Leukemia

Brief of Pharmacotherapeutics of Leukemia for Pharm.D students.

1. What is cancer Cancer is the uncontrolled growth of abnormal cells anywhere in a body . C ancers are subset of neoplasm. A neoplasm is a group of cells that have undergone unregulated growth, forms a mass/lump Life threatening disease

2. 6 doings of Cancer Self sufficiency in growth signaling Insensitivity to anti growth signal Apoptosis Enabling of a limitless replicative potential Induction and sustainment of angiogenesis Activation of metastasis and invasion of tissue

3. OVERALL CANCER STAGING STAGE EXPLAINATION STAGE 0 Carcinoma in situ STAGE 1 Cancers are localized to one part of the body STAGE 2 Locally advanced cancer STAGE 3 Specific type of cancer STAGE 4 Metastasized cancer

4. CANCER MENIFESTATIONS LOCAL Compression of blood vessels Ischemia Pain Bleeding Infection Altered tissue function SYSTEMIC Fatigue Cachexia Bleeding and hemorrhage Anemia Impaired organ function Abnormal hormone production

5. TNM CLASSIFICATION TUMOR NODE METASTASIS

6. LEUKEMIA Dr.Pooja Sharda Janardan

7. Leukemia is characterized by proliferation of myeloid tissue(bone marrow and spleen) and abnormal increase in number of granulocytes, myelocytes and myeloblasts in circulating blood. Results in accumulation of dysfunctional cells because of loss of regulation in cell division Myeloblast is unipotent stem cell which will differentiate into one of actors of granular series

8. Myelocyte is a young cell of granulocytic series Granulocytes are category of white blood cells Also known as polymorphonuclear leukocytes (shape variation) Leukemia is group of malignnat disorder, affecting the blood and blood forming tissue of bone marrow, lymph system and spleen. The rate at which leukemia progresses and how the cells replace the normal blood and marrow cells are different with each type of leukemia.

9. Sign and Symptoms P ain  in the bones or J oints S wollen lymph nodes  Fever N ight sweats Fatigue B leeding and  Bruising F requent infections, D iscomfort or swelling in the abdomen, W eight loss

10. Types Acute lymphocytic leukemia (ALL )- A lso called acute lymphoblastic leukemia and acute lymphoid leukemia ALL is typically associated with having more B lymphatic cells than T cells. B and T cells play active roles in preventing the body from infections and germs and destroying cells that have already become infected. B cells particularly help prevent germs from infecting the body while T cells destroy the infected cells.

11. Acute lymphocytic leukemia symptoms Fever Weakness Fatigue Headaches Loss of appetite Pale skin Vomiting Body aches Bleeding gums Frequent infections Nose bleeding Easy bruising Swollen lymph nodes around the neck, underarm, stomach or groin Shortness of breath Weight loss

12. STAGES OF ALL B-cell ALL staging Early pre-B ALL Common ALL Pre-B ALL Mature B-cell  T-cell ALL staging Pre-T ALL Mature T-cell ALL

13. Acute myeloid leukemia Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, is a fast-growing form of cancer of the blood and bone marrow. AML is the most common type of acute leukemia. It occurs when the bone marrow begins to make blasts cells that have not yet completely matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to ward off infections.

14. In AML, the bone marrow may also make abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemia) cells begin to crowd out the normal white blood cells, red blood cells and platelets that the body needs. One of the main things that differentiates AML from the other main forms of leukemia is that it has eight different subtypes, which are based on the cell that the leukemia developed from

15. The types of acute myelogenous leukemia include: Myeloblastic (M0) - on special analysis Myeloblastic (M1) - without maturation Myeloblastic (M2) - with maturation Promyeloctic (M3) Myelomonocytic (M4) Monocytic (M5) Erythroleukemia (M6) Megakaryocytic (M7)

16. Undifferentiated AML   - M0: In this stage of acute myelogenous leukemia, the bone marrow cells show no significant signs of differentiation. Myeloblastic leukemia - M1: Bone marrow cells show some signs of granulocytic differentiation with or without minimal cell maturation. Myeloblastic leukemia - M2: Maturation of the bone marrow cells is beyond the promyelocyte (early granulocyte) stage. Varying amounts of granulocyte maturation may be observed.

17. Promyelocytic leukemia - M3: Most of the abnormal cells are early granulocytes, between myeloblasts and myelocytes in their stage of development. The cells contain many small particles and have nucleuses of varying size and shape. Myelomonocytic leukemia - M4: In this stage of acute myelogenous leukemia, the bone marrow and circulating blood have variable amounts of monocytes and differentiated granulocytes in them. The percentage of monocytes and promonocytes in the bone marrow is greater than 20 percent. There may also be an increased number of granular leukocytes called eosinophils , a type of granulocyte that often has a two-lobed nucleus.

18. Monocytic leukemia - M5: This subset is further divided into two different categories. The first is characterized by poorly differentiated monoblasts with lacy-appearing genetic material. The second subset is characterized by a large number of monoblasts , promonocytes and monocytes . The proportion of monocytes in the bloodstream may be higher than that in the bone marrow. Erythroleukemia - M6: This form of leukemia is characterized by abnormal red blood cell-forming cells, which make up over half of the nucleated cells in the bone marrow.

19. Megakaryoblastic leukemia - M7 :  The blast cells in this form of leukemia look like immature megakaryocytes (giant cells of the bone marrow) or lymphoblasts (lymphocyte-forming cells). M7 leukemia may be distinguished by extensive fibrous tissue deposits (fibrosis) in the bone marrow.

20. Sign and Symptoms Frequent infections and fever Anemia Easy bleeding or bruising Joint and bone pain Liver inflammation Cyanosis Blurred vision Fatigue Sudden unconsciousness

21. Chronic myeloid leukemia  Also known as chronic myelogenous leukemia, chronic myeloid leukemia (CML) is a form of cancer that affects the bone marrow and blood . It begins in the blood-forming cells of the bone marrow and then, over time, spreads to the blood. Eventually, the disease spreads to other areas of the body.

22. CML can change from slow progressing into a rapidly growing, acute form of leukemia that can spread to almost any organ in the body . CML is associated with an abnormal chromosome known as the Philadelphia chromosome ( Ph chromosome ) The breaks in both chromosomes cause the BCR and ABL genes, which combine to create the cancer gene

23. Symptoms Easy bleeding Unexplained weight loss Fever Loss of appetite Night sweats Pale skin Sudden unconsciousness

24. Chronic lymphocytic leukemia Chronic lymphocytic  leukemia (CLL ) is a typically slow-growing cancer that begins in lymphocytes in the bone marrow and extends into the blood. It can also spread to lymph nodes and organs such as the liver and spleen. CLL develops when too many abnormal lymphocytes grow, crowding out normal blood cells and making it difficult for the body to fight infection.

25. Signs and Symptoms N ight sweats E nlarged lymph nodes Anemia Leukopenia : Thrombocytopenia Swollen lymph nodes Enlarged liver or spleen

26. Hairy cell leukemia Hairy cell leukemia (HCL) is a rare subtype of chronic lymphocytic leukemia (CLL) that progresses slowly. HCL is caused when bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. This type of leukemia gets its name from the way the cells look under the microscope—with fine fragments that make them look "hairy."

27. S ymptoms Weakness or feeling tired Recurrent infections and fevers Easy bruising or bleeding Shortness of breath Unexplained weight loss Pain or a feeling of fullness below the ribs Painless lumps in the neck, underarm, stomach or groin Swollen lymph nodes

28. Risk factors for leukemia Gender Age Blood disorders Family history Congenital syndromes Exposure to Radiation Exposure to Chemicals Exposure to Electromagnetic fields Smoking

29. Diagnosis X-ray PET/CT scan MRI Ultrasound CT scan 2D echocardiogram Pulmonary function test Lumbar puncture

30. Diagnostic in leukemia AML ALL CML CLL WBC ↑ in 60%, may be N or ↓ ↑ in 50%, may be N or ↓↓ ↑↑ commonly 100 × 109–250 × 109 L− Commonly ↑ Differential WBC Mainly myeloblasts Mainly lymphoblasts Granulocytes ↑↑, especially neutrophils, myelocytes , basophils and eosinophils <10% blasts present >5 × 109 L−1 monoclonal lymphocytes RBC Severe anaemia Severe anaemia Anaemia common Anaemia in 50% of patients, generally mild

31. AML ALL CML CLL Platelets ↓↓ ↓↓ Usually ↑, may be N or ↓ ↓ in 20–30% Bone marrow aspiration and trephine Predominantly blasts Predominantly blasts Hypercellular blasts < 10% Lymphocytic infiltration Lymph adenopathy Rare Common Rare Common Cytogenetic analysis Important abnormalities detected Important abnormalities detected Presence of Ph chromosome Splenomegaly 50% 60% Usual and severe Usual and moderate Other features DIC, high urate High urate , CNS involvement ↑ Serum uric acid Immune paresis

32. Treatment for AML Chemotherapy Radiation therapy Chemotherapy with stem cell transplant Other drug therapy New types of treatment are being tested in clinical trials. Targeted therapy

33. Radiation therapy Radiation is sometimes used to treat leukemia that has spread outside of the bone marrow and blood, such as to the brain and spinal fluid, or to the testicles. Radiation to the whole body is often an important part of treatment before a stem cell transplant

34. It is used (rarely) to help shrink a tumor (myeloid sarcoma) if it is pressing on the trachea (windpipe) and causing breathing problems. Radiation can be used to reduce pain in an area of bone that is invaded by leukemia, if chemotherapy hasn’t helped.

35. Chemotherapy with stem cell transplant Chemotherapy is given to kill cancer cells. Healthy cells, including  blood forming cells, are also destroyed by the cancer treatment.  Stem cell transplant is a treatment to replace the blood-forming cells.  Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

36. Stem cell transplant Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm. The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown). The patient receives stem cells through a catheter placed into a blood vessel in the chest.

37. Other drug therapy Arsenic trioxide and  all-trans retinoic acid (ATRA) are anticancer drugs that kill leukemia cells, stop the leukemia cells from dividing, or help the leukemia cells mature into white blood cells. These drugs are used in the treatment of a subtype of AML called acute  promyelocytic leukemia

38. Targeted therapy Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.  Monoclonal antibody therapy is one type of targeted therapy being studied in the treatment of adult AML. Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell.

39. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly

40. CHEMOTHERAPY

41. Amsacrine May interfere into DNA and inhibit topoisomerase II, resulting in breaking of DNA double-strand, arrest of the S/G2 phase of the cell cycle, and cell death . Side effect- Nausea, Vomiting, alopecia, loss of libido, erectile dysfunction, bloody color of gums, lips bruising \ Inreractions - Flavonoids, caffeine, codeine, B-blockers, adrenaline, digoxin, ivermectin

42. Mitoxantrone T ype II topoisomerase inhibitor D isrupts DNA synthesis and DNA repair in both healthy cells and cancer cells by intercalation between DNA bases. 30mg/15ml injection available Side effects- U pper respiratory tract infection, urinary tract infection, fungal infection, fungal skin infection, sepsis, alopecia, amenorrhea, cardiac arrhythmia, constipation, diarrhea, ECG abnormality , gastrointestinal hemorrhage

43. CLL

44. F ludarabine C yclophosphamide R ituximab FCR is used to treat chronic lymphocytic leukemia (CLL) and some types of non-Hodgkin lymphoma. FCR – oral over 3 days  FCR – oral over 5 days  FCR – as a drip (intravenous) over 3 days.

45. FCR CYCLE FCR – oral over 3 days Day 1  - Infusion of rituximab fludarabine and cyclophosphamide PO For the first cycle only, the rituximab may be repeated on day 2. Day 2 and 3 fludarabine and cyclophosphamide tablets PO Day 4 to 28 No chemotherapy for the next 25 days. At the end of the 28 days, you start your second cycle of FCR. 

46. FCR – oral over 5 days Day 1  - Infusion of rituximab   fludarabine and cyclophosphamide tablets. For the first cycle only, the rituximab may be repeated on day 2. Day 2 to 5  Fludarabine and cyclophosphamide tablets. Day 6 to 28 You will then have no chemotherapy for the next 23 days. At the end of the 28 days, you start your second cycle of FCR. 

47. FCR – as a drip (intravenous) over 3 days Day 1  - fludarabine , cyclophosphamide and rituximab into a vein. For the first cycle only, the rituximab may be repeated on day 2. Day 2 and 3 F ludarabine and cyclophosphamide IV Day 4 to 28 You will then have no chemotherapy for the next 25 days. At the end of the 28 days, you start your second cycle of FCR. 

48. Fludarabine Alkylating agent 25 mg/1mL IV 10mg-50mg PO Inhibts DNA polymerase, ribonucleotide reductase and DNA primase , thus inhibits DNA synthesis

49. Side effects Nausea /vomiting, diarrhea, headache, muscle aches or pains, tiredness, loss of appetite, sores in the mouth, injection site reaction, hyper sensitivity Interactions- Warfarin , enoxaparin , vaccines, pentostatin , natalizumab , rituximab , heparin, montuelokast Monitoring- Blood clotting time, bleeding time, INR,

50. Cyclophosphamide - Anti metabolite 500mg-1000mg/vial 50mg-250mg PO Side effects- Nausea or vomiting, loss of appetite, stomach pain or upset, diarrhea, temporary hair loss, Delay wound healing ,Missed menstrual periods, changes in skin color (darkening), Nail clubbing

51. Rituximab - 50mg-100mg Monoclonal antibodies Targets and attaches to the CD20 protein found on the surface of blood cells with cancer and some healthy blood cells Side effects- Hypersensitivity, injection site reaction, lipodystrophy , pruritis , increased thirst or urination, swelling of the hands or feet, or tingling of the hands or feet.

52. Ibrutinib Kinase inhibitors Ibrutinib  is an inhibitor of Bruton's tyrosine kinase (BTK). 140mg- 720mg TDS/QID a day for 7-9 months FDI- citrus fruits DDI- furosemide , metoprolol , digoxin , cycloserine , quinidine , COX2 inhibitors

53. Side effects- Diarrhea, nausea, vomiting, decreased appetite, headache, joint/muscle pain, swelling of ankles/legs/feet, numbness, tingling of arms/legs, anxiety, constipation, dizziness, or tiredness

54. Chlorambucil Nitrogen mustered alkylating agent Stops tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate 5mg initially

55. Obintuzumab Obinutuzumab   binds and destroys CD20 on B cells. 25 mg/mL Side effects- Hypersensitivity, injection site reaction, lipodystrophy , pruritis , increased thirst or urination, swelling of the hands or feet, or tingling of the hands or feet, clotting of blood DDI- Antithrombin III human, Azathioprine, clopidogrel , etoricoxib , xanthine derivatives

56. Venetoclax W orks by slowing or stopping the growth of cancer cells . BCL-2  inhibitors Side effect- Thrombocytopenia, fatigue, nausea, vomiting, constipation, fatigue, fever, back pain, headache, cough DDI- A ntifungals,clarithromycin , protease inhibitors,  ciprofloxacin,diltiazem ,  verapamil,  amiodarone , azithromycin, captopril, , carbamazepine, phenytoin, rifampin, efavirenz , etravirine ,  modafinil , warfarin, digoxin

57. Systemic therapies used for CML Targeted therapy- Inhibits BCR-ABL tyrosine kinase enzyme known as tyrosine kinase inhibitors or TKIs. Gefitinib Erlotinib Sorafenib   Sunitinib Dasatinib Chemotherapy Immunotherapy

58. CHEMOTHERAPY

59. Immunotherapy I nterferon has re-emerged as an option in CML treatment, with the advent of pegylated formulations. Pegylation is a chemical process designed to increase a drug’s stability and retention time in the blood, while allowing for reduced dosing frequency. Pegylated interferon requires less frequent administration and is better tolerated by patients.

60. Side effects Dementia, retrograde amnesia, Mood swings , Flu -like symptoms such as muscle aches, fatigue, fever, chills, headaches, nausea and vomiting, Low red blood cell, white blood cell and platelet counts