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Plasmablastic Lymphoma (PBL) - Complete Hematologist Reference

Overview

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Epidemiology and Risk Factors

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Sites of Involvement

• Oral cavity/jaw - most classic (HIV-associated)
• Gastrointestinal tract - common in HIV-negative cases
• Lymph nodes - particularly in immunocompetent patients
• Skin, bone marrow, CNS, sinonasal tract
• Most patients present with advanced-stage disease (Stage III-IV)

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Pathology and Immunophenotype

Key IHC Panel

• Quick Compendium of Clinical Pathology, 5th ed.: "Neoplastic cells are CD38+, CD138+, IRF4/MUM1+, cIg+, CD45−, CD20−, and EBV+; CD56 is usually negative, in contrast to plasmacytoma/plasma cell myeloma; HHV8 is negative, in contrast to primary effusion lymphoma; MYC gene aberrations are detected in 50% of cases."

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Differential Diagnosis

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Molecular Biology

• MYC rearrangements: present in ~50% of cases - most commonly t(8;14) - and are more frequent in HIV-associated PBL. Confer adverse prognosis.
• IRF4 mutations: found in a subset, relevant for targeted therapy planning.
• JAK-STAT pathway activation: present in many cases, emerging therapeutic target.
• RAS-RAF pathway: activated in some cases.
• NOTCH signaling: implicated in plasmablastic differentiation.
• No BCL2 rearrangements (distinguishing from DLBCL double-hit).

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Prognostic Factors

Adverse prognostic factors (validated):

• Age ≥ 60 years
• Advanced clinical stage (III-IV)
• High or high-intermediate IPI score
• MYC gene rearrangement
• Prior organ transplant status (worst outcomes in multicenter US data)

Relatively favorable:

• HIV-positive status (somewhat paradoxically - these patients tend to be younger and have HAART-responsive immune reconstitution)
• Stage I-II disease
• EBV positivity (some data suggest this is not independently adverse)

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Treatment

No international standard-of-care exists. Treatment is empirical and protocol-driven.

First-Line Therapy

Novel Agent Additions (Frontline)

Landmark Clinical Trials

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🔬 LANDMARK TRIAL 1: AMC-105 (NCT04139304) - The current most important prospective trial

• Full name: AIDS Malignancy Consortium 105 - Daratumumab + DA-EPOCH in newly diagnosed PBL
• Design: Multicenter, open-label feasibility study (Phase I/II)
• PI: Ariela Noy (Memorial Sloan Kettering)
• Patients: 15 enrolled; 14 Stage IV; 8 HIV-positive; median age not specified
• Regimen: Daratumumab 16 mg/kg IV weekly (days 1, 8, 15) for cycles 1-3, then day 1 for cycles 4-6; combined with DA-EPOCH x 6 cycles (21-day cycles)
• Primary endpoint: % completing ≥3 cycles
• Results (July 2024 cutoff):
  • 11/15 (73%) enrolled; 11/12 (92%) evaluable met primary endpoint
  • 10/12 (83%) achieved complete response (CR)
  • 1-year PFS: promising (median FU 10 months, 95% CI 6-16.1 months)
• Status: Ongoing; published in Blood 2024 supplement (PMID: Noy et al., ASH 2024)
• Significance: First prospective data for daratumumab in PBL; CR rate of 83% is exceptionally high for this disease

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🔬 LANDMARK TRIAL 2: DALYA Trial (NCT04915248) - Relapsed/Refractory PBL

• Full name: Daratumumab + Bortezomib + Dexamethasone in R/R PBL
• Sponsor: Fondazione Italiana Linfomi (ONLUS)
• Design: Phase 2, open-label
• Regimen: Daratumumab + Bortezomib + Dexamethasone (DVd) in R/R PBL
• Status: Active/ongoing as of 2025
• Significance: First dedicated Phase 2 trial specifically in R/R PBL; combines two plasma-cell active agents

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🔬 LANDMARK STUDY 3: Castillo et al. 2019 - Bortezomib + EPOCH (Br J Haematol)

• Retrospective multicenter study demonstrating bortezomib + EPOCH is effective frontline
• Established the proof-of-concept for proteasome inhibitor addition to standard chemotherapy in PBL
• Led to wide adoption of bortezomib combinations before prospective data emerged

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🔬 LANDMARK STUDY 4: LYSA Group - Tchernonog et al. 2017 (Ann Oncol)

• 135 patients - largest single dataset at time of publication
• Identified age, LDH, and stage as key prognostic factors
• Confirmed EBV positivity (~60%), MYC aberrations (~50%), poor outcomes with CHOP
• Foundation for the modern prognostic models

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🔬 LANDMARK STUDY 5: Castillo et al. 2015 - "The Biology and Treatment of PBL" (Blood) [PMID: 25636338]

• Seminal comprehensive review synthesizing 10+ years of case series data
• Defined the biological framework: plasmablastic differentiation, MYC role, EBV mechanisms
• Established PBL as distinct from DLBCL, PEL, and myeloma
• Benchmark reference for all subsequent trials

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Relapsed/Refractory Disease

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HIV Management

• HAART (antiretroviral therapy) must be optimized concurrently with chemotherapy
• Drug-drug interactions with chemotherapy regimens must be carefully managed (especially with boosted PI regimens and vincristine/etoposide - CYP3A4 interactions)
• Integrase inhibitor-based HAART is preferred during lymphoma treatment
• HAART-era outcomes significantly better than pre-HAART

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Emerging & Investigational Targets (2025-2026)

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Summary of Key Publications

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Active Clinical Trials (2025-2026)

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Key Hematologist Take-Aways

1. CD20-negative - do not use rituximab routinely; it adds toxicity without proven benefit
2. EPOCH is the preferred backbone but new 2026 data shows it is not definitively superior to CHOP
3. Daratumumab (anti-CD38) is the most promising addition to frontline therapy - AMC-105 shows 83% CR
4. Bortezomib is biologically rational but large multicenter data failed to show frontline OS benefit
5. MYC rearrangement testing should be routine - present in 50%, drives biology and prognosis
6. BCMA-targeted therapies (bispecifics, ADCs) are the next frontier in R/R disease
7. Enroll in clinical trials - the disease is too rare for definitive RCT data outside of cooperative group studies
8. Optimize HAART concurrently in HIV-positive patients; use integrase inhibitor-based regimens
9. Outcomes are improving: Historical median OS 8-15 months; modern cohort (2026) median OS 5 years

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DA-EPOCH: Administration & Dose Adjustment - Complete Guide

What is DA-EPOCH?

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Drugs and Roles

In PBL, rituximab is omitted (CD20 negative). Daratumumab may be added on days 1, 8, 15 (cycles 1-3) and day 1 (cycles 4-6) as per AMC-105 protocol.

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Cycle 1: Starting Doses

Note: Some protocols use prednisone 60 mg/m² BID (as in original CALGB 50303 reference) - verify your institutional protocol. Most current protocols use once daily.

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Infusion Setup - Critical Practical Details

The 96-Hour Continuous Infusion (Days 1-4)

1. Single bag - All three drugs combined in one bag, changed every 24 hours (4 bags total). Requires compatibility confirmation from pharmacy. Most convenient.
2. Separate bags - Each drug in a separate infusion, running simultaneously via multi-lumen CVC.
3. Ambulatory pump - Patient goes home with pump; requires robust nursing support and patient education.

Day 5 Cyclophosphamide

• Give as IV bolus after the 96-hour infusion is complete (i.e., after the 4 bags finish)
• Mesna: required at many institutions (260-370 mg/m² IV before cyclophosphamide, then PO at hours 4 and 8). Check local protocol.
• Hydration pre- and post-cyclophosphamide as per local policy.

G-CSF (Day 6 onwards)

• Start filgrastim Day 6 (24 hours after cyclophosphamide)
• Continue daily SC until ANC > 5000/µL after the nadir (nadir typically Day 10-12)
• STOP G-CSF at least 24 hours before next cycle starts

⚠️ Pegfilgrastim (6 mg SC on Day 6): acceptable but use with caution. Original DA-EPOCH dosing was validated using daily filgrastim. Pegfilgrastim may alter nadir timing and affect the dose-adjustment algorithm. CALGB 50303 required Study Chair approval for pegfilgrastim use. Many centres now use peg-G-CSF routinely with careful monitoring.

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Blood Count Monitoring (Essential for Dose Adjustment)

• Example days from start of cycle: Days 9, 12, 15, 18

• Pre-treatment ANC ≥ 1.0 × 10⁹/L AND platelets ≥ 75 × 10⁹/L (some protocols require platelets ≥ 100 × 10⁹/L)
• If not met: delay up to 2 weeks, use daily G-CSF support, recheck daily
• If still not recovered after 2-week delay: reduce 1 dose level below last cycle

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Dose Adjustment Rules (Cycle 2 Onwards)

The Golden Rule:

Dose adjustments apply to doxorubicin, etoposide, and cyclophosphamide only. Vincristine and prednisone doses are NEVER adjusted (up or down) for hematologic toxicity.

Based on ANC Nadir of Previous Cycle:

Based on Platelet Nadir:

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Dose Level Table (The Full Escalation Paradigm)

Key rules from the table:

• Below Level 1: cyclophosphamide drops first (to 600, then 480); etoposide and doxorubicin stay at minimum (50 and 10 mg/m²/day)
• Above Level 1: all three drugs escalate together (etoposide, doxorubicin, cyclophosphamide increase by 20%)
• Vincristine = fixed at 0.4 mg/m²/day (total 1.6 mg/m² over 96h) - NO cap in most protocols
• Prednisone = fixed at 60 mg/m²/day throughout

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Practical Worked Example

• Day 9: ANC 0.8 → above 0.5 ✓
• Day 12: ANC 0.3 → below 0.5 (measurement 1)
• Day 15: ANC 0.6 → above 0.5 ✓
• Day 18: ANC 1.2 → above 0.5 ✓
• Platelets nadir: 45 (above 25) ✓

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• All 4 measurements ≥ 0.5 → Escalate to Level 2 for Cycle 3
• Etoposide: 60 × 1.7 = 102 mg/day
• Doxorubicin: 12 × 1.7 = 20.4 mg/day
• Cyclophosphamide: 900 × 1.7 = 1530 mg

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Supportive Care Essentials

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Non-Haematologic Dose Modifications

Renal Impairment Adjustments:

Hepatic Impairment Adjustments:

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Special Note for HIV-Positive Patients (PBL context)

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Quick Reference Summary Card

CYCLE STRUCTURE: 21 days
START: ANC ≥ 1.0 and Plt ≥ 75 (or 100)

INFUSION (Days 1-4, 96h CIVI via central line):
  Etoposide    50 mg/m²/day
  Doxorubicin  10 mg/m²/day  
  Vincristine  0.4 mg/m²/day [NEVER dose-adjust]

BOLUS Day 5:
  Cyclophosphamide  750 mg/m²  (+ mesna)

ORAL Days 1-5:
  Prednisone  60 mg/m²/day  [NEVER dose-adjust]

G-CSF (Day 6 → ANC > 5000 post-nadir)

MONITORING: CBC twice weekly (Days 9,12,15,18)

NEXT CYCLE DOSE ADJUSTMENT:
  ANC nadir ≥0.5 ALL times  →  ↑ 1 level (20% up)
  ANC nadir <0.5 on 1-2x   →  = same level
  ANC nadir <0.5 on ≥3x    →  ↓ 1 level (20% down)
  Platelet nadir <25        →  ↓ 1 level (always)

ONLY adjust: Etoposide + Doxorubicin + Cyclophosphamide
NEVER adjust: Vincristine, Prednisone

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R-CHOP: Complete Protocol - Dosing, Administration & Cycling

Drug Acronym Breakdown

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Standard Doses (Every Cycle, Day 1)

Prednisolone dose note: UK protocols (NSSG 2024) use 40 mg/m²/day. US protocols (CALGB, eviQ) use a flat 100 mg/day. The original GELA/MInT trial used 40 mg/m²/day. Check your institutional protocol - both are accepted.

Vincristine cap: NEVER exceed 2 mg total dose regardless of BSA. A 2.0 m² patient still gets 2 mg, not 2.8 mg. This cap is mandatory.

Doxorubicin is a VESICANT - ensure patent IV access. Central line preferred but good peripheral IV is acceptable for bolus if no extravasation risk. Vincristine is also a vesicant.

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Cycle Frequency & Number of Cycles

R-CHOP-14 vs R-CHOP-21: The UK NCRI phase III trial (1,080 patients) showed R-CHOP-14 is NOT superior to R-CHOP-21 for OS, PFS, or response rate. R-CHOP-21 remains the standard. R-CHOP-14 is only used in specific high-risk situations or institutional preference.

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Day-by-Day Schedule (R-CHOP-21)

Day 1:   ALL IV drugs + Start prednisolone PO
Day 2:   Prednisolone PO (morning)
Day 3:   Prednisolone PO (morning)
Day 4:   Prednisolone PO (morning)
Day 5:   Prednisolone PO (morning) - LAST DAY
Day 6:   G-CSF starts (filgrastim 5 µg/kg SC)
Day 7:   G-CSF continues
Day 8:   G-CSF continues
Day 9:   G-CSF continues
Day 10:  G-CSF - LAST DAY (5 days total, days 6-10)
Days 11-21: Recovery / monitoring
Day 22:  START NEXT CYCLE (if counts allow)

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Administration Order on Day 1 (Exact Sequence)

Pre-medications (≥30-60 min before rituximab):

1. Paracetamol 1000 mg PO
2. Chlorphenamine (chlorpheniramine) 10 mg IV
3. Prednisolone 100 mg PO (take at least 30-60 min before rituximab - Day 1 dose)
4. Withhold antihypertensives for 12 hours before rituximab (hypotension risk during infusion)

Chemotherapy sequence:

1. Rituximab 375 mg/m² IV (graded infusion - see below) - wait 30 min observation after completion before starting chemo
2. Antiemetics (ondansetron 8 mg IV/PO + dexamethasone 8-16 mg IV) - 30 min before chemotherapy
3. Doxorubicin 50 mg/m² IV bolus (over 10 min)
4. Vincristine 1.4 mg/m² (max 2 mg) IV in 50 mL NaCl 0.9% over 10 min
5. Cyclophosphamide 750 mg/m² IV bolus (over 10 min)
6. IV flush + adequate oral hydration (minimum 3 litres/24h after cyclophosphamide)

Note: Cycles 2 onwards - same order; hydrocortisone 100 mg IV available on standby for rituximab infusion reactions.

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Rituximab Infusion Rate Protocol (Critical)

Cycle 1 (First infusion - standard rate):

Cycles 2 onwards (if Cycle 1 well tolerated):

Rapid Infusion (Cycles 2+ if first dose well tolerated):

• Rituximab can be given as a rapid infusion over 90 minutes (Sehn et al.): 20% of dose over first 30 min, then 80% over next 60 min. Saves significant clinical time and reduces resource use. Requires institutional policy approval.

If infusion reaction occurs:

• Pause the infusion immediately
• Give hydrocortisone 100 mg IV + chlorphenamine 10 mg IV
• Wait until reaction resolves, then restart at half the previous rate
• For severe reactions (bronchospasm, hypotension): stop and do not re-challenge that day

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When to Start the Next Cycle (Day 22 Decision)

If fit and well despite ANC 0.5-1.0, some protocols allow proceeding with 100% doses + G-CSF support. Discuss with consultant.

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Dose Modifications Between Cycles

Key difference from DA-EPOCH: R-CHOP doses are NOT routinely escalated between cycles. Adjustments are made only for toxicity.

Haematological Dose Modifications (Cyclophosphamide + Doxorubicin):

Rule: Dose reductions are not re-escalated in subsequent cycles without consultant approval. If a third dose reduction becomes necessary, consider stopping treatment.

Vincristine Dose Modifications:

Vincristine neuropathy is cumulative. Check for new symptoms at every cycle visit.

Doxorubicin Modifications:

Renal Impairment:

Hepatic Impairment:

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G-CSF Protocol

R-CHOP-21 (Primary prophylaxis - recommended):

• Filgrastim 5 µg/kg/day SC, starting Day 6, for 5 days (Days 6-10)
• OR Pegfilgrastim 6 mg SC, single dose on Day 6 (≥24h after chemotherapy)
• Stop G-CSF at least 24 hours before next cycle

R-CHOP-14 (mandatory):

• G-CSF is compulsory with every cycle - without it, Day 14 restart is not feasible
• Pegfilgrastim preferred for convenience

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Supportive Care - Complete Schedule

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Pre-cycle Assessment (Every Cycle, Day 22)

• CBC with differential - ANC + platelets must meet thresholds
• LFTs + bilirubin - for doxorubicin/vincristine dose adjustment
• U&E + creatinine - for cyclophosphamide adjustment
• Bone profile (calcium, phosphate)
• Glucose (steroid effect)
• Neurological examination - vincristine neuropathy assessment
• ECG when clinically indicated
• Echocardiogram - before starting if baseline cardiac risk; repeat if cumulative doxorubicin approaches 400 mg/m²

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Restaging / Response Assessment

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R-CHOP-21 vs R-CHOP-14: Quick Comparison

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Worked Dosing Example

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Quick Reference Card

R-CHOP-21 CYCLE STRUCTURE

DAY 1:
  Pre-meds:  Paracetamol 1g PO + Chlorphenamine 10mg IV
             Prednisolone 100mg PO (30-60 min before R)
             Withhold antihypertensives
  
  Rituximab  375 mg/m²  IV graded infusion  [FIRST]
  (observe 30 min after completion)
  Antiemetics: ondansetron 8mg IV
  Doxorubicin  50 mg/m²  IV bolus 10 min  [VESICANT]
  Vincristine  1.4 mg/m² (MAX 2mg)  IV 10 min  [VESICANT]
  Cyclophosphamide  750 mg/m²  IV bolus 10 min

DAYS 2-5: Prednisolone 100mg PO morning only

DAYS 6-10: G-CSF (filgrastim 5µg/kg SC daily)
           OR Pegfilgrastim 6mg SC Day 6 only

DAY 22: Check ANC ≥1.0 + Plt ≥75 → START NEXT CYCLE

TOTAL: 6 cycles (21 days each)

DOSE ADJUSTMENTS:
  Doxorubicin + Cyclophosphamide only (reduce for toxicity)
  Vincristine: reduce/omit for neuropathy
  Prednisolone + Rituximab: rarely modified

NEVER adjust Rituximab for haematological toxicity
NEVER exceed 2mg vincristine

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Rituximab 700 mg - Complete Administration Guide

Step 1: Vial Calculation

• 100 mg / 10 mL vial
• 500 mg / 50 mL vial

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Step 2: Preparation / Dilution

Never give undiluted. Never IV push or bolus. Never shake.

• 0.9% Sodium Chloride (NaCl) - preferred
• OR 5% Dextrose in Water (D5W)

Practical tip: Use a 1000 mL NaCl 0.9% bag, withdraw 300 mL from it, then inject the 70 mL rituximab → total = 700 mL at 1 mg/mL. OR use a 500 mL bag for smaller volumes but this gives ~1.3 mg/mL - still within the 1-4 mg/mL range.

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Step 3: Pre-medications (Mandatory - before infusion starts)

In R-CHOP context, the prednisolone taken orally is already your steroid premedication. No additional IV steroid needed unless a reaction occurs. Withhold antihypertensive medications for 12 hours before rituximab (hypotension risk during infusion).

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Step 4: Infusion Rate Schedule

USE AN INFUSION PUMP - mandatory for rate control.

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CYCLE 1 (First-ever rituximab infusion) - Standard Graded Rate

Only escalate to next rate if no infusion-related reactions (IRR). If any reaction at a given rate, stay at that rate or slow down.

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CYCLES 2 ONWARDS (if Cycle 1 was well tolerated) - Faster Rate

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RAPID INFUSION (Cycles 2+ only, if Cycle 1 fully tolerated, no IRR at all)

Requires institutional approval + confirmed tolerance at Cycle 1.

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Step 5: Monitoring During Infusion

• Hydrocortisone 100 mg IV
• Chlorphenamine 10 mg IV
• Adrenaline (epinephrine) 1:1000 - for severe anaphylaxis
• Salbutamol nebuliser
• IV fluids wide open

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Step 6: Managing Infusion-Related Reactions (IRR)

Grade 1-2 IRR (Mild - Moderate: fever, chills, rigors, rash, urticaria):

1. PAUSE infusion immediately
2. Give hydrocortisone 100 mg IV + chlorphenamine 10 mg IV
3. Give paracetamol 1 g PO/IV if not already given
4. Wait until symptoms fully resolve (usually 15-30 min)
5. Restart at 50% of the rate at which the reaction occurred
6. Escalate slowly as tolerated

Grade 3-4 IRR (Severe: bronchospasm, hypotension, angioedema, anaphylaxis):

1. STOP infusion immediately - do NOT restart that day
2. Call emergency team
3. Adrenaline 0.5 mg IM (1:1000) if anaphylaxis (hypotension + bronchospasm)
4. IV hydrocortisone 200 mg IV
5. Chlorphenamine 10 mg IV
6. IV fluid bolus if hypotensive
7. Salbutamol nebuliser if bronchospasm
8. Monitor in resuscitation area
9. Future rituximab infusions: discuss with consultant - may require extended pre-medication, slower rate, or discontinuation

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Step 7: After Infusion

• Observe patient for at least 30 minutes after infusion completes before discharge
• Document: total time, any reactions, rates used, observations
• Flush IV line with NaCl 0.9%
• Proceed to CHOP chemotherapy (doxorubicin, vincristine, cyclophosphamide) after the 30-min observation period

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Complete Summary Table

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One-Line Infusion Pump Settings for 700 mL bag at 1 mg/mL

Cycle 1:
  Set 50 mL/hr → 30 min → Set 100 → 30 min → Set 150 → 30 min →
  Set 200 → 30 min → Set 250 → 30 min → Set 300 → 30 min →
  Set 400 mL/hr → run to completion

Cycle 2+:
  Set 100 mL/hr → 30 min → Set 150 → 30 min → Set 200 → 30 min →
  Set 250 → 30 min → Set 300 → 30 min → Set 400 mL/hr → run to completion