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Simplified Graded Infusion Strategy for Mitigation of Oxaliplatin Hypersensitivity

Published:January 18, 2022DOI:https://doi.org/10.1016/j.clcc.2022.01.006

      Abstract

      Background

      Hypersensitivity reactions (HSRs) to oxaliplatin present a therapeutic challenge. The standard desensitization protocol consists of 12 infusion steps with 3 drug dilutions, often in an inpatient setting. Several years ago we implemented a simplified outpatient graded infusion protocol for oxaliplatin with 2 drug dilutions and 3 infusion steps.

      Materials and Methods

      We performed a retrospective analysis of our experience to define the safety and outcomes associated with this simplified, ambulatory, graded infusion strategy.

      Results

      Between January 1, 2011 and December 1, 2020, 374 patients who had experienced an oxaliplatin-related HSR were treated via a 3-step graded infusion in the outpatient setting. Of these 374 patients, 283 (76%) did not experience a subsequent HSR, while 91 (24%) did experience a breakthrough HSR. Of the 374 patients, 19 (5%) experienced a grade 3 or 4 HSR. Three patients (0.8%) were hospitalized. There was no grade 5 (fatal) HSRs. Overall, the 374 patients received a median additional 3 cycles of oxaliplatin (range 1-41). The most common reasons for treatment discontinuation were disease progression (35%), breakthrough HSRs (24%), completion of treatment (21%), and toxicity other than HSR (20%). Fifteen patients who experienced breakthrough HSRs during a graded infusion were subsequently treated with the standard 12-step desensitization. Five of these 15 patients had an HSR during their initial desensitization and 5 developed an HSR on subsequent 12-step desensitizations. Thus, treatment was discontinued in 67% of these 15 patients due to persistent HSRs.

      Conclusion

      Our data indicate that the simplified 3-step graded infusion protocol is a safe outpatient strategy for patients with a history of HSR to oxaliplatin.

      Keywords

      Introduction

      Oxaliplatin is a critical component of many first line regimens for colorectal, gastroesophageal and pancreatic cancer, both in the metastatic and peri-operative settings. Like other platinum agents, oxaliplatin is an alkylating compound that forms DNA crosslinks, disrupting essential processes such as DNA replication and transcription, ultimately driving apoptosis.
      • Graham J.
      • Mushin M.
      • Kirkpatrick P.
      Oxaliplatin.
      The most common dose-limiting toxicities of oxaliplatin are peripheral neuropathy, and bone marrow suppression.
      • Andre T.
      • Boni C.
      • Mounedji-Boudiaf L.
      • Navarro M.
      • Tabernero J.
      Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.
      In addition, 15%-25% of patients treated with repeated doses of oxaliplatin develop a hypersensitivity reaction (HSR), which are considered to be potentially life-threatening in approximately one-third of cases.
      • Polyzos A.
      • Tsavaris N.
      • Gogas H.
      • Souglakos J.
      • Vambakas L.
      Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.
      • Suenaga M.
      • Mizunuma N.
      • Shinozaki E.
      • Matsusaka S.
      • Chin K.
      Management of allergic reactions to oxaliplatin in colorectal cancer patients.
      • Siu S.W.
      • Chan R.T.
      • Au G.K
      Hypersensitivity reactions to oxaliplatin: experience in a single institute.
      • Madrigal-Burgaleta R.
      • Berges-Gimeno M.P.
      • Angel-Pereira D.
      • Ferreiro-Monteagudo R.
      • Guillen-Ponce C.
      Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment.
      Treatment options for patients who require discontinuation of oxaliplatin are often limited.
      Desensitization protocols to chemotherapy emerged in the 1990s as a strategy to circumvent the limitations of HSRs, and now play an important role in the treatment of large numbers of cancer patients.
      • Castells M.
      Rapid desensitization for hypersensitivity reactions to medications.
      These protocols involve the administration of the causative drug using a series of sequential steps in which the dose is gradually increased under close clinical supervision.
      • Castells M.
      Rapid desensitization for hypersensitivity reactions to medications.
      The standard desensitization protocol for patients who experience HSRs to oxaliplatin consists of 12 infusion steps with 3 different drug dilutions.
      • Castells M.
      Rapid desensitization for hypersensitivity reactions to medications.
      • Castells M.C.
      • Tennant N.M.
      • Sloane D.E.
      • Hsu F.I.
      • Barrett N.A.
      Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.
      • Lee C.W.
      • Matulonis U.A.
      • Castells M.C.
      Carboplatin hypersensitivity: a 6-h 12-step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE-mediated reactions.
      • Castells Guitart M.C
      Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century.
      At many centers, initial desensitizations are often performed in the inpatient setting in consultation with an allergist, although accumulating evidence suggests that these procedures can be carried out safely in outpatient units
      • Castells M.C.
      • Tennant N.M.
      • Sloane D.E.
      • Hsu F.I.
      • Barrett N.A.
      Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.
      • Lee C.W.
      • Matulonis U.A.
      • Castells M.C.
      Carboplatin hypersensitivity: a 6-h 12-step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE-mediated reactions.
      • Castells Guitart M.C
      Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century.
      • Sloane D.
      • Govindarajulu U.
      • Harrow-Mortelliti J.
      • Barry W.
      • Hsu F.I.
      Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.
      • O'Malley D.M.
      • Vetter M.H.
      • Cohn D.E.
      • Khan A.
      • Hays J.L.
      Outpatient desensitization in selected patients with platinum hypersensitivity reactions.
      • Botsen D.
      • Lepoix E.
      • Mazza C.
      • Brasseur M.
      • Grange A.
      Oxaliplatin-desensitization procedure is safe and feasible in an outpatient cancer unit in France.
      Several years ago, extrapolating from our experience with carboplatin, our institution implemented a simplified ambulatory graded infusion protocol with only 2 drug dilutions, and 3 infusion steps. A 10-fold dilution (8.5 mg/m2 in 100 mL) is infused over 3 hours (10 mL during the first 60 minutes and 90 mL over 120 minutes). If tolerated, the remaining dose is infused during the next 3 hours. The total infusion times of the 12-step and the graded infusion protocols are comparable; however, the graded infusion requires fewer drug dilutions, infusion steps, and nursing assessments. Moreover, it is administered entirely in the ambulatory setting, significantly reducing treatment costs.
      To define the safety and outcomes associated with this graded infusion strategy, we performed a retrospective study of patients treated with oxaliplatin desensitizations at our institution over a ten-year period. We postulated that a graded infusion strategy would be easily implemented in ambulatory and community settings, thus allowing more patients with a history of oxaliplatin HSRs to continue treatment.

      Methods

      Study Population and Study Design

      We obtained Institutional Review Board approval to analyze the electronic medical record of all patients with a history of HSRs to oxaliplatin who were treated with desensitization protocols at our institution between January 1, 2011, and December 1, 2020. Patients who might have experienced mild HSRs and, at the discretion of their oncologist, did not undergo a standardized desensitization protocol, would not have been identified in our automated search algorithm, and so are not included.
      All patients who received oxaliplatin as part of a clinical trial were excluded from the study. Medication administration records, clinician and nursing assessments, telephone/electronic communications, emergency room and inpatient notes were reviewed. Clinician and nursing notes were used to identify the type and severity of baseline and breakthrough HSRs. Patients’ records were reviewed from initiation of oxaliplatin through 6 weeks after oxaliplatin discontinuation.

      Graded Challenge Oxaliplatin Administration

      Patients were premedicated with dexamethasone (20 mg IV), famotidine (20 mg IV) and diphenhydramine (50 mg IV). At least 30 minutes were allowed between the last administered premedication and the start of oxaliplatin. Two drug dilutions of oxaliplatin were prepared: bag 1, containing 10% of the total dose in 100 mL, and bag 2, containing 90% of the total dose in 250 mL (Table 1). Oxaliplatin was administered over 6 hours in 3 steps: 10 mL of bag 1 (1% of the total dose) was infused over the first hour, followed by the remaining 90 mL of bag 1 (9% of the total dose) over 2 hours, and finally bag 2 over 3 hours (Table 1). A second dose of diphenhydramine (25 mg IV) was administered prior to bag 2.
      Table 1Oxaliplatin Graded Infusion Protocol.
      Premedications: dexamethasone 20 mg IV, famotidine 20 mg IV, diphenhydramine 50 mg IV.
      Bag 110% of total dose in 100 mL10 mL (10% of total dose) over the first hour, THEN

      90 mL (90% of total dose) over 2 hours
      Bag 290% of total dose in 250 mLOver 3 hours. Second dose of diphenhydramine (25 mg IV) prior to bag 2.
      Nursing staff who performed graded infusions were assigned no more than 2 patients at any given time. The charge nurse was notified, and patients undergoing desensitizations were assigned an infusion room adjacent to the nursing station. Vital signs were checked at 15 and 60 minutes after initiation of the graded challenge, and every 1 hour thereafter. A crash cart was routinely stationed outside desensitization rooms. The same protocol was followed for all patients independent of the severity of the baseline HSR.

      Statistical Analysis

      Type and severity of HSRs, and reasons for treatment discontinuation are presented by absolute numbers and relative frequency tables. Number of treatment cycles are presented as median and range. HSRs were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Table 2).
      Table 2Grading System of Infusion Reactions (CTCAE version 5.0).
      Grade 1Grade 2Grade 3Grade 4Grade 5
      Mild transient reaction; infusion interruption not indicated; intervention not indicated.Therapy or infusion interruption indicated but responds promptly to treatment; prophylactic medications indicated for <= 24 hrs.Not rapidly responsive to medication or brief interruption; recurrent symptoms following improvement; hospitalization indicated.Life-threatening consequences; urgent intervention indicated

      Death

      Results

      We identified 374 patients who experienced HSRs to oxaliplatin and were treated with a graded infusion strategy between January 1, 2011, and December 1, 2020. Of the 374 patients, 56% were women, 87% had colorectal (CRC) or pancreatic cancer, and 73% had stage IV disease (Table 3). Patients received a median of 7 cycles (range 1-28) before experiencing HSRs. Of the baseline HSRs, 248 (66%) were grade 2, 105 (28%) were grade 3 and 21 (6%) were grade 4. All 374 patients experienced symptoms consistent with a type I HSR. The most common symptoms included pruritus (51%), erythema (41%), facial flushing (37%), and dyspnea (22%) (Table 3). A total of 8 patients (2%) were referred to the emergency department for their baseline HSRs, of whom one was hospitalized after he experienced rigors and persistent hypotension, which were attributed to a grade 4 anaphylactic reaction. The patient was admitted to the ICU for 2 days for vasopressor support, and the total length of hospital stay was 6 days.
      Table 3Patient Characteristics (n = 374).
      Female sex – no. (%)208(56)
      Age – median (range)57(19-94)
      Cancer Type – no. (%)
      CRC275(74)
       Pancreatic49(13)
       Gastroesophageal19(5)
       Cholangiocarcinoma13(3)
       Appendiceal12(3)
       Other6(2)
      Stage – no. (%)
       II4(1)
       III97(26)
       IV273(73)
      Severity of baseline HSRs – no. (%)
       Grade 2248(66)
       Grade 3105(28)
       Grade 421(6)
      Type of baseline HSRs – no. (%)
       Pruritus191(51)
       Erythema153(41)
       Flushing140(37)
       Dyspnea83(22)
       Oropharyngeal dysesthesias76(20)
       GI symptoms66(18)
       Rigors53(14)
       Chest pain52(13)
       Urticaria50(13)
       Angioedema47(13)
       Cough33(9)
       Back pain23(6)
       Hypertension SBP >17018(5)
       Hypotension SBP < 9013(3)
       Bronchospasm12(3)
       Hypoxia SaO2% < 92%10(3)
      SBP: systolic blood pressure.
      Of the 374 patients undergoing the simplified 3-step graded infusion, 283 (76%) did not experience a subsequent HSR, while 91 (24%) did experience a breakthrough HSR: 46 patients (12%) during cycle 1 of the graded challenge, 40 (11%) during cycles 2-5, and 5 (1%) after >5 desensitization cycles (range 1-13 cycles). Of the 374 patients, 72 (19%) experienced a grade 2 HSR, and 19 (5%) experienced a grade 3 or 4 HSR. There were no grade 5 (fatal) HSRs. The most common breakthrough HSRs were erythema (11%), rigors (7%), pruritus (7%), and facial flushing (5%) (Table 4). Of the 91 breakthrough HSRs, 89 (98%) were classified as type I HSRs, and 2 (2%) were classified as type II immune-mediated reactions, including 1 case of acute hemolysis, and one case of combined acute hemolysis and drug-induced immune thrombocytopenia.
      Table 4Outcomes of Oxaliplatin Graded Infusion.
      Desensitization cycles – median (range) (SD)3(1-41)
      Reason for treatment discontinuation – no. (%)
       Progression of disease130(35)
       Breakthrough HSRs91(24)
       Completion of treatment77(21)
       Treatment-related toxicity76(20)
      Severity of breakthrough HSRs – no. (%)
       Grade 272(19)
       Grade 312(3)
       Grade 47(2)
       Grade 50(0)
      Type of breakthrough HSRs – no. (%)
       Erythema41(11)
       Rigors26(7)
       Pruritus26(7)
       Facial Flushing20(5)
       Back pain13(3)
       Dyspnea12(3)
       GI symptoms11(3)
       Urticaria9(2)
       Chest pain9(2)
       Hypertension SBP > 1709(2)
       Cough6(2)
       Oropharyngeal dysesthesias5(1)
       Bronchospasm2(0.5)
       Hypoxia SaO2 < 92%2(0.5)
       Hypotension SBP < 902(0.5)
       Angioedema2(0.5)
      SBP: systolic blood pressure.
      Three patients (0.8%) were hospitalized for management of breakthrough HSRs. A 41-year-old man developed acute hematuria, rigors, and fever during his sixth graded challenge cycle. He was referred to the emergency department, where he was found to have acute anemia, elevated LDH and direct bilirubin, and an undetectable haptoglobin, consistent with acute hemolysis. He was admitted for 4 days. A 59-year-old man developed hematuria, rigors and dyspnea during his fourth desensitization cycle and was subsequently admitted for 3 days for management of acute hemolysis and drug-induced immune thrombocytopenia. Lastly, a third patient aged 28-years-old who was on oxygen therapy at baseline was hospitalized for hypoxemic respiratory failure, which was thought to be multifactorial, due to extensive pulmonary metastatic disease, bacterial pneumonia, and oxaliplatin-induced bronchospasm. He was admitted to the intensive care unit for 2 days and required high-flow nasal canula but not mechanical ventilation. Length of hospital stay was 5 days.
      The most common reasons for discontinuation of the graded infusion challenge were disease progression (35%), breakthrough HSRs as noted above (24%), completion of treatment (21%), and toxicity other than HSR (20%). (Table 4). Overall, the 374 patients received a median additional 3 cycles of oxaliplatin (range 1-41) on the graded infusion protocol.
      Fifteen patients who experienced breakthrough HSRs during graded challenges were subsequently treated with the standard 12-step protocol. This subset of patients received a median of 2 cycles on the 12-step protocol (range 1-4). Five patients (33%) had an HSR during their initial 12-step desensitization, and 5 (33%) developed an HSR on subsequent cycles (82% were grade 2, 9% grade 3 and 9% grade 4). Thus, treatment was discontinued in two thirds of these patients due to persistent HSRs. The most common recurrent HSRs were facial flushing (50%), pruritus (30%), urticaria (30%), and erythema (30%). There were no differences in terms of type or severity of HSRs, symptoms experienced, or patient characteristics in these 10 cases compared to the rest of the cohort.

      Discussion

      Because of the need for close clinical supervision and longer infusion times, desensitization protocols are inconvenient for patients and clinical staff, and are associated with increased healthcare costs, particularly when carried out, as they often are, in the inpatient setting.
      Although prior studies have proposed various desensitization strategies,
      • Castells M.
      Rapid desensitization for hypersensitivity reactions to medications.
      • Castells M.C.
      • Tennant N.M.
      • Sloane D.E.
      • Hsu F.I.
      • Barrett N.A.
      Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.
      • Lee C.W.
      • Matulonis U.A.
      • Castells M.C.
      Carboplatin hypersensitivity: a 6-h 12-step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE-mediated reactions.
      • Castells Guitart M.C
      Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century.
      • Sloane D.
      • Govindarajulu U.
      • Harrow-Mortelliti J.
      • Barry W.
      • Hsu F.I.
      Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.
      there are no formal guidelines or accepted standards of care, and management decisions are often based on expert opinions of oncologists and/or allergists. The standard desensitization protocol at multiple institutions uses 3 different drug dilutions and 12 infusion steps. Initial desensitizations are often performed in the inpatient setting and transitioned to ambulatory units if patients tolerate the procedure.
      • Castells M.
      Rapid desensitization for hypersensitivity reactions to medications.
      • Castells M.C.
      • Tennant N.M.
      • Sloane D.E.
      • Hsu F.I.
      • Barrett N.A.
      Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.
      • Lee C.W.
      • Matulonis U.A.
      • Castells M.C.
      Carboplatin hypersensitivity: a 6-h 12-step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE-mediated reactions.
      • Castells Guitart M.C
      Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century.
      • Sloane D.
      • Govindarajulu U.
      • Harrow-Mortelliti J.
      • Barry W.
      • Hsu F.I.
      Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.
      In some institutions, these are done under the direction and supervision of allergists.
      Here we present data of 374 patients treated at our institution with an ambulatory graded infusion strategy that only requires 2 drug dilutions and 3 infusion steps. All patients were managed in our outpatient chemotherapy units, and all were managed without requirement for consultation or the assistance of an allergist. To our knowledge, this is the largest study to evaluate any desensitization strategy for drug-related HSRs. Our data suggest that this simplified outpatient graded infusion strategy is safe and effective at preventing severe breakthrough HSRs. Of the 374 patients, 12% experienced breakthrough HSRs requiring treatment discontinuation on the first graded infusion cycle, and an additional 12% experienced an HSR on a subsequent graded infusion cycle. These data are comparable to those of other retrospective studies evaluating the 12-step desensitization protocol, which showed breakthrough reactions in 28%-58% of patients undergoing desensitization to platinum agents.
      • Polyzos A.
      • Tsavaris N.
      • Gogas H.
      • Souglakos J.
      • Vambakas L.
      Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.
      • Suenaga M.
      • Mizunuma N.
      • Shinozaki E.
      • Matsusaka S.
      • Chin K.
      Management of allergic reactions to oxaliplatin in colorectal cancer patients.
      • Siu S.W.
      • Chan R.T.
      • Au G.K
      Hypersensitivity reactions to oxaliplatin: experience in a single institute.
      • Madrigal-Burgaleta R.
      • Berges-Gimeno M.P.
      • Angel-Pereira D.
      • Ferreiro-Monteagudo R.
      • Guillen-Ponce C.
      Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment.
      ,
      • Sloane D.
      • Govindarajulu U.
      • Harrow-Mortelliti J.
      • Barry W.
      • Hsu F.I.
      Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.
      Of the 374 patients treated with the graded challenge, only 19 (5%) experienced a grade 3 or 4 HSR. There were no grade 5 (fatal) HSRs. Consistent with other studies, the overwhelming majority (98%) of breakthrough reactions were classified as type I HSRs. Of the 3 patients requiring hospitalization, 2 were admitted for type II immune-mediated hemolytic anemia, and thrombocytopenia. These type II immune-mediated reactions are an exceedingly rare complication of oxaliplatin treatment and are not prevented with desensitization.
      • Polyzos A.
      • Tsavaris N.
      • Gogas H.
      • Souglakos J.
      • Vambakas L.
      Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.
      ,
      • Cernadas J.R.
      • Brockow K.
      • Romano A.
      • Aberer W.
      • Torres M.J.
      General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.
      ,
      • Desrame J.
      • Broustet H.
      • Darodes de Tailly P.
      • Girard D.
      • Saissy J.M
      Oxaliplatin-induced haemolytic anaemia.
      We identified only 2 case reports of patients with a history of type I HSRs to platinum drugs who subsequently experienced non–IgE-mediated HSRs.
      • Perez-Alzate D.
      • Blanca-Lopez N.
      • Somoza M.L.
      • Ruano F.J.
      • Montero G.S.
      Anaphylaxis and severe immune hemolytic anemia during the course of desensitization with carboplatin.
      ,
      • Vyskocil J.
      • Tucek S.
      • Kiss I.
      • Fedorova L.
      • Nevrlka J.
      • Zdrazilova-Dubska L.
      Type II hypersensitivity reactions after oxaliplatin rechallenge can be life threatening.
      As in the 2 patients presented here, both cases had tolerated several cycles of desensitization with no type I HSRs.
      A small subset of patients was transitioned to the 12-step strategy after failing the graded infusion. Two-thirds of these patients continued to experience HSRs, and only 6 patients received more than 2 cycles on the 12-step desensitization. Therefore, although the standard 12-step desensitization is an option, it appears to be of limited usefulness for most patients who experience HSRs on our simplified schedule.
      In summary, our data indicate that our simplified graded infusion strategy is a safe, and effective outpatient strategy for continuing oxaliplatin treatment in patients experiencing HSRs to oxaliplatin. Compared with other HSR mitigation strategies, this approach is less challenging from a technical and logistical perspective, does not require specific expertise or consultation from allergists, and is manageable in a standard outpatient chemotherapy infusion setting, thus allowing more patients with a history of HSRs to continue treatment without incurring inpatient management. In addition, because the graded infusion requires fewer drug dilutions and infusion rates than a 12-step process, it requires less nursing time and so is likely to result in decreased healthcare costs and improved patient and staff satisfaction.

      Clinical Practice Points

      Hypersensitivity reactions (HSRs) to chemotherapy present a therapeutic challenge. The standard desensitization protocol for patients who experience HSRs to oxaliplatin consists of 12 infusion steps with 3 different drug dilutions, often carried in the inpatient setting.
      Several years ago, our institution implemented a simplified ambulatory graded infusion protocol with 2 drug dilutions, and 3 infusion steps. To define the safety and outcomes associated with this simplified graded infusion strategy, we performed a retrospective study of patients treated with oxaliplatin desensitizations at our institution. Of the 374 patients, 12% experienced breakthrough HSRs on the first graded infusion cycle, and an additional 12% experienced an HSR on a subsequent desensitization cycle. Only 19 (5%) experienced a grade 3 or 4 HSR. There were no grade 5 (fatal) HSRs. These data are comparable to those of other retrospective studies evaluating the 12-step desensitization protocol.
      Our data indicate that our simplified graded infusion is a safe and effective outpatient strategy for patients experiencing HSRs to oxaliplatin. Compared with other desensitization strategies, this approach is less challenging from a technical and logistical perspective, does not require expertise or consultation from allergists, and is manageable in a standard outpatient chemotherapy unit, thus allowing more patients with a history of HSRs to continue treatment without incurring inpatient management. In addition, because the graded infusion requires fewer drug dilutions and infusion rates than a 12-step process, it requires less nursing time and so is likely to result in decreased healthcare costs and improved patient and staff satisfaction.

      Disclosure

      This work was supported by grants from the National Institute of Health (P30 CA 008748, T32‐CA009512, to Memorial Sloan Kettering Cancer Institute), and the Conquer Cancer Foundation (2021YIA-8302348290, to S.A.) Study concept: L.S., S.A. Data collection: L.S, S.A. Data analysis and interpretation: All authors Manuscript preparation: All authors. Critical revision: All authors. Final approval: L.S., S.A.

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