doxorubicin in patients with previous cardiac disease. \200 Main toxicities: myelosuppres sion; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian failure ; infertility; organ failure. Risk of TLS: ensure premedicated with allopurinol or rasburicase and good hydration. Consider 1 or 2 G-CSF prophylaxis. 720 CHAPTER 15 Protocols and procedures ChlVPP Indication HL in elderly patients unfi t for ABVD or other intensive 1st-line treat- ment. Possible salvage treatment in relapse. Schedule 28d cycle (Table 15.10). Table 15.10 ChIVPP Days Drug Dose Route 6mg/m2/d (max. 10mg) 6mg/m2 (max. 10mg) 1 \200\22314 Chlorambucil PO IVI in 50mL 0.9% saline over 5 \200\22310min 1 & 8 Vinblastine 100mg/m2/d (max. 150mg) PO 1 \200\22314 Procarbazine 1 \200\22314 Prednisolone 40mg PO in a.m. with food Administration \200 Out-patient regimen. \200 Consider sperm banking or egg-harvesting. \200 Add allopurinol 300mg/d (100mg if creatinine clearance <20mL/ min) throughout 1st treatment cycle. Antiemetic therapy for moderately emetogenic regimens. \200 Consider H2-antagonist or PPI . \200 Alcohol prohibited with procarbazine; avoid tyramine containing foods. \200 In p atients with renal failure, consider dose reduction of procarbazine if creatinine >180micromol/L. In patients with hepatic dysfunction, reduce vinblastine dose to 50% if bilirubin 26 \200 \22351micromol/L or AST 60 \200\223180IU/L; omit vinblastine if bilirubin >51micromol/L and AST/ALT >180IU/L; consider dose reduction of chlorambucil in severe hepatic dysfunction. Repeat treatment cycle when neutrophils >1.0 \227 109/L and platelets >100 \227 109/L, otherwise delay 1 week. Main toxicities: myelosuppression; constipation; peripheral neuropathy; stomatitis; alopecia; steroid side eff ects; ovarian failure; infertility. 721 ChlVPP 722 CHAPTER 15 Protocols and procedures CODOX-M/IVAC R Indication Burkitt lymphoma or Burkitt-like (gray-zone) lymphoma. Schedule Administer 2 alternating cycles of each regimen, i.e. A/B/A/B. Start each regimen as soon as possible after regeneration of neutrophils to >1.0 \227 109/L and unsupported p latelets to >75 \227 109/L. In low-risk patients (low IPI) 3 cycles of CODOX-M can be cons idered (Tables 15.11 and 15.12). Table 15.11 Regimen A: CODOX-M Days Drug Dose Route Cyclophosphamide 800mg/m2 1 IVI in 500mL 0.9% saline over 30min 200mg/m2/d IVI in 250mL 0.9% 2 \200\2235 saline over 15min \227 4d 1.5mg/m2 (max. 2mg) 40mg/m2 IV bolus 1 & 8 Vincristine 1 Doxorubicin IVI in 50mL 0.9% Saline over 5 \200\22310min Cytarabine a MTX b 70mg 300mg/m2 IT injection 1 & 3 IVI in 250mL 0.9% saline over 60min 10 2700mg/m2 15mg/m2 IVI in 1L 0.9% saline over 23h Calcium folinate c 11 IV 36 h after start of MTX; repeat 3hrly for 12 h then 15mg/m2 IV/PO 6hrly until serum MTX level <5 \227 10 \210\2228 M G-CSF (fi lgrastim or lenograstim) 5mcg/kg/d or 263mcg/d* SC 13 until neutrophils >1.0 \227 109/L MTXa Calcium folinatea 15 12mg IT injection 15mg PO 24h after IT MTX 16 a In patients with CNS involvement at diagnosis, intensifi ed CNS therapy is required durin g the fi rst 2 cycles: cytarabine 70mg IT on d1, 3, & 5; MTX 12.5mg IT on d15 & 17; calcium folinate 15mg on d16 & 18. b MTX should only be given if creatinine clearance >50mL/min/m2 . UK trials have used a lower dose of MTX than the original published regimen. Reduce MTX d ose in patients aged >65 years (d10: 100mg/m2 IVI over 60min then 900mg/m2 IVI over 23h). A lkalinize urine to pH \211 7 with 3L/m2 IV fl uids plus NaHCO3 from 24h prior to start of MTX until serum MTX level <5 x 10 \210\2228 M (i.e. until calcium folinate no longer requir ed). Check serum MTX levels every 24h from 48h after start of MTX infusion. c If 48h serum MTX level >2 \22710 \210\2226 M (2.0micromols/L) dose of calcium folinate should be double d. Calcium folinate may be administered PO after 24h of IV administration if patient not vo miting. Consider higher dose of G-CSF if >80kg (368 mcg/d). 723 CODOX-M/IVAC R Table 15.12 Regimen B: IVAC Days Drug Dose Route 60mg/m2/d 1 \200\2235 Etoposide IVI in 500mL 0.9% saline over 60min Mesna a 300mg/m2/d 1 \200\2235 IV bolus or IVI over 15min immediately before ifosfamide 1500mg/m2/d IVI mixed with ifosfam ide in 500mL 0.9% saline over 60min 900mg/m2/d IVI in 500mL 0.9% saline over 12h Ifosfamide b 1500mg/m2/d IVI over 60min mixed with 1 \200\2235 Mesna in 500mL 0.9% saline Cytarabine c 2g/m2 every 12h (4 doses) IVI in 1L 0.9% saline over 3h 1 & 2 MTX d 12mg IT injection 5 Calcium folinated 6 15mg PO 24h after IT MTX G-CSF (fi lgrastim or lenograstim) 5mcg/kg/d or 263mcg/de SC 7 until neutrophils >1.0 \227 109/L a In patients aged >65 years, reduce mesna doses to 200mg/m2 IVI over 15min, 100mg/m2 over 60min with ifosfamide & 600mg/m2 over 12h. b In patients aged >65 years, reduce ifosfamide dose to 1000mg/m2 IVI over 60min. c Add prednisolone 0.5% eye drops tds for 5 \200\2237d du ring & after cytarabine. In patients aged >65 years, reduce cytarabine dose to 1g/m2 IVI ov er 3h every 12h (total 4 doses). d In patients with CNS involvement at diagnosis, intensifi ed CNS therapy is required during the fi rst two cycles: MTX 12.5mg IT on d5; calcium foli nate 15mg PO on d6; cytarabine 70mg IT on d7 & 9. e Consider higher dose of G-CSF if >80kg (368 mcg/d). 724 CHAPTER 15 Protocols and procedures Administration \200 Very intensive in-patient regimen; insert tunneled central venous catheter if possible. Discuss risk of infertility and consider sperm storage. Often no time for egg harvesting due to clinical urgency of treatment. Check creatinine clearance before high-dose MTX. \200 High risk of TLS; start IV hydratio n with \211 4.5 L/m2/d with furosemide PRN to maintain urine output. Commence rasburicase (0.2mg/kg for 5 \200\2237d) or allopurinol 300mg/d. \200 Consider an tibiotic and antiviral prophylaxis. \200 Antifungal prophylaxis. \200 Prophylactic PPI, omeprazole 20mg od or equivalent. \200 CODOX-M highly emetogenic on d1, use 5-HT3 antago nist plus metoclopramide 10mg qds or domperidone 20mg qds for 2d or cyclizine 50mg tds IV/ SC continuous infusion 150mg/d. IVAC d1 \200\2235 very highly emetogenic, use 5-HT3 antagonist plus dexamethasone 8mg bd plus metoclopramide or domperidone or cyclizine. Main toxicities: myelosuppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; organ failure; ovarian failure; infert ility. Some centers add rituximab 375mg/m2 to each cycle. 725 CODOX-M/IVAC R 726 CHAPTER 15 Protocols and procedures CTD and CTDa Indications \200 Multiple myeloma. \200 AL amyloid. CTD schedule 21d cycle (Table 15.13). Table 15.13 CTD Days Drug Dose Route 1, 8, 15 Cyclophosphamide 500mg/d PO PO 1 \200\22321 Thalidomide 50mg/d for 3 weeks then 100mg/d for 3 weeks then 200mg/d 1 \200\2234 & 15-18 Dexamethasonea 40mg/d PO a Reduce d1 \200\2234 only from cycle 4 onwards. CTDa (attenuated) schedule 28d cycle (Table 15.14). Table 15.14 CTDa Days Drug Dose Route 1, 8, 15, 22 Cyclophosphamide 500mg/d PO PO 1 \200\22321 Thalidomide 50mg/d for 4 weeks increasing by 50mg/d every 4 weeks to 200mg/d 1 \200\2234 & 15 \200\22318 Dexamethasonea 20mg/d (alternative: 20 \200\22340mg weekly on d1, 8, 15, 22) PO a Reduce d1 \200\2234 only from cycle 4 onwards. Administration \200 Out-patient regimens. \200 CTDa in elderly patients with co-morbidi ties. \200 Women of childbearing potential must have negative pregnancy test within 24h before starting thalidomide; All patients should be enrolled in a pregnancy-prevention program. Add allopurinol 300mg od PO (100mg if signifi cant renal impairment) for 1st cycle. Consider VTE prophylaxis: add aspirin (75mg/d) for patients at standard risk of thrombosis; add prophylactic dose LMWH for high- risk patients. Antiemetic therapy for mildly emetogenic regimens. \200 Commence H2 antagonist or PPI. 727 CTD AND CTDa Consider regular laxative. \200 Do not give cyclophosphamide if serum creatinine >300micr omol/L after rehydration. Consider G-CSF if treatment delays are prolonged or frequent. \200 Omit thalidomide for 1 cycle if grade 3/4 constipation, neuropathy, fatigue, sedation, rash, tremor, or oedema; r eintroduce at 50mg/d. Repeat for 4 \200\2236 cycles. \200 Main toxicities: myelosuppression; haemorrhagic cysti tis; teratogenicity; sedation (take thalidomide at bedtime); dry skin or rash; peripheral neurop athy; dizziness; bradycardia and syncope; alopecia (mild); constipation (often requiring la xatives); i risk of thromboembolic events; steroid side eff ects. 728 CHAPTER 15 Protocols and procedures DHAP R Indications \200 Salvage chemotherapy for relapsed/refractory NHL and HL. \200 follo wed by mobilization of peripheral blood stem cells. Schedule 21 \200\22328d cycle depending on count recovery (Table 15.15). Table 15.15 DHAP R Days Drug Dose Route 375mg/m2 \200\2231 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h 1 \200\2234 Dexamethasone 40mg/d a100mg/m2 a2g/m2 \2272 PO in the morning with food IVI in 500mL 0.9% saline over 1h 1 Cisplatin IVI in 1L 0.9% saline over 3h twice 12h apart 2 Cytarabine a Cap surface area at 2m2. Administration \200 In-patient regimen. \200 Ensure adequate venous access by inserting a dual-lumen tunneled central venous catheter. Discuss risk of infertility and consider sperm storage. \200 Main toxicities: severe myel osuppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian failure ; infertility; conjunctivitis/iritis. Allopurinol 300mg od PO (100mg if renal impairment) for 1st cycle. \200 Consider aciclovi r prophylaxis. \200 Antiemetic therapy for highly emetogenic regimens. \200 Aggressive pre- and post-hydration including potassium/magnesium supplementation is required with cisplatin. Prednisolone 0.5% eye-drops qds until 5d after completion of chemotherapy. Standard antimicrobial prophylaxis as dictated by local policy to cover duration of severe neutropenia. G-CSF daily starting day +5 optional to shorten neutropenia and necessary to mobilize peripheral blood stem cells. Reduce cisplatin to 75% dose if creatinine clearance 45 \200\22360mL/ min, 50% dose if creatinine clearance 30 \200\22345mL/min; do not give if creatinine cleara nce <30mL/min. Creatinine clearance should be assessed before each course of treatment. Cytarabine should be used with caution in severe renal impairment; consider reducing dose of cytarabine if hepatic impairment. Delay next cycle for 1 week if neutrophils <1.0 \227 109/L or platelets <100 \227 109/L. 729 DHAP R Patients with HL and those in whom stem cell collection is planned within 2 weeks must receive irradiated cellular blood components to prevent transfusion-ass ociated GvHD. 2 \200\2236 cycles in total but usually consolidated with high-dose therapy and autologous stem cell transplant in responding patients <65 years of age. 730 CHAPTER 15 Protocols and procedures ESHAP R Indications \200 Treatment of refractory/relapsed aggressive NHL and HL. \200 Mobilization of peripheral blood stem cells. Schedule 21 \200\22328d cycle as soon as neutrophils >1.0 \227 109/L and platelets (unsup- ported) >100 \227 109/L (Table 15.16). Table 15.16 ESHAP R Days Drug Dose Route 375mg/m2 a2g/m2 40mg/m2/d IVI in 250mL 0.9% saline over 60min 25mg/m2/d IVI in 1L 0.9% sali ne over 24h 0 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h IVI in 500mL 0.9% saline over 2h 1 Cytarabine 1 \200\2234 Etoposide 1 \200\2234 Cisplatin 1 \200\2235 Methylprednisolone 500mg/d IVI in 100mL 0.9% saline over 30min a Consider 1g/m2 if >70 years old Administration \200 In-patient regimen. \200 Ensure adequate venous access by inserting a dual-lumen tunneled central venous catheter. Severe myelosuppression (neutrophils <0.1 \227 109/L and platelets <20 \227 109/L) is expected. Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for 1st cycle. Discuss risk of infertility and consider sperm storage. \200 Antiemetic therapy for highl y emetogenic regimens. \200 Aggressive pre- and post-hydration including potassium/magnes ium supplementation required with cisplatin. Prednisolone 0.5% eye-drops qds until 5d after completion of chemotherapy. Mouth care (nystatin and chlorhexidine mouthwash). \200 Antibacterial and antifungal prop hylaxis until neutrophil recovery \211 1.0 \227 109/L. Consider H2 antagonist or PPI. \200 Consider starting G-CSF on d7 either to shorten neutr openia or to facilitate peripheral blood stem cell collection around d16. Reduce cisplatin to 50% dose if creatinine clearance 40 \200\22360mL/min; do not give if creatinine clearance <40mL/min. Reduce cytarabine to 50% dose and omit etoposide if serum bilirubin >50micromol/L. Creatinine clearance should be assessed before each course of treatment. 731 ESHAP R Patients with HL and those in whom stem cell collection is planned within 2 weeks must receive irradiated cellular blood components to prevent transfusion-ass ociated GvHD. 2 \200\2236 cycles in total but usually consolidated with high-dose therapy and autologous stem cell transplant in responding patients <65 years of age. Main toxicities: myelosuppression; neuropathy; ototoxicity; nephrotoxicity; cytarabine syndrome, including conjunctivitis; mucositis; alopecia; steroid side eff ects; ovarian failure; infertility. 732 CHAPTER 15 Protocols and procedures FC R Indications \200 CLL. \200 NHL (including LPC-lymphoma, WM, MCL). Schedule 28d cycle (Table 15.17). Table 15.17 FC R Days Drug Dose Route a375 mg/m 1 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h b24 mg/m2/d PO Fludarabine Cyclophosphamide b150 mg/m2/d PO 1 \200\2235 1 \200\2235 a In CLL: rituximab 375 mg/m2 cycle 1 given fractionated over 2d. Rituximab dose 500 mg/ m2 from cycle 2. b Alternative schedule IV: cyclophosphamide 250mg/m2/d d1 \200\2233 and fl u darabine 25mg/ m2/d d1 \200\2233. Administration \200 Out-patient regimen. \200 Allopurinol 300mg od PO (100mg if signifi cant renal impairment) for 1st cycle. Oral systemic Pneumocystis jirovecii prophylaxis according to local protocol (generally co-trimoxazole 480mg bd 3d per week) throughout treatment and for 8 weeks after completion. Consider aciclovir prophylaxis. \200 Antiemetic therapy for moderately emetogenic regimen s. \200 Reduce to 50% doses if renal impairment (creatinine clearance 30 \200\22360mL/min ); do not give if creatinine clearance <30mL/min. \200 Delay next cycle for 1 week if neu trophils <1 \227 109/L or platelets <75 \227 109/L. All cellular blood components should be irradiated for 1 year after therapy to prevent transfusion associated GvHD. Administer 6 cycles. \200 In LPC-lymphoma and WM rituximab is omitted from cycle 1 due to a possible fl are-eff ect (rise in paraprotein). Discuss risk of infertility and consider sperm storage. \200 Consider G-CSF as 1 or 2 prophylaxis. \200 Main toxicities: severe cytokine release syndrome (usually occurs within 1 \200\2232h of the 1st rituximab infusion) of fever, headache, rigors, fl ushing, n ausea, rash, URTI symptoms; tumor lysis syndrome; myelosuppression; alopecia: opportunistic infections; GI upset, chiefl y diarrhea, autoimmune haemolytic anemia; infertility; ovaria n failure; haemorrhagic cystitis. 733 ICE R ICE R Indications \200 Treatment of refractory/relapsed aggressive NHL and HL. \200 Mobilizat ion of peripheral blood stem cells. Schedule 14d cycle (Table 15.18). Table 15.18 ICE R Days Drug Dose Route Rituximaba 375mg/m2 1 IVI in 500mL 0.9% saline over 3 \200\2235h 100mg/m2/d IVI in 500mL \200\2231L 0.9% saline over 30-60mins 1 \200\2233 Etoposide 5g/m2 IV continuous infusion in 1L 0.9% saline over 24h 2 Ifosfamide 5g/m2 2 Mesna (mixed with Ifosfamide) Carboplatinb IV continuous infusion over 24h AUC 5 (capped at 800mg) IVI in 250mL 0.9% saline over 1h 2 7 \200\22314 G-CSFc (fi lgrastim 5mcg/kg/d or 263mcg/dd SC or lenograstim) a An initial dose of rituximab is administered 48h before initiation of cycle 1 (d2); patie nts completing 3 cycles receive 4 doses of rituximab. b Calculate creatinine clearance (CrC l). c Double G-CSF dose on fi nal cycle and continue until end of stem cell collection. d H igher dose G-CSF if >80kg: 368mcg/d. Administration \200 Intensive in-patient regimen; insert tunneled central venous catheter if possible. Discuss risk of infertility and consider sperm storage. \200 Allopurinol 300mg od PO (100 mg if signifi cant renal impairment) for 1st cycle. Consider antibacterial infection prophylaxis with ciprofl oxacin. \200 Consider oral anti fungal prophylaxis. \200 Consider aciclovir prophylaxis. \200 Antiemetic therapy for hi ghly emetogenic regimens. \200 Delay next cycle if neutrophils <1.0 \227 109/L or platel ets <50 \227 109/L at d15. Patients who achieve CR or PR with ICE R should proceed to autologous stem cell transplantation. Main toxicities: myelosuppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian failure ; organ failure; infertility. 734 CHAPTER 15 Protocols and procedures Lenalidomide/dexamethasone Indications \200 Multiple myeloma. \200 AL amyloid. Schedule 1 28d cycle (Table 15.19). Table 15.19 Lenalidomide-dexamethasone Days Drug Dose Route 1 \200\22321 1 \200\2234a Lenalidomide 25mg PO Dexamethasone 20 \200\22340mg PO a Additional 4d pulses may be given, e.g. on d8 \200\22311 d15 \200\22318, where rapid d isease reduction is needed at the start of the course. Administration \200 Out-patient regimens. \200 Weekly cyclophosphamide 500mg PO can be added. \200 Add allopurinol 300mg od PO (100mg if signifi cant renal impairment) for 1st cycle. Antiemetic therapy not generally required. \200 Commence H2 antagonist or PPI. \200 Tre atment is continued for as long as response is maintained. Consider stopping dexamethasone after 6 cycles. If neutrophils <0.5 \227 109/L post treatment interrupt treatment. Once recovered to \211 0.5 \227 109/L, re-start treatment at lower dosing. Dose reduction in renal impairment: CrCl 30 \200\22349mL/min lenalidomide dose 10mg OD; CrCl <30 (not requiring dialysis) dose 15mg every other day; CrC L <30 (requiring dialysis) dose 5mg od (taken after dialysis on dialysis days). Main toxicities: teratogenicity; myelosuppression; muscle cramps; constipation or diarrhea; rash; i risk of thromboembolic events; haemorrhagic cystitis, if cyclophosphamide included . 735 MPT MPT Indications \200 Multiple myeloma. Schedule 28d cycle (Table 15.20). Table 15.20 Lenalidomide-dexamethasone Days Drug Dose Route Melphalana 4mg/m2 40mg/m2 1 \200\2237 PO PO 1 \200\2237 Prednisolone 1 \200\22328 Thalidomide 50mg increased to 100 mg after cycle 1. PO a Consider dose reduction or reduce number of days in elderly patients or patients with com orbidities. Administration \200 Out-patient regimens. \200 Schedule for older patients. \200 Add allopurinol 300mg od PO (100mg if signifi cant renal impairment) for 1st cycle. Women of childbearing potential must have negative pregnancy test within 24h before starting thalidomide. All patients should be enrolled in a pregnancy prevention program. \200 Consider VTE prop hylaxis: add aspirin (75mg/d) for patients at standard risk of thrombosis; add prophylactic dose LMWH for high- risk patients. Antiemetic therapy for mildly emetogenic regimens. \200 6 cycles. \200 Main toxicities: myelosuppression; teratogenicity; dry skin or rash; sedation; peripheral neuropathy; const ipation (often requiring laxatives); dizziness; bradycardia and syncope; i risk of thromboe mbolic events; steroid side eff ects; ovarian failure; infertility. 736 CHAPTER 15 Protocols and procedures Mini-BEAM R Indications \200 Salvage therapy of refractory/relapsed NHL and HL. \200 Mobilization o f peripheral blood stem cells. Schedule 1 \200\2232 cycles (Table 15.21). Table 15.21 Mini-BEAM R Days Drug Dose Route 375mg/m2 60mg/m2 0 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h IVI in 250mL 5% dextrose over 1h; avoid storage in PVC container for >24h 1 Carmustine 100mg/m2 bd IVI in 100mL 0.9% saline over 30min 75mg/m2 Etoposide Melphalana,b 30mg/m2 2 \200\2235 Cytarabine IVI in 500mL 0.9% saline over 1h 2 \200\2235 IV bolus in 100mL 0.9% saline within 30min reconstitution 6 a Ensure adequate diuresis is achieved before administering melphalan. b Ensure that melpha lan is administered on a weekday; Mondays or Tuesdays provide optimal timing for stem cell collection. Administration \200 In-patient regimen. \200 Ensure adequate venous access by inserting a dual-lumen tunneled central venous catheter. Severe myelosuppression (neutrophils <0.1 \227 109/L and platelets <20 \227 109/L) is expected. Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for 1st cycle. Antiemetic therapy for moderately emetogenic regimens. \200 Mouth care. \200 Consider a ntibacterial and antifungal prophylaxis. \200 Consider H2 antagonist or PPI. \200 Consi der starting G-CSF on d9 either to shorten neutropenia or to facilitate peripheral blood stem cell collection around d18. Note: do not use mini-BEAM if creatinine clearance \211 40mL/min. \200 Patients with HL and those in whom stem cell collection is planned within 2 weeks must receive irradiated cellular blood components to prevent transfusion-ass ociated GvHD. A 2nd course can be given when neutrophils >1.0 \227 109/L and platelets (unsupported) >10 0 \227 109/L; generally 4 \200\2236 weeks. \200 Consolidate in responding patients with high-dose therapy and autologous stem cell transplant. Main toxicities: prolonged (>7d) myelosuppression, with risk of infections and hemorrhage; alopecia; mucositis; pulmonary toxicity; ovarian failure; infert ility. 737 NORDIC SCHEDULE (R-MAXI-CHOP & R-HIGH-DOSE CYTARABINE) Nordic schedule (R-maxi-CHOP and R-high-dose cytarabine for MCL) Indications MCL (1st line in fi t patients; followed by PBSCH). Schedule: 6 cycles (alternating R-maxi-CHOP and R-high dose cytarabine) (Tables 15.22 and 1 5.23). Table 15.22 R-maxi-CHOP (cycles 1, 3, 5) Day Drug Dose Route 375mg/m2 a 1200mg/m2 75mg/m2 1.4mg/m2 (max. 2 mg) 1 Rituximab IV IV 1 Cyclophosphamide IV 1 Doxorubicin IV 1 Vincristine 1 Prednisolone 100mg Oral a Omit rituximab cycle 1. Give with cycle 3 & 5. Table 15.23 R-High-dose cytarabine (cycle 2, 4, 6) Day Drug Dose Route 375mg/m2 a 3000mg/m2 twice daily (4 doses total) Consider 2000mg/m2 if >60 years 1 Rituximab IV IV 1+2 Cytarabine a Additional rituximab cycle 6 d9. Administration \200 In-patient regimen. \200 Dual-lumen tunneled central venous cathete r required. \200 Allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for 1st cycle. Antiemetic therapy for highly emetogenic regimen for all cycles. \200 Consider antibacter ial and antifungal prophylaxis. \200 Consider H2 antagonist or PPI. \200 Consider start ing G-CSF on d5 to shorten neutropenia. \200 Dose reduction for renal/hepatic impairment as per to local guidelines. Main toxicities: TLS; prolonged myelosuppression, with risk of infections and hemorrhage; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; cons tipation; haemorrhagic cystitis; cytarabine syndrome (includes fever, myalgia, bone pain, r ash and conjunctivitis); severe cytokine release syndrome; ovarian failure; infertility. 738 CHAPTER 15 Protocols and procedures PMitCEBO Indications Salvage NHL, particularly >60 yrs old. Schedule 2-weekly for 6 \200\2238 cycles (Table 15.24). Table 15.24 PMitCEBO Day Drug Dose Route 7mg/m2 300mg/m2 150mg/m2 1.4mg/m2 (max. 2mg) 10,000IU/m2 1 Mitoxantrone IV IV 1 Cyclophosphamide IV 1 Etoposide IV 8 Vincristine IV 8 Bleomycin Prednisolone 50mg daily week 1-4 then alternate days PO Administration \200 In-patient regimen. \200 Discuss infertility. \200 Ensure adequat e venous access by inserting a dual-lumen tunneled central venous catheter. Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for 1st cycle. Antiemetic therapy for highly emetogenic regimen for d1 and for moderately emetogenic regimens d8. Consider antibacterial and antifungal prophylaxis. \200 Consider H2 antagonist or PPI. \200 Consider starting G-CSF on d9 to shorten neutropenia. \200 Main toxicities: myelosu ppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; skin reactions to bleomycin; pulmonary toxicity; steroid side eff ects; rigors with bleomycin; ovarian failure; infertility. 739 R-BENDAMUSTINE R-Bendamustine Indications \200 NHL. \200 CLL. NHL schedule 28d cycle (Table 15.25). Table 15.25 R-Bendamustine Days Drug Dose Route 375mg/m2 90 \200\223120mg/m2 1 Rituximab IV IV 1, 2 Bendamustine CLL schedule 28d cycle (Table 15.26). Table 15.26 R-Bendamustine Days Drug Dose Route 375mg/m2 fractionated in cycle 1 over 2d, then 500mg/m2 on d1 from cycle 2 70 \200\223100mg /m2 1 Rituximab IV IV 1, 2 Bendamustine Administration \200 Out-patient regimens. \200 Add allopurinol 300mg od PO (100mg if si gnifi cant renal impairment) for 1st cycle. Antiemetic therapy for highly emetogenic regimens. \200 Commence H2 antagonist or PPI. \200 No dose reduction required if CrCl>10mL/min. Liver impairment: bilirubin (micromol/L) <21: 100% dose; 21 \200\22351: 70% dose; >51: no data available. Main toxicities: severe cytokine release syndrome (usually occurs within 1 \200\2232h of th e 1st rituximab infusion; myelosuppression; hypersensitivity reactions to bendamustine (e.g . rash, urticaria); alopecia; TLS (ensure pre-medicated with allo-purinol and good hydratio n); ovarian failure; infertility. 740 CHAPTER 15 Protocols and procedures R-CHOP Indication B-cell NHL (standard treatment). Schedule 21d or 14d cycle (Table 15.27). Table 15.27 R-CHOP Day Drug Dose Route 375mg/m2 1 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h 750mg/m2 IVI in 250mL 0.9% saline over 30min 1 Cyclophosphamide 1.4mg/m2 (max. 2mga) 50mg/m2 IV bolus 1 Vincristine IV bolus 1 Doxorubicin 1 \200\2235 Prednisolone 100mg PO in a.m. with food a Max. 1mg for patients>70 years. Administration \200 Out-patient regimen. \200 Consider sperm banking or egg-harvesting. \200 Add allopurinol 300mg/d (100mg if creatinine clearance <20mL/min) throughout 1st treatment cycle. Antiemetic therapy for moderately emetogenic regimens. \200 CNS prophylaxis with intrathe cal MTX should be administered for certain patients (see E Chapter 5). Some guidelines use high IPI (4 \200\2235) as indication for IT. For patients with BM, testicular, orbital, par anasal/nasopharyngeal or paraspinal involvement prophylaxis should be considered. In patients with renal impairment, reduce cyclophosphamide dose to 75% for creatinine clear ance 10 \200\22350mL/min and to 50% for clearance <10mL/min. In patients with hepatic dysfunction, reduce doxorubicin dose by 50% for bilirubin 1.5 \200\2233 \227 ULN and to 25% for bilirubin >3 \227 ULN. Repeat treatment when neutrophils \211 1.0 \227 109/L and platelets \211 100 \227 109/L. Standard 6 cycles. \200 Main toxicities: myelosuppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian failure ; infertility; organ failure. Risk of TLS: ensure pre-medicated with allopurinol or rasburicase and good hydration. 741 R-CVP AND CVP R-CVP and CVP Indications \200 Low-grade NHL. \200 CLL. Schedule 21d cycle (Table 15.28). Table 15.28 R-CVP & CVP Day Drug Dose Route 375mg/m2 1 Rituximab IVI in 500mL 0.9% saline over 3 \200\2235h 750mg/m2 1.4mg/m2 (max. 2mg)a IV bolus 1 Cyclophosphamide IVI in 50mL 0.9% saline over 5 \200\22310min 1 Vincristine 1 \200\2235 Prednisolone 100mg/d PO in a.m. with food a Consider maximum 1mg vincristine in patients >70 years. Administration \200 Out-patient regimen. \200 Add allopurinol 300mg/d (100mg/d if creat inine clearance <20mL/ min) for 1st cycle. Antiemetic therapy for moderately emetogenic regimens. \200 Repeat treatment when neutrop hils >1.0 \227 109/L and platelets \211 100 \227 109/L; reduce cyclophosphamide to 75% dose if neutrophils 1.0 \200\2231.49 \227 109/L and platelets \211 100 \227 109/L and reduce to 50% dose if neutrophils 0.5 \200\2231.0 \227 109/L and/or platelets 50 \200\223100 \227 109/L; omit cyclophosphamide if neutrophils <0.5 \227 109/L and/or platelets <50 \227 109/L. 6 \200\2238 cycles. \200 Main toxicities: severe cytokine release syndrome; myelosuppress ion; alopecia; mucositis; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian fa ilure; infertility. TLS rare. 742 CHAPTER 15 Protocols and procedures Rituximab: monotherapy and maintenance therapy Indications \200 CD20+ NHL and LPD. \200 Used as monotherapy, in combination with chemotherapy and as maintenance. Monotherapy schedule for FL Single 28d cycle (Table 15.29). Table 15.29 Rituximab monotherapy Days Drug Dose Route 375mg/m2 IVI in 500mL 0.9% saline over 3 \200\2235h 1, 8, 15, 22 Rituximab Maintenance schedules for FL (Tables 15.30 and 15.31). Table 15.30 Rituximab maintenance for FL in fi rst response Months Drug Dose Route 375mg/m2 IVI in 500mL 0.9% saline over 3 \200\2235h 2-monthly for 2 years (12 infusions) Rituximab Table 15.31 Rituximab maintenance for FL in second response Months Drug Dose Route 375mg/m2 IVI in 500mL 0.9% saline over 3 \200\2235h 3-monthly for 2 years (8 infusions) Rituximab Administration \200 In combination regimens rituximab may be given 1 \200\2232d before chemotherapy if logistically required. Monitor closely for cytokine release syndrome: fever, chills, rigors within fi rst 2h usually. Less common side eff ects include: fl ushing, angioedema, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, vomiting, tumor pain and fe atures of TLS, bronchospasm, hypotension. \200 Interrupt rituximab infusion if severe dys pnoea, bronchospasm, or hypoxia. Care should be taken in patients with high WCC with the 1st infusion of rituximab and fract ionation of the 1st dose should be considered. Maintenance in FL and MCL recommended. 743 STANFORD V Stanford V Largely replaced by ABVD. Indications \200 HL. \200 Schedule: 12 weeks of ch emotherapy comprising 3 cycles of 28d followed 2 \200\2234 weeks later by IFRT in patients with disease >5cm and if appropriate/i ndicated (Table 15.32). Table 15.32 Stanford V Days Drug Dose Route 25mg/m2 a 6mg/m2 a 1 & 15 Doxorubicin Vinblastine b IV bolus IVI in 50mL 0.9% saline over 5 \200\22310min 1 & 15 500mg/m2 a IV bolus 1 Chlormethine (mustine) 1 \200\22328 c 40mg/m2 on alternate days a 1.4mg/m2 (max. 2mg) a 5000 units/m2 60mg/m2/d a Prednisolone PO in a.m. with food Vincristine d IVI in 50mL 0.9% saline over 5 \200\22310min 8 & 22 Bleomycin e IVI in 250mL 0.9% saline over 1h 8 & 22 IVI in 250mL 0.9% saline over 45min 15 & 16 Etoposide a Cap surface area at 2m2 for calculating dose. b Reduce vinblastine dose to 4mg/m2 after 2 nd cycle for patients >50. c Taper prednisolone dose by 10mg every other day during weeks 1 0 \200\22312. d Reduce vincristine dose to 1mg/m2 after 2nd cycle for patients >50. e Admin ister hydrocortisone 100mg IV before infusion of bleomycin unless dexamethasone used as ant iemesis therapy. Administration \200 Intensive regimen with severe myelosuppression. \200 Discuss risk o f infertility and consider sperm storage or egg-harvesting. \200 Consider IV hydration fo r patients with bulk disease. \200 Allopurinol 300mg od PO (100mg if creatinine clearance <20mL/ min) for fi rst 4 weeks. Antiemetic therapy for highly emetogenic regimens. \200 Commence H2 antagonist or PPI. \200 Oral systemic Pneumocystis jirovecii prophylaxis according to local protocol recommended (generally co-trimoxazole 480mg bd 3d per week) throughout treatment a nd for 8 weeks after completion. Antifungal and antiviral prophylaxis. \200 Consider regular laxatives. \200 In patients with renal impairment, when creatinine clearance <60mL/min administer 80% mustine dose, 85% etoposide dose and 75% bleomycin dose; <30mL/min omit mustine, administer 75% etoposide dose <60mL/min. 744 CHAPTER 15 Protocols and procedures In patients with hepatic dysfunction, if bilirubin 1 \200\2232 \227 ULN reduce doxorubicin , vinblastine, vincristine and etoposide doses to 50%; 2 \200\2234 \227 ULN reduce doses t o 25%; >4 \227 ULN omit doxorubicin, vinblastine, and etoposide. If neutrophils 0.5 \200\2231.0 \227 109/L, administer 65% doses of doxorubicin, mustine, v incristine and etoposide but 100% dose of other drugs; if <0.5 \227 109/L delay doxorubici n, mustine, vincristine and etoposide by 1 week but no delay or dose reduction of other dru gs. If dose reduction or delay is required, administer G-CSF SC on d3 \200\2237 and d17 \200\22321 of each cycle. No dose reductions or delay if platelets >10 \227 109/L; if <10 \227 109/L, transfuse platelets to maintain count >10 \227 109/L. 745 Chapter 16 Hematological investigations Full blood count 746 Blood fi lm 746 Plasma viscosity 746 ESR 747 Haematinic assays 747 Hem oglobin electrophoresis 747 Haptoglobin 748 Schumm \200\231s test 748 Kleihauer test 748 Re ticulocytes 749 Urinary haemosiderin 750 Ham \200\231s test 751 Immunophenotyping 752 Cytog enetics 754 Human leucocyte antigen (HLA) typing 756 746 CHAPTER 16 Hematological investigations Full blood count Rapid analysis by the latest-generation automated blood counters using eit her forward-angle light scatter or impedance analysis provides enumer- ation of leucocytes, erythrocytes, and platelets and quantifi cation of hemoglobin and MCV, plus derived values for haematocrit, MCH, and MCHC, red cell distribution width (a measure of cell size scatte r), mean platelet volume and platelet distribution width, and a 5-parameter diff erential l eucocyte count. The counter also fl ags samples which require direct morphological assessme nt by examination of a blood fi lm. Sample: peripheral blood EDTA; the sample should be ana lyzed in the laboratory within 4h. Blood \201 lm Morphological assessment of red cells, leucocytes, and platelets should be performed by an experienced individual of all samples in which the FBC has revealed any res ult signifi cantly outside the n range, samples in which a fl ag has been indicated by the automated counter and if clinically indicated. A manual diff erential leucocyte count may b e performed and may diff er from that produced by the automated counter most notably in pat ients with hematological disease aff ecting the leucocytes. Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 4h. May be made directly from drop o f blood or EDTA sample, air-dried, and fi xed. Plasma viscosity This test is a sensitive but non-specifi c index of plasma protein changes which result from infl ammation or tissue damage. The plasma viscosity is unchanged by hae matocrit 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 aff ected by age, exercise, and pregnancy. Sample: peripheral blood EDTA; the sample should be analyzed in the laboratory within 24h. 747 ESR ESR This test is a sensitive but non-specifi c index of plasma protein changes which result from infl ammation or tissue damage. The ESR is aff ected by haematocrit variations, red c ell abnormalities (e.g. poikilocytosis, sickle cells), and delay in analysis and is therefo re less reliable than measure- ment of the plasma viscosity. The ESR is aff ected by age, s ex, menstrual cycle, pregnancy, and drugs (e.g. OCP, steroids). Sample: peripheral blood ED TA; the sample should be analyzed in the laboratory within 4h. Haematinic assays Measurement of the serum B12 and red cell folate are necessary in the inv estigation of macrocytic anemia, and serum ferritin in the investiga- tion of microcytic an emia, in order to assess body stores of the relevant haematinic(s). Serum folate levels are an unreliable measurement of body stores of folate. The serum ferritin may be elevated as an acute phase protein in patients with underlying neoplasia or infl ammatory disease (e.g. rheumatoid arthritis) and may give an erroneously n level in an Fe defi cient patient. Sam ple: clotted blood sample and peripheral blood EDTA. Hemoglobin electrophoresis This test is performed in the diagnosis of abnormal hemoglobin p roduc- tion (haemoglobinopathies or thalassaemia). It is usually performed on cellulose ace tate at alkaline pH (8.9) but may be performed on citrate agar gel at acid pH (6.0) to dete ct certain haemoglobins more clearly. Hemoglobin electrophoresis has been largely replaced by HPLC analysis. Sample: peripheral blood EDTA. 748 CHAPTER 16 Hematological investigations Haptoglobin The serum haptoglobin should be measured in patients with suspected haemolysis (extravascular or intravascular) and is frequently reduced in patients with haemolysis. Low concentrations of haptoglobin may be found in hepatocellular disease. It should generally be accompanied by estimation of the serum methaemalbumin, free plasma hemoglobin, and urina ry haemosiderin. Sample: clotted blood. Schumm \200\231s test This spectrophotometric test for methaemalbumin (which has a distinc- tive absorption band at 558nm) should be measured in patients with suspected intravascular haemolysis and may be abnormal in patients with signifi cant extravascular (generally sple nic) haemolysis. It should generally be accompanied by estimation of the serum haptoglobin level, free plasma hemoglobin, and urinary haemosiderin. Sample: heparinized blood or clott ed blood. Kleihauer test The Kleihauer test which exploits the resistance of fetal red cells to acid elution should be performed on all Rh(D) \210\222ve women who deliver a Rh(D) +ve infant. Fetal cells appear as darkly staining cells against a back- ground of ghosts. An estimate o f the required dose of anti-D can be made from the number of fetal cells in a low power fi eld. Sample: maternal peripheral blood EDTA. 749 RETICULOCYTES Reticulocytes De \201 nition \200 Immature RBCs formed in marrow and found in normal peripheral blood. Represent an intermediate maturation stage in marrow between the nucleated red cell and the mature red cell. No nucleus but retain some nucleic acid. Detection and measurement \200 Demonstrated by staining with supravital dye for the nucle ic acid. \200 Appear on blood fi lm as larger than mature RBCs with fi ne lacy blue staining strands or dots. Some modern automated blood counters using laser technology can measure levels of reticulocytes directly. Usually expressed as a % of total red cells, e.g. 5%, though absolute numbers can be derived from this and total red cell count. Causes of i reticulocyte counts Marrow stimulation due to: \200 Bleeding. \200 Haemolys is. \200 Response to oral Fe therapy. \200 Infection. \200 Infl ammation. \200 Poly cythaemia (any cause). \200 MPDs. \200 Marrow recovery following chemotherapy or radiot herapy. \200 EPO administration.