CME CREDIT INFORMATION

NON-HODGKINS LYMPHOMAS
Non-Hodgkin's Lymphoma (NHL) can be divided into aggressive and indolent types, and they can be formed from either B-cells or T-cells. In the US each year, nearly 54,000 people are diagnosed with NHL. It is the most common type of blood malignancy in the US.

FOLLICULAR LYMPHOMA
Follicular lymphoma is an indolent form of NHL and comprises approximately 20 to 30 percent of NHL cases diagnosed in the US. For follicular lymphomas, once therapy is initiated, a rituximab-containing regimen has resulted in the highest rates of complete response and improvements in progression-free survival over chemotherapy alone. Currently, there are several chemotherapy strategies (single agent or combinations) that are used in the first-line setting. The role of radio-immunotherapy in the first-line setting is also area of interest in the treatment of follicular lymphoma. The treatment of relapsed disease is more challenging.

DIFFUSE LARGE B-CELL LYMPHOMA (DBLC)
DLBCL, accounts for approximately 30 percent of United States NHL cases. The mainstay of therapy for DLBCL is treatment with R-CHOP.

Currently, much of the clinical research conducted focuses on ways to induce high-quality responses and long duration of response. In an effort to further enhance the significant activity of R-CHOP as initial treatment of DLBCL, clinical trials are currently studying numerous new regimen combinations, which will be discussed in great detail in the symposium.

Treatment of relapsed or refractory DLBCL includes consideration of multiple high-dose, non-cross-resistant combination systemic therapy regimens with or without consolidation autologous stem cell transplantation (ACST). For example, the activity of lenalidomide in the treatment of relapsed or refractory aggressive NHL has been demonstrated in several clinical trials.

Standard treatment of relapsed or recurrent NHL has traditionally included autologous or allogeneic stem cell transplant for appropriate candidates, radio-immunotherapy or rituximab. In November 2008 the FDA approved bendamustine for the treatment of relapsed or refractory indolent lymphoma. Additionally, numerous other investigational agents are being evaluated.

CUTANEOUS T-CELL LYMPHOMA (CTCL)
The incidence of Cutaneous T-cell Lymphoma (CTLC) is an estimated 1,500 new cases per year in the US versus 59,000 for all types of NHL. Treatment of CTCL depends upon the type and stage of the disease. Localized disease is usually treated topically with agents such as retinoids, nitrogen mustards or ultraviolet light.

Widespread CTLC disease is treated by any of a variety of agents. Bexarotene is one agent that is FDA approved for CTLC. Denileukin diftitox is another drug approved for treating CTCL. Vorinostat and romodepsin, both HDAC (histone deacetylase inhibitors) are FDA approved for treating CTCL.

PERIPHERAL T-CELL LYMPHOMA (PTCL)
Peripheral T-cell lymphoma (PTCL) represent a l subgroup of non-Hodgkin lymphomas that historically, are difficult to diagnose. This subtype of lymphoma is also relatively uncommon with only a few thousand new patients diagnosed per year in the USA. Pralatraxate is currently the only drug approved by the FDA to treat PTLC. Investigational drugs used to treat this subtype of lymphoma include the HDAC inhibitors, bortezomib, and some bcl-2 inhibitors.

CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm in the family of the non-Hodgkin's lymphomas. It is the most common type of the four major types of leukemia and it accounts for one-third of all leukemias. About 15,490 new cases of CLL will be diagnosed in 2009 in the US. In 95 percent of people with CLL it is a B lymphocyte malignancy. It is estimated that nearly 90,000 people in the US are now living with or are in remission from CLL. This malignancy is more common in people who are 60 years and older than in younger adults. The number of people with CLL starts to increase after age 50. A small number of people are diagnosed with CLL in their 30s and 40s.

Patients who have intermediate- and higher-risk CLL are usually treated with combination chemotherapy and/or monoclonal antibody therapy. Such treatment is often an alkylating agent and/or a purine analog with either alemtuzumab, ofatumumab or rituximab.

MYELOID MALIGNANCIES
Chronic Myeloid Leukemia (CML)
CML accounts for 15 percent of adult leukemias, and the median age of onset is 67 years. If left untreated, CML will progress from a chronic phase to a blast phase over approximately three to five years, leading to rapid disease progression and death. The hallmark of CML is the molecular presence of the Philadelphia chromosome.

The 2001 FDA approval of imatinib mesylate, a specific inhibitor of the bcr-abl tyrosine kinase, marked a revolutionary breakthrough in the management of CML, leading to durable major cytogenetic responses in 87 percent and complete cytogenetic responses in 76 percent of treated patients. Importantly, five-year overall survival exceeds 90 percent, with 84 percent of patients free of disease progression while continuing on treatment.

Some patients develop acquired resistance that may be related to mutations in bcr-abl and resultant conformational changes in the tyrosine kinase binding domain. Two next generation drugs are available to treat CML patients failing imatinib, dasatinib and nilotinib.

Acute Myeloid Leukemia (AML)
Acute myeloid leukemia is a rapidly progressing cancer of the blood and bone marrow characterized by an overgrowth of abnormal blood cells that quickly crowd out the healthy blood cells needed by the body. The NCI estimated that more than 13,000 patients would be diagnosed with AML in 2009, and nearly 9,000 deaths would occur as a result of the disease that same year. The average age of a patient with AML is 67 years old, with diagnoses very rarely occurring before the age of 40. Due to the fast-growing nature of AML, it is important for patients to be treated promptly upon diagnosis to minimize the risk of the disease progression. Induction chemotherapy, the standard front-line AML therapy, is associated with high toxicity, including bone marrow suppression and increased risk of infection, which often limits use in elderly patients with a poor prognosis.

Untreated AML is a uniformly fatal disease, and even with adequate therapy, the five-year survival rate among all risk groups combined is approximately 22 percent, diminishing to only 5 percent among those with poor-risk cytogenetics.

Despite our increasing understanding about the biology of AML, the prognosis is poor for the majority of the patients. Allogeneic stem cell transplantation is a curative option, however, only a small percentage of patients are candidates for this procedure. First-line treatment for AML includes induction chemotherapy with cytarabine and an anthracycline in an effort to reduce leukemic burden and induce disease remission, followed by consolidation strategies utilizing various doses and sequences of similar agents with or without stem cell transplantation.

For salvage therapy in patients who fail to achieve remission remaining options include allogeneic stem cell transplantation if a suitable matched donor can be found, and an FDA-approved therapy, gemtuzumab ozogamicin (an anti-CD33 antibody with evidence of activity in relapsed or refractory AML of the elderly) or enrollment into a clinical trial for treatment with an investigational agent.

Myelodysplastic Syndromes (MDS)
The myelodysplastic syndromes (MDS) are extremely heterogeneous in nature and may present with a variety of peripheral blood cytopenias. The transformation of MDS to AML is the ultimate disease complication leading to patient morbidity and mortality, with treatment goals of MDS focused on supportive care and reducing the risk of incipient progression to AML.

MDS are diagnosed in slightly more than 10,000 people in the United States yearly for an annual age-adjusted incidence of 3.4/100,000 people. The vast majority of low- and moderate-risk patients are initially managed with low intensity chemotherapy. Those with higher-risk disease may be managed with induction chemotherapy, similar to regimens utilized in AML, or preferably with allogeneic hematopoietic stem cell transplant if a donor is available. Both azacitadine and decitabine are approved by the FDA for treating MDS in all risk subsets, but azacitadine is the only agent of the two currently administered in the outpatient setting that has recently demonstrated improved overall survival versus standard care, even in patients with higher-risk disease.

MULTIPLE MYELOMA
Multiple Myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10 percent of all hematologic malignancies. The utility of lenalidomide or bortezomib in combination with dexamethasone and other agents has traditionally lead to substantial rates of objective and complete response, as well as subsequent successful ASCT.

In the setting of poor ASCT candidates, induction chemotherapy frequently includes the well-studied alkylating agent melphalan with steroids and/or thalidomide. However, as in the context of planned ASCT, the newer agents lenalidomide and bortezomib are now used in the front-line setting.

Relapsed or refractory myeloma is considered a salvage situation, and acceptable regimens in this setting include monotherapy and various combinations with the following lenalidomide, dexamethasone, bortezomib, vorinostat, thalidomide, doxorubicin, cyclophosphamide, etoposide, and cisplatin.