Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

The impact of early versus late tocilizumab administration in patients with cytokine release syndrome secondary to immune effector cell therapy

Introduction Cytokine release syndrome is a life-threatening hyper-inflammatory state induced by immune effector cell therapy. Anti-interleukin 6-(IL-6) therapy, such as tocilizumab, is the standard treatment for cytokine release syndrome since it reverses symptoms without compromising immune effector cell therapy efficacy. Glucocorticoids are reserved for refractory or severe cytokine release syndrome due to concern for attenuating antitumor activity. Optimizing the timing of tocilizumab could avoid glucocorticoid use and improve outcomes. This study assesses tocilizumab timing on patient outcomes and healthcare resource utilization. Methods This is a retrospective single-institution analysis of 28 patients who received tocilizumab for cytokine release syndrome secondary to immune effector cell therapy. Patients were categorized into two groups: Early Tocilizumab (within 24 h) or Late Tocilizumab groups (more than 24 h) from fever onset. The composite primary endpoint was glucocorticoid use, intensive care unit admission, or inpatient mortality. Secondary outcomes include comparing the various presentations of cytokine release syndrome, need for vasopressors, length of stay, rates of neurotoxicity, and C-reactive protein and ferritin trends. Results The Early Tocilizumab group presented with more rapid fever onset (35 vs.113 h, P = 0.017) and higher maximum cytokine release syndrome grade (Median, Grade 2 vs. Grade 1, P = 0.025). Additionally, the Early Tocilizumab group required more doses of tocilizumab (Median, 2 vs. 1, P = 0.037). Despite the difference in cytokine release syndrome presentation, the primary composite endpoint was not statistically different between groups. Conclusion Earlier onset of fever appears to be associated with more severe, progressive cytokine release syndrome requiring multiple doses of anti-interleukin-6 therapy. Prompt and aggressive tocilizumab treatment could be protective against the negative consequences of cytokine release syndrome.

Plasma Exchange to Treat Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome after Anti-CD19 Chimeric Antigen Receptor-T Cell Infusion: A Case Report

Adoptive cell immunotherapy with chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical outcomes. However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most significant toxicities during this therapy and can be life-threatening. We described a 12-year-old juvenile who had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia (r/r B-ALL). The patient was recruited into our phase I clinical trial concerning ssCAR-T-19 (anti-CD19 CAR-T cells with shRNA targeting IL-6), and 5*106 /kg of engineered ssCAR-T-19 cells were administered. After infusion, the patient underwent a typical CRS reaction, with fever and increased cytokine levels. He was treated with antipyretic drugs, methylprednisolone, and tocilizumab, but the effect was limited. He developed coagulation abnormalities, multiple organ dysfunction, lung infection and ICANS. Apart from the necessary supportive and symptomatic treatment, plasma exchange was performed three times in four days while methylprednisolone pulse was performed for two consecutive days. After that, the body temperature, heart rate, and especially the cytokine levels declined. But digestive tract hemorrhage occurred to him and he was transferred to intensive care unit. To make things worse, he developed acute respiratory failure and received intubation and mechanical ventilation. In addition, symptomatic treatment such as suppression of stomach acid and anti-infection was given. The bleeding was controlled, and his respiratory function improved, and the CRS and ICANS-related symptoms were relieved. He received extubation and was transferred back to the general ward. Additionally, abone marrow smear showed no lymphoblast cells, and minimal residual disease in bone marrow was negative on day +22 and day +30. The patient was eventually discharged in a normal condition. In conclusion, CRS and ICANS as two most common toxicities after CAR-T therapy, which often cause patient death. Several methods such as anti-IL-6 therapy and/or corticosteroids have been adopted in the management guidelines of CRS and ICANS except plasma exchange. This case shows the validity of plasma exchange in a patient with severe CRS and ICANS after receiving ssCAR-T.

Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome

Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies. However, its use is associated with serious adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can present with aphasia, mutism, somnolence, seizures, signs of increased intracranial pressure and rarely cerebral edema. Corticosteroids (CS) and IL-6 inhibitors are first line treatment for CRS and ICANS. Prolonged CS use has been associated with decreased over-all survival in CAR T-cell treated patients. Data on effective treatments for CART T-cell induced neurotoxicity is limited, especially in steroid-refractory ICANS. Blood-brain barrier (BBB) disruption and infiltration of myeloid and immune effector cells into the central nervous system are implicated in the pathogenesis of ICANS. This likely explains the role of intrathecal chemotherapy, which has been described in literature for treatment of steroid-refractory ICANS. Here, we report the outcomes of two patients with refractory DLBCL who developed severe ICANS after receiving axicabtagene ciloleucel (axi cel) and treated with intrathecal (IT) chemotherapy. Case Presentation Our first case is of a 66 year old male with diagnosis of R/R DLBCL, who was treated with R-CHOP, followed by R-GemOx, with no response then received axi cel. Patient developed grade 2 CRS and grade 1 ICANS (National Cancer Institute Common Terminology Criteria for Adverse Effects v4.03) on day +2 post infusion, treated with tocilizumab and dexamethasone with good response initially. While tapering dexamethasone on day +5, he developed grade 3 CRS and grade 3 ICANS. Brain MRI did not show any intracranial abnormality and EEG showed no seizure activity. Lumbar puncture (LP) was done on day +7 and showed opening pressure of 32 cm H2O, and 12 lymphocytes. He was started on IV solumedrol and tocilizumab was resumed. CRS improved while neurotoxicity progressed to grade 4 prompting intubation and mechanical ventilation on day +8. On day +9, patient received intrathecal methotrexate 12 mg and hydrocortisone 50 mg. On day +12, neurotoxicity improved to grade 1 and patient was extubated on day +13. Steroid taper stopped on +17. Despite disease response, patient remained hospitalized at day +45 for deconditioning and vocal cord paralysis related to a lengthy hospital stay and intubation. He was eventually discharged, however passed away on day +49 from complications of prolonged hospitalization. Our second case is of a 69 year old female with a diagnosis of R/R DLBCL with CNS involvement, treated with RCHOP x6 followed by salvage chemotherapy with refractory disease, She then received axi cel. Patient developed grade 1 CRS on day +4, treated with tocilizumab and dexamethasone, and patient responded well. On day +9, she developed grade 2 CRS and grade 3 ICANS. At that time, dexamethasone was switched to pulse dose solumedrol and tocilizumab was continued. CT head showed no acute intracranial abnormality and EEG did not show any epileptiform activity. LP showed opening pressure of 21, and 84 lymphocytes. On day +11, patient's CRS resolved, however ICANS developed to grade 4 and patient received 12 mg intrathecal methotrexate and hydrocortisone 50 mg for steroid-refractory ICANS. The very next day, patient showed significant neurological improvement. Steroid taper was initiated and patient's ICANS resolved on day +16. MRI brain showed decrease in size of nodular enhancement along periventricular white matter and left occipital area corresponding to treatment response. She was discharged on day +28 and continues to do well one year out of axi cel infusion Conclusion Our abstract adds to the sparse literature about the use IT chemotherapy in cases with severe ICANS. It also highlights its importance as an alternative potential therapy to high doses and prolonged courses of corticosteroids which is associated with increased morbidity and mortality. Steroid-refractory ICANS has limited treatment options and further evaluation of the use of IT chemotherapy in large scale studies is warranted. Disclosures Kahn: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genetech: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Fazal: Agios: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Lister: Oncology Analytics: Other: Academic Board.

EBV Positive DLBCL Is Effectively Treated with Commercial CAR T Cell Therapy but Is Associated with Higher Rates of Severe Immune Effector Cell Associated Neurologic Syndrome (ICANS): A Single Institution Experience

Introduction: CAR T-cell therapy (CART) has revolutionized the treatment landscape of aggressive B cell lymphoma (aBCL) in the relapsed/refractory (r/r) setting, including high-risk groups such as high grade B cell lymphoma (HGBCL), primary refractory disease, and chemo-resistant relapses. To date, however, there has been no data reported, on the outcomes of patients with Epstein-Barr virus positive (EBV+) DLBCL, NOS. EBV+ DLBCL, NOS is a high-risk group of aBCL characterized by the incorporation of EBV into the malignant cells, with the chronic inflammation associated with EBV infection being thought to contribute to DLBCL pathogenesis. It has been shown to be less responsive to standard chemotherapy with high relapse rates and overall poor prognosis. In the present study, we analyze outcomes and toxicities of patients with EBV+ DLBCL, NOS treated with CD19CART. Methods: We retrospectively analyzed charts of patients treated with commercially available CD19CAR T-cell products for the treatment of aBCL at City of Hope (COH) between April 2018 and March 2021. EBV status was determined by immunohistochemical stains from EBER in situ hybridization on paraffin embedded tissues. Patients were included in the analysis if they had positive or negative EBER staining, referred as EBV+ or EBV-, respectively. The investigation was approved by the COH IRB. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using ASTCT criteria (Lee et al. BBMT 2019). Demographics were analyzed with descriptive statistics. Univariate analysis was performed by Chi Square test. Results: Seventy-three patients had tumor samples that were evaluable for analysis, 92% (n=67) were negative for EBER and 8% (n=6) were positive for EBER. In the entire cohort, the median age was 62 years (range, 21-90), and included 18% (n=13) transformed follicular lymphoma, 73% (n=53) DLBCL, NOS, and 10%(n=7) DH. The median number of prior lines of therapy was 2 (range, 2-6) and 15% (n=11) patients had prior autologous stem cell transplant. Comparing the EBV+ patients to the EBV-, the CR rate was 67% (n=4) vs 58% (n=34), with 16% (n=1) PR vs 27% (n=15) (ORR 83% vs 74%). With a median follow up of 17.0 months (range, 3.6-38.3), 33% (n=2) of EBV+ patients had progressed vs 42% (n=28). In the EBV+ DLBCL, NOS group, 3 CR patients had absence of detectable EBV PCR in the peripheral blood at the time of CART; 1 CR patient did not have clinical indication for EBV viral load (VL) evaluation (EBV PCR not measured); 1 PR and 1 PD patients had detectable viremia. At the time of analysis, 31% (n=21) of EBV- patients died vs 33% (n=2) of EBV+ patients, both with non-CR response to CAR T and persistent EBV VL during therapy. In terms of toxicity, overall CRS rates were similar with 83% (n=5) in the EBV+ patients and 86% (n=58) in EBV- patients. Although overall incidences of ICANS were similar between the two groups (50% [n=3] vs 45% [n=30]), grade 3 ICANS was higher in EBV+ patients (50% [n=3]) than in EBV- patients( 7.5% [n=5]; p = 0.02). EBV VL did not correlate with CRS or neurotoxicity. Conclusion: We present a retrospective analysis of EBV+ DLBCL, NOS patients treated with CART at our institution. Based on our analysis, despite the limited number of cases, the CART is an effective therapy for EBV+ DLBCL,NOS with response rates similar to what has been reported in the literature for other aBCL groups. Responses appear to be improved if EBV VL is undetectable at the time of CART. Interestingly, we demonstrate a statistically significant higher rates of grade 3 ICANS in patients with EBV+ DLBCL,NOS. Our data suggests that close monitoring for ICANS during CART should be considered in EBV+ DLBCL patients with early therapeutic intervention to prevent severe toxicity. Further investigation of a larger cohort of EBV+ DLBCL patients, as well as a deeper analysis of inflammatory markers and EBV viremia in these patients undergoing CART may provide further insight to response and toxicity profile. Disclosures Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Herrera: Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Gilead Sciences: Research Funding. Budde: Mustang Bio, Inc: Research Funding; Gilead: Consultancy; Merck, Inc: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; IGM Biosciences: Research Funding; Roche: Consultancy; BeiGene: Consultancy; Novartis: Consultancy. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria.

Feasibility of a Supportive Mobile Health App for Chimeric Antigen Receptor T-Cell Therapy

BACKGROUND: The operationalization of chimeric antigen receptor (CAR-T) therapy for hematologic malignancies can be complex for patients and their caregivers. In the weeks before CAR-T therapy, patients must process large amounts of information and coordinate logistics involving caregivers, lodging, and transportation. Immediately following CAR-T therapy, patients must be monitored closely for toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the months following CAR-T therapy, patients may be referred back to local oncologists without a clear plan for managing potential late effects such as hypogammaglobulinemia or neuropsychiatric complications (Chakraborty 2021). Mobile health (mHealth) apps may be able to improve the patient experience during CAR-T therapy by facilitating care coordination, home-based toxicity monitoring, and patient education (Banerjee 2021). By empowering patients and caregivers to better understand CAR-T therapy and actively participate in their care, mHealth tools may ultimately augment workflows for CAR-T clinics as well. However, the feasibility and acceptability of such supportive mHealth apps during CAR-T therapy have not been established. STUDY DESIGN: We have designed a "Companion for CAR-T" mHealth app to assist with care coordination, toxicity monitoring, and patient education during CAR-T therapy. Key components of the app are summarized in the Figure. In brief, pre-CAR-T components include educational videos and dynamic calendars to assist patients with coordinating logistics. Post-CAR-T components include app-based prompts to input body temperature daily, an electronic Immune Effector Cell-Associated Encephalopathy (eICE) screening tool for ICANS that can be administered by caregivers, and a patient-specific long-term survivorship care plan. Global app components include an 'Appointment Companion' to facilitate patient-provider discussions during appointments as well as a digital CAR-T wallet card to convey key health-related information to other healthcare providers. We plan to investigate the "Companion for CAR-T" app through a pilot study of 20 patients receiving commercially available CAR-T therapies for any hematologic malignancy at our institution. Co-primary endpoints include (1) app feasibility, defined as the percentage of patients who access all 5 core modules shown in the Figure at least once; and (2) app acceptability, defined as the percentage of patients who agree that the app was helpful during their experience with CAR-T therapy. Secondary endpoints include the incidence of fevers or eICE deficits recorded via the app. Exploratory endpoints include longitudinal trends in patient-reported outcomes such as emotional distress at each clinic visit. DISCUSSION: If feasibility and acceptability of the "Companion for CAR-T" app are demonstrated through this pilot study, we plan to launch a multicenter randomized Phase 2 study of this mHealth tool versus usual care to assess its effect on perceived stress and decisional conflict. Other important steps for our group include the translation of app content into different languages and the provision of tablet computing devices for patients who do not own smartphones. Once validated and expanded in these aforementioned ways, potential strengths of the "Companion for CAR-T" app include its ability to be personalized easily with information specific to individual CAR-T therapies, malignancies, and centers. Figure 1 Figure 1. Disclosures Banerjee: Sanofi: Consultancy; SparkCures: Consultancy; Pack Health: Research Funding. Sykes: Patient Discovery Solutions, Inc.: Current Employment. Shah: Amgen: Consultancy; Indapta Therapeutics: Consultancy; Sutro Biopharma: Research Funding; Sanofi: Consultancy; Teneobio: Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; GSK: Consultancy; Kite: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; CSL Behring: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; CareDx: Consultancy. Andreadis: Incyte: Honoraria; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; GenMAB: Research Funding; Merck: Research Funding; Novartis: Research Funding; Epizyme: Honoraria; Crispr Therapeutics: Research Funding; Atara: Consultancy, Honoraria; Karyopharm: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; BMS/Celgene: Research Funding. Martin: Amgen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy; Janssen: Research Funding; Sanofi: Research Funding. Shore: Patient Discovery Solutions, Inc.: Current Employment. Sodowick: Patient Discovery Solutions, Inc.: Current Employment. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees.

NCMP-20. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS) – A MULTICENTER RETROSPECTIVE STUDY

BACKGROUND Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy, termed immune effector cell-associated neurotoxicity syndrome (ICANS), are common and potentially devastating. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a well-established marker of neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, retrospective multicenter study compares pre-infusion NfL to known post-infusion risk factors for developing ICANs including white blood cell (WBC) count, platelet count, C-reactive protein (CRP), fibrinogen, and ferritin levels. METHODS Inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion Day 3 or Day 5 WBC, Platelet, CRP, fibrinogen, and ferritin were obtained from the medical record. Group comparisons were done using log-rank tests with a Bonferroni-derived significance threshold, followed by receiver operating characteristic (ROC) curve classification. RESULTS Prior to infusion, individuals who ultimately developed ICANS had elevations in NfL ([87.6 v 29.4 pg/ml], p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Among known post-infusion risk factors, only post-infusion Day 3 ferritin (p = 0.004) and Day 5 ferritin (p = 0.003) differed between groups. Classification was inferior for both time points (Day 3 AUC = 0.87, specificity 0.71; Day 5 AUC 0.87, specificity 0.86). CONCLUSION Pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. Our findings suggest the risk of developing ICANS reflects pre-existing host-factors. Foreknowledge of ICANS development of may permit early, aggressive (preemptive or prophylaxis) ICANS-directed therapies, improving patient outcomes.

Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines .