr Opin Oncol 18(4):316–320, 2006.

13. Maloney D, Grillo-López A, Bodkin D, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 15:3266–3274, 1997.

14. Berinstein NL, Grillo-López AJ, White CA, et al: Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 9(9):995–1001, 1998.

15. Cheson B: Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol 28(21):3525–3530, 2010.

16. Wierda W, Padmanabhan S, Chan G, et al: Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: Results from the phase II international study. Blood 118(19):5126–5129, 2011

17. Wierda W, Kipps T, Mayer J, et al: Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28(10):1749–1755, 2010.

18. Abraham J: Ofatumumab for fludarabine- and alemtuzumab-refractory CLL. Commun Oncol 7(4):151–152, 2010. Available at: http://www.communityoncology.net/co/journal/articles/0704151.pdf.

19. Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. NEJM 363(19):1812–1821, 2010.

20. Chen R, Gopal A, Smith S, et al: Results from a pivotal phase II study of brentuximab vedotin (SGN-35) in patient with relapsed or refractory Hodgkin lymphoma (HL). J Clin Oncol 29(suppl 15): abstr 8031, 2011.

21. Pro B, Advani R, Brice P, et al: Durable remissions with brentuximab vedotin (SGN-35): Updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). J Clin Oncol 29 (suppl): abstr 8031, 2011.

22. Jaglowski S, Alinari L, Lapalombella R, et al: The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 116(19):3705–3714, 2010.

23. Stilgenbauer S, Zenz T, Winkler D, et al: Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. Blood 27(24):3994-4001.

24. Keating M, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99:3554–3561, 2002.

25. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radiotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20(15):3262–3269, 2002.

26. Krishnan A, Nademanee A, Fung HC, et al: Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 26(1):90–95, 2008.

27. Kaminski M, Zelenetz A, Press O, et al: Pivotal study of iodine-131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphoma. J Clin Oncol 19(19):3918–3928, 2001.

28. Kaminski M, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352(5):441–449, 2005.

29. Press O, Unger J, Maloney D, et al: An update of a phase II trial of CHOP allowed by tositumomab/iodine I-131 tositumomab (Bexxar) for front-line treatment of advanced stage, follicular lymphoma: SWOG 9911. Blood 106: abstr 352, 2005.

30. O’Brien S, Guilhot F, Goldman J, et al: International randomized study of interferon STI571 (IRIS) 7-year follow-up: Sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML_CP) treated with imatinib (IM). Blood 112: abstr 186, 2008.

31. Saglio G, Kim DW, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362(24):2251–2259, 2010.

32. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chornic-phase chronic myeloid leukemia. N Engl J Med 362(24):2260–2270, 2010.

33. Harnicar S: Phamacotherapy for chronic myelogenous leukemia: A case-based approach. J Natl Compr Canc Netw 9(Suppl 3):S25–S35, 2011.

34. Salie R, Silver R: Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk 10(5):331–335, 2010.

35. Saglio G, Kim D, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259, 2010.

36. Kerkelä R, Grazette L, Yacobi R, et al: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12(8):908–916, 2006.

37. Dibella NJ: First-line treatment of chronic myeloid leukemia: Imatinib versus nilotinib and dasatinib. Community Oncology 8(2):65–72, 2011.

38. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270, 2010.

39. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25(21):3109–3115, 2007.

40. Mann BS, Johnson JR, He K, et al: Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res 13(8):2318–2322, 2007.

41. Piekarz R, Frye R, Turner M, et al: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27(32):5410–5417, 2009.

42. Fenaux P, Mufti G, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 10(3):223–232, 2009.

43. Fenaux P, Mufti G, Hellstrom-Lindberg E, et al: Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28(4):562–569, 2010.

44. de Lima M, Giralt S, Thall PF, et al: Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: A dose and schedule finding study. Cancer 116(23):5420-5431, 2010.

45. Raj K, Mufti GJ: Azacitidine (Vidaza®) in the treatment of myelodysplastic syndromes. Ther Clin Risk Manag 2(4):377–388, 2006.

46. Marks PW: Decitabine for acute myeloid leukemia. Expert Rev Anticancer Ther 12(3):299–305, 2012.

47. Cashen AF, Schiller GJ, O’Donnell M, et al: Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28(4):556–561, 2010.

48. Fisher RI, Bernstein SH, Kahl BS: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874, 2006.

49. Micromedix. Bortezomib. Available at: www.micromedix.com.

50. Wilkes G, Barton-Burke M: Oncology Nursing Drug Handbook. Sudbury, MA, Jones and Bartlett, 2011.

51. Micromedix. Dasatinib. Available at: www.micromedix.com.