PHARMACOTHERAPY III PHCY 510 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY III PHCY 510 Lecture 14 Neoplastic Disorders “Leukemia & Lymphoma” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

Hematologic Malignancies Cancers arising from hematopoietic cells and lymphoid tissue are termed “hematologic malignancies,” This includes leukemias, lymphomas, plasma cell disorders, and myeloproliferative disorders. Chemotherapy is the primary treatment. Leukemias Derived from cytogenetic alterations in hematopoietic cells. 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.

Leukemias are further classified as acute or chronic. Acute leukemia is characterized by the expansion causes large numbers of early progenitor cells (blasts) in bone marrow. 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). 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.

Clinical Manifestations Chronic Leukemia: CML is a triphasic disease : the initial phase (months to years), the median phase (5 years) and the accelerated phase (progressive) 30% asymptomatic. malaise, weight loss and night sweats, hepato-splenomegaly CLL: Patients are of increased risk of infection, hemolytic anemia, night sweats, weight loss, hepato-splenomegaly, lymphadenopathy,. Survival varies from 2 to 20 years. thrombocytopenia, non-Hodgkin’s lymphoma

Treatment Patients with ALL affecting brain are treated with intrathecal methotrexate (MTX) or cranial irradiation because cytotoxics poorly pass the BBB. ALL treatments generally include: methotrexate, cytorabine, prednisolone, vincristine, 6-mercaptopurine. AML treatment generally include: daunorubicin, etoposide, mitoxantrone, fludarabine. CML treatment include: hydroxycarbamide (hydroxyurea) (brings the WBC under control within 1-2 weeks), interferon, imatinib, BMT CLL: there is no cure. All treatments are palliative specially in lymphadenopathy. Drugs include: chlorambucil, cyclophosphamide, prednisolone, fludarabine

BMT = bone marrow (stem cell) transplantation: Life-saving technique start with conditioning therapy including high dose cyclophosphamide or melphalan or busulpham (ablative therapy) for 2-3 days followed by infusion of harvested stem cells. Allogenic (Allograft) BMT: uses donor bone marrow, ablative therapy and infusion

Allogeneic Hematopoietic Cell Transplant A HCT has the potential to cure CML and is the treatment of choice for young patients with chronic-phase CML. A human leukocyte antigen (HLA)-matched sibling donor is available. If a HLA-matched sibling is not available, a matched unrelated donor may be used, but with a higher risk of rejection. Most recommendations for unrelated donor transplants for CML have included an upper age limit for patients of 35 to 45 years

Autologous Hematopoietic Stem Cell Transplant Autologus (Autograft) BMT: uses own patient bone marrow, ablative therapy and infusion. By using an infusion of Ph chromosome-negative autologous peripheral blood progenitor cells. It may be necessary to provide post transplant maintenance therapy such as INF-α to patients receiving autografts. Autografting may prove useful for patients without matched donors or who are outside the age limit to tolerate allogeneic grafting.

Complications of BMT Acute graft versus host disease (GVHD) caused by T-lymphocytes in the donated marrow. Life threatening disease. May lead to multi-organ failure with a high mortality rate (infection). Risk increases with age (>45 years) Occurs within 100 days of BMT Fever, rash, diarrhoea and liver dysfunction Prophylaxis: cyclosporine, Methotrexate for 6-12 months post BMT Treatment: high dose methylprednisolone + cyclosporine

Lymphomas 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). They are aggressive diseases and fatal if not treated.

Hodgkin (HL) and Non‐Hodgkin (NHL) Lymphomas Characterized by enlarged abnormal lymph nodes with anaemia Risk factors for HL include glandular fever, HIV and genetic link Etiology for NHL may include malaria infection, use of immunosuppressants, insecticides, Crohn’s disease High grade NHL is fatal within months, but very responsive to therapy Symptoms: painless lymph-adenopathy, hepato-spleno-megaly, weight loss, fever, sweats Diagnosed by CBC, BMA, lymph node biopsy, Medications include: doxorubicin, vincristine, etposide, procarbazine, prednisolone, cyclophosphamide, fludarabine,

Patient Care Patient and family must be aware of long term treatment complications, success rate and ADRs Common complications: mucositis, febrile neutropenia, GVHD, cancer, cardiotoxicity RBCs for anaemia and platelets for thrombocytopenia and bleeding Renal, hepatic and other concomitant diseases Endogenous infections from gut respiratory tract and skin are prevented by giving prophylactic anti-infectives and encourage oral hygiene. Neutropenia: managed by GCSF therapy.

Colorectal Cancer Colorectal cancer is a malignant neoplasm involving the colon, rectum, and anal canal. Development of a colorectal neoplasm is a multistep process of genetic alterations of normal bowel epithelium structure and function leading to unregulated cell growth, proliferation, and tumor development. Adenocarcinomas account for more than 90% of tumors of the large intestine.

Clinical Manifestations Patients with early-stage colorectal cancer are often asymptomatic, and lesions are usually detected by screening procedures. Blood in the stool is the most common sign; however, any change in bowel habits, vague abdominal discomfort, or abdominal distention may be a warning sign. Approximately 20% of patients with colorectal cancer present with metastatic disease. The most common site of metastasis is the liver, followed by the lungs and then bones.

Primary prevention is aimed at preventing colorectal cancer in at risk population = Chemoprevention with celecoxib is one of the preventive measures. Secondary prevention preventing malignancy in a population that has already manifested an initial disease process Screening: Digital rectal examination and annual occult fecal blood testing starting at age 50 years and examination of the colon every 5 or 10 years depending on the procedure. The goals of treatment are to eradicate micrometastatic disease, prevent recurrence and alleviate symptoms. Chemotherapy is the primary treatment modality for metastatic colorectal cancer. Surgical removal of the primary tumor is the treatment of choice for most patients with operable disease Fluorouracil (5-FU) and Capecitabine are the most widely used chemotherapeutic agents.

Breast Cancer The strongest risk factors are female gender and increasing age. Additional risk factors include: – endocrine factors (e.g., late age at first birth, estrogen therapy), – genetics (e.g., personal and family history, mutations of tumor suppresser genes) – environment (e.g. radiation exposure). Breast cancer spreads via the bloodstream early in the course of the disease, resulting in relapse and metastatic disease after local therapy. The most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.

The initial sign in more than 90% of women with breast cancer is a painless lump that is typically solitary, unilateral, solid, hard, irregular, and nonmobile. Less common initial signs are pain and nipple changes. More advanced cases present with prominent skin edema, redness, warmth, and induration (rigid). Symptoms of metastatic breast cancer include bone pain, difficulty breathing, abdominal enlargement, jaundice, and mental status changes. It is common to detect breast cancer during routine screening mammography in asymptomatic women.

Diagnosis Initial workup should include a careful history, physical examination of the breast, mammography, and possibly ultrasound. Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or a mass that is palpable on physical examination. Stages of breast cancer: – Stages 0 – II: Early Breast Cancer – Stage III: Locally Advanced Breast Cancer – Stage IV: Advanced or Metastatic Breast Cancer

Treatment The goal of therapy with early and locally advanced breast cancer is cure. The goals of therapy with metastatic breast cancer are to improve symptoms, improve quality of life, and prolong survival. Surgery alone can cure most patients with localized cancers and approximately half of those with stage II cancers. Doxorubicin-containing regimens are popular. Taxanes are a newer class against metastatic breast cancer. Tamoxifen is the gold standard for adjuvant endocrine therapy because of decreased recurrence and mortality. Prevention: Tamoxifen, 20 mg daily, reduced the incidence by 48%.