ACUTE MYELOGENOUS LEUKEMIA AND RELATED CONDITIONS

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1 NEW PERSPECTIVES IN THE TREATMENT OF HEMATOLOGIC MALIGNANCIES * Amy Hatfield, PharmD, BCOP ; MiKaela Olsen, RN, MS ; Sandy Allen-Bard, RN, MSN, NPc ; Connie Zanzig Augustyniak, RN, BSN ; Deborah Blamble, PharmD, BCOP ; Chris Fausel, PharmD, BCOP # ; Mollie Moran, MS, CNP**; and Amy Robbins, PharmD, BCOP ABSTRACT Hematologic malignancies, although all are cancers of the blood-forming organs, constitute a broad spectrum of disease. This paper focuses on a subset of hematologic malignancies: acute myelogenous leukemia and the 2 related conditions of promyelocytic leukemia and myelodysplastic syndromes; and the lymphoid malignancies, chronic lymphocytic leukemia, non-hodgkin s lymphoma, and multiple myeloma. Disease epidemiology, classification schemes, *This article is based on a roundtable symposium held in Orlando, Florida, in December Clinical Specialist, Hematologic Malignancies, Department of Pharmacy, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland. Oncology and Stem Cell Transplant Clinical Nurse Specialist, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland. Leukemia Service, Weill Cornell Medical Center, New York, New York. Nurse Clinician, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois. Clinical Specialist, Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas. # Clinical Pharmacist, Hematology/Oncology/BMT, Indiana University Cancer Center, Indianapolis, Indiana. **Nurse Practitioner/Hematologic Malignancies Program, Ohio State University, Arthur G. James Cancer Hospital, Columbus, Ohio. Clinical Specialist, Malignant Hematology/Stem Cell Transplant, Methodist Healthcare-University Hospital, Memphis, Tennessee. Address correspondence to: Amy Hatfield, PharmD, BCOP, Clinical Specialist, Hematologic Malignancies, Department of Pharmacy, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie 180, Baltimore, MD ahatfie2@jhmi.edu. treatment regimens, and patient management issues are covered, with particular emphasis placed on current investigational therapies. A brief discussion of reimbursement issues also is included. (Adv Stud Med. 2007;7(4): ) ACUTE MYELOGENOUS LEUKEMIA AND RELATED CONDITIONS ACUTE MYELOGENOUS LEUKEMIA Acute myelogenous leukemia (AML), which is characterized by the uncontrolled production of immature granular leukocytes, newly afflicts adults each year in the United States and is responsible for 8990 deaths annually. 1 It is primarily a disease of the elderly, with a median age at diagnosis of 70 years. 2 For the past 3 decades, AML has been classified using the French- American-British (FAB) classification system published in In 2001, the World Health Organization (WHO) published a new classification strategy that incorporates morphology, cytogenetics, molecular genetics, and immunologic markers. 4 Both classification systems are currently used and are shown in Table 1. 5 Common symptoms of AML include fever, fatigue, weight loss/anorexia, shortness of breath, anemia, easy bruising or bleeding, petechiae (small red or purple spots on the skin caused by broken capillaries), bone/joint pain, and persistent or frequent infections. Acute myelogenous leukemia is diagnosed initially with a complete blood count (CBC), which may reveal an abnormally high number of white blood cells Johns Hopkins Advanced Studies in Medicine 105

2 Table 1. WHO and FAB Classification of AML WHO Subtype AML with characteristic genetic abnormalities AML with AML/ETO translocation AML with CBFβ/MYH11 translocation APL; primarily PML/RAR α translocations AML with MLL abnormalities AML with an FLT3 mutation AML with multilineage dysplasia AML and MDS, therapy-related Alkylating agent-related AML and MDS Topoisomerase II inhibitor-related AML AML not otherwise categorized Acute myeloblastic leukemia, minimally differentiated Acute myeloblastic leukemia without maturation Acute myeloblastic leukemia with maturation Acute myelomonocytic leukemia Acute monoblastic leukemia and acute monocytic leukemia Acute erythroid leukemias Acute megakaryoblastic leukemia AML/transient myeloproliferative disorder in Down syndrome Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma Acute leukemias of ambiguous lineage FAB Subtype (leukocytosis) and is confirmed and classified through bone marrow aspiration and subsequent cytogenetic testing. Successful treatment of AML requires the control of bone marrow and systemic disease, which is primarily achieved through systemically administered combination chemotherapy. Treatment of initial disease generally consists of induction and consolidation therapy. AML induction therapy The most commonly used induction regimens for AML are the 7+3 regimens, named after the 7 days of continuous intravenous cytarabine (ara-c) plus an anthracycline (eg, daunorubicin, epirubicin, or idarubicin), given as single intravenous doses for the first 3 days of treatment. Variations may include the addition of or substitution with other agents, such as etoposide, M3 M0 M1 M2 M4 M5 M6 M7 AML = acute myelogenous leukemia; APL = acute promyelocytic leukemia; CBFβ = core binding factor β; FAB = French-American-British; FLT3 = FMS-like tyrosine kinase 3; MDS = myelodysplastic syndrome; MLL = myeloid/lymphoid or mixed lineage leukemia; MYH11 = myosin heavy chain 11; PML = promyelocytic leukemia; RAR α = retinoid acid receptor α; WHO = World Health Organization. Data from National Cancer Institute. 5 6-thioguanine, and mitoxantrone. 5 Cytotoxic induction regimens result in a complete remission in up to 65% of patients with AML. 5 However, AML arising from myelodysplastic syndromes (MDS) or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. AML consolidation therapy Consolidation therapy is generally recommended for patients with AML to maintain remission. Options for consolidation therapy include ara-c based chemotherapy regimens and high-dose chemotherapy or chemoradiation therapy with stem cell transplant (SCT). Nontransplant consolidation therapy using ara-c containing regimens, which may include from 1 to more than 4 cycles, can result in long-term disease-free survival rates of 20% to 50%. 5 Allogeneic bone marrow transplantation results in the lowest incidence of leukemic relapse, with disease-free survival rates during first complete remission ranging from 45% to 60%, whereas autologous SCT results in disease-free survival rates of 35% to 50%. However, because SCT can cure approximately 30% of patients who experience relapse following chemotherapy, some investigators reserve it for early first relapse or second complete remission, particularly for patients who are not in poor-risk prognostic groups. 5 Treatment of relapsed AML Despite aggressive therapy, 50% to 70% of patients with AML who achieve complete remission ultimately relapse. 6 For patients with relapsed AML, the only proven potentially curative therapy is SCT, if one has not already been performed. Commonly used chemotherapy regimens for relapsed disease include MEC (mitoxantrone, etoposide, and intermediatedose ara-c), HAM (high-dose ara-c and mitoxantrone), gemtuzumab, and TAM (topotecan, ara-c, and mitoxantrone). 5 Because of the low remission rates and short disease-free survival of patients with relapsed disease, patients should be offered participation in a clinical trial if available. AML: patient management issues Standard 7+3 induction regimens are associated with many toxicities, such as nausea/vomiting, oral mucositis, and neutropenia. 7 Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate, and 106 Vol. 7, No. 4 May 2007

3 empiric antibiotic and antifungal agents should be administered to patients who are profoundly neutropenic. Granulocyte or white blood cell transfusion may be necessary for patients with aplastic marrow and serious infections who do not respond to antibiotics. Skin toxicities, including rash and hand-foot syndrome (ie, palmar-plantar erythrodysesthesia), can also be problematic. 8 Treatment of skin toxicities is primarily palliative; prophylactic steroids may be used to prevent or lessen severity, and emollients can help maintain moisture in the skin. Induction therapy also is associated with a high risk of myelosuppression, which generally requires a 4-week hospital stay during treatment because of a need for close and frequent monitoring. Similar strategies should be employed during consolidation therapy, particularly for patients receiving dose-intensive cytarabine-based chemotherapy, which can be complicated by severe neurologic and/or pulmonary toxic effects. 5 Many consolidation regimens also are associated with a high incidence of diarrhea. 9,10 Tailoring new AML therapies for patients with specific molecular and cytogenetic abnormalities has the potential to more directly inhibit the underlying disease process and to be associated with less toxicity, which is attractive for elderly patients and those with a poor performance status. Examples include the FMSlike tyrosine kinase 3 (FLT3) inhibitors, which are designed to block the activity of the FLT3 transmembrane tyrosine kinase. Mutations in FLT3, which are independent, poor-risk prognostic features, are found in 30% of patients with AML. 11 Another example is gemtuzumab ozogamicin, which was approved in the United States in 2000 for relapsed CD33+ AML in patients older than 60 years who are not candidates for high-dose chemotherapy. However, toxicities associated with gemtuzumab use, particularly liver dysfunction and veno-occlusive disease, in addition to prolonged neutrophil and platelet recovery times, have become major issues, limiting its use. 12 Several additional investigational agents for AML are currently in clinical trials, as summarized in Table 2. ACUTE PROMYELOCYTIC LEUKEMIA Acute promyelocytic leukemia (APL) is a distinct subtype of AML and is classified as AML subtype M3 in the FAB system (Table 1). Compared to AML, APL has a lower median age of onset (approximately 40 years) and is largely curable. 13 APL is characterized primarily by the chromosomal abnormality t(15;17). This translocation involves break points in the retinoid acid receptor α (RAR α) and promyelocytic leukemia (PML) genes, leading to production of the aberrant fusion protein PML/RAR α, which is largely responsible for the APL phenotype. Signs and symptoms of APL are similar to other subtypes of AML. However, APL is associated with coagulopathy as a result of disseminated intravascular coagulation and fibrinolysis. Patients often present with significant signs of bleeding, bruising, or thromboses. The role of the t(15;17) aberration in APL also makes this disease uniquely sensitive to the drug all-trans retinoic acid (ATRA), a derivative of vitamin A. The majority of induction regimens consist of ATRA combined with an anthracycline (eg, daunorubicin or idarubicin), which results in a clinical remission in approximately 90% of patients. 5 Treatment of relapsed APL Approximately 10% to 30% of patients with APL will not respond to or will relapse from first-line ATRA therapy Arsenic trioxide (ATO) has been identified as an active agent in patients with relapsed APL, with approximately 85% of patients achieving remission following ATO treatment In a small study (n = 16), gemtuzumab also has demonstrated an 88% remission rate as a single agent in relapsed APL, although it has not yet been approved in this setting. 21 APL: patient management issues Treatment with ATRA or ATO is associated with the development of APL differentiation syndrome (previously referred to as retinoic acid syndrome 22,23 ), which results from the biologic response of APL to treatment. 24 This syndrome manifests as fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, with or without leukocytosis. Differentiation syndrome usually responds well to early treatment with systemic corticosteroids. Prolongation of the QT/QTc interval is commonly observed in association with ATO treatment, necessitating frequent electrocardiographic monitoring in addition to electrolyte monitoring to ensure proper maintenance of potassium and magnesium levels. 25 This is particularly important when considering that certain patients with APL may be receiving other agents that also influence the QT/QTc interval, such as certain antiemetics, antibiotics, and sleep aids. Despite these issues, ATRA and ATO have attractive toxicity profiles compared to conventional Johns Hopkins Advanced Studies in Medicine 107

4 chemotherapeutic agents. Therefore, combinations of ATRA and ATO, with or without gemtuzumab, are currently being evaluated as front-line treatment of APL, with promising results thus far. 26,27 MYELODYSPLASTIC SYNDROMES Myelodysplastic syndrome represents a group of conditions characterized by 1 or more peripheral blood cytopenias secondary to bone marrow dysfunction. MDS is thought to arise from mutations in bone marrow stem cells that impair differentiation of blood precursor cells into mature cells. Clonal expansion of the aberrant cells, including abnormal myeloid progenitors and unusually small megakaryocytes, results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone marrow blasts rises over a particular cutoff, then transformation to AML is said to have occurred in approximately 30% of patients with MDS, the disease will eventually evolve to AML. 28 Symptoms of MDS include anemia, bleeding, easy bruising, fatigue, infections, and splenomegaly or hepatosplenomegaly. Like AML, MDS is predominantly a disease of the elderly; 80% to 90% of all patients with MDS are over the age of Diagnosis of MDS is performed in a similar manner as that of AML, and includes CBC, bone marrow Table 2. Investigational Agents for AML Agent Stage of Development Comments FLT3 inhibitors Lestaurtinib Phase III Manageable toxicity profile Drug-drug interaction: cannot be used with azole antifungals (eg, voraconazole and fluconazole) or other macrolide antibiotics PKC412 Phase I/II Hypomethylating agents Decitabine Phase III Requires 5 sequential days of IV dosing 5-azacytidine Phase II Subcutaneous dosing Farnesyltransferase inhibitors Tipifarnib Phase III Severe toxicity, including neurotoxicity, mental status changes, nephrotoxicity, nausea/vomiting, diarrhea, LFT abnormalities, and skin rash Lonafarnib Phase II Similar GI toxicities as tipifarnib BMS Phase I Histone deacetylase inhibitors Vorinostat (suberoylanilide hydroxamic acid) Phase I/II Associated with GI toxicities (ie, nausea, vomiting, or diarrhea) Valproic acid Phase II MS-275 Phase I/II Cytotoxic chemotherapy agents VNP40101M Phase III 1-time, single dosing is convenient Not effective for proliferating disease Prolonged myelosuppression Clofarabine Phase III Acceptable toxicity profile except skin rash, hyperbilirubinemia, LFT abnormalities, and transaminitis Rarely septic episodes and SIRS, which require prophylactic hydrocortisone Perceived as expensive Miscellaneous agents Oblimersen sodium Phase I Bcl-2 inhibitor Used before therapy to make cells more sensitive to chemotherapy Valspodar Phase I/II Multidrug resistance inhibitor Sorafenib Phase I/II Inhibitor of Raf, PDGF, and VEGFR AML = acute myelogenous leukemia; FLT3 = FMS-like tyrosine kinase 3; GI = gastrointestinal; IV = intravenous; LFT = liver function test; PDGF = platelet-derived growth factor; SIRS = systemic inflammatory response syndrome; VEGFR = vascular endothelial growth factor receptor. 108 Vol. 7, No. 4 May 2007

5 aspiration, and subsequent cytogenetic testing. MDS was first classified into subtypes by the FAB working group in 1982 (Table 3). 30,31 However, a newer classification system with more categories and reclassification of 2 subtypes was introduced by the WHO in The WHO system accounts for some cytogenetic findings not addressed by the FAB classification, particularly recognition of del(5q) (also called 5q- syndrome), a condition characterized by the loss of the long ( q ) arm of chromosome 5, which results in the absence of certain genes that encode hematopoietic growth factors. Treatment of MDS Acute myelogenous leukemia that occurs as a leukemic transformation from MDS is much less responsive to chemotherapy than de novo AML. 28 Thus, prevention or delay of this process through drug treatment and supportive care are imperative for a favorable prognosis. Considering the age of the MDS population, many patients elect to receive supportive care alone. Supportive care options include blood and platelet transfusions for anemia and thrombocytopenia, respectively, and monitoring and antibiotic therapy for neutropenia. Repeated transfusions can lead to iron overload, which is generally treated with deferasirox or deferoxamine. However, these agents are associated with serious side effects, including gastrointestinal toxicities and hearing and visual problems. 32,33 In addition to supportive care, MDS treatments may be categorized as low- and highintensity therapies. The International Prognostic Scoring System, which includes information on disease stage, the number of cell types affected, and cytogenetics, helps practitioners determine the choice of therapy. Low-intensity therapy includes growth factor support, which may consist of erythropoietin, filgrastim, pegfilgrastim, and sargramostin. Several targeted therapies have recently been approved for the treatment of MDS and/or its symptoms. Two hypomethylating agents, azacytidine and decitabine, were approved by the US Food and Drug Administration (FDA) for MDS in 2004 and 2006, respectively. Both of these agents result in response rates approaching 17%. 34,35 The immunomodulatory drug (IMiD) lenalidomide, a derivative of thalidomide, was approved in 2005 for the treatment of anemia associated with 5q- syndrome. Lenalidomide has been shown to result in a hematologic response in 56% of patients with MDS-associated anemia. 36 Treatment issues associated with these approved agents and investigational therapies for MDS are presented in Table 4. High-intensity therapy for MDS consists of cytotoxic chemotherapy and SCT. However, because of the age of this population, few patients can tolerate these treatments. Furthermore, relapses following high-intensity therapy are common. 28 The most frequently used agents in this setting include topotecan, ara-c, etoposide, and melphalan. Clofarabine, a newer purine nucleoside analog that is approved for the treatment of pediatric acute lymphoblastic leukemia, is also being evaluated in clinical trials for the treatment of MDS. CHRONIC LYMPHOCYTIC LEUKEMIA Chronic lymphocytic leukemia (CLL) is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues. Each year, this disease newly afflicts individuals and is responsible for 4500 deaths in the United States. 1 CLL occurs primarily in middle-aged and elderly adults, with increasing frequen- Table 3. Classification of MDS FAB Subtypes Refractory anemia Refractory anemia with ringed sideroblasts Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation Chronic myelomonocytic leukemia WHO Subtypes Refractory anemia Refractory cytopenia with multilineage dysplasia Refractory anemia with ringed sideroblasts Refractory anemia with excess blasts MDS, unclassifiable MDS associated with del(5q) Reclassified from MDS to: Acute myeloid leukemia, identified as AML with multilineage dysplasia following an MDS Myelodysplastic/myeloproliferative diseases AML = acute myelogenous leukemia; FAB = French-American-British; MDS = myelodysplastic syndrome; WHO = World Health Organization. Data from Bennett et al 30 and Harris et al. 31 Johns Hopkins Advanced Studies in Medicine 109

6 Table 4. Recently Approved and Investigational Agents for MDS Agent Stage of Development Comments Hypomethylating agents 5-azacytidine Approved in 2004 for MDS Subcutaneous dosing Decitabine Approved in 2006 for MDS Requires 5 days of IV dosing Immunomodulatory drugs Thalidomide Phase I/II Associated with nervous system toxicities, particularly peripheral neuropathy Lenalidomide Approved in 2005 for anemia associated Less neurotoxicity than thalidomide with 5q- syndrome Labeling includes boxed warning about risk of neutropenia and thrombocytopenia as well as thromoboembolic complications; treatment requires frequent monitoring Farnesyltransferase inhibitors Tipifarnib Phase II GI toxicities Lonafarnib Phase III Associated with severe diarrhea BMS Phase I Histone deacetylase inhibitors Vorinostat (suberoylanilide Phase I/II Associated with GI toxicities (ie, nausea, vomiting, hydroxamic acid) or diarrhea) Valproic acid Phase II MS-275 Phase I/II Cytotoxic chemotherapy agents Clofarabine Phase II Miscellaneous agents Arsenic trioxide Phase I/II QT prolongation AMG 531 Phase II Thrombopoiesis-stimulating fusion protein GI = gastrointestinal; IV = intravenous; MDS = myelodysplastic syndrome. cy in successive decades of life. 37 CLL is more common in females than males. Symptoms of CLL include enlarged lymph nodes, swelling or discomfort in the abdomen from enlarged spleen, persistent fatigue, anemia, bleeding and bruising easily, frequent infections, fever or night sweats, and unexplained weight loss. Diagnosis of CLL is primarily achieved by CBC, bone marrow aspiration, and biopsy to demonstrate the presence of abnormal B cells in the blood, bone marrow, and tissues, respectively. Identification of characteristic patterns of surface markers on these malignant cells, which is done through immunophenotyping, is critical for staging. The Rai and Binet classification systems are the most commonly used staging systems for CLL (Table 5). 38,39 Certain prognostic variables, including immunoglobulin variable region heavy chain gene mutations, numerous chromosomal abnormalities, CD38 immunophenotype, and ζ chain-associated protein kinase levels, also may be evaluated when determining treatment strategies; however, none of these have been adopted as standards. 40 TREATMENT OF CLL Because CLL is most often a slow-growing cancer, Rai stage 0, I, and II disease are often not treated. However, the presence of certain symptoms, including weight loss greater than 10% within 6 months, fevers for 2 weeks, night sweats, extreme fatigue, worsening anemia and/or thrombocytopenia, autoimmune cytopenias, progressive splenomegaly, progressive lymphadenopathy, and lymphocyte doubling time of 6 months, warrant treatment initiation for many patients with early-stage CLL. 41 Chemotherapy plays an important role in CLL treatment. Single-agent fludarabine is one of the most active agents, resulting in overall response rates exceeding 75%. 42 Fludarabine is often combined with cyclophosphamide as the FC regimen. Although not US FDA-approved for CLL, 110 Vol. 7, No. 4 May 2007

7 off-label rituximab, a monoclonal antibody directed against CD20, is commonly added to either fludarabine monotherapy or fludarabine/cyclophosphamide (FCR) 43 ; both of these combinations have essentially been accepted as a new standard of care for CLL, with FCR achieving a molecular complete remission (mcr) in 99% of previously untreated patients. 44,45 Alemtuzumab, a monoclonal antibody directed against the CD52 antigen, was approved in 2001 for the treatment of B-cell CLL in patients who have been treated with alkylating agents, such as chlorambucil, and whose disease no longer responds to fludarabine. Alemtuzumab has been shown to result in mcr rates as high as 38%. 46,47 Other treatment options for CLL include SCT and radiation therapy. Allogeneic SCT is the only curative treatment for CLL. 48 One study reported 5-year progression-free survival following allogeneic SCT of 78% in previously untreated patients and 31% in chemotherapy-refractory patients, suggesting this modality is most effective as initial treatment. 49 However, the advanced age of most patients with CLL precludes SCT in the majority of this population. Autologous SCT has not demonstrated efficacy in patients with CLL thus far. 48 Low-dose radiation therapy of 1 nodal area or the spleen can often shrink lymph node tumors in untreated sites. No treatment regimens have been established as standard for relapsed CLL. Options for relapsed disease include chemotherapy, allogeneic SCT, and enrollment in clinical trials. However, many older patients or patients with a lower performance status may elect palliation alone so that myelosuppression or infection risk may be avoided. CLL: PATIENT MANAGEMENT ISSUES Fludarabine-associated toxicities are relatively frequent and occasionally severe. 48 These include myelosuppression and lymphosuppression, the latter of which requires Pneumocystis carinii, Candida spp, and herpes simplex infection prophylaxis. Autoimmune hemolytic anemia, long-term hematopoietic stem cell damage, and secondary AML also may occur. With the exception of infusion reactions, the addition of rituximab to the FCR regimen does not appear to produce any additional toxicity. 45 Alemtuzumab also is associated with infusion reactions, necessitating constant monitoring during infusions and gradual escalation to the indicated maintenance dose at therapy initiation and after therapy interruptions of at least 7 days. Furthermore, alemtuzumab is associated with profound immunosuppression and associated infectious complications, including cytomegalovirus reactivation and Epstein-Barr virus lymphoproliferative disease. 48 As shown in Table 6, several additional targeted therapies are currently under investigation for treatment of CLL. Table 5. CLL Staging Systems Stage 0 Stage I Stage II Stage III Stage IV Rai Staging System Absolute lymphocytosis (>15 000/mm 3 ) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia Absolute lymphocytosis with either hepatomegaly or splenomegaly, with or without lymphadenopathy Absolute lymphocytosis and anemia (Hgb <11 g/dl) with or without lymphadenopathy, hepatomegaly, or splenomegaly Absolute lymphocytosis and thrombocytopenia (< /mm 3 ) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia Binet Classification Clinical stage A: No anemia or thrombocytopenia and >3 areas of lymphoid involvement (Rai stages 0, I, and II) Clinical stage B: No anemia or thrombocytopenia with 3 areas of lymphoid involvement (Rai stages I and II) Clinical stage C: Anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement CLL = chronic lymphocytic leukemia; Hgb = hemoglobin. Johns Hopkins Advanced Studies in Medicine 111

8 Table 6. Investigational Agents for CLL Agent Mechanism of Action Stage of Development Comments Rituximab acd20 mab Phase II/III Widely used off-label Lumiliximab acd23 mab Phase II/III 3-AP Ribonucleotide reductase Phase I Associated with myelosuppression and inhibitor methemoglobulinemia Requires monitoring for pulmonary toxicity Requires non-pvc tubing Flavopiridol/alvocidib Cyclin-dependent kinase Phase I/II Fatal tumor lysis syndrome inhibitor Diarrhea Lenalidomide IMiD Phase II/III Same as in other disease states 3-AP = 3-aminopyridine-2-carboxaldehyde- thiosemicarbazone; CLL = chronic lymphocytic leukemia; IMiD = immunomodulatory drug; mab = monoclonal antibody; PVC = polyvinyl chloride. Table 7. NHL Nomenclature: Comparative Classification and Treatment Options Revised European American Working Formulation Rappaport Classification Lymphoma Classification Treatment Options Indolent (Low-Grade) A. Small lymphocytic B. Follicular, small cleaved C. Follicular, mixed small cleaved, and large cell Diffuse, well-differentiated lymphocytic Nodular, poorly differentiated lymphocytic Nodular, mixed lymphocytic and histiocytic Chronic lymphocytic leukemia Mucosa-associated lymphoid tissue follicle center cell, follicle center cell, follicular grade I Follicle center cell, follicular grade II Depending on stage at presentation: Radiotherapy, single-agent therapy, biologic therapy, combination therapy, watchful waiting Intermediate-Grade D. Follicular, large cell E. Diffuse, small cleaved F. Diffuse, mixed small and large G. Diffuse, large cell Nodular histiocytic Diffuse, poorly differentiated lymphocytic Diffuse, mixed lymphocytic and histiocytic Diffuse histiocytic Follicle center cell, follicular grade III Mantle cell Follicle center cell, diffuse small cell; large B cell; rich in T cell Diffuse large B cell Combination chemotherapy, usually with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without biotherapy and, depending on the bulk of the tumor, radiotherapy; consider transplant at relapse Aggressive (High-Grade) H. Immunoblastic, large cell I. Lymphoblastic J. Small, noncleaved Burkitt s Diffuse histiocytic Lymphoblastic Undifferentiated, Burkitt s and non-burkitt s Diffuse large B cell Precursor B lymphocytic Burkitt s high-grade B cell, Burkitt s-like Intensive combination chemotherapy NHL = non-hodgkin s lymphoma. Data from Waldman Vol. 7, No. 4 May 2007

9 NON-HODGKIN S LYMPHOMA The lymphomas are a large group of cancers originating in lymphoid tissue. Hodgkin s lymphoma is a specific type of lymphoma named after the physician who first described it, Thomas Hodgkin; all other lymphomas are collectively called non-hodgkin s lymphoma (NHL). In the United States, NHL is the fifth most common site of newly diagnosed cancer, the seventh leading cause of cancer death in women, and the ninth leading cause of cancer death in men. 1 There are approximately 30 types of NHL, which can be broadly classified into 3 categories: low-grade (indolent), intermediate-grade, and high-grade (aggressive). As shown in Table 7, NHL may be further subclassified according to the predominant malignant cell type using 1 of many different classification systems. 50 Indolent lymphomas are slower growing and have fewer symptoms, whereas higher grade lymphomas grow more quickly. The most common symptom of NHL is painless swelling of the lymph nodes in the neck, axillae (armpits), or groin. Other symptoms may include unexplained fever, night sweats, unexplained weight loss and anorexia, constant fatigue, pruritus, and reddened patches on the skin. If NHL is suspected, a diagnosis may be confirmed through imaging of affected nodes and molecular cytogenetic analysis of biopsied tissue. Many chromosomal abnormalities serve as hallmarks of NHL, including several subtype-specific aberrations. Treatment of NHL depends on subtype and stage. Staging is primarily achieved using chest and abdominal computed tomographic scans. The most commonly used staging system for NHL is the Ann Arbor system, which is described in Table 8. 51,52 In addition to stage assignment, this system also categorizes patients according to the absence (A) or presence (B) of any of the following symptoms: unexplained loss of more than 10% body weight in the 6 months before diagnosis; unexplained fever with temperatures greater than 38ºC; and drenching night sweats. 51,52 Treatment options for NHL include cytotoxic chemotherapy, radiation therapy, SCT, and biologic therapy. TREATMENT OF NHL Most patients with indolent NHL are not diagnosed until advanced stages. Although these patients typically respond to initial therapy, almost all experience recurrence. Initial treatment for indolent disease may include cytotoxic chemotherapy, biologic therapy with rituximab, external-beam radiation therapy (XRT), and SCT, although optimal strategies for XRT and SCT have not yet been established. Physicians may also choose watchful waiting, as some studies have shown that select patients with stage I and II NHL who receive no initial therapy have equivalent survival as those who undergo immediate treatment. 53 A multitude of combination cytotoxic chemotherapy regimens have been used for treatment of indolent and aggressive NHL. In recent years, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CHOP (rituximab + CHOP) have become 2 of the most commonly used regimens. 54 Other NHL regimens include (but are not limited to) BEACOPP (bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone), ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), ICE (ifosfamide, carboplatin, and etoposide), CVP (cyclophosphamide, vincristine, and prednisone), C- MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone), and FND (fludarabine, mitoxantrone ± dexamethasone); rituximab can be used in combination with any of these regimens. 54 Table 8. Ann Arbor Staging System for NHL Stage I II III IV Description Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)* Involvement of 2 lymph node regions on the same side of the diaphragm (II) or localized involvement of 1 associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE) Involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E) Disseminated (multifocal) involvement of 1 extralymphatic sites with or without associated lymph node involvement of isolated extralymphatic organ involvement with distant (nonregional) nodal involvement *The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. NHL = non-hodgkin s lymphoma. Data from American Joint Committee on Cancer 51 and National Cancer Institute sponsored study of classifications of non-hodgkin s lymphomas: summary and description of a working formulation for clinical usage. 52 Johns Hopkins Advanced Studies in Medicine 113

10 Table 9. Selected Biologic Agents for Indolent NHL Agent Mechanism of Action Stage of Development Comments Rituximab αcd20 mab Approved Lumiliximab αcd23 mab Phase I Galiximab αcd80 mab Phase I/II Ibritumomab tiuxetan Radiolabeled Approved Challenging to administer αcd20 mab Prolonged myelosuppression Tositumomab and iodine Radiolabeled Approved Patients must be counseled about exposing others I131 tositumomab αcd20 mab Bendamustine Alkylating agent Phase III Must take infectious precautions hydrochloride Risk of secondary leukemias Bortezomib Proteasome Approved for relapsed mantle High incidence of thrombocytopenia, nausea/ inhibitor cell lymphoma in December 2006 vomiting, and peripheral neuropathy Must hydrate and monitor for hypotension NHL = non-hodgkin s lymphoma; mab = monoclonal antibody. A new chemotherapeutic agent, bendamustine, is currently being evaluated both as a single agent and with rituximab in indolent NHL. Bendamustine is an investigational novel hybrid cytotoxic agent that is differentiated from conventional alkylating anticancer therapies in its apparent multifunctional mechanism of action; it kills cells by damaging their DNA and triggering apoptosis (programmed cell death), in addition to by disrupting cell division. 55,56 Other investigational agents that are currently being evaluated in the treatment of indolent NHL are highlighted in Table 9. Patients with NHL have many unique considerations, because of age and the fact that the majority are treated as outpatients. Patient management issues associated with treatment of NHL are addressed in Table 10. MULTIPLE MYELOMA Multiple myeloma is a cancer of the bone marrow that newly afflicts people in the United States each year, with individuals dying from the disease. 1 The majority of patients with myeloma are older than 65 years. 57 Multiple Table 10. Patient Management Issues Associated with Treatment of Indolent NHL Issue Patients are more likely to be outpatients and to receive different therapies at different clinics Placement of central line may not be necessary up front Risk of tumor lysis syndrome Risk of neutropenia (particularly in elderly patients) Risk of GI disturbances, particularly in elderly patients Fertility and sexual function issues GI = gastrointestinal; NHL = non-hodgkin s lymphoma. Management Strategies Communication between clinics is imperative to ensure patients do not receive too much cumulative anthracyclines Patients (particularly elderly) should be followed up at home to monitor steroid-related side effects (eg, agitation and glucose level changes) Consider peripheral infusion of chemotherapy regimens to avoid potential reactions to vesicant therapies Use prophylactic allopurinol Recheck laboratory values every 2 days Do not administer steroids for nausea if patient is receiving steroids within combination chemotherapy Administer prophylactic pegfilgrastim Reduce chemotherapy doses based on performance status (rather than age) as necessary to ensure proper bowel function Educate patients up front Bank sperm and eggs (if possible) 114 Vol. 7, No. 4 May 2007

11 myeloma is characterized by the overproduction of malignant plasma cells, called myeloma cells, which circulate in the blood and tend to aggregate together to form tumors called plasmacytomas. Plasmacytomas in the bone marrow lead to neutropenia, anemia, and thrombocytopenia, whereas those that lodge in bones can cause damage and weakening, leading to pain and sometimes fractures. All myeloma cells produce an identical, nonfunctional immunoglobulin called monoclonal protein (M-protein), which is secreted into the blood and urine. M-protein can overload the kidneys, leading to abnormal kidney function and sometimes renal failure. Multiple myeloma is diagnosed through imaging (to assess skeletal damage) and blood and urine work for detection of elevated serum proteins, including M-protein, β2-microglobulin, and albumin, which may be indicative of myeloma and resultant kidney dysfunction. The International Staging System for multiple myeloma was published in 2005 and is widely used to differentiate patients with myeloma (Table 11). 58 However, as myeloma remains an incurable disease with high mortality, most treatment decisions are made based on age and performance status rather than stage. INITIAL TREATMENT OF MULTIPLE MYELOMA On diagnosis, first-line treatment of multiple myeloma is typically high-dose chemotherapy and bone marrow transplant, if the patient can tolerate it. 59,60 The most frequently used first-line chemotherapy regimens are VAD (vincristine, doxorubicin, and dexamethasone) and CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). However, most patients with myeloma are elderly and thus cannot tolerate high-dose chemotherapy regimens. For the past 40 years, a less intense regimen, MP (melphalan and prednisone), has been the standard of care for elderly patients with myeloma who are ineligible for high-dose therapy. 61 In recent years, 3 targeted therapies have been added to the multiple myeloma treatment armamentarium: the IMiDs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. All 3 agents, which are most commonly used in combination with dexamethasone, are approved for relapsed/refractory multiple myeloma, and thalidomide also is approved as a first-line agent. In untreated patients with myeloma, thalidomide, lenalidomide, and bortezomib have demonstrated response rates of 63%, 91%, and 80% to 88%, respectively, when combined with dexamethasone TREATMENT OF RELAPSED MULTIPLE MYELOMA All patients with myeloma eventually relapse. As mentioned above, the targeted therapies thalidomide, lenalidomide, and bortezomib are all US FDA-approved for the treatment of relapsed/refractory multiple myeloma. These agents are generally used as monotherapy or in combination with dexamethasone, although novel combinations of thalidomide, lenalidomide, and bortezomib with each other, with other chemotherapeutic agents (eg, melphalan and cyclophosphamide), and with investigational agents also are being explored. New agents that are currently being evaluated in multiple myeloma include ATO, liposomal doxorubicin, temsirolimus, and the FLT3 inhibitor, lestaurtinib. MULTIPLE MYELOMA: PATIENT MANAGEMENT ISSUES Thalidomide and lenalidomide are associated with an increased risk of thromboembolic complications, most commonly deep vein thrombosis and pulmonary embolism; combination with dexamethasone appears to further increase this risk. 62,66 Other adverse effects including neuropathy, constipation, sedation/vertigo, and bradycardia may complicate therapy with thalidomide and lenalidomide. 67,68 Patients receiving these regimens should be placed on anticoagulants, although the optimal prophylactic anticoagulation strategy has not yet been established. Bone pain can be very problematic for patients with myeloma. Treatment with bisphosphonates, such as pamidronate and zoledronic acid, given every 3 to 4 weeks has been shown to decrease pain and fracture risk when used in patients with multiple myeloma. 69,70 Radiation therapy also can be used for palliation of bone lesions. Table 11. International Staging System for Multiple Myeloma Median Stage Criteria Survival, mo I Serum β 2 -microglobulin 62 <3.5 mg/l Serum albumin 3.5 g/dl II Not stage I or III 44 III Serum β 2 -microglobulin 5.5 mg/l 29 Reprinted with permission from Greipp et al. J Clin Oncol. 2005; 23: Johns Hopkins Advanced Studies in Medicine 115

12 As many patients with myeloma experience kidney dysfunction and renal failure, it may be necessary to administer hemodialysis and myeloma treatment simultaneously. Although dose reduction is often necessary, the 2 therapies can be successfully coadministered, however an increase in gastrointestinal toxicity may occur. 71 A large number of investigational agents, including targeted therapies, have been successfully integrated into the treatment paradigm for hematologic malignancies. As new agents are adopted into practice, nursing and pharmacy staff will be challenged to safely and properly administer these drugs and manage their associated side effects to ensure patient quality of life. Targeted therapies have the potential to enable a greater number of patients with leukemia, lymphoma, and myeloma to live longer and more comfortable lives. REIMBURSEMENT AND MANAGEMENT ISSUES ASSOCIATED WITH TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES As a multitude of targeted therapies for leukemia, lymphoma, and myeloma become available, healthcare providers are faced with a variety of new reimbursement issues. Many of these agents, particularly antibody drugs, are associated with a high cost; practitioners may encounter resistance in the reimbursement of such agents, particularly if they have not been US FDA-approved for use in a particular disease state or their superiority has not been established using evidence-based medicine practices. For many patients, access to such agents may be available only through enrollment in clinical trials. Many of the new therapies available for hematologic malignancies can be administered orally or subcutaneously, and thus on an outpatient basis. Patients who receive these medications are therefore not monitored in the same manner as those who receive therapy as inpatients; new strategies for monitoring these patients should be developed, such as through followup phone calls and/or office visits. Furthermore, hospital staff may not have access to such agents in an inpatient setting, thus when patients are admitted for treatment of drug-related side effects and/or monitoring, they may find it difficult to continue on their outpatient medications. It is highly recommended that when a patient enters a hospital, all medications that were being used at home should be brought in a plastic bag and given to the nursing staff on admission. This practice is being adopted by a growing number of treatment centers to ensure that patients can seamlessly continue their oral medications. CONCLUSIONS REFERENCES 1. American Cancer Society. Cancer Facts and Figures Atlanta, Ga: American Cancer Society; Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006;368: Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American- British (FAB) co-operative group. Br J Haematol. 1976; 33: Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: National Cancer Institute. Adult acute myeloid leukemia (PDQ(R)): treatment. Health professional version. Available at: Accessed February 22, Robak T, Wrzesien-Kus A. The search for optimal treatment in relapsed and refractory acute myeloid leukemia. Leuk Lymphoma. 2002;43: Barrios NJ, Tebbi CK, Freeman AI, Brecher ML. Toxicity of high dose Ara-C in children and adolescents. Cancer. 1987;60: Wright LG. Maculopapular skin rashes associated with high-dose chemotherapy: prevalence and risk factors. Oncol Nurs Forum. 2006;33: Seipelt G, Hofmann WK, Martin H, et al. Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin. Ann Hematol. 1998;76: Archimbaud E, Jehn U, Thomas X, et al. Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia. Leukemia. 1999;13: Lee BH, Williams IR, Anastasiadou E, et al. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene. 2005;24: Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7: Seiter K. Acute myelogenous leukemia Available at: Accessed January 18, Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist. 2001;6: Douer D. Advances in the treatment of relapsed acute 116 Vol. 7, No. 4 May 2007

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