APPENDIX 1 Glossary of Cytostatic Drugs A number of antimetabolites or cytostatic agents are employed in treating leukemias and lymphomas. These drugs act through different mechanisms and their correct use requires special knowledge and expertise. We have listed them as follows in alphabetical order. Brief descriptions of the various modes of application, the mechanisms of action, and the common side effects are pro- vided. Details about the dosage of the cytostatic drugs are given in the treat- ment protocols and product information. Amsacrine (m-AMSA) MODE OF APPLICATION: intravenous TYPE OF DRUG: alkylating agent MECHANISM OF ACTION: alkylates and intercalates DNA, inhibitor oftopoisomerase II INDICATIONS: acute myelogenous leukemia, acute lymphoblastic leukemia SIDE EFFECTS: severe myelosuppresson, cardiac toxicity (arrhythmias, heart failure), nausea, vomiting, mucositis, in some cases neurotoxicity, severe local toxicity if paravasate Asparaginase MODE OF APPLICATION: intravenous TYPE OF DRUG: enzyme MECHANISM OF ACTION: depletes cells of L-asparagine INDICATIONS: acute lymphoblastic leukemia SIDE EFFECTS: hypersensitivity and anaphylactic reactions, fever, bronchospasm, reduced synthesis of coagulation factors, increase in liver enzymes, hyperglycemia, rarely pancreatitis, central nervous system toxicity (25-50%) COMMENT: During treatment, a substitution of fresh frozen plasma or fibrinogen and antithrombin III may become necessary. Because of anaphylactic reactions, a test dose should be given first. In case of intolerance, an alternative preparation of asparaginase should be used (e.g., erwinia asparaginase). 333
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APPENDIX 1 Glossary of Cytostatic Drugs
A number of antimetabolites or cytostatic agents are employed in treating leukemias and lymphomas. These drugs act through different mechanisms and their correct use requires special knowledge and expertise. We have listed them as follows in alphabetical order. Brief descriptions of the various modes of application, the mechanisms of action, and the common side effects are provided. Details about the dosage of the cytostatic drugs are given in the treatment protocols and product information.
Amsacrine (m-AMSA)
MODE OF APPLICATION: intravenous
TYPE OF DRUG: alkylating agent
MECHANISM OF ACTION: alkylates and intercalates DNA, inhibitor oftopoisomerase II
SIDE EFFECTS: severe myelosuppresson, cardiac toxicity (arrhythmias, heart failure), nausea, vomiting, mucositis, in some cases neurotoxicity, severe local toxicity if paravasate
Asparaginase
MODE OF APPLICATION: intravenous
TYPE OF DRUG: enzyme
MECHANISM OF ACTION: depletes cells of L-asparagine
INDICATIONS: acute lymphoblastic leukemia
SIDE EFFECTS: hypersensitivity and anaphylactic reactions, fever, bronchospasm, reduced synthesis of coagulation factors, increase in liver enzymes, hyperglycemia, rarely pancreatitis, central nervous system toxicity (25-50%)
COMMENT: During treatment, a substitution of fresh frozen plasma or fibrinogen and antithrombin III may become necessary. Because of anaphylactic reactions, a test dose should be given first. In case of intolerance, an alternative preparation of asparaginase should be used (e.g., erwinia asparaginase).
333
334 Cytostatic Drugs
Bleomycin
MODE OF APPLICATION: intravenous, in some cases also intracavitary, topical, intraarterial
TYPE OF DRUG: antibiotic
MECHANISM OF ACTION: intercalates DNA, induces DNA breaks
INDICATIONS: lymphomas, other malignant tumors
SIDE EFFECTS: fever, myalgias, anorexia, skin pigmentation, rash, mucositis, alopecia, pneumonitis (may progress to lung fibrosis), occasionally hypersensitivity reactions, minor myelosuppression
COMMENT: Pulmonary toxicity may be severe in older patients, in patients with chronic lung disorders, or after thoracic irradiation. If higher dose therapy is planned, lung function should be controlled regularly.
Carmustin (BCNU)
MODE OF APPLICATION: intravenous
TYPE OF DRUG: nitrosourea
MECHANISM OF ACTION: bifunctional alkylating agent, induces DNA breaks
INDICATIONS: lymphomas, solid tumors
SIDE EFFECTS: prolonged myelosuppression, cumulative lung toxicity, nausea, vomiting, in some cases hepatic and renal toxicity, in some cases neurotoxicity
Chlorambucil
MODE OF APPLICATION: oral
TYPE OF DRUG: alkylating agent
MECHANISM OF ACTION: alkylates DNA, RNA, induces DNA breaks
INDICATIONS: chronic lymphocytic leukemia (CLL), other low-grade lymphomas
SIDE EFFECTS: leukopenia, minor gastrointestinal discomfort, rarely neurotoxicity, sterility at high doses, pulmonary toxicity
Cladribine (2-CDA)
MODE OF APPLICATION: intravenous
TYPE OF DRUG: alkylating agent
MECHANISM OF ACTION: alkylates DNA, RNA, induces DNA breaks
INDICATIONS: CLL, other low-grade lymphomas
SIDE EFFECTS: leukopenia, minor gastrointestinal discomfort, rarely neurotoxicity, sterility at high doses, pulmonary toxicity
Cytostatic Drugs
Cyclophosphamide
MODE OF APPLICATION: intravenous, oral
TYPE OF DRUG: oxazaphosphorin (bifunctional alkylating agent)
MECHANISM OF ACTION: alkylates DNA and RNA, imduces DNA breaks
335
INDICATIONS: lymphomas, leukemias, solid tumors, immunosuppression, conditioning for bone marrow transplantation
COMMENT: Hemorrhagic cystitis can be prevented if adequate hydration (>200 mLlh) and mesna are given. Mesna should always be given when cyclophosphamide is administered at >400 mg/m2/d. If renal function is compromised, the dosage of cyclophosphamide has to be adapted accordingly.
Cytosine-Arabinoside (ARA-C)
MODE OF APPLICATION: intravenous, subcutaneous, intrathecal
TYPE OF DRUG: antimetabolite, analogue of deoxycytidine
MECHANISM OF ACTION: incorporates into DNA, inhibits DNA polymerases, S-phasespecific
INDICATIONS: acute and chronic leukemias, malignant lymphomas
SIDE EFFECTS: myelodepression, gastrointestinal toxicity (nausea, vomiting, rarely pancreatitis), pulmonary toxicity at high doses, alopecia, keratoconjunctivitis, rash, neurotoxicity (at higher doses and in older patients severe cerebellar syndrome, other neurologic disturbances)
Dacarbacine (OTIC)
MODE OF APPLICATION: intravenous
TYPE OF DRUG: alkylating agent
MECHANISM OF ACTION: methylates DNA
INDICATIONS: lymphomas, other malignancies
SIDE EFFECTS: severe nausea and vomiting, myelosuppression, alopecia, less frequent: hepatotoxicity, diarrhea, thrombophlebitis
Daunorubicin
Mainly used in the treatment of acute leukemias; daunorubicin belongs to the class of anthracyclin-antibiotics; for details see Doxorubicin.
336
Doxorubicin
MODE OF APPLICATION: intravenous
TYPE OF DRUG: anthracycline antibiotic
Cytostatic Drugs
MECHANISM OF ACTION: intercalates DNA, forms free oxygen radicals, inhibits topoisomerase II
INDICATIONS: lymphomas, solid tumors
SIDE EFFECTS: myelosuppression, acute and chronic cardiotoxicity, mucositis, nausea, alopecia, severe tissue necrosis in case of paravasates
COMMENT: The cumulative cardiotoxicity (dilative cardiomyopathy) limits the total dose to 450-550 mg/m2• Risk factors are mediastinal irradiation, previous cardiac disease.
Epirubicin
Used for the treatment of lymphomas, belongs to the class of anthracyclin-antibiotics, for details see Doxorubicin.
Etoposide (VP-16)
MODE OF APPLICATION: intravenous, oral
TYPE OF DRUG: derivative of epipodophyllotoxin (alkaloid)
MECHANISM OF ACTION: complexes with topoisomerase II, induces DNA breaks
INDICATIONS: leukemias, lymphomas, solid tumors
SIDE EFFECTS: bone marrow depression, especially neutropenia, alopecia, some nausea, some patients experience allergic or anaphylactic reactions, rarely neuropathy
Fludarabine
MODE OF APPLICATION: intravenous
TYPE OF DRUG: antimetabolite (purine analogue)
MECHANISM OF ACTION: inhibits enzymes of DNA synthesis
INDICATIONS: low-grade lymphomas
SIDE EFFECTS: myelosuppression, some nausea, hepatotoxicity, neurotoxicity (encephalopathy at high doses), protracted immunosuppression
Cytostatic Drugs
Hydroxyurea
MODE OF APPLICATION: oral
TYPE OF DRUG: antimetabolite
MECHANISM OF ACTION: inhibits ribonucleotide reductase
337
INDICATIONS: chronic myelogenous leukemia, other myeloproliferative syndromes
SIDE EFFECTS: short-acting myelosuppression; some gastrointestinal toxicity; rarely pigmentation; renal, hepatic, and neurologic side effects (dose adjustment in renal failure necessary)
Idarubicin
Used for the treatment of acute leukemias and lymphomas, belongs to the class of anthracyclin-antibiotics, for details see doxorubicin.
Ifosfamide
MODE OF APPLICATION: intravenous
TYPE OF DRUG: alkylating agent (derivative of cyclophosphamide with a particular toxicity profile)
MECHANISM OF ACTION: alkylates DNA and RNA, induces DNA breaks
INDICATIONS: lymphomas, other malignancies
SIDE EFFECTS: myelosuppression, nausea, vomiting, mucositis, diarrhea, hemorrhagic cysitis (see Cyclophosphamide), alopecia, acute CNS toxicity (encephalopathy, cerebellar syndrome, ataxia, seizures; especially in older patients and higher dosage)
COMMENT: Hemorrhagic cystitis can be prevented if adequate hydration (>200 mL/h) and mesna are given. If renal function is compromised, the dosage of cyclophosphamide has to be adapted accordingly. The infusion of Na bicarbonate is recommended for the prophylaxis of CNS toxicity.
Lomustin (CCNU)
MODE OF APPLICATION: oral
TYPE OF DRUG: alkylating agent (nitrosourea derivative)
MECHANISM OF ACTION: alkylates DNA and RNA
INDICATIONS: Hodgkin's disease, solid tumors
SIDE EFFECTS: nausea, stomatitis, alopecia, delayed myelotoxicity, less frequent renal and hepatic toxicity
SIDE EFFECTS: nausea, bone marrow toxicity, liver toxicity (cholestasis), fever, skin rash
COMMENT: If concomitant allopurinol is given, the dose of mercapturin has to be reduced to 25-40%.
Methotrexate
MODE OF APPLICATION: intravenous, oral, intrathecal
TYPE OF DRUG: antimetabolite
MECHANISM OF ACTION: inhibits dihydrofolate reductase
INDICATIONS: leukemias, lymphomas, other malignancies
SIDE EFFECTS: myelosuppression, severe mucositis (dose dependent), nausea, diarrhea, hepatic, renal and pulmonary toxicity, skin rash, acute encephalopathy
COMMENT: At high doses of methotrexate, measurement of plasma levels and "rescue" with folinic acid are important.
Pentostatin (Desoxycoformine)
MODE OF APPLICATION: intravenous
TYPE OF DRUG: antimetabolite
MECHANISM OF ACTION: purine analogue, inhibits adenosine deaminase
INDICATIONS: hairy cell leukemia, other low-grade non-Hodgkin's lymphomas
SIDE EFFECTS: myelosuppression, nausea, less frequent hepatic and renal toxicity
Cytostatic Drugs
Procarbacin
MODE OF APPLICATION: oral
TYPE OF DRUG: alkylating agent
MECHANISM OF ACTION: alkylates DNA, methylates nucleic acids
INDICATIONS: lymphomas
339
SIDE EFFECTS: myelosuppression, nausea, vomiting, skin toxicity, in some cases renal, hepatic, central nervous toxicity
6-Thioguanine
MODE OF APPLICATION: oral
TYPE OF DRUG: antimetabolite
MECHANISM OF ACTION: inhibits purine synthesis, incorporated into DNA
INDICATIONS: leukemias
SIDE EFFECTS: myelodepression, some nausea, diarrhea, cholestasis
Vincristine, Vindesine
MODE OF APPLICATION: intravenous
TYPE OF DRUG: vinca alcaloids
MECHANISM OF ACTION: inhibit function of microtubuli, inhibit DNA-dependent RNA polymerases
INDICATIONS: lymphomas, leukemias, other malignancies
SIDE EFFECTS: nausea, vomiting, pulmonary toxicity, myelosuppression (minor with vincristine, major with vindesine), diarrhea, constipation, stomatitis, mouth ulcers
major neurotoxicity (especially with vincristine, cumulative, dose limiting: peripheral neuropathy, paresthesias, autonomous neuropathy, rarely ataxia, seizures)
Designation
CDI
CD2
CD3
CD4 CD5 CD6 CD7 CD8 CD9
CDlO
CDlla CDIIb
CDIlc
CDl2 CD 13 CDl4 CD15 CD16
CD 17
CD18
APPENDIX 2
CD Nomenclature for Human Leukocyte Antigens
Cellular distribution Function, comments
Cortical thymocytes, dendritic Role in antigen presentation cells
Pan T cell, NK cells Receptor for sheep red blood cells, interaction with CD48 and CD58
Pan T cell Signal transduction from T-cell receptor
T -helper subset Binds to class II MHC antigen Pan T, B-cell subset Marker for B-CLL T -cell subset Early T-cell marker Expressed on T-ALL T suppressor cells Coreceptor in antigen recognition Broad (platelets, lymphoid
progenitors, activated active lymphocytes)
Immature, some mature B cells CALLA-antigen, expressed in pre-B-ALL, some lymphomas, kidney, intestine, brain
Leukocytes Adhesion Granulocytes, monocytes, NK Adhesion
cells Granulocytes, monocytes, Adhesion
macrophages, NK cells Monocytes, granulocytes Monocytes, granulocytes Membrane metalloprotease Monocytes Receptor for lipopolysaccharide Granulocytes, monocytes Lewis x antigen NK cells, granulocytes, mast Fc receptor III
CD47 Broad tissue expression Integrin-associated protein, absent on Rhnull erythrocytes
CD48 Hematopoietic cells CD49a Monocytes, activated T cells Subunit of alphal-integrin
(VLA-lalpha) CD49b Monocytes, platelets, T and B Subunit of integrin-a2
cells CD49c Cultured adherent cell lines Subunit of integrin-a3 CD49d Most leukocytes Subunit of integrin-a4 CD4ge T cells, monocytes, platelets, Subunit of integrin-a5
activated B cells CD49f T cells, monocytes, Subunit of integrin-a6
nonlymphoid tissues CD50 Leukocytes ICAM-3, mediates adhesion CD51 Platelets and endothelial and Alpha subunit of vitronectin
other cells receptor CD52 Leukocytes CD53 Leukocytes and other cells CD54 Hematopoietic and ICAM-l, mediates adhesion, T-cell
nonhematopoietic cells activation CD55 Broad expression Decay-accelerating factor CD56 NK cells, T-cell subpopulation, isoform of NCAM, cell-cell
neural tissue interactions CD57 Subset of NK cells and T -cells CD58 Most hematopoietic cells, other LFA-3 adhesion ligand for CD2
cells CD59 Many cells Complement protectin (via GPI
anchor) CD60 T -cell subset, platelets CD6l Platelets, monocytes, Integrin ~3 subunit (combines with
megakaryocytes, endothelial CD4l and with CD5l) cells
(continued)
344 HLA Nomenclature
CD Nomenclature for HLA (continued)
Designation Cellular distribution Function, comments
CD62E Endothelial cells E-selectin (adhesion of leukocytes) CD62L Most hematopoietic cells L-selectin (homing of
endothelial cells CD94 NK cells, subset of T cells CD95 Activated lymphocytes,
monocytes, fibroblasts, cell lines
CD96 Activated T cells, NK cells, T -cell lines
CD97 Granulocytes, monocytes, activated T and B cells
CD98 Monocytes, some other cells CD99 Pan leukocyte CD 100 B cells, T cells, NK cells, most
myeloid cells CDlOl Monocytes, granulocytes,
mucosal T cells CD 102 Most leukocytes, vascular
endothelium CDI03 Intraepitheliallymphocytes CD 104 Desmosomes of epithelia CD 105 Endothelial cells CD 106 Vascular endothelium, dendritic
cells, some other cells CD 107 Granulocytes, T cells, other
cells Cdw108 Some lymphoid and other cells CDI09 Platelets, activated T cells,
umbilical vein endothelial cells
CD1l7 Hematopoietic progenitors, mast cells, some AMLs
CD120a,b Low-level expression on many cells
Receptor for urokinase plasminogen activator
Receptor for C5a (G proteincoupled receptor)
Receptor for IgA
Thy-l
345
Binds protease-inhibitor complexes
Member of TNF receptor superfamily (induces apoptosis)
ICAM-2, major LFA-lligand on endothelial cells
Integrin nE subunit Integrin ~4 subunit Endoglin (receptor for TGF~) VCAM-l
Lysosome-associated membrane protein
Govalb alloantigen
c-kit
TNF receptors (type I and II)
(continued)
346 HLA Nomenclature
CD Nomenclature for HLA (continued)
Designation Cellular distribution Function, comments
CD134 Activated T cells Member of TNF receptor family, co stimulates T-cell proliferation
CD135 Hematopoietic stem cells FLT-3, receptor for FLT-3/flk-2 ligand
Cdw137 Activated T, B cells, monocytes Costimulation of T-cell growth CD138 Immature B cells, plasma cells Syndecan-l CDl47 Activated cells Extracellular matrix
metalloproteinase inducer CDl48 Broad expression Cdw150 Immature thymocytes, some B
cells CD151 Platelets, megakaryocytes,
monocytes CD152 Activated T lymphocytes Binds CD80, CD86 CD153 Activated T cells CD30 ligand CD154 Activated T cells CD40 ligand CD161 Natural killer cells, some T cells CD162 Granulocytes, monocytes, most Ligand for selectins
Serum vitamin B 12 Serum folate C-reactive protein Serum ~_rmicroglobulin Total protein IgG IgA IgM IgD
APPENDIX 3
Laboratory Values
Normal range
Males: 13.5-17.5 g/dL Females: 11.5-15.5 g/dL Males: 4.5-6.5 x 10 9/L Females: 3.9-5.6 x 10 91L Males: 40-52% Females: 36-48%
80-95 fL 30-35 g/dL
0.5-2.5% or 50-100 000 x 10 91L 4000-10,500/111 2500-7500/111 1500-4000/111 200-800/111
40-500/111 0-100/111
150,000-440,000/111 250-450 lUlL 0.3-2 gIL
<10 mg/L or 17 IlmollL 4-9Ilg/L
Males: 80-150 Ilg/dL or 14-27 IlmollL Females: 60-140 Ilg/dL or 11-251lmollL Males: 40-350 Ilg/L Females: 20-250llglL
347
160-900 ng/L 3.0-15 IlglL <5 mg/L
1.2-2.4 mglL 60-80 gIL
6-16.5 gIL 0.8-4.0 gIL 0.5-2.0 giL <100 U/mL
(continued)
348
Parameter
IgE Fibrinogen Activated PTT Prothrombin time Thrombin time D-dimer
Laboratory Values
Laboratory Values (continued)
Normal range
25-150 U/mL 2-4 gIL
26-35 s 12-14 s
± 3 s of control <0.5 mg/L
All laboratory values depend on the methods used and may vary in different age and ethnic groups. The values in the table can only be considered as an approximate range.
APPENDIX 4
Specific Program Requirements for Residency Education in Hematology
(Accreditation Council for Graduate Medical Education, Version 7/99)
CLINICAL EXPERIENCE
Clinical experience must include opportunities to observe and manage patients with a wide variety of blood diseases on both an inpatient and an outpatient basis. The resident must be given opportunities to assume continuing responsibility for acutely and chronically ill patients in order to observe the evolution of blood diseases as well as the benefits and adverse effects of therapy. Inpatient assignments should be of sufficient duration to permit continuing care of a majority of the patients throughout their hospitalization.
AMBULATORY MEDICINE EXPERIENCE
The program must provide residents with experiences in an ambulatory care setting at least one day each week over the 24 months of training. In addition, the program must provide residents with continuity experiences, each at least 6 months in duration, throughout the residency program.
TECHNICAL AND OTHER SKILLS
1. The program must provide residents with the opportunity to develop competence to work effectively as part of a multidisciplinary team.
2. The program must provide the opportunity for residents to gain competence or expertise in the performance and (where applicable) interpretation of the following:
349
350 Residency Education Requirements
a. Bone marrow aspiration and biopsy, including preparation, staining, examination, and interpretation of blood smears, bone marrow smears, bone marrow aspirates, and touch preparations and interpretation of bone marrow biopsies
b. Use of chemotherapeutic agents and biologic products through all therapeutic routes
c. Correlation of clinical information with the findings of cytology, histology, immunodiagnostic and imaging techniques
3. The program should provide experience or observation of the following: a. Apheresis procedures b. Performance and interpretation of partial thromboplastin time, pro
thrombin time, platelet aggregation, and bleeding time and other standard coagulation assays
c. Bone marrow or peripheral stem cell harvest for transplantation d. Fine needle aspiration and biopsy
SPECIFIC PROGRAM CONTENT
The residents must have formal instruction, clinical experience, or opportunities to acquire knowledge in the following:
1. Morphology, physiology, and biochemistry of blood, marrow, lymphatic tissue, and the spleen
2. Related basic fields, including immunology, basic and clinical pharmacology and pharmacokinetics, cell and molecular biology, tumor immunology, molecular genetics, and prenatal diagnosis
3. Basic molecular and pathophysiologic mechanisms, diagnosis and therapy of diseases of the blood, including anemias, diseases of white blood cells and stem cells, and disorders of hemostasis and thrombosis
4. Etiology, epidemiology, natural history, diagnosis, pathology, staging, and management of neoplastic diseases of the blood, blood-forming organs, and lymphatic tissues
5. Measurement of the complete blood count, including platelets and white cell differential, using automated or manual techniques with appropriate quality control
6. Immunophenotyping, cytochemical studies, and cytogenetic and DNA analysis of neoplastic disorders of blood, blood-forming organs, and lymphatic tissues
7. Molecular mechanisms of hematopoietic and lymphopoietic malignancies, including the nature of oncogenes and their products.
8. Relevant chemotherapeutic drugs, biologic products, and growth factors and their mechanism of action, pharmakokinetics, clinical indications, and limitations
Residency Education Requirements 351
9. Multiagent chemotherapy protocols and combined modality therapy for hematopoietic and lymphopoietic malignancies
10. Management and care of indwelling venous access catheters 11. Principles and application of radiation medicine to hematopoietic and lym
phopoietic malignancies 12. Management of the neutropenic and the immunocompromised patient 13. Effects of systemic disorders and drugs on the blood, blood-forming
organs, and lymphatic tissues 14. Allogeneic and autologous bone marrow or peripheral blood stem cell trans
plantation and the nature and management of posttransplant complications 15. Tests of hemostasis and thrombosis for both congenital and acquired dis
orders and regulation of anti thrombotic therapy 16. Treatment of patients with disorders of hemostasis and the biochemistry
and pharmacology of coagulation factor replacement therapy 17. Transfusion medicine, including the evaluation of antibodies, blood com
patibility, and the use of blood-component therapy and apheresis 18. Indications and applications of imaging techniques in patients with blood
disorders 19. Personal development, attitudes, and coping skills of physicians and other
health-care professionals who care for critically ill patients 20. Pain management in patients with blood disorders 21. Rehabilitation and psychosocial aspects of clinical management of patients
with hematologic disorders 22. Hospice and home care 23. Recognition and management of paraneoplastic disorders 24. Clinical epidemiology and medical statistics, including clinical study and
experimental protocol design, data collection, and analysis 25. Participation in a tumor board 26. Human immunodeficiency virus-related malignancies 27. Care and management of geriatric patients with hematologic disorders
Abciximab, arterial thrombosis treatment, 308
ABO blood group system, hemolytic disease of the newborn, 90, 91 overview, 317, 318
Acanthocytosis, definition and associated conditions, 63
Acenocoumarol, bioavailability, 311 complications, 312 drug interactions, 312, 313 mechanism of anticoagulation activity,
311 monitoring of therapy, 311, 312
Acquired immunodeficiency syndrome (AIDS), see also Human immunodeficiency virus,
Hemophilia, clinical presentation, 284, 286 complications of treatment, 288, 296 factor IX deficiency in type B, 284 factor VIII deficiency in type A, 283,
284 laboratory findings, 286 treatment, 286, 287
Index
Hemorrhagic disorders, see also specific disorders,