Graft-Versus-Host Disease

Bone Marrow Transplantation (2005) 36, 831–837. doi:10.1038/sj.bmt.1705132; published online 5 September 2005

OKT3 muromonab as second-line and subsequent treatment in recipients of stem cell allografts with steroid-resistant acute graft-versus-host disease

S Knop1, H Hebart2, H Gscheidle2, E Holler3, H-J Kolb4, D Niederwieser5 and H Einsele1

  1. 1Department of Hematology and Oncology, Wuerzburg University Hospital, Wuerzburg, Germany
  2. 2Department of Hematology and Oncology, Tuebingen University Hospital, Tuebingen, Germany
  3. 3Department of Hematology, University Hospital, Regensburg, Germany
  4. 4Department of Hematology, Grosshadern University Hospital, Munich, Germany
  5. 5Department of Hematology and Oncology, University Hospital, Leipzig, Germany

Correspondence: Dr S Knop, Department of Hematology and Oncology, Wuerzburg University Hospital, Klinikstrasse 6–8, 97070 Wuerzburg, Germany. E-mail: knop_s@medizin.uni-wuerzburg.de

Received 30 March 2005; Accepted 9 July 2005; Published online 5 September 2005.

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Abstract

We retrospectively evaluated response to monoclonal antibody directed against CD3 (OKT3) treatment in 43 patients with steroid-resistant acute graft-versus-host disease (aGvHD) following allogeneic hematopoietic cell transplantation. Median duration of OKT3 therapy was 9 (range, 1–20) days. In all, 20 cycles were administered as second-line and 28 as third-plus line treatment. Side effects were mild to moderate. Overall response rate was 69 with 12% complete remissions and best response in skin involvement. Proportional reduction of concomitant steroids was higher in responding patients. Five patients (12%) achieved durable responses. Pharmacokinetic studies of OKT3 showed adequate plasma levels (greater than or equal to1000 ng/ml) in 13 of 17 evaluable patients after a median of 6 (1–11) days on treatment. OKT3 became undetectable shortly after discontinuation of therapy. Median survival for all patients was 80 (2 to 2474+) days. There was a trend for better survival for patients on second-line vs third-plus line treatment (146 vs 46 days; P=0.07) and significant longer survival for patients with grade II when compared to those with grade III/IV aGvHD (206 vs 47 days; P=0.039). We conclude that salvage treatment with OKT3 shows considerable efficiency, however, sometimes of transient nature, and is well tolerated in patients with corticosteroid-resistant aGvHD.

Keywords:

stem cell transplantation, graft-versus-host disease, monoclonal antibody, OKT3

Acute graft-versus-host disease (aGvHD) accounts for considerable morbidity and mortality, thus being a major obstacle to successful outcome after allogeneic bone marrow transplantation (BMT). Incidence of aGvHD of grades II to IV is 30–50% in patients receiving a graft from a human leucocyte antigen (HLA) identical sibling1 and is even higher with increasing HLA disparity between donor and recipient.2 In patients with severe aGvHD (grades III and IV) mortality rates are estimated to be 70–100%.3 Methylprednisolone at a dose of 2 mg/kg is established as first-line treatment of aGvHD.1, 3, 4 Response rate to this regimen in patients transplanted from a nonidentical donor is only 50%.5 No consensus exists neither on the exact definition of corticosteroid-resistant aGvHD nor on the best second-line treatment.1, 5 Most commonly, the term 'steroid-resistant aGvHD' is assigned to a lack of improvement or progression of GvHD despite administration of corticosteroids for several days.1, 6, 7 Salvage treatment is difficult after failure of steroids. A variety of polyspecific and monoclonal antibodies has been investigated in this setting, including thymoglobulin,1 anti-CD2,7 and anti-CD36 antibodies. Initial response rates after conversion to antibody treatment were approximately 60%;1, 6, 7 however, the 1 year survival rate is less than 25%.6 Monoclonal antibody directed against CD3 (OKT3) is a monoclonal murine IgG2a antibody directed against the CD3 antigen on T-lymphocytes that has proven effective in transplant settings of both solid organs and bone marrow.8, 9 After administration of OKT3, a fast clearance of virtually all CD3+ blood lymphocytes can be observed. In a study investigating the underlying mechanisms, lymphopenia was found to be due to rapidly increased adhesion capacity of CD2+ CD3+ cells. In this report, we describe the response rates and side effects of OKT3 treatment in 43 patients with steroid-refractory aGvHD.

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Patients and methods

Patient selection

We retrospectively evaluated 43 patients from three transplant centers (Tuebingen University Hospital, Munich Grosshadern University Hospital, Germany, Innsbruck University Hospital, Austria) who were treated with muromonab OKT3 for steroid-resistant aGvHD of grades II–IV. The study had been approved by the institutional review boards of all centers contributing to the investigation. Median age was 39 (range, 17–58) years. All subjects had received myeloablative conditioning regimens for hematologic malignancies: 30 patients for CML in first to third chronic phase; eight patients for AML; two patients for ALL; and one patient each for high-risk myelodysplastic syndrome (MDS), idiopathic myelofibrosis and multiple myeloma. Clinical data are displayed in Table 1.


Staging of aGvHD

Severity of aGvHD had been evaluated prospectively in all patients according to the criteria of Glucksberg et al.10 It was assessed in the major target organs (skin, liver, gut), and all patients were assigned a grade of overall severity of GvHD (grades I–IV; Table 2).


Definition of steroid refractoriness

In all centers, patients who did not experience improvement of their aGvHD of grades II–IV or whose GvHD worsened while on treatment with methylprednisolone (2 mg/kg body weight (BW)) of at least 48 h were uniformly considered to have steroid-refractory aGvHD, while subjects showing exacerbation of aGvHD during steroid reduction were excluded.

Criteria and assessment of response

Remission criteria following treatment with OKT3 were assessed according to Martin et al:11 complete response (CR): disappearance of all signs of GvHD in all organ systems; partial response (PR): improvement in at least one organ system and no worsening in another organ system; no change (NC): no significant change in any organ system; progressive disease (PD): worsening in one organ system without improvement in any other organ. Severity of aGvHD was assessed the day when OKT3 treatment was initiated and after 3, 7, 10, 13 and 30 days irrespective of whether the patients were on antibody treatment or not, and on days +100 and +365 with respect to transplant.

Treatment schedule

After confirmation of steroid resistance of aGvHD in a given patient, treatment with OKT3 (Orthoclone®, Janssen-CILAG, Neuss, Germany) was initiated at a dose of 5 mg intravenously. The antibody was administered once daily until response or progression of GvHD was documented. The patients remained on OKT3 treatment for a median of 9 (range, 1–20) days. The time from initiation to first stop of OKT3 is defined as one cycle of antibody therapy. Specific immunosuppressive treatment comprising steroids as well as cyclosporine A (CsA) was to be continued and methylprednisolone to be rapidly tapered during administration of OKT3.

Measurement of plasma concentrations of OKT3

In 17 out of the 43 patients, OKT3 plasma levels were evaluated by ELISA before and during treatment with the monoclonal antibody as described before.12 A microtiter plate (Immulon 1 strips) coated with goat anti-mouse IgG H+L polyclonal antibody was used to capture muromonab Orthoclone OKT3 in the patient plasma. Horseradish peroxidase conjugated goat anti-mouse IgG Fc-specific antibody was used as probe.

Evaluation of anti-OKT3 antibodies

For detection of human-anti-mouse antibodies (HAMA) quantification was performed in 17 of 43 patients by ELISA as well.13 Immulon 1 microtiter strips coated with Orthoclone OKT3 were used as the capture antibody. Horseradish peroxidase goat anti-human IgG conjugate was used as probe.

Statistical analysis

The cumulative probability of survival according to disease severity (aGvHD grade II vs III/IV) and time of treatment with the antibody (second-line vs third-plus-line treatment) was analyzed using Kaplan–Meier curves and log-rank statistics. Univariate analysis was performed by Pearson's chi2-test. Statistical calculations were performed with SAS for Windows, Release 8.0, SAS Institute Inc., Cary, NC, USA.

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Results

Prior treatment

A total of 20 patients received OKT3 as second-line and 23 as third-plus-line (third-line, n=13; fourth-line, n=10) treatment regimens. All patients had at least received steriods (methylprednisolone 2 mg/kg) for greater than or equal to48 h. For the 20 subjects on second-line treatment for their aGVHD this was the sole pretreatment. Third-line cohort: 10 patients received increased steroid doses up to 25 mg/kg followed by OKT3, and three patients anti-TNFalpha antibody followed by OKT3. Fourth-line cohort: five patients were administered increased steroid doses followed by anti-TNFalpha antibody and finally by OKT3. Two patients received increased steroid doses followed by ATG and finally by OKT3. One patient each received increased steroid doses followed by anti-IL2 antibody or by the monoclonal antibody BMA031 (IgG2b; directed against constant regions of human alpha/beta T-cell receptor), respectively, and both subsequently OKT3. Steroid reduction during antibody treatment was possible in 40 of 42 evaluable patients. Mean rate of reduction of methylprednisolone was 51% (range, 0–90%) and was higher in patients achieving at least CR (55%) when compared to patients without remission (42%) (P=0.08).

Response to treatment with muromonab OKT3

We identified 43 patients who received 48 treatment cycles of muromonab OKT3. In all, 20 cycles of OKT3 were given as second-line and 28 as third-plus-line (third-line, n=14; fourth-line, n=14) treatment regimens. Four patients received a second and one patient a third course of the antibody after the presence of HAMA had been excluded. In all, 10 patients (23.3%) were treated for grade II aGvHD, while 33 patients (76.7%) for grades III and IV GvHD. In all, 36 patients had skin involvement, 30 patients gut involvement and in 23 patients liver GvHD had been diagnosed. A total of 42 patients were evaluable for response to treatment. Best response to OKT3 as assessed above was chosen to classify a patient's overall response.

Five patients (11.9%) showed a CR and 24 patients (57.1%) a PR to OKT3 treatment, for an overall response rate of 69%. High response rates were seen in skin (88.8%) and gut (53.3%) GvHD, while improvement in liver GvHD was documented only in 8.7%. The response rate in patients with aGvHD grade II was 90% and compared favorably to the 63% response in grade III/IV disease. Response rates were highest in patients receiving OKT3 as second-line treatment (79%), but also 54% of third- and even 60% of fourth-line patients responded. One patient in the second-line group and two patients each in the third- and fourth-line group showed CRs. Median time from institution of OKT3 to response was 3 (range, 1–13) days and median response duration in the patients achieving CRs or PRs for whom follow-up is available was 8 (range, 1–43) days. Initial pattern and response to treatment is shown in Table 2. Four patients with progressive aGvHD after OKT3 treatment received an additional administration of the antibody for 4–10 days. Partial response was observed in two of the four patients. One of those patients with subsequent relapse received a third cycle of OKT 3 without response (Table 3). At a median of 9 (range, 1–58) days from completion of OKT3 administration, 23 of 42 patients (54.8%) for whom adequate data are available, showed progressive aGvHD and only five patients (12%) achieved durable (greater than or equal to30 days) remission of their GvHD. Salvage treatment was successful in nine patients, two of whom improved on a further cycle of OKT3.


OKT3 plasma levels and anti-OKT3 antibody assessment and response to treatment

OKT3 plasma levels were assessed in 17 patients, 16 of whom achieved at least PR. Median duration of OKT3 treatment in those patients was 10 (3–20) days. Plasma levels equal or above 1000 ng/ml were achieved by 13 of 16 patients who received treatment for at least 5 days after a median treatment of 6 (1–11) days. Nine patients remained on OKT3 treatment for greater than or equal to10 days; however, a significant further increase in the plasma level after 10 days of therapy was only documented in two patients. Plasma levels of OKT3 became undetectable after a median of 4 (3–11) days after discontinuation of murmonab. Median plasma concentration at best response was 985.6 (range, 401.9–1879) ng/ml and was observed after a median of 10 (5–20) days of treatment and remained constantly high for 9 (3–16) days under continued administration. No significant anti-OKT3 antibody formation was found in any of the patients in whom analysis was performed.

Drug-related toxicities

Acute adverse reactions were observed in 26 of the 43 patients (60%) following administration of OKT3. The symptoms typically developed immediately after administration of the antibody and were those of the cytokine release syndrome (CRS), which is known to be associated with OKT3 therapy.14 None of the events that were graded according to the WHO scale were of grade III/IV. Acute adverse reactions are displayed in Table 4.


Infections

CMV infections were observed in 23 of the 43 patients treated with muromonab (53.5%). Four patients developed CMV pneumonitis. CMV colitis and hepatitis were diagnosed in one patient each. Herpes simplex infections were documented in eight (18.6%) patients, one of whom developed hepatitis. Neither patient developed post-transplant lymphoproliferative disease. Bacterial infections were documented in seven (16.3%) patients, four out of whom developed septicemia. Two patients with pneumonia and one patient with sepsis died due to bacterial infections. Fungal infections were observed in 13 patients (30.2%) with 12 cases of invasive aspergillosis and one case with invasive candidosis. Seven patients died from their fungal infections.

Survival and causes of death

Median overall survival for all patients calculated from the first dose of OKT3 was 80 (2 to 2474+) days. Patients who received OKT3 as second-line treatment had a median survival of 146 (3 to 1595+) days and patients with third-plus-line treatment of 46 (2 to 2474+) days. The difference was not statistically significant (P=0.07). The 10 patients with moderately severe GvHD (grade II) had a median survival of 205.5 (9 to 1600+ days) while the 33 patients with grade III/IV survived for a median of 46.5 (2 to 2474+) days. This was a statistically significant difference (P=0.039). Primary cause of death was acute and chronic GvHD in 31.6 and 2.6%, respectively. Further considerable causes of death were infections with a rate of 44.7% (aspergillosis, 19%; CMV-pneumonitis, 11%). Relapse of the underlying malignancy accounted for 10.6% of deaths, while 7.9% of patients died of ARDS and one patient from myocardial infarction.

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Discussion

aGvHD in recipients of HLA-identical hematopoietic cell allografts has an incidence of 30–50%.1 CSA and methotrexate (MTX) alone or in combination are most commonly used for prophylaxis.15, 16 Once established, treatment of aGvHD is difficult. Corticosteroids are used as standard therapy.4, 6, 17 However, two major problems have to be overcome: response rates to initial treatment are moderate5 and responses not durable.1 Lack of improvement on corticosteroid therapy for several days is observed in approximately 50% of cases16 which then is defined as steroid-resistant aGvHD.1, 6, 7

In our study, as was in previous reports, current immunosuppressive treatment was continued; however, a rapid taper of steroids was included in the treatment plan.1, 25 Steroid reduction was possible in 40 out of 42 patients: at the end of OKT3 administration, responding patients received 45% but nonresponders 58% of their initial steroid dose (P=0.08). Relatively common, polyclonal antibodies, for example, Thymoglobulin®, are used as a salvage treatment in order to achieve a more efficient depletion of alloreactive T cells.1, 18 Since activation of T lymphocytes of donor origin is one major aspect in the afferent phase of aGvHD, both anti-pan T lymphocyte and anti-cytokine monoclonal antibodies have been investigated in steroid-resistant GvHD.5, 6, 7 Muromonab OKT3 is directed against the CD3 antigen on all mature T cells and was first used in rejection after transplantation of solid organs.9 Subsequently, treatment of aGvHD in recipients of hematopoietic cell allografts was reported. Overall response rates in these small series ranged from 71 to 90%.19, 20, 21

This investigation of 43 patients with steroid-resistant aGvHD who received 48 cycles of muromonab OKT3, although being a retrospective analysis, is the largest series reported up to now. Most of the patients had severe and treatment-resistant aGvHD (33 patients (76.7%) grade III and IV GvHD, 28 [58.3%] cycles were administered as third-plus line treatment). We observed an overall response rate of 69% (CR, 11.9% and PR, 57.1%) with skin and gut involvement (88.8 and 53.3%, respectively) improving more frequently than liver GvHD (8.7%). Interestingly, high-response rates of approximately 60% were seen even in patients who received OKT3 as third-plus-line treatment and remarkably four of the five CRs were achieved by third-plus-line patients (Table 3). Owing to the high proportion of patients with progressive disease after several previous treatments (23 out of 42 patients received the antibody as third-plus-line therapy) our population has to be considered as high-risk rather than as standard-risk collective. This would mean that response rates might be even higher in a less heavily pretreated group.

A rapid cortisone taper leading to steroid reduction of 51% during the course of OKT3 treatment was achieved for all patients with pronounced lower median steroid levels at the end of treatment in patients with CR or PR. However, since some patients with OKT3 as third- and fourth-line treatment received relatively high doses of steroids, response in these groups may have been due to an additional effect of steroids and the antibody. The impact of OKT3 in patients with the antibody as fourth-line treatment is somewhat difficult to assess. Owing to the high number of different approaches before, the stand-alone effect of OKT3 may be overestimated. Median survival with respect to the time of treatment showed a trend to longer survival for patients on second- when compared to third-plus-line treatment. A significant difference for survival rates was found when comparing patients with grade II aGvHD and subjects with grade III and IV disease. In our series, however, the majority of patients (77%) had severe GvHD. Typically, response of GvHD varies with involved organ systems and is best for the skin, while liver disease often shows only moderate improvement.1, 7 That was observed also in our study both with respect to severity of GvHD and to the number of previous treatment modalities. Tolerability of muromonab OKT3 was acceptable. The adverse reactions were all of mild to moderate intensity and included the symptoms of the cytokine-release syndrome as described before.14

Patients with intensive immunosuppression for GvHD are at high risk for developing especially fungal and CMV infections due to low numbers of T cells and aGvHD itself.3, 22, 23 We observed a rate of CMV infections of 53.5% and of invasive fungal infections of 30.2%. CMV infections during therapy with muromonab OKT3 reported in previous studies had been lower;21, 22 however, in this study a higher proportion of patients (76.7%) had grades III and IV disease. The rate of fungal infections we observed was high (30.2%) as typically is in this patient population. Since T-cell depleted grafts are associated with a high risk of post-transplant lymphoproliferative disorder (PTLD),24 we were specially interested in the incidence of EBV infections. No PTLD developed in any of the patients.

This favorably compares to other series with administration of both anti-thymocyte globulin1 as well as of a humanized, non FcR-binding anti-CD3 monoclonal antibody.25 In the first, PTLD incidence was 25% in the latter two of seven patients with progressive rises in EBV DNA copies died of PTLD, with consecutive requirement of administration of rituximab to subsequent patients. The association between the type of immunosuppression and development of PTLD is not clear. In the study with the engineered anti-CD3 antibody, visilizumab, response rate of aGvHD was higher than in our investigation.25 However, the high incidence of PTLD after visilizumab might reflect a possible disadvantage of more profound T-cell depletion when compared to OKT3 as administered in this study.20, 26

Two major problems in the treatment of aGvHD were the often transient nature of response and progression following initial successful treatment. This may be due to the relatively short half-life of the immunosuppressive drug. In our study, five subjects had duration of remissions of at least 30 days and 23 (53.5%) experienced progression of aGvHD at a median of 9 days from discontinuation of OKT3. This would argue for blocking rather than profound depletion of GvHD effector cells.

Even sequential administration of three monoclonal antibodies with maintenance therapy of an anti-IL2 receptor antibody resulted in a progression rate of 44%. While pharmacologic features of muromonab OKT3 are well understood, relatively little is known about the optimal duration of treatment. The observation of clearance of virtually all CD3 positive cells within minutes after the administration of the antibody8, 22 is attributable to an upregulation of CD11a/CD18 as well as of CD11b/CD18 on T lymphocytes.

This promotes adhesiveness to their endothelial counterstructures as intercellular adhesion molecule (ICAM)-1 and -2.8 In vitro analyses showed the appropriate concentration of OKT3 to block T-cell function to be 1000 mug/l.22 Typically, muromonab OKT3 is administered for 10–14 days. True serum levels between 500 and 1000 ng/ml, that can be considered as adequate concentrations, are detected around day 3 after start of infusion.27 In our study, 17 patients were analyzed for OKT3 levels. Plasma levels of at least 1000 ng/ml were achieved by 13 of 16 patients with treatment duration of five or more consecutive days after a median treatment of 6 (1–11) days. No significant increase in the plasma level occurred after extending treatment for more than 10 days. Monoclonal antibody levels became undetectable after a median of only 4 (3–11) days after discontinuation of muromonab.

This is a significantly faster clearance of the immunosuppressive agent as compared to anti-thymocyte globulin. With the latter, subtherapeutic levels can be expected around day 15 after transplantation, as recently described.28 Thus, maintenance therapy with OKT3 might be necessary given at lower doses, since frequent relapses after discontinuation of the drug can be attributable to the relatively short half-life. However, a relationship between doses of OKT3 and an increased risk of severe infections has to be considered. In terms of response to treatment, median OKT3 plasma concentration was 985.6 (range, 401.9–1879) ng/ml at best response for a median of 9 days, which is in accordance to the above results.

This level was achieved after a median treatment duration of 10 (5–20) days. These data would support introducing either a loading dose or tailored drug dosing by monitoring plasma levels. Prolonged application of OKT3 might on the one hand make responses more durable on the other hand expose patients to opportunistic infections. In conclusion, our results demonstrate muromonab OKT3 to be an effective and, for the respective setting, safe drug regimen for therapy of patients with steroid-resistant aGvHD. However, one has to be aware of the retrospective nature of the analysis.

Adequate plasma levels can be expected in general already after a relatively short treatment period, whereas prolongation of OKT3 beyond 10 days will probably not be beneficial. In this study, overall response rate was 69% even though 76.7% of patients had severe disease and more than half of the cycles were administered as third-plus-line therapy. As expected, these patients are at high risk for opportunistic infections, with invasive fungal infections and CMV reactivation being the most critical. Pre-emptive and prophylaxis strategies and highly effective drugs are mandatory in the given situation. The results of this retrospective study provided the basis for an ongoing, randomized trial to prospectively evaluate muromonab OKT3 compared to high-dose steroids (10 mg/kg BW) in graft recipients with steroid-resistant aGvHD as defined by not responding to methylprednisolone 2 mg/kg BW.

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References

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