Bone Marrow Transplantation (2001) 28, 47–49
`© 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00
`www.nature.com/bmt
`
`m
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`Graft-versus-host disease
`
`Treatment of severe steroid refractory acute graft-versus-host disease
`with infliximab, a chimeric human/mouse antiTNF␣ antibody
`
`G Kobbe, P Schneider, U Rohr, R Fenk, F Neumann, M Aivado, L Dietze, R Kronenwett,
`A Hu¨nerlitu¨rkoglu and R Haas
`
`Department of Haematology, Oncology and Clinical Immunology, Heinrich Heine University Du¨sseldorf, Germany
`
`Summary:
`
`Acute graft-versus-host disease (aGVHD) is a serious
`complication of allogeneic peripheral blood stem cell
`transplantation (PBSCT). Patients with severe aGVHD
`not responding to treatment with steroids have a poor
`prognosis. We treated four patients with severe aGVHD
`refractory to steroids with infliximab, a chimeric
`human/mouse antiTNF␣ antibody. Patients (CML 2,
`MM 1, AML 1) developed grade III–IV GVHD at a
`median of 34 days (range 15–76) after myeloablative
`PBSCT (two), donor lymphocyte infusion for relapsed
`CML (one) or non-myeloablative PBSCT (one), respect-
`ively. All patients had severe intestinal involvement in
`addition to skin and/or liver disease and had received
`treatment with high-dose steroids (four) for a median
`of 11 days (range 5–17) in addition to CsA (four) and
`MMF (three). Infliximab (10 mg/kg) was given once a
`week until clinical
`improvement. In three of
`four
`patients a complete resolution of diarrhea and signifi-
`cant
`improvement of skin and liver disease were
`observed. Two patients received one, one patient two
`and one patient three infliximab infusions. At present
`two patients are alive ⬎200 days after therapy, one with
`limited cGVHD. Two patients died, one of progressive
`malignant disease without GVHD and one of refractory
`GVHD. Infliximab is apparently an active drug for the
`treatment of aGVHD. Bone Marrow Transplantation
`(2001) 28, 47–49.
`graft-versus-host disease; TNF-␣; infliximab
`Keywords:
`
`Acute GVHD causes significant morbidity and mortality
`after allogeneic haematopoietic cell transplantation despite
`the use of effective prophylactic regimens. Following acti-
`vation by recipient antigen-presenting cells, alloreactive
`donor-derived T cells expand and induce an inflammatory
`process that results in the clinical picture of aGVHD.1 Ster-
`oids are the treatment of choice in aGVHD ⬎II° and induce
`
`remissions in the majority of patients. Individuals who fail
`steroid therapy have been treated with a variety of agents
`including MMF, ATG, OKT3 and antibodies to the
`interleukin-2 receptor alone or in combination.2,3 Response
`rates have varied between 15 and 60%, but, in part due
`to infectious complications and relapse of the underlying
`disease, survival has been low. Early studies have sug-
`gested a beneficial effect of treatment strategies that block
`the activity of TNF␣, which is the key cytokine in the
`inflammatory cascade of aGVHD.4 We treated four patients
`with severe steroid refractory GVHD with the chimeric
`anti-TNF␣ antibody infliximab (Remicade; Centocor,
`Leiden, The Netherlands), which is approved for the clini-
`cal use in rheumatoid arthritis and Crohn’s disease.
`
`Case 1
`
`A 40-year-old male patient with CML in first chronic phase
`was given an allogeneic peripheral blood stem cell (PBSC)
`transplant (4.07 × 106 CD34+ cells per kg) from his HLA-
`identical sister after conditioning with busulfan (16 mg/kg)
`and cytoxan (120 mg/kg). He received CsA and MMF for
`GVHD prophylaxis. The post-transplant clinical course was
`uneventful until at day 15, when the patient developed
`acute GVHD III–IV with cutaneous, hepatic and severe
`intestinal involvement. Steroid treatment was initiated, but
`the diarrhea continued. After 5 days with steroids
`⬎10 mg/kg/day without improvement he received a single
`dose of infliximab (10 mg/kg). Stool frequency started to
`decline after 4 days. Within 2 weeks the diarrhea disap-
`peared completely. The patient later developed recurrent
`CMV antigenemia and pulmonary mycosis which was suc-
`cessfully treated with ganciclovir and liposomal ampho-
`tericin B. He experienced a second episode of GVHD 3
`months later while on low dose CsA, which then resolved
`after treatment with steroids. He is alive at day 292, in
`molecular CR of his CML with limited chronic GVHD.
`
`Case 2
`
`Correspondence: Dr G Kobbe, Department of Haematology, Oncology and
`Clinical Immunology, Heinrich Heine University Du¨sseldorf, Moorenstr.
`5, 40225 Du¨sseldorf, Germany
`Received 23 February 2001; accepted 19 April 2001
`
`A 48-year-old man with CML in first chronic phase
`received a T cell-depleted PBSC graft (3.32 × 106 CD34+
`cells per kg)
`from a matched unrelated donor. The
`
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`m
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`48
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`Infliximab for steroid refractory GVHD
`G Kobbe etal
`
`conditioning regimen consisted of melphalan (140 mg/m2),
`thiotepa (10 mg/kg),
`cytoxan (120 mg/kg) and ATG
`(40 mg/kg). GVHD prophylaxis was CsA. On day 103 he
`experienced a cytogenetic relapse. Following repeated
`donor lymphocyte infusions with increasing cell numbers
`and three doses of interferon alpha the patient experienced
`acute cutaneous GVHD with involvement of the complete
`body surface which transiently improved with treatment
`with CsA, and steroids (5 mg/kg/day). During steroid taper
`at a dose of 3.5 mg/kg/day the skin worsened again and
`grade IV gastrointestinal GVHD occurred. The patient
`received two doses of infliximab (10 mg/kg, once a week).
`Skin and gastrointestinal
`involvement
`improved 5 days
`after the first dose and the diarrhea disappeared 2 weeks
`after the second dose. The patient developed multifocal pul-
`monary mycosis, CMV antigenemia, generalized seizures
`and severe wasting but was successfully treated with lipo-
`somal amphotericin B and ganciclovir. He is now alive, off
`steroids and amphotericin B, in molecular CR with limited
`chronic GVHD 275 days after treatment.
`
`Case 3
`
`A 41-year-old female with multiple myeloma IgA lambda
`received an autologous PBSC transplant after conditioning
`with melphalan (200 mg/m2). For consolidation she was
`treated with an allogeneic PBSC transplant from her HLA-
`identical
`sister
`after
`conditioning with
`fludarabin
`(90 mg/m2) and 2 Gy TBI followed by CsA and MMF. The
`patient engrafted but suffered from an early relapse of the
`myeloma with multiple extramedular tumors. Following
`withdrawal of immunosuppression she developed complete
`
`donor chimerism and acute GVHD with liver (grade 3) and
`gastrointestinal (grade 4) involvement which was refractory
`to treatment with high-dose steroids (⬎10 mg/kg/day), CsA
`and MMF. After 11 days on steroids she received one dose
`of infiximab (10 mg/kg). The diarrhea improved after 5
`days and completely disappeared within 3 weeks. Bilirubin
`and liver enzymes declined 26 days after treatment. Unfor-
`tunately the myeloma progressed rapidly and the patient
`died 99 days after transplantation without signs of GVHD.
`
`Case 4
`
`A 49-year-old female was treated with an allogeneic
`transplant (7.7 × 106 CD34+
`peripheral blood stem cell
`cells/kg) from her HLA-identical brother for secondary
`AML in first remission. She received conditioning with
`busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg)
`followed by CsA and MMF for GVHD prophylaxis. On day
`76 the patient developed aGVHD with cutaneous (grade 2),
`hepatic (grade 1) and intestinal (grade 4) involvement.
`After 11 days on high-dose steroids without substantial
`improvement she received the first dose of infliximab. A
`total of three doses (5 mg/kg, 10 mg/kg and 10 mg/kg) were
`given without improvement. The patient then received sal-
`vage treatment with ATG (75 mg/kg) and later pentostatin
`but died of progressive GVHD 125 days after transplan-
`tation.
`
`Discussion
`
`chimeric
`a
`is
`(Remicade; Centocor)
`Infliximab
`mouse/human IgG1kappa antibody that binds with high affin-
`
`Table 1
`
`Summary for four patients with severe steroid refractory acute GVHD treated with infliximab
`
`Age/Sex
`Diagnosis
`Acute GVHD (grade)
`Organ involvement (grade)
`
`Diarrhea at the start of steroids (ml)
`Bilirubin at the start of steroids (mg/dl)
`Steroid treatment before infliximab (days)
`Additional treatment
`Number of infliximab doses
`Side-effects during infliximab infusion
`Diarrhea at the start of infliximab (ml)
`Interval to intestinal improvement (days)
`Interval to stool normalization (days)
`Bilirubin at the start of infliximab (mg/dl)
`Maximal bilirubin (mg/dl)
`Interval to bilirubin normalization (days)
`Response
`Additional salvage treatment
`Response to salvage treatment
`Chronic GVHD
`Outcome (day)
`
`Case 1
`
`Case 2
`
`Case 3
`
`Case 4
`
`40/M
`CML
`IV
`skin (2)
`liver (3)
`intestinal (4)
`⬎2000
`2.9
`5
`CsA/MMF
`1
`—
`⬎2000
`4
`8
`1.4
`6.8
`29
`CR
`—
`—
`limited
`alive (+292)
`
`48/M
`CML
`IV
`skin (3)
`—
`intestinal (4)
`a
`0.7
`17
`CsA
`2
`—
`⬎2000
`5
`17
`0.4
`—
`—
`CR
`—
`—
`limited
`alive (+275)
`
`41/F
`MM
`IV
`—
`liver (3)
`intestinal (4)
`⬎1500
`1.5
`11
`CsA/MMF
`1
`—
`⬎2000
`5
`20
`4.5
`11.6
`39
`CR
`—
`—
`—
`deadb
`
`49/F
`AML
`IV
`skin (2)
`liver (4)
`intestinal (4)
`⬎1000 bloody
`1.6
`11
`CsA/MMF
`3
`—
`⬎1000 bloody
`—
`—
`0.7
`34.6
`—
`PD
`ATG, Pentostatin
`PD
`—
`deadc
`
`aPatient developed grade 4 intestinal GVHD while on steroids for cutaneous GVHD.
`bPatient died of progressive myeloma without signs of GVHD.
`cPatient died of GVHD.
`
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`ity to soluble and transmembrane forms of human TNF␣.
`Binding to soluble TNF␣ results in the neutralization of its
`activity, whereas binding to the transmembrane form of
`TNF␣ causes lysis of the affected cell by activation of
`complement and induction of antibody-mediated cellular
`toxicity.5 Both mechanisms may have contributed to the
`clinical response observed in the three patients described
`above. Very likely depletion of TNF␣ producing cells is
`the main reason for the long-lasting clinical effects of
`infliximab in Crohn’s disease and rheumatoid arthritis. In
`both diseases a single dose of infliximab can induce clinical
`remissions in patients with disease refractory to standard
`treatment.6,7 A significant number of patients experience a
`relapse of their autoimmune disease about 2 months after
`the first infusion. Patient 1 in our series also suffered from
`recurrent GVHD 3 months after the first episode which then
`improved with steroids. Couriel et al8 observed a response
`rate of 70% in patients receiving infliximab for the treat-
`ment of steroid-refractory aGVHD. Patients with involve-
`ment of the gastrointestinal tract had the greatest benefit
`(85% response). As a limitation of the study of Couriel
`et al, patients were treated with ATG and/or daclizumab,
`in addition to infliximab. Therefore clinical improvement
`may be attributed to one of these substances or a combi-
`nation of all. The responses observed in the patients treated
`in our institution demonstrate that infliximab alone has a
`significant activity in severe steroid-resistant aGVHD.
`Two of the four patients in our group developed serious
`infectious complications including CMV antigenemia and
`aspergillosis. How far suppression of TNF␣ activity con-
`tributed to the development of these infections is not clear.
`Reactivation of CMV is closely linked to the development
`of aGVHD, and aspergillosis also occurs frequently in
`patients
`receiving
`intensive
`immunosuppression
`for
`aGVHD. However, randomized placebo-controlled studies
`in rheumatoid arthritis and Crohn’s disease have suggested
`an increased incidence of infections in patients treated with
`infliximab. Other side-effects included the development of
`
`Infliximab for steroid refractory GVHD
`G Kobbe etal
`
`autoantibodies and possibly an increased incidence of lym-
`phoma. Animal studies with neutralization of TNF␣ after
`allogeneic stem cell
`transplantation have shown an
`increased risk of leukemic relapse. In contrast both patients
`with CML in our series entered molecular remission despite
`immunosuppressive therapy and treatment with infliximab
`suggesting a persistence of the graft-versus-leukemia effect
`at least in patients with CML. We conclude that infliximab
`is a promising new agent for the treatment of aGVHD
`especially in cases with gastrointestinal involvement.
`
`References
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`4 Piguet PF, Grau GE, Allet B et al. Tumor necrosis
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`5 Scallon BJ, Moore MA, Trinh H et al. Chimeric anti-TNF-␣
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`Bone Marrow Transplantation
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