Graft Versus Host Disease Treatment & Management

Updated: Jan 27, 2020
  • Author: Romeo A Mandanas, MD, FACP; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
  • Print
Treatment

Medical Care

Acute GVHD

Primary prophylaxis for acute graft versus host disease (GVHD) includes the following:

  • The criterion standard for prophylaxis is cyclosporine for 6 months and short-course methotrexate (MTX) in T-cell–replete allogeneic hematopoietic cell transplantation (HCT); cyclosporine levels should be kept above 200 ng/mL.

  • Tacrolimus is frequently substituted for cyclosporine, especially in unrelated-donor transplantation, because it may improve the control of GVHD, though not survival. The addition of prednisone to the prophylactic regimen also reduces the incidence of GVHD but does not change overall survival. [47]

  • Antithymocyte globulin (ATG) given before HCT significantly reduces the risk of grade III or IV acute GVHD and extensive chronic GVHD, but it does not alter survival, possibly because of the increased risk of infection. [48] Ex-vivo depletion of T-cells has also been tried (in the 1980s), but transplantation-related mortality was not reduced compared with standard treatments in patients receiving HLA-matched grafts.

  • Other agents that have been studied for GVHD prophylaxis include combinations with or substitutions by other agents such as mycophenolate mofetil, [5] sirolimus, [22] pentostatin, alemtuzumab [49] keratinocyte growth factor (KGF), cyclophosphamide, [50] and suberoylanilide hydroxamic acid (SAHA).

  • Extracorporeal photopheresis (ECP) is an immunomodulatory procedure in which lymphocytes are collected and mixed with 8-methoxypsoralen (which intercalates into the DNA of the lymphocytes), rendering them susceptible to apoptosis when exposed to ultraviolet light. The lymphocytes are then returned to the patient. ECP has been used as part of a conditioning regimen together with pentostatin and total body irradiation, with very promising results. [35]

Primary therapy for acute GVHD includes the following:

  • For skin GVHD of stage I or II, observation or a trial of topical corticosteroids (eg, triamcinolone 0.1%) may be used.

  • Begin systemic treatment in patients with grade II-IV acute GVHD. Treatment consists of continuing the original immunosuppressive prophylaxis (cyclosporine or tacrolimus) and adding methylprednisolone. Doses have been in the range of 1-60 mg/kg, but the most common starting dosage is 2 mg/kg/d given in 2 divided doses. Median time to resolution of acute GVHD is 30-42 days. In patients who respond to initial therapy, short-term tapering treatment with prednisone to a cumulative dose of 2000 mg/m2 is effective and expected to minimize steroid-related complications.

  • Other therapies are ATG, sirolimus [4, 51] , mycophenolate mofetil, anti–interleukin-2 (IL-2) receptor, anti-CD5–specific immunotoxin, and a pan T-cell ricin A-chain immunotoxin (XomaZyme). These agents can be used alone or in combination. No data from well-conducted controlled trials have shown the superiority of any of those over any other therapies.

  • Novel therapies have included the addition of ex vivo cultured mesenchymal cells derived from unrelated donors to conventional steroid therapy; this approach produced initial response rates of 90%, although 31% of patients required a second-line agent to control the disease. [52]

Failure of initial therapy is defined as any of the following:

  • Progression of acute GVHD after 3 days
  • No change after 7 days
  • Incomplete response after 14 days of treatment with methylprednisolone

Secondary therapy is usually initiated in steroid-refractory cases. Secondary therapy for acute GVHD includes the following:

  • ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy) have a response rate of about 40%.

  • Sirolimus [51]

  • Infliximab (an IgG1 murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of tumor necrosis factor–alpha [TNF-α]) has a high response rate, but opportunistic infections (especially noncandidal invasive fungal infections) result in a high mortality rate. [6, 7]

  • Etanercept (a soluble dimeric TNF-α receptor 2 that can be given as a subcutaneous injection) competes for TNF-α binding, thus rendering it inactive. Higher response rates are seen with etanercept plus steroids (82%) versus steroids alone (66%) as primary therapy for acute GVHD). [53, 54]

  • Mycophenolate mofetil (MMF) at 2 g daily, when added to the steroid regimen, caused an overall response rate of 62%. [5]

  • Ruxolitinib was approved by the US Food and Drug Administration (FDA) in May 2019 for the treatment of steroid-refractory acute GvHD in patients aged 12 years or older. Approval was based on data from REACH1, an open-label, multicenter trial, in which patients with steroid- refractory acute GVHD treated with ruxolitinib had an overall response rate of 59% and a complete response rate of 31%. [55, 56]

  • Psoralen and ultraviolet A irradiation (PUVA) may be beneficial for cutaneous lesions of GVHD and may improve survival in some patients with steroid-resistant GVHD. ECP, in a phase II study, achieved a 60% response in steroid-refractory GVHD 3 months following the initiation of treatment. More responses were observed in patients with skin involvement only than in patients with liver or gut involvement. [10]

  • Approximately 12% of patients with GVHD resistant to cyclosporine may respond to conversion to tacrolimus. In patients who develop cyclosporine-related neurotoxicity, therapy can be switched to and maintained with tacrolimus, which stabilizes and resolves neurologic abnormalities.

Other therapies for acute GVHD include the following:

  • ABX-CBL is an immunoglobulin M (IgM) murine monoclonal antibody that recognizes CD147 and initiates killing by means of complement-mediated lysis. ABX-CBL induced complete responses in 13 of 26 subjects with corticosteroid-refractory GVHD. [57]

  • Visilizumab is a humanized anti-CD3 monoclonal antibody with a mutated IgG2 isotype and selective apoptotic activity in activated T cells. It has produced promising responses in many patients, but posttransplantational lymphoproliferative disease is a problem. [58]

  • Pentostatin has shown limited benefit in steroid-refractory acute GVHD [59]

Chronic GVHD

The following measures can substantially reduce the risk of chronic GVHD [60] :

  • Administration of rabbit ATG or alemtuzumab in the conditioning regimen before HCT
  • Administration of high-dose cyclophosphamide on days 3 and 4 after HCT

If chronic GVHD does develop, early recognition and treatment, before disability ensues, is critical. Used alone, prednisone 1 mg/kg every other day decreases treatment-related mortality rates (21% vs 40%) compared with prednisone combined with azathioprine, which is associated with a survival rate of 61% in patients with standard-risk chronic GVHD (no thrombocytopenia).

The addition of cyclosporine 6 mg given every 12 hours every other day in patients at high risk for GVHD with thrombocytopenia may improve survival rates from 26% to 52%. It may also improve functional performance to near-normal in long-term survivors by significantly decreasing the incidence of disabling scleroderma. However, infections are a frequent cause of morbidity and mortality in patients with high-risk chronic GVHD.

The addition of tacrolimus to steroids was associated with a high response rate of 72%. However, it led to a high chronic-GVHD–related mortality (34%) and a significant need for salvage therapy (47%).

Thalidomide has been reported as effective primary treatment for chronic GVHD because of its TNF-modulating effect. The 3-year survival rate is about 48%, with a diminished incidence of infection in long-term survivors.

Secondary therapy for chronic GVHD includes the following:

  • In August 2017, the FDA approved ibrutinib as the first drug for chronic GVHD in adults who have failed at least 1 systemic treatment. Ibrutinib is a Bruton’s tyrosin kinase (BTK) inhibitor. Inhibition of BTK enzymatic activity diminishes signaling to B-cell surface receptors that activate B-cell trafficking, chemotaxis, and adhesion. Approval of ibrutinib was based on a single-arm trial in 42 patients with chronic GVHD whose symptoms persisted despite standard treatment with corticosteroids. GVHD symptoms improved in 67% of patients after ibrutinib treatment, and in 48% of patients the improvement of symptoms lasted for up to 5 months or longer. [8, 9]

  • Steroid-refractory chronic GVHD has been treated with azathioprine, alternating cyclosporine/prednisone, or thalidomide, with approximately similar survival rates. Clofazimine, an antileprosy agent, has also been effective in treating cutaneous and oral lesions of chronic GVHD and may be useful as a steroid-sparing agent because adverse effects and infections appear to be minimal.

  • MMF is now the most commonly used agent used to treat steroid-refractory chronic GVHD. Responses of 90% and 75% in first and second line settings are seen when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments. MMF does not seem to increase the rate of infections or relapse. [5]

  • PUVA therapy plays a role in patients with refractory cutaneous chronic GVHD. In 1 study, it resulted in a 78% response rate and improvement in a few extracutaneous sites.

  • Extracorporeal photopheresis, a modification of PUVA treatment, has also shown benefit, with best responses in the skin (59%), liver (71%), eye (67%), and oral mucosa (77%). [10]   A prospective trial of extracorporeal photopheresis (ECP) for chronic GVHD found significant disease response (62%) in a highly pretreated cohort. ECP was associated with a clinically significant decrease in median prednisone dose (0.36 to 0.14 mg/kg, P < .001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. [11]

  • The anti-CD20 monoclonal antibody rituximab produced a clinical response rate of 70% mainly for musculoskeletal and cutaneous chronic GVHD. These responses were durable through 1 year after initiation of therapy and allowed a 75% reduction in steroid doses. [12]

  • Ruxolitinib [55]

  • Pentostatin at a dose of 4 mg/m2 IV every 2 weeks for 6 months produced 50% response rates in patients with chronic GVHD who failed 2 prior immunosuppressive regimens. Aggressive infection prophylaxis was necessary with steroid tapering, antibiotics, antifungals, and antiviral agents.

  • Low-dose (100-cGy) total lymphoid irradiation to thoracoabdominal areas can lead to partial or complete improvement in some patients.

  • Imatinib has shown an overall response rate of 79% at 6 months for patients with refractory GVHD with fibrotic features where antibodies activating the platelet-derived growth factor receptor pathway have been reported. [61]

Other supportive care for chronic GVHD includes the following:

  • Pain control with analgesics for patients with painful mouth sores allows for oral intake. Oral beclomethasone may improve oral intake, nausea, and diarrhea without causing systemic or local toxicity.

  • Octreotide can control secretory diarrhea in enteric GVHD. Manage severe diarrhea with octreotide, intravenous hydration to prevent dehydration, and total parenteral nutrition in patients with severe malabsorption.

  • Antiviral prophylaxis (eg, for herpes simplex, cytomegalovirus [CMV]) can prevent oropharyngeal infection and interstitial pneumonia in patients with refractory GVHD.

  • Antifungal agents (eg, new triazoles, liposomal amphotericin B) may be useful for preventing and treating serious mycotic infections. Posaconazole is approved for prophylaxis against invasive aspergillosis in patients undergoing treatment for GVHD. [62]

  • Retinoic acid is used for ocular sicca syndrome, and pilocarpine (Salagen), for oral sicca manifestations.

  • Clonazepam is used to treat neuromuscular manifestations (eg, muscular aches, cramping, carpal spasm).

  • Ursodeoxycholic acid treatment for abnormalities in liver function can result in improvement of hepatic chronic GVHD; it can reduce elevated bilirubin levels by as much as 30%.

  • Patients receiving chronic corticosteroid therapy are at risk for osteoporosis and fractures. For women, estrogen replacement, calcium supplements, and antiosteoporosis agents (eg, Fosamax, calcitonin) should be considered.

  • Patients with stage IV skin GVHD are best treated in the burn unit, where the staff should pay meticulous attention to skin and wound care, nutrition, and infection control.

 

Next:

Surgical Care

Surgical consultations are required mainly for the insertion of central venous access devices, such as infusion ports and pheresis catheters.

Previous
Next:

Consultations

In patients with severe dermal involvement of chronic GVHD, burn care speeds re-epithelialization and closure of the portals of infection. Plastic surgery may be necessary for skin allografting from the marrow donor in certain severe cases of dermal involvement due to chronic GVHD.

Patients with eye manifestations of chronic GVHD require ophthalmologic examination, follow-up, and treatment.

Previous
Next:

Diet

Institute gut rest and hyperalimentation for patients with acute GVHD and severe diarrhea. Patients should slowly advance to a bland diet or to the bananas, rice cereal, applesauce, and toast (BRAT) diet as tolerated.

Previous
Next:

Activity

Encourage patients who are receiving corticosteroid therapy to maintain an active lifestyle and to participate in a mild-to-moderate exercise program.

Previous
Next:

Prevention

To minimize graft versus host disease (GVHD), donor and host factors should be addressed, as follows:

  • Refinement of methods to select the donor based on molecular characterization of HLA class I and II antigens may minimize HLA disparity between the donor and recipient and therefore decrease the incidence of GVHD; for example, Japanese researchers recommend that reported that mismatched HLA-C*14:02 should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation, as it is a potent risk factor for severe acute GVHD and mortality [63]

  • Use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative patient appears to reduce the risk of both CMV infection and GVHD in the recipient

  • Laminar airflow protective isolation with gut decontamination can decrease the incidence of GVHD and improve survival in patients with aplastic anemia undergoing bone marrow transplantation

Posttransplantational immunosuppressive prophylaxis

Single agents or combinations of agents have been used to prevent acute GVHD. The most common effective regimen consists of cyclosporine administered for 180 days combined with a short course of methotrexate administered on days 1, 3, 6, and 11. The combination is better than either agent administered alone. In one study, the addition of prednisone on days 7-180 further reduced the incidence of acute GVHD from 23% to 9%.

Tacrolimus, a more potent immunosuppressant than cyclosporine, is also being used in combination with methotrexate and appears to be more effective than cyclosporine at preventing acute GVHD, especially in patients receiving a transplant from an unrelated donor. The cumulative incidence of chronic GVHD also seems to be less with the tacrolimus-methotrexate combination (48%) than with the cyclosporine-methotrexate combination (64%). [47]  Prolonged immunosuppression (extending beyond the usual day 180) may be indicated for patients at high risk for chronic GVHD (ie, patients who have had acute GVHD).

In a phase II trial that compared three regimens for prevention of GVHD after HCT with reduced-intrensity conditioning, the combination of tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding better GVHD-free, relapse-free survival compared with tacrolimus, methotrexate, and bortezomib or tacrolimus, methotrexate, and maraviroc. [64]

Antibody prophylaxis with intravenous immunoglobulin (IVIG), when administered weekly through day 90 after transplantation, reduces the incidence and mortality rate of acute GVHD. Continuing IVIG treatment from day 90 to day 360 after transplantation did not seem to change the cumulative incidence of chronic GVHD in treated patients compared with a control group that was not receiving IVIG. [65]

In a prospective, multicenter, open-label, randomized phase 3 study, the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. [66]

Marrow T-cell depletion by in vitro methods (eg, soybean-lectin agglutination, counterflow centrifugation, use of antibodies against T lymphocytes or their subsets) can substantially reduce the incidence and severity of acute and chronic GVHD (50% in T cell–depleted HLA-identical marrows). However, the overall survival rate is not improved because of increased incidence of graft failure and recurrent leukemia. In long-term survivors who received T cell–depleted unrelated donor marrows, chronic GVHD still occurred in 85%.

In vivo T-cell depletion by the addition of anti–T-cell globulin to standard cyclosporine-methotrexate prophylaxis decreased the incidence of both acute and chronic GVHD without affecting relapse or nonrelapse mortality or compromising overall survival in recipients of matched unrelated donor transplants in a randomized, open-label, multicenter, phase 3 trial. [23]

Prevention is the most important aspect in managing transfusion-associated GVHD. Encourage the hospital's blood bank to automatically irradiate all blood products that may be transfused into high-risk patients.

Previous