Immunotherapy toxicity management

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Meghan Mooradian, MD
Boston, MA

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Grading toxicity

CTCAE

Diarrhea, colitis

  • Grade 1: Asymptomatic; clinical or diagnostic observations only; grade 1 diarrhea <4x/day above baseline; intervention not needed
  • Grade 2: Abdominal pain, mucus or blood in stool; grade 2 diarrhea frequency 4-6/day above baseline
  • Grade 3: Severe abdominal pain; grade 3 diarrhea >7x/day above baseline
  • Grade 4: Life threatening consequences

*GI consult is warranted in any patient who meets criteria for grade 2 diarrhea/colitis with negative infectious stool work up

Endocrinopathy

Hypophysitis:

  • Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
  • Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL
  • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL
  • Grade 4: Life-threatening consequences; urgent intervention indicated

Hypothyroid

  • Grade 1: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
  • Grade 2: Symptomatic; thyroid replacement indicated; limiting instrumental ADL
  • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization indicated
  • Grade 4: Life-threatening consequences; urgent intervention indicated

Hyperthyroid

  • Grade 1: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
  • Grade 2: Symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL
  • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization indicated
  • Grade 4: Life-threatening consequences; urgent intervention indicated

Liver, hepatic

  • Grade 1: AST, ALT > ULN - 3x ULN; total bilirubin > ULN - 1.5xULN
  • Grade 2: AST, ALT > 3 - <5xULN; ULN; total bilirubin >1.5x - 3xULN
  • Grade 3/4: AST, ALT > 5xULN; total bilirubin > 3xULN

Lung, pneumonitis

  • Grade 1: Asymptomatic, diagnostic observation only
  • Grade 2: Symptomatic, limiting instrumental ADLs; medical intervention warranted
  • Grade 3: Severe symptoms; limiting ADLs; oxygen-indicated
  • Grade 4: Life-threatening respiratory compromise; urgent intervention required (i.e. intubation)

Kidney, renal (Nephritis)

  • Grade 1: Creatinine level increase of >0.3 mg/dl; creatinine 1.5-2x above baseline
  • Grade 2: Creatinine 2-3x above baseline
  • Grade 3: Creatinine >3x above baseline or greater than 4.0 mg/dl; hospitalization required
  • Grade 4: Life-threatening consequences; dialysis required

Rheumatology

Arthritis

  • Grade 1: Mild pain with inflammatory symptoms: erythema, or joint swelling
  • Grade 2: Moderate pain associated with signs of inflammation, erythema, or joint swelling; limiting instrumental ADL
  • Grade 3: Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage (e.g., erosion); disabling; limiting self-care ADL

Skin, dermatologic

Maculopapular rash: the most frequent event with checkpoint inhibitors, the fourth version of the CTCAE classification proposes:

  • Grade 1: macules/papules covering < 10% the body surface area (BSA) with or without symptoms (e.g. pruritus, burning, tightness)
  • Grade 2: macules/papules covering 10%–30% BSA with or without symptoms (e.g. pruritus, burning, tightness); limiting instrumental activities of daily living (ADL)
  • Grade 3: macules/papules covering > 30% BSA with or without associated symptoms; limiting self-care ADL

Guidelines

Evaluation

Monitoring guidelines for identification of immune-related adverse events (irAEs)

  • Patients should receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs prior to initiating therapy and throughout treatment and survivorship.
  • There should be a high level of suspicion that new symptoms are treatment related.
  • Recommend weekly toxicity visits for patients on combination CTLA-4/PD-1 inhibition while on therapy; every 2 or 3 week visits are reasonable for patients on single agent PD-1/PD-L1 or CTLA-4 inhibitors

Pre-treatment evaluation

  • Detailed physical examination, including dermatologic assessment
  • Detailed history including personal and family history of auto-immune disease
  • History of bowel habits
  • Baseline lab evaluation: CBC, CMP, TSH
  • Consider hepatitis serologies (HBsAg, HBsAb, HBcAb, hCAb), T-spot
  • Consider baseline troponin, BNP

Endocrinopathy

  • ACTH
  • AM cortisol with cosyntropin stimulation test
  • TSH
  • FSH
  • LH
  • Prolactin
  • Testosterone
  • MRI brain in cases of suspected hypophysitis
  • HgA1c, C-peptide, ests for antibodies (glutamic acid decarboxylase [GAD65], anti-insulin, anti-islet cell A, zinc transporter 8]) in cases of suspected ICI-induced T1DM
  • Endocrine referral

Liver, hepatic

  • Liver function tests (LFTs) or comprehensive metabolic panel (CMP)
  • Hepatitis B & C serologies
  • Liver/abdominal CT/MRI/ultrasound imaging

Kidney, renal

  • BUN/creatinine, basic metabolic panel (BMP)
  • Renal imaging (CT/MRI/ultrasound imaging)
  • Total protein (spot), protein/creatinine ratio, urine sodium, urine urea, urine creatinine (for calculating FeNa and FeUrea)
  • Nephrology consultation and kidney biopsy when indicated

Neurologic

  • Electromyography (EMG) +/- nerve biopsy
  • Muscle biopsy if myositis is suspected
  • Lumbar puncture and brain MRI in evaluation of cognitive dysfunction and concern for encephalitis, meningitis and encephalopathy.

*Neurology consultation is recommended for all neurologic irAEs grade 2 and higher

Ocular

  • Ophthalmology exam
  • Though ophthalmologic referral is necessary in ALL cases of visual complaints, certain tests can be performed by the oncologist in the office:
    • Examination for visual acuity, which can be done using an eye chart on a smart phone with the patient wearing reading glasses for near vision or glasses for distant vision, as necessary;
    • Color vision;
    • Red reflex; pupils (equal, round, reactive), including testing for an afferent pupillary defect, which can indicate optic nerve or extensive retinal disease;
    • Penlight inspection of the anterior part of the eye.

Pancreas

  • Amylase
  • Lipase

Skin, dermatologic

  • Complete history and physical exam, documenting % body surface area (BSA) involved ad evaluating for mucosal membrane involvement
  • Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition linked to another systemic disease or unrelated primary skin disorder.
  • Basic labs: CBC, CMP
  • Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a screening antinuclear antibody (ANA) test, SS-A/Anti-Ro, and SS-B/Anti-La if the rash is predominantly photodistributed or demonstrating photosensitivity
  • Dermatology referral with skin biopsy, when indicated

Management

General organ agnostic recommendations

The following are general recommendations that should be followed irrespective of affected organs. For organ-specific management,

Per the ASCO guidelines[6], clinicians should manage toxicities as follows:

  • In general, ICI therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities.
  • Hold ICI for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values revert to grade 1 or less.
  • Hold ICI for grade 3 toxicities and initiate high-dose corticosteroids prednisone 1 to 2 mg/kg/day or methylprednisolone IV 1 to 2 mg/kg/day).
    • Corticosteroids should be tapered over the course of at least 4 to 6 weeks. If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, should consider additional immune modulatory agents (such as Infliximab (Remicade) for ICI-induced colitis)
  • When symptoms and/or laboratory values revert to grade 1 or less, re-challenging with ICIs may be offered; however, caution is advised, especially in those patients with early-onset irAEs.
    • Dose adjustments are not recommended.
  • In general, grade 4 toxicities warrant permanent discontinuation of ICI with the exception of endocrinopathies that have been controlled by hormone replacement.

Management of frequent toxicities

Infusion Reaction

Grade 1: Mild transient reaction

MGMT: Infusion rate may be decreased or infusion temporarily interrupted until resolution of the event

Grade 2: Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (see below)

MGMT: Acute: anti-histamines, NSAIDS, potential use of IV corticosteroids; Consider ppx mgmt: anti-histamines (e.g., Fexofenadine (Allegra) the night prior and morning of infusion);

** Consider reduced the rate of infusion upon re-initiation or subsequent infusion

Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae

MGMT: Acute: anti-histamines, NSAIDS, IV corticosteroids; Ppx mgmt: anti-histamines (e.g., Fexofenadine (Allegra) the night prior and morning of infusion) ;

** Reduce rate of infusion upon re-initiation or subsequent infusion

Consider referral to allergist

Grade 4: Life-threatening consequences; urgent intervention indicated

MGMT: Acute: anti-histamines, NSAIDS, IV corticosteroids; likely permanent discontinue ICI

Skin, dermatologic

Pruritus: a frequent event with checkpoint inhibitors, often can be treated supportively with topicals, anti-histamines with continuation of ICI

· Topical lotions/emollients – menthol containing hydrate skin and provide pruritus relief in mild cases (i.e. Gold Bond)

Topical steroids

Oral anti-histamines

· If intense, limiting quality of life: oral corticosteroid – e.g., Prednisone (Sterapred) 0.5 to 1mg/kg/day tapered over 1 to 2 weeks; and dermatology referral

Maculopapular rash: the most frequent event with checkpoint inhibitors, the fourth version of the CTCAE classification proposes:

• Grade 1: macules/papules covering < 10% the body surface area (BSA) with or without symptoms (e.g. pruritus, burning, tightness);

MGMT: avoid skin irritants; topical steroids, anti-histamines; continue ICI;

• Grade 2: macules/papules covering 10%–30% BSA with or without symptoms (e.g. pruritus, burning, tightness); limiting instrumental activities of daily living (ADL);

MGMT: avoid skin irritants; topical steroids, anti-histamines +/- oral agents if needed; continue ICI;

Non-urgent dermatology referral; consider skin biopsy

• Grade 3: macules/papules covering > 30% BSA with or without associated symptoms; limiting self-care ADL;

MGMT: avoid skin irritants; if mild – moderation systemic steroids 0.5 to 1 mg/kg/day Prednisone (Sterapred) for 3 days then taper off; if more severe wean consider IV Methylprednisolone (Solumedrol) (1-2mg/kg) and slower taper over 2-4 weeks; can consider re-trial of ICI depending on severity of rash and dermatology recommendation;

Dermatology referral with biopsy

Endocrinopathy:

Hypophysitis

Hypophysitis
Grade CTCAE Description* Management
1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated • Hold ICI if ≥ grade 2 irAE until work up is completed and appropriate hormone replacement is started

• If central adrenal insufficiency: start physiologic steroid replacement: Hydrocortisone (Cortef) ~10 mg/m2 (HC 15 mg am, 5 mg at 3 pm)

○ Periodic assessment (e.g., every 3 months in the first year, every 6 months thereafter): clinical monitoring and repeat hormone levels (am cortisol and ACTH and/or low dose cosyntropin stimulation test) to assess recovery

• If central hypothyroidism: start thyroid hormone (Levothyroxine 1 mcg/kg)

○ Repeat thyroid function testing 6–8 weeks after initiation of thyroid hormone and then periodically (e.g., every 3 months in the first year and every 6 months thereafter) to assess recovery

• If central hypogonadism, repeat hormone levels in 2 to 3 months and consider testosterone in men or HRT in women if appropriate for cancer type

For severe/life-threatening symptoms such as adrenal crisis, severe headache, visual field deficiency:

• Hospitalize as appropriate.

• High dose corticosteroid (e.g., Prednisone (Sterapred) 1 mg/kg/day) (or equivalent dose of Methylprednisolone (Solumedrol)) in the acute phase, followed by taper over 1 month.

• Adrenal crisis should be managed per standard guidelines.

• If central hypothyroidism, replace thyroid hormone (see above) after corticosteroids have been initiated

2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL
3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent intervention indicated

Hypothyroidism

Hypothyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated • Hold ICI for ≥grade 3 irAEs

• ICI can be continued after resolution of symptoms to grade 2 or better.

• Start standard Levothyroxine thyroid replacement therapy: initial dose can be the full dose (1.6 mcg/kg) in young, healthy patients, but a reduced dose of 25 to 50 mcg should be initiated in elderly patients with known cardiovascular disease.

• Repeat TSH and free T4 testing after 6 to 8 weeks and adjust thyroid hormone dose accordingly. If TSH is above reference range, increase thyroid hormone dose by 12.5 mcg to 25 mcg

• After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s status changes

• After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s status changes

2 Symptomatic; thyroid replacement indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL; hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated

Hyperthyroidism

Hyperthyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated • Hold ICI for ≥ grade 3 irAEs

• Standard therapy for hyperthyroidism should be followed

Thyroiditis is self-limiting and has 2 phases:

○ In the hyperthyroid phase, patients may benefit from beta blockers if symptomatic (e.g., Atenolol 25 to 50 mg daily, titrate for HR < 90 if BP allows). Monitor closely with regular symptom evaluation and free T4 testing every 2 weeks.

○ Introduce thyroid hormones (see hypothyroidism management) if the patient becomes hypothyroid (low free T4/T3, even if TSH is not elevated).

Graves’ disease should be treated per standard guidelines.

2 Symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL; hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated

Hepatitis

Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade http://theoncologist.alphamedpress.org/content/early/2018/06/29/theoncologist.2018-0174.full.pdf+html

  • Diagnostic testing such as viral serologies, liver ultrasound, cross sectional imaging, and liver biopsy may help in the diagnosis of immune related hepatitis in select patients.
  • Patients with underlying cirrhosis are an at risk population for whom current grading criteria may underestimate the severity of liver inflammation.
  • Severe immune related hepatitis is best managed by a multi-disciplinary team that includes a hepatologist.
  • Most patients with immune related hepatitis respond to corticosteroids, but a substantial fraction require treatment with a secondary immunosuppressive agent.
    • "For hospitalized patients, patients with grade 4 disease, or patients who incompletely respond to prednisone, we consider IV Methylprednisolone (Solumedrol) 0.5 to 1 mg/kg b.i.d. For patients who incompletely respond to corticosteroids, or who flare during a steroid taper, several other agents have been reported to have efficacy in the second line. These include Azathioprine (Imuran) (1–2 mg/kg), Mycophenolate mofetil (CellCept) (500–1,000 mg b.i.d.), or Tacrolimus (Prograf) (dosed based on blood trough levels targeting 8–10). Importantly, before using azathioprine, the FDA recommends testing for Thiopurine S-methyltransferase (TPMT) genotype or enzyme function, as patients with decreased TPMT activity are at high risk for developing lifethreatening bone marrow suppression"

Neurologic

Myocarditis

Immune Checkpoint Inhibitor-Associated Myocarditis http://theoncologist.alphamedpress.org/content/early/2018/05/25/theoncologist.2018-0130.full.pdf

  • The incidence of immune checkpoint inhibitor (ICI)-associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients
  • The prevalence of myocarditis has been reported to be higher with combination immune therapies.
  • Myocarditis with ICI’s typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.Myocarditis is often difficult to diagnose.
  • The risk factors for ICI-associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus.
  • The optimal management of myocarditis associated with ICI’s is unclear but most cases are treated with high-dose steroids

Special Populations

Patients with underlying Auto-immune disease:

  • Retrospective studies have examined the safety of immunotherapy (single agent CTLA-4 and PD-1 inhibition) in patients with metastatic melanoma and non-small cell lung cancer, respectively (1-3).
  • Results across these studies were similar, approximately a quarter of patients experienced a new irAE and a quarter experienced an exacerbation of a pre-existing AID, the majority of which were mild (grade 1,2).
  • Flares occurred more often in those with active AID symptoms than those with clinically inactive disease and patients with pre-existing rheumatologic AIDs had the highest propensity to flare.
  • Most cases were effectively managed with corticosteroid administration and patients could often be continued on ICI. Across studies, there was only one grade 5 event which occurred in a patient with baseline psoriasis treated with ipilimumab who died of presumed immune-related colitis.
  • The overall response rates seen in these trials was comparable to the historical standards in patient without an AID.

1. Johnson DB, Sullivan RJ, Ott PA, et al: Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2016, 2:234-240.https://jamanetwork.com/journals/jamaoncology/fullarticle/2473508

2. Menzies AM, Johnson DB, Ramanujam S, et al: Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017, 28:368-376.https://academic.oup.com/annonc/article/28/2/368/2669811

3. Leonardi GC, Gainor JF, Altan M et al. Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non–Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. Journal of Clinical Oncology 2018, 36:19, 1905-1912 https://clf1.medpagetoday.com/content/pdf/reading-room/asco/JCO.IT.Leonardi052818.pdf

HIV positive population

  • This patient population is routinely excluded from clinical trial enrollment of immune checkpoint inhibition
  • Retrospective reviews have documented the safety/efficacy of the use of immune checkpoint inhibitors in small cohort

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non–Small Cell Lung Cancer https://www.jto.org/article/S1556-0864(18)30270-3/fulltext

  • "Report of seven cases of patients with HIV and advanced NSCLC who were treated with anti–PD-1 therapy. Three partial responses were observed and treatment with immunotherapy was well-tolerated among these seven patients with only grade 1-2 adverse events occurring. When data were available, the HIV VL did not markedly change, and the CD4 count remained under control while on treatment. No IRIS, opportunistic infections, or other AIDS-defining illnesses were identified while on treatment"

Patients with interstitial lung disease

  • This patient population is routinely excluded from clinical trial enrollment of immune checkpoint inhibition
  • Data is limited to case reports:

Efficacy and safety of nivolumab in non‐small cell lung cancer with preexisting interstitial lung disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026605/

  • Retrospectively review of the medical records of 216 NSCLC patients who had received nivolumab therapy. The existence of ILD in these patients was determined by lung computed tomography findings; 26 patients had ILD. The efficacy of nivolumab was measured: overall response rate (ORR), progression‐free survival (PFS) duration; lung toxicity was captured by evaluating the incidence, severity, and outcome of nivolumab‐related ILD.
    • ORR and median PFS of the ILD and non‐ILD groups were 27% versus 13% (P = 0.078) and 2.7 (95% confidence interval [CI], 1.7–5.3) versus 2.9 months (95% CI 2.1–3.4; P = 0.919), respectively.
    • Incidences of total and severe nivolumab‐related pneumonitis were significantly higher in the ILD group than in the non‐ILD group (31% vs. 12%, P = 0.014 and 19% vs. 5%, P = 0.022, respectively). No death from nivolumab‐related pneumonitis occurred

References

  1. Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC) - Adverse event grading for clinical trials
  2. CTCAE 5x7" small booklet format local backup
  3. CTCAE 8.5x11" letter size format local backup
  4. ESMO: Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines (2017)
  5. SITC: Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group
  6. 6.0 6.1 ASCO: Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline
  7. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015 Dec;26(12):2375-91. link to original article correction of Figure 2 PubMed