Rituximab (Rituxan) desensitization protocol

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. This study was conducted in the United States. The reason for the study was that an unanswered question at the time was whether adding an immune checkpoint inhibitor would improve outcomes.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Paclitaxel (Taxol) 175 or 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript PubMed NCT02998528

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This desensitization protocol is one example of what is used in clinical practice for patients who require treatment with Rituximab (Rituxan), yet have a history of hypersensitivity to it, and for which there are no equally effective alternatives. Desensitization will not affect the incidence of non-IgE mediated reactions such as serum sickness, Stevens-Johnson syndrome, exfoliative dermatitis, hemolytic anemia, maculopapular rash, drug fever, or interstitial nephritis.

Preparation & setting

1. The provider should obtain an complete allergy history of the prior allergic reaction(s), ensure that the previous reaction was not a type of erythema multiforme, and clarify whether the reaction was consistent with an anaphylaxis or a less well-described rash.
2. Patients are generally admitted to an area, such as an intensive care unit (ICU), where there can be 1:1 nursing supervision of the infusion. Patients who have successfully tolerated previous desensitizations may be considered by physician discretion on a case-by-case basis for lower acuity settings such as the inpatient oncology floor or outpatient infusion center.
3. A signed consent for the chemotherapy regimen should be obtained from the patient.
4. Patients who are using beta-blockers or ACE (angiotensin converting enzyme) inhibitors should ideally have these discontinued prior to desensitization, since they can lower the threshold for anaphylaxis or blunt treatment effects.
5. A blood pressure cuff should be at the bedside, and a peak flow meter should be available if needed.
6. A qualified physician or nurse must be in the patient room for the first 15 minutes after the first dose during the protocol and for 5 minutes after each subsequent dose. A physician must be available by page during the protocol.

Concentrations of Rituximab (Rituxan) & administration parameters

Three different solutions containing Rituximab (Rituxan) at different concentrations are to be prepared as described below.

• This Ritixumab desensitization spreadsheet can be used to to calculate the necessary solutions based on the target dose of Rituximab (Rituxan).
• In the tables below, x is the target dose, in milligrams (calculated based on the mg/m² dosage from the chemotherapy regimen) of Rituximab (Rituxan) to be administered.

Solution #	Dilution	Total amount of drug in solution	Volume	Concentration
1	1/100th dilution	x/100 mg	250 mL	x/25,000 mg/mL
2	1/10th dilution	x/10 mg	250 mL	x/2500 mg/mL
5	standard concentration	x mg	250 mL	x/250 mg/mL

These three solutions are to be administered as follows:

Step #	Solution #	Rate	Time per step	Volume per step	Dose/step	Cumulative dose
1	1	2 mL/H	15 min	0.5 mL	x/50,000 mg	x/50,000 mg
2	1	5 mL/H	15 min	1.25 mL	x/20,000 mg	(x/50,000 mg) + (x/20,000 mg)
3	1	10 mL/H	15 min	2.5 mL	x/10,000 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg)
4	1	20 mL/H	15 min	5 mL	x/5000 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg)
5	2	5 mL/H	15 min	1.25 mL	x/2000 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg)
6	2	10 mL/H	15 min	2.5 mL	x/1000 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg)
7	2	20 mL/H	15 min	5 mL	x/500 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg) + (x/500 mg)
8	2	40 mL/H	15 min	10 mL	x/250 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg) + (x/500 mg) + (x/250 mg)
9	3	10 mL/H	15 min	2.5 mL	x/100 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg) + (x/500 mg) + (x/250 mg) + (x/100 mg)
10	3	20 mL/H	15 min	5 mL	x/50 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg) + (x/500 mg) + (x/250 mg) + (x/100 mg) + (x/50 mg)
11	3	40 mL/H	15 min	10 mL	x/25 mg	(x/50,000 mg) + (x/20,000 mg) + (x/10,000 mg) + (x/5000 mg) + (x/2000 mg) + (x/1000 mg) + (x/500 mg) + (x/250 mg) + (x/100 mg) + (x/50 mg) + (x/25 mg)
12	3	80 mL/H	172.8894 min	230.5325 mL	x*0.92213 mg	x mg

• There will be leftover solutions after the completion of the desensitization protocol
• Total time to administer: 337.9 minutes
• Total dose: x mg

Supportive medications

• Diphenhydramine (Benadryl) 25 to 50 mg IV 20 to 30 minutes prior to the start of rituximab
• Famotidine (Pepcid) 40 mg PO or 20 mg IV 20 to 30 minutes prior to the start of rituximab
• Lorazepam (Ativan) 0.5 to 1 mg PO prn anxiety 20 to 30 minutes prior to the start of rituximab
• Montelukast (Singulair) 10 mg PO 12 hours prior to the start of rituximab
• Diphenhydramine (Benadryl) 25 to 50 mg PO/IV prn allergic reaction and Epinephrine (Epipen) 0.3 mg IM prn allergic reaction as noted below:
  • If the patient develops a mild reaction, such as fever, self-limiting rash, itching, mild chest tightness, abdominal or back pain, nausea, another dose of Diphenhydramine (Benadryl) 25 to 50 mg PO/IV may be given. Observe until the reaction improves, then resume the infusion at the point where it was stopped. If the reaction does not improve within 30 minutes, contact the allergist on call.
  • If the patient develops a moderate to severe reaction, such as acute dyspnea or angioedema, and/or acute hypotension, stop protocol, follow ACLS guidelines to treat, use Epinephrine (Epipen) 0.3 mg IM for hypotension or glottic edema, and nebulized albuterol for bronchospasm. Discuss the event with the attending allergy physician on call. When the patient is stable, the protocol may be resumed (with allergist's guidance regarding the rate at which to restart and with revisions if necessary).

Example orders

Example orders for Rituximab (Rituxan) desensitization protocol

References

1. Castells MC, Tennant NM, Sloane DE, Hsu FI, Barrett NA, Hong DI, Laidlaw TM, Legere HJ, Nallamshetty SN, Palis RI, Rao JJ, Berlin ST, Campos SM, Matulonis UA. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008 Sep;122(3):574-80. Epub 2008 May 27. link to original article contains protocol PubMed