Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

haematopoietic cell transplantation (HCT) recipient

1st line – GVHD standard prophylaxis

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INITIAL
|
haematopoietic cell transplantation (HCT) recipient
1st line – 

GVHD standard prophylaxis

The standard regimens for GVHD prophylaxis in patients undergoing matched related or unrelated donor HCT comprise a calcineurin inhibitor (e.g., ciclosporin or tacrolimus) plus low-dose methotrexate or mycophenolate.​[63][102][103]

The results of one meta-analysis found no difference in all-cause mortality between tacrolimus plus methotrexate and ciclosporin plus methotrexate.[103] However, the former regimen was superior with respect to reducing acute GVHD.[103]

One Cochrane review found mycophenolate and methotrexate to be similarly efficacious for acute GVHD prevention.[102] However, mycophenolate may have a more favourable toxicity profile than methotrexate.[102]

An alternative regimen for GVHD prophylaxis is tacrolimus plus sirolimus.[75][76][77][78]​ A phase 3 trial (Bone Marrow Transplant Clinical Trials Network [BMT CTN] 0402) found no significant difference in incidence of acute GVHD (by day 114) between tacrolimus plus sirolimus and tacrolimus plus methotrexate in patients who had undergone allogeneic HCT from a matched related donor.[78]

Primary options

methotrexate: children and adults: consult specialist for guidance on dose

or

mycophenolate mofetil: children and adults: consult specialist for guidance on dose

-- AND --

ciclosporin: consult specialist for guidance on dose

or

tacrolimus: children and adults: consult specialist for guidance on dose

Secondary options

sirolimus: children and adults: consult specialist for guidance on dose

and

tacrolimus: children and adults: consult specialist for guidance on dose

Consider – abatacept or cyclophosphamide or rabbit antithymocyte immunoglobulin or sirolimus

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INITIAL
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haematopoietic cell transplantation (HCT) recipient
Consider – 

abatacept or cyclophosphamide or rabbit antithymocyte immunoglobulin or sirolimus

Additional treatment recommended for SOME patients in selected patient group

Evidence continues to influence the management of GVHD prophylaxis, and alternative prophylactic treatment strategies may be considered for specific patient populations.

Abatacept (a selective T-cell costimulation modulator) is approved by the US Food and Drug Administration (FDA), in combination with a calcineurin inhibitor and methotrexate, for the prevention of acute GVHD in patients undergoing allogeneic HCT from a matched or 1 allele-mismatched unrelated donor. In one phase 2 randomised trial, the addition of abatacept to standard prophylaxis with a calcineurin inhibitor and methotrexate numerically reduced rates of severe (grade III or IV) acute GVHD, and significantly improved severe acute GVHD-free survival, in patients with haematological malignancies who had undergone HCT from an HLA-matched (8/8) unrelated donor.[66]​ Screen for latent tuberculosis infection and hepatitis prior to starting abatacept. Patients who test positive for tuberculosis should be treated prior to starting treatment. Serious infections have been reported. Patients with a history of recurrent infections or underlying conditions predisposing to infections may be at higher risk. Discontinue abatacept if a serious infection develops. Update vaccinations prior to starting treatment (live vaccines are contraindicated). Consider starting prophylaxis therapy for Epstein-Barr virus and cytomegalovirus infection/reactivation before transplant.

Post-transplant cyclophosphamide, combined with tacrolimus plus mycophenolate, is increasingly favoured for primary GVHD prevention based on results from large-scale, multi-site clinical trials.[63][67][68] In one phase 3 trial of patients undergoing allogeneic HLA-matched HCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common in patients randomised to cyclophosphamide-based prophylaxis (cyclophosphamide, tacrolimus, and mycophenolate) than those assigned to standard prophylaxis (52.7% vs. 34.9%).[67] Post-transplant cyclophosphamide-based prophylaxis is commonly used in patients who have undergone allogeneic HCT from an HLA-haploidentical (i.e., half-matched) donor or unrelated donor.[69][70]

Rabbit antithymocyte immunoglobulin (a polyclonal immunoglobulin G) reduces the cumulative incidence of both acute and chronic GVHD in patients undergoing HCT from unrelated donors. In one randomised phase 3 trial, the addition of rabbit antithymocyte immunoglobulin to standard prophylaxis (ciclosporin or tacrolimus plus methotrexate or mycophenolate) reduced acute GVHD incidence at 30 and 100 days compared with standard prophylaxis (30 days: 22% vs. 37%; 100 days: 50% vs. 65%).[71] At 24 months, this regimen reduced incidence of chronic GVHD (26.3% vs. 41.3%), and led to improved survival (70.6% vs. 53.3%) and reduced use of immunosuppressive therapy.[72] Rabbit antithymocyte immunoglobulin effectively reduces GVHD incidence after HLA-matched sibling donor HCT.[73]

Sirolimus combined with standard prophylaxis (ciclosporin plus mycophenolate) has been reported to lower the incidence of grade II to IV acute GVHD (at day 100) compared with ciclosporin plus mycophenolate alone in patients who have undergone allogeneic HCT from an HLA-matched unrelated donor with non-myeloablative conditioning.[74]

Primary options

abatacept: children 2 to <6 years of age: 15 mg/kg intravenous infusion on the day before transplant, followed by 12 mg/kg on days 5, 14, and 28 after transplant; children ≥6 years of age and adults: 10 mg/kg intravenous infusion on the day before transplant, followed by 10 mg/kg on days 5, 14, and 28 after transplant, maximum 1000 mg/dose

Secondary options

cyclophosphamide: consult specialist for guidance on dose

OR

antithymocyte immunoglobulin (rabbit): consult specialist for guidance on dose

OR

sirolimus: consult specialist for guidance on dose

ACUTE

acute: grade I

1st line – topical corticosteroid

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ACUTE
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acute: grade I
1st line – 

topical corticosteroid

Topical corticosteroids are the standard of care treatment for stage 1 or 2 (overall grade I) skin only GVHD with <50% body surface area rash involvement.

Hydrocortisone should be used on the face, whereas triamcinolone is reserved for use on the body.

If the patient is asymptomatic or if the rash is stable, a period of observation without any interventional treatment may be appropriate.[92]

Primary options

triamcinolone topical: (0.1%) children and adults: apply to the affected area(s) on body twice or three times daily when required

OR

hydrocortisone topical: (0.5%) children and adults: apply to the affected area(s) on face twice or three times daily when required

Plus – calcineurin inhibitor

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ACUTE
|
acute: grade I
Plus – 

calcineurin inhibitor

Treatment recommended for ALL patients in selected patient group

Patients continue on calcineurin therapy during the treatment of acute GVHD, usually at the same dose as the prophylactic regimen.[92]

If a patient has already been tapered off their prophylactic calcineurin inhibitor or it has been discontinued due to toxicities, then it is generally reintroduced (depending on physician discretion and the degree of toxicity).

Doses should be tapered according to response and serum drug levels. These drugs are usually given for a period of several weeks, depending on the institutional protocol and patient response.

Primary options

tacrolimus: children and adults: consult specialist for guidance on dose

OR

ciclosporin: children and adults: consult specialist for guidance on dose

acute: grade II-IV

1st line – systemic corticosteroid

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ACUTE
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acute: grade II-IV
1st line – 

systemic corticosteroid

Systemic corticosteroids are initiated for severe and/or symptomatic skin GVHD and/or any visceral GVHD involvement (grade II-IV).[63][92][105]​​​​​​​[106]​ Methylprednisolone is the standard initial treatment.

Depending on the clinical status of the patient, methylprednisolone may be administered intravenously or orally. If a patient is started on the intravenous route, they will generally be transitioned to oral therapy as soon as possible.

There are no standard corticosteroid tapering schedules. Generally, taper schedules are influenced by the patient's clinical response as well as circumstances (e.g., risk for relapse, presence or absence of infection, or other corticosteroid-related complications). A commonly reported taper schedule is over 8-12 weeks.

Primary options

methylprednisolone: children and adults: 0.5 to 2 mg/kg/day intravenously

More

Plus – calcineurin inhibitor

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ACUTE
|
acute: grade II-IV
Plus – 

calcineurin inhibitor

Treatment recommended for ALL patients in selected patient group

Patients continue on calcineurin therapy during the treatment of acute GVHD; this should be at the therapeutic dose rather than the prophylactic dose.[92]

If a patient has already been tapered off their prophylactic calcineurin inhibitor or it has been discontinued due to toxicities, then it is generally reintroduced (depending on discretion of physician and the degree of toxicity).

Doses should be tapered according to clinical response and serum drug levels. These drugs are usually given for a period of several weeks, depending on the institutional protocol and patient response.

Primary options

tacrolimus: children and adults: consult specialist for guidance on dose

OR

ciclosporin: children and adults: consult specialist for guidance on dose

Consider – topical or oral-topical corticosteroid

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ACUTE
|
acute: grade II-IV
Consider – 

topical or oral-topical corticosteroid

Additional treatment recommended for SOME patients in selected patient group

Adjuvant topical corticosteroids are used if there is any skin involvement present. Hydrocortisone should be used on the face, whereas triamcinolone is reserved for use on the body.

Topically active corticosteroids taken orally (oral-topical corticosteroids) may be used for confirmed cases of acute gastrointestinal GVHD.[108][109] ​The systemic corticosteroid can be tapered in patients who show a clinical response.

Oral-topical corticosteroid formulations have high first-pass metabolism, facilitating local effects while reducing systemic absorption. However, some systemic effects do still occur.

Primary options

triamcinolone topical: (0.1%) children and adults: apply to the affected area(s) on body twice or three times daily when required

OR

hydrocortisone topical: (0.5%) children and adults: apply to the affected area(s) on face twice or three times daily when required

OR

budesonide: children: consult specialist for guidance on dose; adults: 9 mg orally once daily

OR

beclometasone dipropionate: adults: 5 mg orally once daily in the morning

Consider – alternative or additional immunosuppressive agent ± trial entry

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ACUTE
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acute: grade II-IV
|
lack of response or disease progression or corticosteroid toxicity
Consider – 

alternative or additional immunosuppressive agent ± trial entry

Additional treatment recommended for SOME patients in selected patient group

If there is disease progression or lack of response following 3-7 days treatment, additional immunosuppressive therapy is required.[92] Further immunosuppression will, however, increase the risk of life-threatening infections (due to immunosuppression and lymphopenia) and/or multi-organ dysfunction.

There is no standard approach for the treatment of corticosteroid-refractory acute GVHD.[106]​ A variety of agents have been used, and varying response rates have been reported.[110] Entry into a clinical trial may be appropriate.[92]

Alternative immunosuppressive agents should also be considered if a patient develops an unacceptable level of toxicity (i.e., corticosteroid intolerance).[92][106]

Agents that may be considered for additional immunosuppressive therapy include: ruxolitinib, antithymocyte immunoglobulin (ATG), sirolimus, etanercept, alemtuzumab, and pentostatin.[111]​​[114][115][116][117][118][119]​​​​​​​​[120][121]​​​​​​​​[122][123]​​​​​​[124]​​[146]

Extracorporeal photopheresis is being increasingly used as an adjunct treatment to minimise corticosteroid exposure and allow for more rapid corticosteroid tapers.[125]​ It involves peripheral blood mononuclear cells being exposed to photoactivated methoxsalen and ultraviolet-A radiation. ​

Primary options

ruxolitinib: children ≥12 years and adults: 5 mg orally twice daily initially, may increase to 10 mg twice daily after 3 days depending on blood counts

More

OR

antithymocyte immunoglobulin (rabbit): children and adults: consult specialist for guidance on dose

OR

lymphocyte immunoglobulin, anti-thymocyte globulin (equine): children and adults: consult specialist for guidance on dose

OR

sirolimus: children and adults: consult specialist for guidance on dose

OR

etanercept: children and adults: consult specialist for guidance on dose

OR

pentostatin: children and adults: consult specialist for guidance on dose

OR

alemtuzumab: children and adults: consult specialist for guidance on dose

ONGOING

chronic

1st line – systemic corticosteroid

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ONGOING
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chronic
1st line – 

systemic corticosteroid

The recommended first-line therapy for patients with chronic GVHD is a systemic corticosteroid.[92]

National Institutes of Health (NIH) guidelines recommend systemic corticosteroid therapy if three or more organs are involved, or a single organ with a severity score of more than 2.[1] However, close serial monitoring of all organ systems is recommended to promote early detection and intervention directed toward reversing or preventing progression of chronic GVHD manifestations and treatment-associated toxicities.

Ancillary and supportive care therapies are employed in addition to systemic GVHD treatment, and in some cases, their use may circumvent the need for systemic treatment or allow doses of systemic agents to be decreased.

Primary options

methylprednisolone: children and adults: consult specialist for guidance on dose; initial dose may vary depending on organs involved and disease severity

Plus – antibacterial prophylaxis

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ONGOING
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chronic
Plus – 

antibacterial prophylaxis

Treatment recommended for ALL patients in selected patient group

Requires coverage against encapsulated bacteria, in particular Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides.

Phenoxymethylpenicillin is the prophylactic agent of choice when the frequency of penicillin-resistant S pneumoniae is low. Alternatives include azithromycin (particularly for lung involvement) or other macrolides, and newer-generation fluoroquinolones, although drug interactions can cause problems.[92]​ Daily use of trimethoprim/sulfamethoxazole has also been used for this indication, but its efficacy has not been demonstrated.

Antibiotic prophylaxis before dental and other invasive procedures in these patients has not been studied and consensus has not been reached.

Primary options

phenoxymethylpenicillin: children <5 years of age: 125 mg orally twice daily; children ≥5 years of age: 250 mg orally twice daily; adults: 250-750 mg orally twice daily

OR

azithromycin: adults: 250 mg orally once daily or three times weekly

OR

trimethoprim/sulfamethoxazole: children >2 months of age: 2 mg/kg orally once daily; adults: 160/800 mg orally once daily

More

Plus – Pneumocystis prophylaxis

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ONGOING
|
chronic
Plus – 

Pneumocystis prophylaxis

Treatment recommended for ALL patients in selected patient group

Pneumocystis pneumonia <6 months after allogeneic haematopoietic cell transplantation (HCT) is strongly associated with chronic GVHD. All patients who receive immunosuppression after allogeneic HCT should receive Pneumocystis prophylaxis.

It is unknown how long prophylaxis should be continued after stopping immunosuppression and practices vary widely across centres.

Agents used include trimethoprim/sulfamethoxazole, pentamidine, dapsone, and atovaquone. Trimethoprim/sulfamethoxazole also provides prophylaxis against toxoplasmosis and nocardia.

Primary options

trimethoprim/sulfamethoxazole: children >2 months of age: 150 mg/square metre of body surface area orally three times weekly, daily dose given in divided doses every 12 hours; adults: 160/800 mg orally once daily or three times weekly

OR

dapsone: children >1 month of age: 2 mg/kg/day orally, maximum 100 mg/day; adults: 100 mg orally once daily

OR

pentamidine inhaled: children >4 years of age and adults: 300 mg inhaled every 4 weeks

OR

atovaquone: children >13 years of age and adults: 1500 mg orally once daily

Plus – vaccinations

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ONGOING
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chronic
Plus – 

vaccinations

Treatment recommended for ALL patients in selected patient group

Most experts advocate the use of Haemophilus influenzae type b vaccine and influenza vaccine (not live-attenuated).

No live virus, including the live-attenuated influenza vaccine and MMR, should be given.

Household contacts should not be given oral polio vaccine.

Other vaccines that may be considered include diphtheria tetanus toxoid, pneumococcus, and hepatitis B, hepatitis A, meningococcal and human papillomavirus (HPV).

Plus – nutritional support

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ONGOING
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chronic
Plus – 

nutritional support

Treatment recommended for ALL patients in selected patient group

In patients with extensive chronic GVHD, weight loss may result from increased action of glucagon and noradrenaline (norepinephrine), which causes an increase in resting energy expenditure and alteration in fat and carbohydrate oxidation rates.

More than 40% of patients with GVHD are malnourished, so nutritional advice and support is extremely important.

Consider – alternative or additional immunosuppressive agent

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ONGOING
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chronic
Consider – 

alternative or additional immunosuppressive agent

Additional treatment recommended for SOME patients in selected patient group

Alternative immunosuppressive agents should be considered if a patient develops an unacceptable level of toxicity (i.e., corticosteroid intolerance).[92] If there is an inadequate response to initial therapy with a systemic corticosteroid, additional immunosuppression may be required.[92]

Therapeutic choice is informed by agents used for prophylaxis and/or treatment of acute GVHD, specific patient characteristics, and preference of the treating physician and centre.

The NIH working group define failure of initial immunosuppressive therapy or requirement of secondary therapy as follows: progression of chronic GVHD despite optimal first-line therapy; or no improvement after 4-8 weeks of sustained therapy; or inability to taper corticosteroid dosage.[1][129]

Immunosuppressive therapies used in chronic GVHD vary by institutional practice and may include ruxolitinib, ibrutinib, belumosudil, axatilimab, a calcineurin inhibitor (ciclosporin or tacrolimus), rituximab, sirolimus, and pentostatin.[130][131][132][135][136]​​[137][138][139][140]​​​​​​​​​​

Ibrutinib is associated with an increased risk for serious cardiac events including arrhythmias and heart failure. Recommended risk minimisation measures include performing a clinical evaluation of cardiac history and function prior to starting treatment, careful monitoring for signs of cardiac deterioration during treatment, and treatment interruption and/or dose modification if any new-onset or worsening cardiac events are observed.[133][134]

Extracorporeal photopheresis is being increasingly used as an adjunct treatment to minimise corticosteroid exposure and allow for more rapid corticosteroid tapers.[125] It involves peripheral blood mononuclear cells being exposed to photoactivated methoxsalen and ultraviolet-A radiation.

Primary options

ruxolitinib: children ≥12 years of age and adults: 10 mg orally twice daily

More

OR

ibrutinib: children <12 years of age: 240 mg/square metre of body surface orally once daily, maximum 420 mg/dose; children ≥12 years of age and adults: 420 mg orally once daily

OR

belumosudil: children ≥12 years of age and adults: 200 mg orally once daily

OR

axatilimab: children and adults ≥40 kg body weight: 0.3 mg/kg intravenously every 2 weeks, maximum 35 mg/dose

OR

tacrolimus: children and adults: consult specialist for guidance on dose

OR

ciclosporin: children and adults: consult specialist for guidance on dose

OR

rituximab: children and adults: consult specialist for guidance on dose

OR

sirolimus: children and adults: consult specialist for guidance on dose

OR

pentostatin: children and adults: consult specialist for guidance on dose

Consider – antiviral prophylaxis

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ONGOING
|
chronic
Consider – 

antiviral prophylaxis

Additional treatment recommended for SOME patients in selected patient group

Approximately, 30% to 60% of patients develop an episode of zoster during the first year after discontinuing post-transplant prophylaxis. Some experts use long-term antiviral prophylaxis to prevent recurrent herpes simplex virus (HSV) and varicella zoster virus (VZV) infection among allogeneic haematopoietic cell transplantation (HCT) recipients with severe, long-term immunodeficiency, but current evidence does not support routine administration of antiviral prophylaxis for HSV in patients with chronic GVHD. If VZV-seronegative patients with chronic GVHD are exposed to varicella (primary or post-vaccination illness), VZV immunoglobulin should be given within 96 hours.

Cytomegalovirus (CMV) disease after day 100 has become more common. The best strategy to monitor and treat CMV after day 100 has not been defined. Patients with active GVHD, a history of CMV reactivation during the first 3 months, and lymphopenia are at higher risk of CMV reactivation and death. Some centres continue to monitor for CMV infection after day 100 by pp65 anti-genaemia or PCR tests, followed by pre-emptive therapy, based on the individual risk as determined by donor and recipient serology, as follows:

1) CMV seronegative (donor and recipient): No prophylaxis, no anti-genaemia (or PCR) checks.

2) CMV seropositive (donor or recipient): No history of CMV infection: CMV surveillance testing (anti-genaemia or PCR) every 1 to 4 weeks.

3) History of CMV infection or disease: Weekly CMV surveillance testing (anti-genaemia or PCR) and pre-emptive treatment as during the first 100 days.

Some investigators have advocated early empirical treatment of influenza with neuraminidase inhibitors during influenza outbreaks by using prediction rules based on symptoms and signs, although there is no evidence to support this practice.

A randomised trial of pre-emptive therapy for the prevention of CMV disease after allogeneic HCT suggests that low-dose ganciclovir can be as effective as standard-dose ganciclovir in these patients.[147] However, further studies are needed to validate these findings.

Primary options

aciclovir: children and adults: consult specialist for guidance on dose

OR

valaciclovir: children and adults: consult specialist for guidance on dose

Secondary options

ganciclovir: children: consult specialist for guidance on dose; adults: 5 mg/kg intravenously twice daily or 1000 mg orally three times daily

OR

foscarnet: children and adults: 90 mg/kg intravenously once daily

Consider – antifungal therapy

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ONGOING
|
chronic
Consider – 

antifungal therapy

Additional treatment recommended for SOME patients in selected patient group

Invasive mould infections are a significant concern in patients who receive immunosuppressives for GVHD.[148][149]

There is no evidence to support the use of antifungal prophylaxis >75 days after allogeneic haematopoietic cell transplantation (HCT).

Some centres prescribe prophylactic antifungals for patients with chronic GVHD, but this approach remains investigational.

Primary options

fluconazole: children: 3-12 mg/kg orally/intravenously once daily; adults: 100 mg orally/intravenously once daily

OR

voriconazole: children and adults: consult specialist for guidance on dose

OR

micafungin: children: consult specialist for guidance on dose; adults: 50 mg intravenously once daily

Consider – intravenous immunoglobulin

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ONGOING
|
chronic
Consider – 

intravenous immunoglobulin

Additional treatment recommended for SOME patients in selected patient group

Universal administration of intravenous immunoglobulin (IVIG) after allogeneic haematopoietic cell transplantation (HCT) has not been shown to confer clinical benefit and should be avoided.

In patients with hypogammaglobulinaemia caused by other disorders, administration of IVIG to maintain IgG levels >400 mg/dL has been associated with a decreased incidence of severe bacterial infections.

IVIG may be considered for patients >90 days after HCT who have recurrent sinopulmonary infections and serum IgG levels <400 mg/dL.

Some experts recommend monitoring IgG levels and administering IVIG routinely in chronic GVHD, but there are no data demonstrating that this approach improves outcomes.

Treatment course depends on serum IgG levels.

Primary options

normal immunoglobulin human: children and adults: consult specialist for guidance on dose

Consider – trial entry

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ONGOING
|
chronic
Consider – 

trial entry

Additional treatment recommended for SOME patients in selected patient group

Patients should be considered for enrollment in a clinical trial where available.[92]

Consider – emollient

Back
ONGOING
|
chronic
|
intact skin involvement
Consider – 

emollient

Additional treatment recommended for SOME patients in selected patient group

Regular lubrication of dry but intact skin with emollients may decrease pruritus and maintain skin.

Consider – topical corticosteroid

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ONGOING
|
chronic
|
intact skin involvement
Consider – 

topical corticosteroid

Additional treatment recommended for SOME patients in selected patient group

For lesions from the neck down, treatment should begin with low- or mid-strength formulation (e.g., desonide, hydrocortisone, triamcinolone). In unresponsive cases, short-term occlusion of mid-strength corticosteroids with damp towels (wet wraps) increases skin hydration and drug penetration. When this is impractical, higher potency corticosteroids such as fluocinonide may be helpful. The most potent topical corticosteroids (e.g., clobetasol) should not be used under occlusion. The use of wet wraps and mid-strength potency corticosteroids should be limited to 14 consecutive days, if possible.

On the face, axillae and groin, lower-potency corticosteroids (hydrocortisone and desonide) are preferable for long-term use. Emollients may be applied after application, and being occlusive may increase the potency of the corticosteroid.

Primary options

desonide topical: (0.05%) children and adults: apply to the affected area(s) twice daily when required

OR

hydrocortisone topical: (0.5%) children and adults: apply to the affected area(s) twice daily when required

OR

triamcinolone topical: (0.1%) children and adults: apply to the affected area(s) twice daily when required

Secondary options

fluocinonide topical: (0.05%) children and adults: apply to the affected area(s) twice daily when required

Tertiary options

clobetasol topical: (0.05%) children and adults: apply to the affected area(s) twice daily when required, maximum 14 days use

Consider – antipruritic

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ONGOING
|
chronic
|
intact skin involvement
Consider – 

antipruritic

Additional treatment recommended for SOME patients in selected patient group

Pruritus related to GVHD generally responds to immunosuppressive therapy; however, other adjuvant treatments may be useful.

Primary options

hydrocortisone/pramocaine topical: children and adults: apply to the affected area(s) three to four times daily when required

Secondary options

diphenhydramine: children 2-5 years of age: 6.25 mg orally every 4-6 hours when required, maximum 37.5 mg/day; children 6-11 years of age: 12.5 to 25 mg orally every 4-6 hours when required, maximum 150 mg/day; children >11 years of age and adults: 25-50 mg orally every 4-6 hours when required, maximum 300 mg/day

OR

hydroxyzine: children ≤40 kg: 2 mg/kg/day orally given in divided doses every 6-8 hours when required; children >40 kg and adults: 25 mg orally every 6-8 hours when required, maximum 100 mg/day

OR

doxepin: children: consult specialist for guidance on dose; adults: 10-25 mg orally once daily at bedtime when required

Consider – topical calcineurin inhibitor

Back
ONGOING
|
chronic
|
intact skin involvement
Consider – 

topical calcineurin inhibitor

Additional treatment recommended for SOME patients in selected patient group

Reported to improve erythema and pruritus in some patients.

Primary options

tacrolimus topical: (0.03%) children >2 years of age and adults: apply to the affected area(s) twice daily; (0.1%) adults: apply to the affected area(s) twice daily

OR

pimecrolimus topical: (1%) children >2 years of age and adults: apply to the affected area(s) twice daily

Consider – PUVA

Back
ONGOING
|
chronic
|
intact skin involvement
Consider – 

PUVA

Additional treatment recommended for SOME patients in selected patient group

Can be effective, especially if sclerosis is not present. Phototherapy may be administered 2 to 3 times per week. A history of skin cancer, aphakia, or photosensitivity would normally contraindicate this therapy due to the increased risk of skin cancer.

Consider – topical bleaching agent

Back
ONGOING
|
chronic
|
intact skin involvement
Consider – 

topical bleaching agent

Additional treatment recommended for SOME patients in selected patient group

May be used to treat post-inflammatory hyperpigmentation in the setting of inactive disease.

Primary options

hydroquinone topical: (4%) children >12 years of age and adults: apply to the affected area(s) twice daily

OR

tretinoin topical: (0.025 to 0.05%) children >12 years of age and adults: apply to the affected area(s) once daily at bedtime

Consider – specialist wound dressings

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ONGOING
|
chronic
|
non-intact skin involvement
Consider – 

specialist wound dressings

Additional treatment recommended for SOME patients in selected patient group

On denuded skin, specialist dressings and protective films can be used to maintain a moist environment that enhances repair of the epithelium, lysis of necrotic tissue, and phagocytosis of necrotic debris.

Consider – topical antimicrobial

Back
ONGOING
|
chronic
|
non-intact skin involvement
Consider – 

topical antimicrobial

Additional treatment recommended for SOME patients in selected patient group

If indicated, topical antimicrobials such as mupirocin may be useful.

Primary options

mupirocin topical: (2%) apply to the affected area(s) three times daily

Consider – specialist skin therapies

Back
ONGOING
|
chronic
|
non-intact skin involvement
Consider – 

specialist skin therapies

Additional treatment recommended for SOME patients in selected patient group

Difficult wounds are best treated in consultation with a plastic surgeon.

Slow-healing wounds may be treated with hyaluronic acid products, collagen products, or fibroblast and keratinocyte products.

Non-healing wounds that involve the dermis may benefit from platelet-derived growth factor products.

Consider – hyperbaric oxygen therapy

Back
ONGOING
|
chronic
|
non-intact skin involvement
Consider – 

hyperbaric oxygen therapy

Additional treatment recommended for SOME patients in selected patient group

This specialist treatment has been used to treat hypoxic wounds, but may not be widely available.

Consider – topical corticosteroid or tacrolimus

Back
ONGOING
|
chronic
|
mucosal involvement of mouth or oral cavity
Consider – 

topical corticosteroid or tacrolimus

Additional treatment recommended for SOME patients in selected patient group

There are three possible components to this type of disease: mucosal involvement, salivary gland involvement, and sclerotic involvement of mouth and surrounding tissues. Before initiating treatment, infection with HSV, HPV, Candida need to be ruled out. This may require use of viral and bacterial cultures, and/or biopsies.

Persistent or new oral lesions occurring >3 years after allogeneic haematopoietic cell transplantation (HCT) need assessment for secondary cancer (especially squamous cell cancer).

Mainstay of therapy of localised and symptomatic disease is high-potency topical corticosteroid gel used orally. Tacrolimus ointment is an alternative.

Vaseline-based ointments such as topical tacrolimus are generally less effective in the mouth than are alcohol-based corticosteroid gels but are preferable for the treatment of chapped lips caused by GVHD, because high-potency corticosteroids cause irreversible atrophy when applied to the vermillion border of the lips.

Prolonged use of high-potency corticosteroids should be avoided in the very young child because of the potential for greater systemic effects.

Affected area(s) must be dried before treatment is applied, and no food or drink should be consumed for 30 minutes after application.

Primary options

triamcinolone acetonide topical: (0.1% oral paste) apply to the affected area(s) two to three times daily

OR

fluocinonide topical: (0.05% gel) children and adults: apply to the affected area(s) two to three times daily

OR

clobetasol topical: (0.05% gel) children and adults: apply to the affected area(s) two to three times daily

OR

betamethasone dipropionate topical: (0.05% gel) children and adults: apply to the affected area(s) two to three times daily

OR

tacrolimus topical: (0.03%) children >2 years of age and adults: apply to the affected area(s) twice daily; (0.1%) adults: apply to the affected area(s) twice daily

Consider – mouth rinse

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chronic
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mucosal involvement of mouth or oral cavity
Consider – 

mouth rinse

Additional treatment recommended for SOME patients in selected patient group

Mouth rinses may be used when there is more extensive involvement of the entire oral cavity.

Corticosteroid rinses are a good first-line option. Oral manifestations in children generally respond well to dexamethasone rinses. Prolonged use of high-potency corticosteroids should be avoided in the very young child because of the potential for greater systemic effects.

Ciclosporin or azathioprine rinses may be useful in cases refractory to corticosteroids rinses.

These solutions are held and swished in the mouth for 4 to 6 minutes and then spat out. This is repeated 4 to 6 times daily. Food or drink should not be consumed for 30 minutes after.

Mouth washes may need to be compounded by the pharmacy department if the drug is not available in a proprietary liquid formulation.

Consider – topical analgesia

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ONGOING
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chronic
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mucosal involvement of mouth or oral cavity
Consider – 

topical analgesia

Additional treatment recommended for SOME patients in selected patient group

May be helpful when symptomatic mucosal GVHD impairs nutrition.

A mixture of lidocaine with either kaolin/pectin or aluminium hydroxide/magnesium hydroxide/simethicone and diphenhydramine may be used as a mouthwash.

Primary options

lidocaine topical: (2% viscous solution) 15 mL every 3 hours when required (swish around in mouth and spit out), maximum 8 doses/day

OR

aluminium hydroxide/magnesium hydroxide/simethicone: 10-20 mL orally four times daily, maximum 500 mg/day of simethicone

Consider – frequent water sipping + saliva substitute

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ONGOING
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chronic
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salivary gland involvement
Consider – 

frequent water sipping + saliva substitute

Additional treatment recommended for SOME patients in selected patient group

This type of involvement usually manifests as dry mouth, mucoceles, and variable oral sensitivity to hot, cold, spicy, and acidic food; mint flavours such as toothpaste; and carbonated drinks.

Frequent sipping of water and use of sugar-free chewing gum may be sufficient.

Oral moisturisers and saliva stimulants made be used if simple measures are inadequate.

Consider – saliva stimulant

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ONGOING
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chronic
|
salivary gland involvement
Consider – 

saliva stimulant

Additional treatment recommended for SOME patients in selected patient group

In the absence of contraindications (e.g., glaucoma, heart disease, or asthma), treatment with cholinergic agonists may produce a significant increase in salivary secretion.

Primary options

cevimeline: children: consult specialist for guidance on dose; adults: 30 mg orally three times daily

OR

pilocarpine: children: consult specialist for guidance on dose; adults: 5-10 mg orally three times daily

Consider – home fluoride therapy

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ONGOING
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chronic
|
salivary gland involvement
Consider – 

home fluoride therapy

Additional treatment recommended for SOME patients in selected patient group

Even if there is not subjective oral dryness, mild salivary gland dysfunction can increase the risk of tooth decay, and topical fluorides should be offered as a decay prevention strategy.

Consider – systemic and intralesional corticosteroid

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ONGOING
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chronic
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sclerotic oral disease
Consider – 

systemic and intralesional corticosteroid

Additional treatment recommended for SOME patients in selected patient group

Topical therapy alone is insufficient to treat sclerosis of the perioral skin and surrounding tissues.

In this situation, systemic treatment is required.

Adjunctive intralesional corticosteroid injections may be helpful, but long-term therapy is often required to maintain the response.

Primary options

methylprednisolone: children and adults: 1-2 mg/kg/day intravenously

and

triamcinolone acetonide: (40 mg/mL) children and adults: 0.3 to 0.4 mL intralesionally per square centimetre of lesion

Consider – stretching exercises

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ONGOING
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chronic
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sclerotic oral disease
Consider – 

stretching exercises

Additional treatment recommended for SOME patients in selected patient group

Stretching exercises to increase range of motion of the mouth may be helpful in order to counteract the sclerotic disease.

Consider – artificial tears or tear stimulant

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chronic
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eye involvement
Consider – 

artificial tears or tear stimulant

Additional treatment recommended for SOME patients in selected patient group

The use of preservative-free artificial tears reduces superficial punctuate keratopathy, decreases ocular symptoms, and improves the quality of vision. Certain brands may be better tolerated than others, so patients should test different brands to identify the one that provides the most benefit. Thicker formulations may be recommended for patients who need frequent use of artificial tears; ointment may be recommended at bedtime.

For patients who require application of artificial tears more than once every hour, pellets of hydroxypropylcellulose may be more convenient.

Orally administered tear stimulants may be useful but drug interactions, toxicities, and contraindications (glaucoma, heart disease, and asthma) must be reviewed.

Primary options

carmellose ophthalmic: 1-2 drops into the affected eye(s) when required

OR

hydroxypropylcellulose ophthalmic: insert 5 mg pellet into affected eye(s) once or twice daily when required

Secondary options

cevimeline: children: consult specialist for guidance on dose; adults: 30 mg orally three times daily

OR

pilocarpine: children: consult specialist for guidance on dose; adults: 5-10 mg orally three times daily

Consider – corticosteroid, ciclosporin, or autologous serum eye drops

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ONGOING
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chronic
|
eye involvement
Consider – 

corticosteroid, ciclosporin, or autologous serum eye drops

Additional treatment recommended for SOME patients in selected patient group

Used to reduce ocular surface inflammation and usually reserved for control of ocular GVHD exacerbations during tapering of systemic immunosuppression. Consult a specialist for guidance on the use of autologous serum eye drops.

Treatment should be carefully supervised by an ophthalmologist.

Primary options

prednisolone ophthalmic: (1%) children and adults: 1 drop in both eyes two to four times daily

OR

fluorometholone ophthalmic: (0.1%) children >2 years of age and adults: 1 drop in both eyes two to four times daily

OR

loteprednol ophthalmic: (0.5%) adults: 1-2 drops in both eyes four times daily

OR

ciclosporin ophthalmic: (0.05%) adults: 1 drop in both eyes twice daily

Consider – evaporation control

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ONGOING
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chronic
|
eye involvement
Consider – 

evaporation control

Additional treatment recommended for SOME patients in selected patient group

To decrease evaporation, patients should be encouraged to use warm compresses and lid care to maximise the output of the meibomian glands that produce the outer oil layer of tear film that protects against evaporation.

Avoidance of low humidity environments and use of moisture chamber goggles may also decrease evaporation.

Scleral contact lenses may be available in some centres and surgery (tarsorrhaphy) may be necessary in severe cases.

Consider – tear duct occlusion

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ONGOING
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chronic
|
eye involvement
Consider – 

tear duct occlusion

Additional treatment recommended for SOME patients in selected patient group

Temporary (silicone plugs) or permanent (thermal cautery) occlusion of the tear-duct punta may provide benefit in patients with severe sicca syndrome.

Consider – scleral contact lens

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ONGOING
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chronic
|
eye involvement
Consider – 

scleral contact lens

Additional treatment recommended for SOME patients in selected patient group

Fluid-ventilated, gas permeable scleral contact lenses can be used to protect the corneal surface, reducing hyperosmolarity, dessication, and shear forces from the eyelids.

Consider – tarsorrhaphy

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ONGOING
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chronic
|
eye involvement
Consider – 

tarsorrhaphy

Additional treatment recommended for SOME patients in selected patient group

In cases that cannot be managed adequately by medical means, tarsorrhaphy may have a useful role.

Consider – hygiene measures

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chronic
|
vulval and vaginal involvement
Consider – 

hygiene measures

Additional treatment recommended for SOME patients in selected patient group

Reported in 3% of bone marrow recipients and 15% of peripheral blood recipients. Oestrogen deficiency and infections (HPV, HSV, yeast, bacteria, or other gynaecological pathogens) must be ruled out at initial diagnosis and periodically during management of this type of GVHD.

Mechanical and chemical irritants should be avoided. Wash with water rather than soap or feminine wash products. Area should be air-dried and advice given on wiping from front to back. Small amounts of emollients or lanolin cream applied to the vulva (not vagina) may provide some relief from itching or irritation. Water-based vaginal lubricants may also be of benefit.

Consider – topical oestrogen with/without dilator

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ONGOING
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chronic
|
vulval and vaginal involvement
Consider – 

topical oestrogen with/without dilator

Additional treatment recommended for SOME patients in selected patient group

If vulvovaginal symptoms are accompanied by low estradiol levels, topical oestrogen therapy with or without the use of a vaginal dilator should be initiated unless there are absolute contraindications such as increased risk of breast cancer or cardiovascular events.

Primary options

oestrogens, conjugated vaginal: (cream) apply 0.5 to 2 g once daily for 3 weeks then stop for 1 week, repeat cycle

OR

estradiol vaginal: (intravaginal ring) 50-100 micrograms/day ring inserted and replaced every 3 months

More

OR

estradiol vaginal: (intravaginal tablet) 25 micrograms inserted once daily for 2 weeks, then twice weekly thereafter

Consider – topical corticosteroid or calcineurin inhibitor

Back
ONGOING
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chronic
|
vulval and vaginal involvement
Consider – 

topical corticosteroid or calcineurin inhibitor

Additional treatment recommended for SOME patients in selected patient group

If the vulvovaginal region is the only clinical manifestation of chronic GVHD, topical immunosuppressive agents may constitute an adequate primary therapy for controlling mild manifestations.

High-potency corticosteroids are the mainstay of such therapy, although topical calcineurin inhibitors have also been used.

Patients should be advised to monitor for signs or symptoms of candidiasis, HSV, or HPV during treatment.

Primary options

clobetasol topical: (0.05%) adults: apply sparingly to the affected area(s) up to twice daily; consult specialist for further guidance on dose

OR

betamethasone dipropionate topical: (0.05%) adults: apply sparingly to the affected area(s) up to twice daily; consult specialist for further guidance on dose

Secondary options

tacrolimus topical: (0.1%) adults: apply sparingly to the affected area(s) up to twice daily; consult specialist for further guidance on dose

Consider – surgical lysis

Back
ONGOING
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chronic
|
vulval and vaginal involvement
Consider – 

surgical lysis

Additional treatment recommended for SOME patients in selected patient group

If there are extensive vaginal synechiae and complete obliteration of the vaginal canal, surgical lysis with or without vaginal reconstruction may be necessary.

Consider – oral lubricant

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ONGOING
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chronic
|
gastrointestinal tract involvement: odynophagia and dysphagia
Consider – 

oral lubricant

Additional treatment recommended for SOME patients in selected patient group

Oral lubricants such as hydroxyethyl cellulose solutions can be considered.

Consider – oesophageal dilation

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chronic
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gastrointestinal tract involvement: odynophagia and dysphagia
Consider – 

oesophageal dilation

Additional treatment recommended for SOME patients in selected patient group

If a patient has oesophageal webs or strictures confirmed by endoscopy, dilation may be of benefit though this should be done by an experienced gastroenterologist due to the risk of perforation.

Consider – pancreatic enzyme supplementation

Back
ONGOING
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chronic
|
gastrointestinal tract involvement: diarrhoea
Consider – 

pancreatic enzyme supplementation

Additional treatment recommended for SOME patients in selected patient group

If a patient has chronic diarrhoea symptoms, in certain cases, pancreatic enzyme supplementation may be beneficial. Its use is primarily physician- and institution-dependent.

Primary options

pancreatin: children and adults: dose depends on brand, consult product literature for guidance on dose

Consider – ursodeoxycholic acid

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ONGOING
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chronic
|
liver involvement
Consider – 

ursodeoxycholic acid

Additional treatment recommended for SOME patients in selected patient group

Use of ursodeoxycholic acid (ursodiol) can help improve biochemical abnormalities and pruritus in some patients with hepatic chronic GVHD.

Primary options

ursodeoxycholic acid: children: 10-15 mg/kg/day orally given in 3 divided doses; adults: 250-300 mg orally three to four times daily

Consider – inhaled bronchodilator

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ONGOING
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chronic
|
lung involvement
Consider – 

inhaled bronchodilator

Additional treatment recommended for SOME patients in selected patient group

Can be used prior to and in conjunction with inhaled corticosteroids in cases of lung involvement.

Primary options

salbutamol inhaled: (100 micrograms/dose metered dose inhaler) children and adults: 1-2 puffs (100-200 micrograms) every 4-6 hours when required

OR

salbutamol inhaled: (0.63 mg/3 mL or 1.25 mg/3 mL nebulisation solution) children 2-12 years of age: 0.63 to 1.25 mg nebulised every 4-6 hours when required; children >12 years of age and adults: 2.5 to 5 mg nebulised every 4-6 hours when required

Consider – inhaled corticosteroid

Back
ONGOING
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chronic
|
lung involvement
Consider – 

inhaled corticosteroid

Additional treatment recommended for SOME patients in selected patient group

Used in addition to systemic corticosteroids in cases where CT scanning reveals lung involvement.[92]​ Usually used after inhaled bronchodilators.

Primary options

beclometasone inhaled: children 5-11 years of age: 40-80 micrograms twice daily; children ≥12 years of age and adults: 40-320 micrograms twice daily

OR

fluticasone propionate inhaled: children 4-11 years of age: 50-100 micrograms twice daily; children ≥12 years of age and adults: 100-500 micrograms twice daily

Consider – montelukast

Back
ONGOING
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chronic
|
lung involvement
Consider – 

montelukast

Additional treatment recommended for SOME patients in selected patient group

The leukotriene receptor antagonist (LTRA) montelukast may be added to antibiotic prophylaxis and inhaled corticosteroids to improve respiratory symptoms.[92]

In 2020, the US Food and Drug Administration mandated a boxed warning for montelukast because of the risk of serious behaviour- and mood-related adverse effects.[150]

Primary options

montelukast: children 12 months to 5 years of age: 4 mg orally once daily; children 6-14 years of age: 5 mg orally once daily; children ≥15 years of age and adults: 10 mg orally once daily

Consider – pulmonary rehabilitation

Back
ONGOING
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chronic
|
lung involvement
Consider – 

pulmonary rehabilitation

Additional treatment recommended for SOME patients in selected patient group

A properly structured and supervised pulmonary rehabilitation programme may be of benefit in some patients.

Consider – supplementary oxygen

Back
ONGOING
|
chronic
|
lung involvement
Consider – 

supplementary oxygen

Additional treatment recommended for SOME patients in selected patient group

If there is a need for supplemental oxygen (i.e., saturation of oxyhaemoglobin <87% while breathing room air) then the amount of supplementary oxygen should be titrated with the use of a 6-minute walk test conducted according to American Thoracic Society guidelines.[151]

Consider – lung transplantation

Back
ONGOING
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chronic
|
lung involvement
Consider – 

lung transplantation

Additional treatment recommended for SOME patients in selected patient group

Should be considered in appropriate candidates if there is progression or worsening of lung involvement following 2-3 lines of therapy.[92]

Consider – intravenous immunoglobulin

Back
ONGOING
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chronic
|
haematopoietic involvement: cytopenias
Consider – 

intravenous immunoglobulin

Additional treatment recommended for SOME patients in selected patient group

Cytopenia may result from stromal damage, graft failure, drug toxicity, infection, relapse of underlying disease, cytomegalovirus infection, haemolysis, anaemia of chronic disease, and autoimmune processes.

Intravenous immunoglobulin may be effective in certain cytopenias that are not improved after corticosteroid treatment.

Primary options

normal immunoglobulin human: children and adults: consult specialist for guidance on dose

Consider – growth factor

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ONGOING
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chronic
|
haematopoietic involvement: cytopenias
Consider – 

growth factor

Additional treatment recommended for SOME patients in selected patient group

Growth factor use has not been formally evaluated in patients with chronic GHVD.

Used as needed if patient's absolute neutrophil count falls below 0.5 x 10⁹/L (500/microlitre).

Primary options

filgrastim: children and adults: consult specialist for guidance on dose

OR

sargramostim: children and adults: consult specialist for guidance on dose

Consider – antidepressant or anticonvulsant

Back
ONGOING
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chronic
|
neurological involvement
Consider – 

antidepressant or anticonvulsant

Additional treatment recommended for SOME patients in selected patient group

Although rare, it can present as polyneuropathy, myositis, and myasthenia.

Interventions for painful peripheral neuropathies may include use of tricyclic antidepressants, selective serotonin-reuptake inhibitors (SSRIs), or anticonvulsants.

Doses may need to be titrated up every 1 to 2 weeks until symptoms are adequately controlled.

Primary options

amitriptyline: children >5 years of age: 0.1 to 2 mg/kg orally once daily at bedtime; adults: 25-150 mg/day orally

OR

paroxetine: children: consult specialist for guidance on dose; adults: 10-50 mg/day orally

OR

gabapentin: children >12 years of age and adults: 300 mg orally once daily on day 1, followed by 300 mg twice daily on day 2, followed by 300 mg three times daily on day 3, then increase dose according to response, maximum 3600 mg/day

Consider – opioid analgesics

Back
ONGOING
|
chronic
|
neurological involvement
Consider – 

opioid analgesics

Additional treatment recommended for SOME patients in selected patient group

Opioid analgesics are poorly effective when used alone, but may provide some relief and can be an important adjunctive treatment when used in combination with antidepressants or anticonvulsants.

Local protocols should be followed for opioid selection and administration.

Consider – physical and occupational therapy

Back
ONGOING
|
chronic
|
neurological involvement
Consider – 

physical and occupational therapy

Additional treatment recommended for SOME patients in selected patient group

Appropriate for all patients who have a decreased ability to perform activities of daily living or impaired quality of life because of pain or muscle weakness.

Physiotherapy evaluation may be needed every 1 to 3 months.

Consider – physical and occupational therapy

Back
ONGOING
|
chronic
|
musculoskeletal involvement: fasciitis or contractures
Consider – 

physical and occupational therapy

Additional treatment recommended for SOME patients in selected patient group

Joint contractures, limb swelling, and muscle weakness and atrophy are often seen in chronic GVHD.

Physiotherapy incorporates comprehensive neuromuscular examination, testing strength, range of movement in affected joints, limb girth, mobility, stamina, and activities of daily living.

Physical and occupational therapies are then directed at improving these parameters via an outpatient and home-based programme of exercises, stretches, and activities.

Consider – surgical release

Back
ONGOING
|
chronic
|
musculoskeletal involvement: fasciitis or contractures
Consider – 

surgical release

Additional treatment recommended for SOME patients in selected patient group

If contractures are severe and unresponsive to physiotherapy, consideration can be given to surgical intervention to improve range of movement.

Consider – osteoporosis therapy

Back
ONGOING
|
chronic
|
musculoskeletal involvement: osteopenia and osteoporosis
Consider – 

osteoporosis therapy

Additional treatment recommended for SOME patients in selected patient group

When bone mineral density testing indicates osteopenia or osteoporosis, management consists of calcium and vitamin D (as ergocalciferol) supplementation and anti-resorptive therapy. Calcium and vitamin D replacement is justified in deficient states or when patients are post-menopausal or at high risk of developing deficiency, but is not adequate alone in patients with osteoporosis.

If corticosteroid therapy is expected to last >3 months, bone mineral density (BMD) should be measured and antiresorptive therapy started regardless of the results. Preferred agents include hormonal replacement or bisphosphonates. Raloxifene is a secondary option.

Primary options

calcium carbonate: adults: 1000-1500 mg/day orally

More

and

ergocalciferol: adults: 400-800 units orally once daily

and

alendronic acid: adults (prevention): 5 mg orally once daily, or 35 mg orally once weekly; adults (treatment): 10 mg orally once daily, or 70 mg orally once weekly

Secondary options

calcium carbonate: adults: 1000-1500 mg/day orally

More

and

ergocalciferol: adults: 400-800 units orally once daily

and

raloxifene: adults: 60 mg orally once daily

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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