Management of over-anticoagulation: See p522 for details Asymptomatic patient INR >5.0 \200\224stop warfarin and reduce dose by at least 25%. Check INR within 1 week. INR >8.0 \200\224consider oral vitamin K 1 \200\2235mg. Symptomatic patient Moderate bleeding, INR 5.0 \200\2238.0, give vitamin K 1mg slowly IV. I NR >8.0: give vitamin K 1mg and FFP or factor concentrate. Severe bleeding: vitamin K 5mg I V, and concentrate containing factors II, VII, IX and X (e.g. beriplex). Observe in hospita l. Vitamin K reverses over-anticoagulation in 24h. Look for causes of over-anticoagulation e.g. heart failure, alcohol, drugs. 590 Kearon, C. & Hirsh, J. (1997) Management of anticoagulation before and after elective surge ry. N Engl J Med, 336, 1506 \200\2231511. 15-protocols.qxd 10.12.2003 04.32 PM Page 591 Protocols and procedures 591 15-protocols.qxd 10.12.2003 04.32 PM Page 592 Management of needlestick injuries Every doctor dealing with high risk patients is concerned to prevent expo- sure to blood an d body fluids, particularly a needlestick injury. The UK DoH published guidance on post-exp osure prophylaxis (PEP) for HIV in 1997 (tel 0203 9724385 for copy). Your hospital/GP surge ry should have a policy for the prevention and management of contamination incidents \200 \224 check this out. Risk to health care workers 2 types of injury \200\224sharps injury where intact skin is b reached by sharp object contaminated with blood/blood-stained body fluids or unfixed tissue , and contamination injury where blood/blood-stained body fluid comes into contact with muc ous membranes or non-intact skin. HBV and HIV are the 2 major concerns. All health care wor kers should be vacci- nated against HBV. Risk of contracting HIV from percutaneous exposure to HIV-infected blood is 0.3%. The amount of blood injected and a high viral load in the patient \200\231s blood increase the risk. General guidelines Prevention All health care workers must adopt universal precautions when handling blood/blo od stained fluids \200\224wear gloves, avoid blood spillage, use decon- tamination procedu res if spillage occurs, label high risk specimens, care with needles (do not resheath), dis posal in burn bins, etc. Immediate action in event of exposure 2 Encourage bleeding and/or wash under running water. 2 Contact Occupational Health/A&E departments for help. 2 Establish patient status re bloo d-borne viruses. 2 Take blood from patient/test for viruses (with consent). 2 Take blood fr om needlestick victim and store. Check HBV immunity/later tests if necessary. Treatment Decision to treat will be made by an experienced medical staff member. Treatment recommended for \200\230all health care workers exposed to high risk body fluids or tissue s known to be, or strongly suspected to be, infected with HIV through percutaneous exposure , mucous membrane exposure or through expo- sure of broken skin. \200\231 Zidovudine alone given as soon as possible 5 risk of seroconversion by 80% but failures are well described. Prophylaxis with triple therapy now recommended. Treat for 4 wks as soon as possible with: 2 Zidovudine 200mg tds/250mg bd + Lamivudine 150mg bd + Indinavir 800mg tds. A \200\230sta rter pack \200\231 should be available in an accessible place at all times. 592 2 Known exposure to hepatitis B \200\223 No immunity \200\224give HepB Ig 500mg IM; vaccinate immediately. \200\223 Known immunity with HepB Ab >100 IU/L in past 2 yr \200\224no action. \200\223 Immunity \200 \224HepB Ab status not known \200\224give booster dose. 15-protocols.qxd 10.12.2003 04.32 PM Page 593 Protocols and procedures Follow-up Occupational Health Department appointment for advice re further man- agement and tests. Counseling as required. 6 months after the incident a \200\223ve test indicates in fection has not occurred. Report incident to PHLS CDSC tel 0208 2006868. In Scotland to SCI EH tel 0141 9467120. 593 Cardo, D.M. et al. (1997) A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Survei llance Group. N Engl J Med, 337, 1485 \200\2231490. 15-protocols.qxd 10.12.2003 04.32 PM Page 594 Chemotherapy protocols VAPEC-B Vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin Indication Hodgkin \200\231s lymphoma stage IA or IIA only without B symptoms or bulky dise ase. Schedule: 6-week chemotherapy and radiotherapy regimen given once only. Days Drug Dose Route Comments 1 \200\22328 Prednisolone 50mg daily PO Take with food in morning; taper off after days 29 \200\22338; consider adding H2 antagonis t or PPI 35mg/m2 1 & 15 Adriamycin IV Bolus injection via fast-running drip or IVI in 100mL 0.9% saline over 15 min (doxorubicin) Cyclophosphamide 350mg/m2 1 IV IVI in 250mL 0.9% saline over 15min 100mg/m2 for 5 consec. days 15 \200\22319 Etoposide PT Take 1h before food on empty stomach 594 1.4mg/m2 (max 2mg) 8 & 22 Vincristine IV Bolus injection via fast-running drip; dilute in 20mL 0.9% saline as per national guideline 8 & 22 Bleomycin \200 10,000iu/m2 IV IVI in 250mL 0.9% saline over 60 min 36 IF radiotherapy \200 Prescribe hydrocortisone 100mg IV before bleomycin. Administration 2 Involved field radiotherapy is given in week 6, 2 weeks after last dose of chemotherapy. The dose is 30 \200\22340Gy to the initial volume of the disease. 2 Outpatient treatment. 2 Consider sperm banking in males (low risk of infertility). 15-protocols.qxd 10.12.2003 04.32 PM Page 595 Protocols and procedures 2 Oral systemic PCP prophylaxis is recommended for the first 6 weeks. 2 Oral systemic antif ungal prophylaxis is optional. 2 Antiemetic therapy for moderately emetogenic regimens on d ays 1 and 15. 2 Delay doxorubicin, cyclophosphamide or etoposide by 1 week if platelets <100 109/L or neutrophils <1 109/L. 2 Reduce cyclophosphamide to 75% dose if creatinine clearance 10 \200\22350mL/min, 50% dose if creatinine clearance <10mL/min. 2 Reduce doxorubicin, vincristine and etoposide to 50% dose if serum bilirubin 1.7 \200\223 2.5 upper limit normal and 25% if 2.5 \200\2234 upper limit normal. Caution with cycl ophosphamide if hepatic impairment. 2 All cellular blood components should be irradiated indefinitely. 2 Total regimen 6 weeks \200\231 treatment. 595 15-protocols.qxd 10.12.2003 04.32 PM Page 596 ABVD Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine Indication Hodgkin \200\231s disease. Schedule 28 day cycle Day 1 (A) Day 15 (B) 25mg/m2 IV X X Doxorubicin 10,000iu/m2 IV Bleomycin X X 6mg/m2 IV (max l0mg) X X Vinblastine 375mg/m2 IVI in normal saline X X Dacarbazine Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/day throughout first treatment cycle. 2 Antiemetic therapy for moderate emetogenic re gimens. 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat tre atment if WBC >3.5 109/L and platelet count >100 109/L. 2 25% dose reduction if WBC 2 .5 \200\2233.5 109/L or platelets 75 \200\223100 109/L. 2 Delay treatment 1 week if W BC <2.5 109/L or platelets <75 109/L. 2 Treat to complete remission + 2 cycles. 596 15-protocols.qxd 10.12.2003 04.32 PM Page 597 Protocols and procedures 597 15-protocols.qxd 10.12.2003 04.32 PM Page 598 ChlVPP Chlorambucil, vinblastine, procarbazine, prednisolone Indication Hodgkin \200\231s disease. Schedule 28 day cycle 6mg/m2 PO days 1 \200\22314 Chlorambucil 6mg/m2 IV (max. 10mg) Vinblastine days 1 & 8 100mg/m2 PO (max. 150mg) days 1 \200\22314 Procarbazine 40mg/m2 (max 60mg) PO Prednisolone days 1 \200\22314 Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/d throughout first treatment cycle. 2 Antiemetic therapy for moderate emetogenic regi mens. 2 Consider H2-antagonist or PPI. 2 Alcohol prohibited with procarbazine; avoid monoam ine oxidase inhibitors. 2 Repeat treatment when WBC >3.0 109/L and platelets >100 109/L. 2 Treat to complete remission + 2 cycles. 598 15-protocols.qxd 10.12.2003 04.32 PM Page 599 Protocols and procedures 599 15-protocols.qxd 10.12.2003 04.32 PM Page 600 MOPP Chlormethine (mustine), vincristine, procarbazine, prednisolone. Indication Hodgkin \200\231s disease. Schedule 28 day cycle 6mg/m2 IV days 1 & 8 Chlormethine (mustine) 1.4mg/m2 IV (max. 2mg*) Vincristine days 1 & 8 100mg/m2 PO (max. 150mg) days 1 \200\22314 Procarbazine 100mg/m2 PO Prednisolone days 1 \200\22314 Original protocol put no maximum limit on vincristine dosage; higher doses are associated w ith severe neuropathy. Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/d throughout first treatment cycle. 2 Antiemetic therapy for highly emetogenic regime ns. 2 Alcohol prohibited with procarbazine; avoid monoamine oxidase inhibitors. 2 Repeat treatment if WBC >3.5 109/L and platelets >100 109/L. 2 25% dose reduction i f WBC 2.5 \200\2233.5 109/L or platelets 75 \200\223100 109/L. 2 Delay treatment 1 we ek if WBC <2.5 109/L or platelets <75 109/L. 2 Treat to complete remission + 2 cycles . 600 15-protocols.qxd 10.12.2003 04.32 PM Page 601 Protocols and procedures 601 15-protocols.qxd 10.12.2003 04.32 PM Page 602 MOPP/ABVD Chlormethine (mustine), vincristine, procarbazine, prednisolone, adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine. Indication Hodgkin \200\231s disease. Schedule 8 week cycle 6mg/m2 IV days 1 & 8 1.4mg/m2 IV (max. 2mg*) days 1 & 8 100mg/m2 PO (max. 150mg) days 1 \200\22314 100mg/m2 PO days 1 \200\22314 Chlormethine (mustine) Vincristine Procarbazine Prednisolone day 29 X X X X day 43 X X X X 25mg/m2 IV 10,000 units/m2 IV 6mg/m2 IV (max. 10mg) 375mg/m2 IVI in N saline Doxorubicin Bleomycin Vinblastine Dacarbazine Original protocol put no maximum limit on vincristine dosage; higher doses are associated w ith severe neuropathy. Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/d throughout first treatment cycle. 2 Antiemetic therapy for highly emetogenic regime ns. 2 Alcohol prohibited with procarbazine; avoid monoamine oxidase inhibitors. 602 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat treatment i f WBC >3.5 109/L and platelets >100 109/L. 2 25% dose reduction if WBC 2.5 \200\2233. 5 109/L or platelets 75 \200\223100 109/L. 2 Delay treatment 1 week if WBC <2.5 10 9/L or platelets <75 109/L. 2 Treat for 12 months (6 cycles). 15-protocols.qxd 10.12.2003 04.32 PM Page 603 Protocols and procedures 603 15-protocols.qxd 10.12.2003 04.32 PM Page 604 CHOP Cyclophosphamide, doxorubicin, vincristine, prednisolone. Indications 2 Intermediate and high grade non-Hodgkin \200\231s lymphoma. 2 Low grade non-H odgkin \200\231s lymphoma resistant to first-line therapy. Schedule 21 day cycle Day 1 2 3 4 5 750mg/m2 IV X Cyclophosphamide 1.4mg/m2 IV (max. 2mg*) Vincristine X 50mg/m2 IV Doxorubicin X 50mg/m2 (max 100mg) PO Prednisolone X X X X X max 1mg for patients > 70 years Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/d throughout first treatment cycle. 2 Antiemetic therapy for moderately emetogenic re gimens. 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat tre atment when WBC >3.0 109/L and platelets >100 109/L. 2 Treat to complete remission + 2 cycles (max 8 cycles). 604 15-protocols.qxd 10.12.2003 04.32 PM Page 605 Protocols and procedures R-CHOP Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone Indication 2 First line treatment of CD20+ diffuse large B cell lymphoma stage II, III or IV. Schedule 21 day cycle Rituximab 375mg/m2IV Cyclophosophamide 750mg/m2IV Vincristine 1.4mg/m2IV (max 2mg*) Doxorubicin 50mg/m2IV Prednisolone 50mg/m2 PO (max 100mg) Day 1 2 3 4 5 X X X X X X X X X max 1mg for patients>70 years. Administration 2 Outpatient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 3 00mg/d throughout first treatment cycle. 2 Antiemetic therapy for moderately emetogenic reg imen. 2 Administer rituximab after first dose of prednisolone on day 1 before administering chemotherapy. 2 Premedication with paracetamol and chlorpheniramine should be administered before each rituximab infusion. 2 Monitor closely for cytokine release syndrome: fever, chills, rigors 605 within first 2 hours usually. 2 Less common side effects include: flushing, angioedema, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, vomiting, tumor pain and fe atures of tumor lysis syndrome, bronchospasm, hypotension. 2 Interrupt rituximab infusion if severe dyspnoea, bronchospasm or hypoxia. 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat treatment w hen WBC>3.0 X 109 L and platelets >100 X 109/L. 2 Treat to complete remission + 2 cycles, m ax 8 cycles. 15-protocols.qxd 10.12.2003 04.32 PM Page 606 DHAP Dexamethasone, cytarabine, cisplatin Indication 2 Salvage chemotherapy for relapsed/refractory NHL and Hodgkin \200\231s lym- phoma. 2 Mobilization of peripheral blood stem cells. Schedule: 21 \200\22328 day cycle depending on count recovery Days Drug Dose Route Comments 1 \200\2234 Dexamethasone 40mg PO Taken in the morning with food \200 100mg/m2 1 Cisplatin IV IVI in 500mL 0.9% saline over 1h \200 2g/m2 X 2 2 Cytarabine IV IVI in 1L 0.9% saline over 3h twice 12h apart \200 cap surface area at 2m2 Administration 2 In-patient regimen. 2 Ensure adequate venous access by inserting a dual lu men tunneled central venous catheter. 2 Severe myelosuppression (neutrophils <0.2 109/L and need for red cell and platelet transfusion support) should be expected. 2 Allopurinol 300mg od PO (100mg if renal impairment) for first 2 cycles. 2 Consider acyclovir prophylaxis if previous history of VZV or HSV reac- tivation. 2 Antiemetic therapy for highly emetogenic regimens. 2 Aggressive pre- and post-hydration i ncluding potassium/magnesium 606 supplementation is required with cisplatin. 2 Predsol 0.5% eye-drops qds until 5 days after completion of chemotherapy. 2 Standard antimicrobial prophylaxis as dictated by local policy to cover duration of severe neutropenia. 2 G-CSF 5 \200\22310mg/kg SC daily starting day +5 optional to shorten neu- tropenia and ne cessary to mobilize peripheral blood stem cells. 2 Reduce cisplatin to 75% dose if creatini ne clearance 45 \200\22360mL/min, 50% dose if creatinine clearance 30 \200\22345mL/min; do not give if creatinine clearance < 30mL/min. 2 Creatinine clearance should be assessed before each course of treat- ment. 2 Cytarabine should be used with caution in severe renal impairment; consider reducing dose of cytarabine if hepatic impairment. 2 Delay next cycle for 1 week if neutrophils <1.0 109/L or platelets <100 109/L. 15-protocols.qxd 10.12.2003 04.32 PM Page 607 Protocols and procedures 2 Patients with Hodgkin \200\231s lymphoma and those in whom stem cell collection is planne d within 2 weeks must receive irradiated cel- lular blood components to prevent transfusion associated graft versus host disease. 2 2 \200\2236 cycles in total but usually consolidated with high dose therapy and autologou s stem cell transplant in responding patients <65 years of age. 607 15-protocols.qxd 10.12.2003 04.32 PM Page 608 ESHAP Etoposide, methylprednisolone, cytarabine, platinium Indications 2 Treatment of refractory/relapsed NHL and Hodgkin \200\231s lymphoma. 2 Mobili zation of peripheral blood stem cells for NHL and Hodgkin \200\231s lymphoma. Schedule: 21 \200\22328 day cycle as soon as neutrophils >1.0 109/L and platelets (unsup ported) >100 109/L Days Drug Dose Route Comments 2g/m2 1 Cytarabine IV IVI in 500mL 0.9% saline over 2h 40 \200\22360mg/m2 1 \200\2234 Etoposide IV IVI in 250mL 0.9% saline over 60 min 1 \200\2234 Cisplatin 25mg/m2 IV IVI in 1L 0.9% saline over 24h 1 \200\2235 Methylpred. 500mg IV IVI in 100mL 0.9% saline over 30 min Administration 2 In-patient regimen. 2 Ensure adequate venous access by inserting a dual lu men tunneled central venous catheter. 2 Severe myelosuppression (neutrophils <0.1 109/L and platelets <20 109/L) is expected. 2 Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for first 2 weeks. 2 Antiemetic therapy for highly emetogenic regimens. 2 Aggressive pre- and post-hydration i ncluding potassium/magnesium 608 supplementation required with cisplatin. 2 Predsol 0.5% eye-drops qds until 5 days after completion of chemotherapy. 2 Give mouth care (nystatin and chlorhexidine M/W) and oral systemic antibacterial and anti fungal prophylaxis until neutrophil recovery \211 1.0 109/L. 2 Consider H2 antagonist or PPI. 2 Consider starting G-CSF 5mg/kg/day on day 7 either to sh orten neu- tropenia or to facilitate peripheral blood stem cell collection around day 16. 2 Reduce cisplatin to 50% dose if creatinine clearance 40 \200\22360mL/min; do not give if creatinine clearance <40mL/min. 2 Reduce cytarabine to 50% dose and omit etoposide if serum bilirubin >50 mol/L. 2 Creatinine clearance should be assessed before each course of treat- ment. 15-protocols.qxd 10.12.2003 04.32 PM Page 609 Protocols and procedures 2 Patients with Hodgkin \200\231s lymphoma and those in whom stem cell collection is planne d within 2 weeks must receive irradiated cel- lular blood components to prevent transfusion associated graft versus host disease. 2 2-6 cycles in total but usually consolidated with high dose therapy and autologous stem c ell transplant in responding patients <65 years of age. 609 15-protocols.qxd 10.12.2003 04.32 PM Page 610 Mini-BEAM BCNU (carmustine), etoposide, cytarabine, melphalan Indications 2 Treatment of refractory/relapsed NHL and Hodgkin \200\231s lymphoma. 2 To dem onstrate persistent chemosensitivity of tumor. 2 Mobilization of peripheral blood stem cell s. Schedule Days Drug Dose Route Comments 60mg/m2 1 Carmustine IV IVI in 250mL 5% dextrose over 1h; avoid storage in PVC container for >24h 100mg/m2 bd 2 \200\2235 Cytarabine IV IVI in 100mL 0.9% saline over 30 min 75mg/m2 2 \200\2235 Etoposide IV IVI in 500mL 0.9% saline over 1h Melphalan \200 \200 6 30mg/m2 IV IVI in 100mL 0.9% saline within 30 min reconstitution \200 Ensure adequate diuresis before administering melphalan. \200 Ensure that melphalan is administered on a week day (Mondays or Tuesdays provide opt imal timing for stem cell collection). Administration 2 In-patient regimen. 2 Ensure adequate venous access by inserting a dual lu men tunneled central venous catheter. 610 2 Severe myelosuppression (neutrophils <0.1 109/L and platelets <20 109/L) is expected. 2 Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for first 2 weeks. 2 Antiemetic therapy for moderately emetogenic regimens 2 Give mouth care (nystatin and chl orhexidine M/W) and oral systemic antibacterial and antifungal prophylaxis until neutrophil recovery \211 1.0 109/L. 2 Consider H2 antagonist or PPI. 2 Consider starting G-CSF 5mg/kg/d on day 9 either to shor ten neu- tropenia or to facilitate peripheral blood stem cell collection around day 18. 2 Note: do not use mini-BEAM if creatinine clearance \211 40mL/min. 2 Patients with Hodgki n \200\231s lymphoma and those in whom stem cell collection is planned within 2 weeks must receive irradiated cel- lular blood components to prevent transfusion associated graft vers us host disease. 15-protocols.qxd 10.12.2003 04.32 PM Page 611 Protocols and procedures 2 A second course can be given when neutrophils >1.0 109/L and platelets (unsupported) >100 109/L; generally 4 \200\2236 weeks. 2 Consolidate with high dose therapy and in responding patients autolo- gous stem cell transplant. 611 15-protocols.qxd 10.12.2003 04.32 PM Page 612 BEAM (myeloablative conditioning regimen) BCNU (carmustine), etoposide, cytarabine, melphalan Indications High dose chemotherapy consolidation for patients with: 2 Aggressive NHL: chemo sensitive relapse or poor prognostic disease. 2 Hodgkin s lymphoma: refractory or second re mission. 2 Indolent NHL refractory to second-line therapy. Schedule Days Drug Dose Route Comments 300mg/m2 \200\2237 Carmustine IV IVI in 500mL 5% dextrose over 1h; avoid storage in PVC container for >24h 200mg/m2 bd \200\2236 to \200\2233 Cytarabine (inclusive) IV IVI in 100mL 0.9% saline over 30 min 200mg/m2 \200\2236 to \200\2233 Etoposide (inclusive) IV IVI in 1L 0.9% saline over 2h 140mg/m2 \200\2232 Melphalan \200 IV IVI in 250mL 0.9% saline within 60min of reconstitution 0 Thaw and reinfuse haematopoietic stem cells \200 \200 Ensure excretion of melphalan by aggressive hydration ( furosemide (frusemide)). \200 Ensure stem cell dose \211 2.0 106/L CD34+ cells; do not re-infuse stem cells wi thin 24h of melphalan infusion. 612 Administration 2 In-patient regimen. 2 Ensure adequate venous access by inserting a dual lu men tunneled central venous catheter. 2 Severe myelosuppression (neutrophils <0.1 109/L and platelets <20 109/L) is expected. 2 Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for first week. 2 Antiemetic therapy for highly emetogenic regimens. 2 Give mouth care (nystatin and chlorh exidine M/W) and oral systemic antibacterial and antifungal prophylaxis until neutrophil re covery \211 1.0 109/L \200\224refer to local protocol for patients with severe neutrop enia. 2 Consider H2 antagonist or PPI 2 Consider starting G-CSF 5mg/kg/day on day +5 to shorten t he dura- tion of neutropenia. 2 Consider acyclovir antiviral prophylaxis if previous history of VZV or HSV reactivation. 15-protocols.qxd 10.12.2003 04.32 PM Page 613 Protocols and procedures 2 Consider oral systemic PCP prophylaxis for 6 months after count recovery \200\224refer to local protocol. 2 Do not use BEAM if creatinine clearance is <40mL/min 2 All patients must receive irradiat ed cellular blood components for at least 12 months post-SCT to prevent transfusion associ- ated graft versus host disease. 613 15-protocols.qxd 10.12.2003 04.32 PM Page 614 CVP Cyclophosphamide, vincristine, prednisolone. Indications (cid:2) Low grade non-Hodgkin \200\231s lymphoma. (cid:2) Advanced chronic lymp hocytic leukemia. Schedule 21 day cycle Day 1 2 3 4 5 750mg/m2 IV Cyclophosphamide X 1.4mg/m2 IV (max. 2mg)* X Vincristine 60mg/m2 (max 100mg) m2 PO X Prednisolone X X X X max 1mg in patients > 70. Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/d throughout first treatment cycle. 2 Antiemetic therapy for moderately emetogenic re gimens. 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat tre atment when WBC >3.0 109/L and platelets >100 109/L. 2 Treat to complete remission + 2 cycles. 614 15-protocols.qxd 10.12.2003 04.32 PM Page 615 Protocols and procedures 615 15-protocols.qxd 10.12.2003 04.32 PM Page 616 Fludarabine and cyclophosphamide Indications 2 Third line therapy for CLL. 2 Mantle cell lymphoma. Schedule: 28 day cycle Days Drug Dose Route Comments 250mg/m2 IV IV bolus in 50mL 0.9% saline immediately prior to fludarabine IV bolus in 10mL 0.9% saline 1 \200\2233 Cyclophosphamide 25mg/m2 1 \200\2233 Fludarabine IV Alternative oral schedule Days Drug Dose Route Comments 150mg/m2 \200 PO 24mg/m2 \200 PO 1 \200\2235 1 \200\2235 Cyclophosphamide Fludarabine \200 Appropriate rounding to the next available tablet size. Administration 2 Out-patient regimen. 2 Check direct antiglobulin test (DAGT) pre-treatment ; +ve DAGT is a relative contraindication to fludarabine therapy. 2 Allopurinol 300mg od PO (100mg if significant renal impairment) for first 2 cycles. 2 Oral systemic PCP prophylaxis according to local protocol (generally 480mg bd tiw) throug hout treatment and for 8 weeks after comple- tion. 616 2 Consider acyclovir prophylaxis if previous history of VZV or HSV reac- tivation. 2 Antiemetic therapy for moderately emetogenic regimens. 2 Reduce to 50% doses if renal imp airment (creatinine clearance 30 \200\22360mL/min); do not give if creatinine clearance <30 mL/min. 2 Delay next cycle for 1 week if neutrophils <1 109/L or platelets <75 109/L. 2 All cellular blood components should be irradiated for 1 year after therapy to prevent transfusion associated graft versus host disease. 2 Administer 6 cycles. 15-protocols.qxd 10.12.2003 04.32 PM Page 617 Protocols and procedures 617 15-protocols.qxd 10.12.2003 04.32 PM Page 618 FMD Fludarabine, mitoxantrone (mitozantrone), dexamethasone Indications 2 Follicular and other indolent NHL.(beyond second line) 2 Waldenstr m \200 \231s macroglobulinaemia. (beyond second line) 2 Chronic lymphocytic leukemia. (beyond seco nd line) Schedule: 28 day cycle Days Drug Dose Route Comments 25mg/m2 1 \200\2233 Fludarabine IV IV bolus in 10mL 0.9% NaCl or 40mg/m2 PO 10mg/m2 1 Mitoxantrone (mitozantrone) IV Bolus in fast- running drip or infusion in 100mL 0.9% saline over 15 min 1 \200\2235 Dexamethasone 20mg PO/IV Administration 2 Out-patient regimen. 2 Check direct antiglobulin test (DAGT) pre-treatment and after each cycle; positive DAGT is a relative contraindication to fludarabine therapy. 2 Allopurinol 300mg od PO (100mg if significant renal impairment) for first 2 cycles. 2 Oral systemic PCP prophylaxis according to local protocol (generally 480mg bd tiw) throug hout treatment and for 8 weeks after comple- tion. 2 Consider acyclovir prophylaxis if previous history of VZV or HSV reac- 618 tivation. 2 Antiemetic therapy for moderately emetogenic regimens. 2 Consider H2 antagonist or PPI. 2 Reduce fludarabine to 50% dose if renal impairment (creatinine clear- ance 30 \200\22360mL /min); do not give if creatinine clearance <30mL/min. 2 Reduce mitoxantrone (mitozantrone) to 50% dose if serum bilirubin >1.5 upper limit normal and 25% if >3 upper limit normal. 2 Delay next cycle for 1 we ek if neutrophils <1.5 109/L or platelets <100 109/L. 2 All cellular blood components should be irradiated for 1 year after therapy to prevent transfusion associated graft versus host disease. 2 Repeat to maximum clinical response; usually 6 cycles. 15-protocols.qxd 10.12.2003 04.32 PM Page 619 Protocols and procedures 619 15-protocols.qxd 10.12.2003 04.32 PM Page 620 ABCM Adriamycin (doxorubicin), BCNU (carmustine), cyclophosphamide, melphalan Indication Multiple myeloma. Schedule 6 week cycle Day 1 22 30mg/m2 IV X Doxorubicin 30mg/m2 IV X Carmustine 100mg/m2 PO X 4 days Cyclophosphamide X 6mg/m2 PO X 4 days Melphalan X Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/day throughout first treatment cycle. 2 Add infection prophylaxis with cotrimoxazole 2 tabs tiw and nystatin mouthwash/fluconazole 100mg/day. 2 Antiemetic therapy for moderately emetogenic regimens. 2 Repeat treatment when WBC >3.0 109/L and platelets >100 109/L. 2 Treat to plateau phase (normally 4 \200\2238 courses ). 620 15-protocols.qxd 10.12.2003 04.32 PM Page 621 Protocols and procedures 621 15-protocols.qxd 10.12.2003 04.32 PM Page 622 C-VAMP Cyclophosphamide, vincristine, adriamycin (doxorubicin), methylprednisolone Indications 2 Multiple myeloma. Suitable for intensive therapy or resistant to alky- lator therapy. Schedule 21 day cycle Day 1 2 3 4 5 8 15 Vincristine 0.4mg/day cont. IVI X X X X 9mg/m2/day cont. IVI X X X X Doxorubicin Methylprednisolone 1.5g IV/PO X X X X X Cyclophosphamide 500mg IV X X X Administration 2 Out-patient regimen. 2 Indwelling central venous catheter required with am bulatory infusion pump. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/day throughout first treatment c ycle. 2 Add infection prophylaxis with cotrimoxazole 2 tabs tiw and nystatin mouthwash/fluconazole 100mg/day. 2 Antiemetic therapy for mildly emetogenic regimens. 2 Repeat treatment when WBC >2.0 10 9/L and platelets >100 109/L. 2 Treat until maximum paraprotein and bone marrow response (nor- mally 4 \200\2238 courses). 622 15-protocols.qxd 10.12.2003 04.32 PM Page 623 Protocols and procedures 623 15-protocols.qxd 10.12.2003 04.32 PM Page 624 VAD Vincristine, adriamycin (doxorubicin), dexamethasone Indication 2 Multiple myeloma. Suitable for intensive therapy or resistant to alky- lator therapy. Schedule 21 day cycle Day 1 2 3 4 Vincristine (continuous IVI) 0.4mg/day X X X X 9mg/m2/day X X X X Doxorubicin (continuous IVI) Dexamethasone 40mg/day PO X X X X (repeated days 9 \200\22312 and days 17 \200\22320 on first cycle only) Administration 2 Out-patient regimen. 2 Indwelling central venous catheter required with am bulatory infusion pump. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/day throughout first treatment c ycle. 2 Add infection prophylaxis with cotrimoxazole 2 tabs tiw and nystatin mouthwash/fluconazole 100mg/day. 2 Antiemetic therapy for mildly emetogenic regimens. 2 Repeat treatment when WBC >2.0 10 9/L and platelets >100 109/L. 2 Treat until maximum paraprotein and bone marrow response (nor- mally 4 \200\2236 courses). 624 CVAD used in MRC/UKMF Study \200\230Myeloma IX \200\231 adds cyclophosphamide 500mg PO (or IV if pre- ferred) on days 1, 8 and 15 of each cycle. Omit cyclophosphamide in patients wi th a serum creati- nine >300 mol/L. 15-protocols.qxd 10.12.2003 04.32 PM Page 625 Protocols and procedures 625 15-protocols.qxd 10.12.2003 04.32 PM Page 626 Z-DEX Idarubicin (zavedos), dexamethasone Indications Multiple myeloma suitable for intensive therapy or resistant to alkylator thera py. Schedule: 21 day cycle Days Drug Dose Route Comments Total dose 40mg/m2 PO in divided doses over 4 days 1 \200\2234 Idarubicin 1 \200\2234* Dex. 40mg daily PO Take in the mornings; swallow whole with food Dexamethasone (Dex.) also on days 8 \200\22311 and days 15 \200\22318 for the first cycle o nly Administration 2 Out-patient regimen. 2 Add allopurinol 300mg od PO (100mg if significant r enal impairment) for first cycle. 2 Antiemetic therapy for moderately emetogenic regimens. 2 Commence H2 antagonist or PPI. 2 Nystatin and chlorhexidine mouthcare. 2 Oral systemic PCP prophylaxis is recommended until 2 weeks after the end of treatment. 2 Consider oral systemic antibacterial, antiviral and/or antifungal prophy- laxis if patient is neutropenic. 2 Reduce dose of idarubicin by 50% if bilirubin 20 \200\22350 mol/L; caution if 626 bilirubin is >50 mol/L. Maximum cumulative dose = 400mg/m2. 2 Delay treatment for 1 week i f neutrophils <1.0 109/L or platelets <50 109/L. Reintroduce at 300mg or 400mg per dose. 2 Consider G-CSF if treatment delays are prolonged or frequent. 2 Continue to maximal respo nse, usually 4 \200\2236 cycles. 15-protocols.qxd 10.12.2003 04.32 PM Page 627 Protocols and procedures 627 15-protocols.qxd 10.12.2003 04.32 PM Page 628 C-Thal-Dex (CTD) cyclophosphamide, thalidomide, dexamethasone Indications 2 Multiple myeloma: melphalan-resistant disease; myeloma-IX randomi- sation 2 Waldenstr m \200\231s macroglobulinaemia. Schedule: 21 day schedule Days Drug Dose Route Comments 1,8,15 1 \200\22321 Cyclophos. Thalidomide 500mg 100mg for 3 weeks then 200mg PO PO Pregnancy testing as below 1 \200\2234 & 12 \200\22315 Dexamethasone 40mg/day PO Administration 2 Out-patient regimen. 2 Women of childbearing potential must have negative pregnancy test within 24h before starting thalidomide, every 2 \200\2234 weeks while on tha lidomide and 4 weeks after last dose. 2 Add allopurinol 300mg od PO (100mg if significant renal impairment) for first cycle. 2 Antiemetic therapy for mildly emetogenic regimens. 2 Commence H2 antagonist or PPI. 2 Con sider regular laxative. 2 Do not give cyclophosphamide if serum creatinine >300 mol/L afte r rehydration. 2 Omit cyclophosphamide for 3 weeks if neutrophils <1.0 109/L or platelets <100 109/L . Reintroduce at 300mg or 400mg per dose. 2 Consider G-CSF if treatment delays are prolonged or frequent 2 Omit thalidomide for one c ycle if grade 3/4 constipation, neuropathy, fatigue, sedation, rash, tremor or oedema; rein troduce at 50mg/day. 628 2 Treat with full dose warfarin or LMW heparin if thromboembolic event. Stop thalidomide and restart at 50mg/day escalating on the sub- sequent cycle to 100 mg/day. 2 Repeat for 4 \200\2236 cycles 15-protocols.qxd 10.12.2003 04.32 PM Page 629 Protocols and procedures 629 15-protocols.qxd 10.12.2003 04.32 PM Page 630 This page intentionally left blank 630 16-haem Ix.qxd 10.12.2003 04.33 PM Page 631 Hematological investigations 16 Full blood count 632 Blood movie 632 Plasma viscosity 632 ESR 632 Haematinic assays 633 Hemoglobin electrophor esis 633 Hapt oglobin 633 Schumm \200\231s test 633 Kleihauer test 633 Reticulocytes 634 Urinary haemosiderin 635 Ham \200\231s test 636 Immunophenotyping 636 Cytogenetics 638 HLA typing 640 16-haem Ix.qxd 10.12.2003 04.33 PM Page 632 Full blood count Rapid analysis by the latest generation automated blood counters using either forward angle light scatter or impedance analysis provides enumer- ation of leucocytes, erythrocytes and platelets and quantification of hemoglobin, MCV plus derived values for haematocrit, MCH a nd MCHC, red cell distribution width (a measure of cell size scatter), mean platelet volume and platelet distribution width and a 5 parameter differential leu- cocyte count. The coun ter also flags samples which require direct mor- phological assessment by examination of a blood movie. Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 4h. Blood movie Morphological assessment of red cells, leucocytes and platelets should be performed by an e xperienced individual of all samples in which the FBC has revealed any result significantly outside the normal range, samples in which a flag has been indicated by the automated coun ter and if clinically indicated. A manual differential leucocyte count may be performed and may differ from that produced by the automated counter most notably in patients with hemat ological disease affecting the leucocytes. Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 4h. M ay be made directly from drop of blood or EDTA sample, air-dried and fixed. Plasma viscosity This test is a sensitive but non-specific index of plasma protein changes which result from inflammation or tissue damage. The plasma viscosity is unchanged by haematocrit variations and delay in analysis up to 24h and is therefore more reliable than the ESR. It is not aff ected by sex but is affected by age, exercise and pregnancy. 632 Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 24h. ESR This test is a sensitive but non-specific index of plasma protein changes which result from inflammation or tissue damage. The ESR is affected by haematocrit variations, red cell abn ormalities (e.g. poikilocytosis, sickle cells) and delay in analysis and is therefore less reliable than measurement of the plasma viscosity. The ESR is affected by age, sex, menstru al cycle, pregnancy and drugs (e.g. OCP, steroids). Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 4h. 16-haem Ix.qxd 10.12.2003 04.33 PM Page 633 Hematological investigations Haematinic assays Measurement of the serum B12 and red cell folate are necessary in the investigation of macr ocytic anemia, and serum ferritin in the investigation of microcytic anemia in order to ass ess body stores of the relevant haematinic(s). Serum folate levels are an unreliable measur ement of body stores of folate. The serum ferritin may be elevated as an acute phase protei n in patients with underlying neoplasia or inflammatory disease (e.g. rheumatoid arthritis) and may give an erroneously normal level in an iron deficient patient. Sample: clotted blood sample and peripheral blood EDTA. Hemoglobin electrophoresis This test is performed in the diagnosis of abnormal hemoglobin produc- tion (haemoglobinopa thies or thalassaemia). It is usually performed on cellulose acetate at alkaline pH (8.9) b ut may be performed on citrate agar gel at acid pH (6.0) to detect certain haemoglobins mor e clearly. Hemoglobin electrophoresis has been largely replaced by HPLC analysis. Sample: peripheral blood EDTA. Haptoglobin The serum haptoglobin should be measured in patients with suspected intravascular haemolysi s and is frequently reduced in patients with extravascular haemolysis. It should generally be accompanied by estima- tion of the serum methaemalbumin, free plasma hemoglobin and urin ary haemosiderin. Sample: clotted blood. 633 Schumm \200\231s test This spectrophotometric test for methaemalbumin (which has a distinc- tive absorption band at 558nm) should be measured in patients with sus- pected intravascular haemolysis and may be abnormal in patients with significant extravascular (generally splenic) haemolysis. It s hould generally be accompanied by estimation of the serum haptoglobin level, free plasma he moglobin and urinary haemosiderin. Sample: heparinised blood or clotted blood. Kleihauer test The Kleihauer test which exploits the resistance of fetal red cells to acid elution should be performed on all Rh(D) negative women who deliver a 16-haem Ix.qxd 10.12.2003 04.33 PM Page 634 Rh(D) positive infant. Fetal cells appear as darkly staining cells against a background of ghosts. An estimate of the required dose of anti-D can be made from the number of fetal cel ls in a low power field. Sample: maternal peripheral blood EDTA. Reticulocytes Definition 2 Immature RBCs formed in marrow and found in normal peripheral blood.