1. Applied Therapeutics

2.  Leukemias are hematologic malignancies that are derived from cytogenetic alterations in hematopoietic cells. Biologically, they originate in the bone marrow before disseminating to systemic tissues.  Leukemias are classified based on the cell of origin (myeloid or nonlymphocytic and lymphocytic) and clinical course. Myeloid leukemias include disorders of granulocytes, monocytes, erythrocytes, and platelets. Lymphocytic leukemias include disorders of B and T lymphocytes. Leukemias are further classified as acute or chronic.

3.  Acute leukemia is characterized by the expansion and differentiation arrest of immature hematopoietic cells. This expansion causes large numbers of early progenitor cells (blasts) to appear in the bone marrow. Leukemic blasts develop a growth advantage that leads to failure of the bone marrow to produce adequate numbers of functional mature blood cells.  If the blasts have lymphoid features, the leukemia is classified as acute lymphocytic leukemia (ALL). If the blasts have myeloid features, the leukemia is classified as acute myeloid leukemia (AML).

4.  Chronic leukemias follow a more insidious onset and course than acute leukemias and are associated with proliferation of more mature hematopoietic cells.  Chronic lymphocytic leukemia (CLL) is characterized by overproduction of mature lymphocytes.  Chronic myeloid (or granulocytic) leukemia (CML or CGL) is associated with overproduction of mature neutrophils or granulocytes. Deposition of these cells in various organs, as well as high numbers in vascular spaces, have profound and unique consequences that are discussed in subsequent cases.

5.  The lymphomas are a heterogeneous group of hematologic malignancies that originate in lymphoid tissues. A lymphoma may arise within single or multiple lymph nodes or in extranodal sites commonly involving the lymphoid tissue of the gastrointestinal (GI) tract, central nervous system (CNS), or numerous other sites.  The two major types of lymphomas are Hodgkin disease (HD) and non–Hodgkin lymphoma (NHL).

6.  Plasma cell disorders include a group of neoplasms that arise from antibody-secreting B cells that overproduce excessive amounts of a monoclonal immunoglobulin or part of a monoclonal immunoglobulin (light chains).  If the monoclonal protein is in the IgM subclass, the disease is called “ Waldenström macroglobulinemia,” and the malignant cells are called “plasmacytoid lymphocytes.” If the monoclonal protein is in the IgG (70% of cases) or IgA (20% of cases) subclass or if only monoclonal light chains are present in blood, the disease is called “ multiple myeloma,” and the malignant cells are called “plasma cells.” Multiple myeloma is the most common plasma cell disorder, accounting for 14% of all hematologic malignancies.

7.  AML is far more common in adults than in children.  For a definitive diagnosis of AML to be made, the bone marrow aspirate must contain more than 20% leukemic blast cells. A normal bone marrow aspirate would typically contain less than 5% blasts.

8.  Goal of Therapy  The leukemic cells populating blood are abnormal and incapable of fighting infection. Their rapid proliferation is also suppressing RBC and megakaryocyte production in the bone marrow.  The goal of the initial chemotherapy is to clear the bone marrow and peripheral blood of all blast cells in the hope that normal blood cell components can regenerate.

9.  Standard induction chemotherapy for AML includes an anthracycline (either daunorubicin or idarubicin) and cytarabine, an antimetabolite.  Tretinoin and Arsenic Trioxide for Acute Promyelocytic Leukemia  Tretinoin or “All Trans-Retinoic Acid” (ATRA) induces promyelocyte differentiation and maturation. In clinical trials, ATRA has induced complete remissions in approximately 90% of patients with APL.  Arsenic trioxide (ATO) has also been evaluated in the treatment of patients with APL.

10.  Tumor Lysis Syndrome  Chemotherapy resulted in rapid lysis of the blast cells and the release of their cellular contents into the blood. A hypercellular bone marrow with a very high number of blast cells can also lead to rapid lysis of the blast cells and the release of cellular contents.  Typical metabolic abnormalities associated with tumor lysis syndrome (TLS) are hyperuricemia, hyperphosphatemia, hypocalcemia, and uremia.

11.  Myelosuppression  Patients receiving cytarabine and idarubicin induction therapy develop profound anemia, granulocytopenia (e.g., WBC count <100/mm 3 ) and thrombocytopenia (<20,000 platelets/mm 3 ) shortly after therapy is initiated that persists for 21 to 28 days. All infectious complications must be considered life threatening in severely immunocompromised patients.

12.  The two most common types of childhood leukemia are acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), with the former accounting for 75% of cases and the latter for approximately 19%.  ALL is the most common childhood cancer, accounting for approximately 30% of all malignancies in children.

13.  Allopurinol Interaction  Xanthine oxidase, the enzyme inhibited by allopurinol, also converts mercaptopurine to 6- thiouric acid. Thus, allopurinol may markedly increase the plasma concentrations of oral mercaptopurine by inhibiting first-pass metabolism, and this may lead to toxicity.

14.  The agents most commonly used in remission induction therapy are vincristine (Oncovin), prednisone (Deltasone), dexamethasone (Decadron), asparaginase (Elspar), pegaspargase (Oncaspar), and daunorubicin (Cerubidine).  The prednisone or dexamethasone dose is not routinely tapered at the end of induction treatment.

15.  All treatment protocols for childhood ALL use some form of CNS preventive therapy, although different regimens are used. The first successful CNS prophylaxis treatments were craniospinal radiation with or without IT methotrexate, which markedly reduced the CNS relapse rate.  To avoid the myelosuppression and reductions in spinal growth due to craniospinal irradiation, the standard CNS preventive therapy was modified to 2,400 cGy of cranial irradiation, along with IT methotrexate.

16.  CML is a myeloproliferative disorder characterized by unregulated stem cell proliferation in the bone marrow and an increase in mature granulocytes in the peripheral blood.  Common clinical symptoms on presentation include fatigue, fever, anorexia, and weight loss. Approximately 50% to 70% of patients present with a leukocyte count >100,000/mm 3.

17.  In newly diagnosed patients who present with very high leukocyte counts (>100,000/mm 3 ), the initial goal of therapy is to reduce leukocytosis and its related symptoms.  Hydroxyurea is still the most common agent used for initial leukocyte reduction.  Imatinib (Gleevec) is a tyrosine kinase inhibitor that occupies the adenosine triphosphate binding site of several tyrosine kinase molecules and prevents phosphorylation of substrates that are involved in regulating the cell cycle.

18.  CLL is a chronic lymphoproliferative disorder characterized by an excess of functionally incompetent B-cell lymphocytes derived from a single stem cell clone. CLL should be included in the differential diagnosis of any adult with persistent lymphocytosis (>5,000 lymphocytes/mm 3 in peripheral blood).

19.  Indications for treatment initiation in CLL include significant anemia and/or thrombocytopenia, progressive disease demonstrated by lymphadenopathy, hepatomegaly, splenomegaly, a lymphocyte doubling time <6 months, persistent B symptoms (fever, night sweats, and weight loss), and recurrent infection.

20.  Initial Therapy  Chlorambucil  Fludarabine  Cladribine  Rituximab  Alemtuzumab  Salvage Therapy  Second-line therapy should be selected based on criteria similar to those used for initial management. Relapsed patients are classified as fludarabine naive, fludarabine sensitive (relapse more than 6 months post treatment), or fludarabine refractory.

21.  Lymphomas are a heterogeneous group of disorders that arise from malignant transformation of lymphocytes (B cells, T cells, or natural killer [NK] cells) in the lymphoid system.  Patients with slow-growing indolent lymphomas such as typically present with painless generalized lymphadenopathy that can be either transient or persistent.  Presentation of fast-growing aggressive lymphomas is variable; most patients present with lymphadenopathy and extranodal involvement. The most common extranodal sites include the GI tract, skin, bone marrow, sinus, or central nervous system. Fever (>38°C), night sweats, and weight loss (>10% of body weight over 6 months) are defined as B symptoms.

22.  Aggressive Lymphomas  Aggressive and highly aggressive lymphomas are potentially curable. Patients with nonbulky (<10 cm) localized stage I/II disease without B symptoms were typically treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for three to eight cycles with or without radiotherapy.

23.  Indolent Lymphoma  The goal of therapy for indolent lymphomas is typically palliative because few patients will be cured of disease. However, the progression of the disease is typically very slow, and median survival is 8 to 12 years after diagnosis.  Treatment of localized disease, defined as nonbulky stage I or II, includes radiation with or without systemic therapy.

24.  Hodgkin lymphoma (or HD) can occur at any age.  Presentation can be limited to a single lymph node or to an extralymphatic organ or site, or it can involve multiple lymph nodes and extralymphatic organs.  Hodgkin lymphoma is one of the few malignancies that is typically curable, even in the advanced stages.

25.  Multiple combination chemotherapy regimens have been developed; however, none have demonstrated superiority to ABVD in patients with advanced Hodgkin lymphoma.  Other regimens evaluated include MOPP…  Relapsed Disease  Patients with relapsed Hodgkin lymphoma have two main treatment options: salvage chemotherapy with or without radiation therapy, or high-dose chemotherapy with autologous stem cell support.

26.  MM is a malignancy of fully differentiated B lymphocytes called “plasma cells.” Proliferation and accumulation of plasma cells leads to excessive antibody (immunoglobulin) production, typically IgG or IgA.  A variety of clinical manifestations can be seen and are related to excessive immunoglobulin production, plasma cell infiltration, and immune deficiency.

27.  Initial Therapy  Thalidomide is an immunomodulatory agent with antiangiogenic properties, which are effective in patients with MM.  Dexamethasone is moderately effective as induction therapy alone and in combination, but has significant adverse effects, including hyperglycemia, insomnia, and increased infection risk.

28.  Combination therapy with vincristine, doxorubicin, and dexamethasone is another option for patients eligible for autologous HCT.  The conventional VAD (vincristine, doxorubicin [Adriamycin], dexamethasone) regimen is a 4- day infusional treatment that was historically preferred over melphalan-based regimens because the response was more rapid and caused less myelosuppression.  In patients ineligible for autologous HCT, melphalan-based regimens are appropriate for induction therapy.

29.  Hematopoietic Cell Transplantation  Efforts to improve the outcome of MM treatment have led to the investigation of high- dose chemotherapy (e.g., melphalan 200 mg/m 2 ) with autologous stem cell support and nonmyeloablative regimens with allogeneic stem cell support.

30.  Bisphosphonates  The efficacy of IV pamidronate and zoledronic acid for the prevention of skeletal fractures in myeloma patients with osteolytic bone lesions or osteopenia has been established and guidelines for their use developed.