Graft-Versus-Host Disease

Long-term follow-up of corticosteroid refractory acute GVHD treated with an Inolimomab-based algorithm: a single center experience

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Abstract

Acute corticosteroid refractory GVHD (aGVHD) remains a challenging problem after allogeneic hematopoietic SCT. Even though immunosuppressive therapies may achieve a response, unsatisfactory aGVHD control and toxicity of high cumulative doses of corticosteroids are frequent, notably with an increased infection rate. We report long-term follow-up of 33 consecutive patients who developed corticosteroid refractory aGVHD in our institution, treated homogeneously according to a unique algorithm combining an induction treatment (Inolimomab, 0.3 mg/kg per day), an associated immunosuppression (Mycophenolate Mofetil) and a predefined management of partial responses (PR) by the switch from Cyclosporin to Tacrolimus, together with an intensive infectious monitoring and supportive care. In this cohort, 17 patients (52%) achieved a complete response (CR) and 14 patients (42%) a PR, which converted to CR for 12 patients after Tacrolimus introduction. Transplant related mortality (TRM) was 15.5% and 29.7% at 1 and 3 years, respectively. OS was 54.5% at 3 years. Multivariate analysis identified CR after Inolimomab therapy as the unique prognostic factor on OS. Among the 30 evaluable patients, 19 (63%) developed extensive chronic GVHD. This Inolimomab-based algorithm allows for an efficient control of corticosteroid refractory aGVHD in a high proportion of patients with low toxicity, and deserves further investigation.

Introduction

Allogeneic hematopoietic SCT (HSCT) is an effective treatment procedure for various malignant and nonmalignant hematologic disorders. Over the past few years, alternatives to myeloablative HSCT have been successfully developed with reduced-intensity conditioning procedures and diversification of HSCT sources allowing for an increased number of indications (25 000 allogeneic HSCT per year worldwide) and a lower transplant related mortality (TRM).1 Nevertheless, acute GVHD (aGVHD), mostly corticosteroid refractory forms (10–50% of aGVHD), contribute to an important morbidity and mortality, and thus remain a major challenge.2 To date, there is no consensus for the treatment of refractory aGVHD. Historic management of refractory aGVHD consisted in giving antithymocyte globulin (ATG), which actually leads to poor results. Indeed, 28–57% of patients may respond (partial and complete responses (CR)) to ATG.2, 3, 4, 5 New therapies have been developed such as mAbs targeting the IL-2 receptor (Inolimomab, Daclizumab and Basilixumab), as well as the TNFor CD52.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 The murine Ab Inolimomab recognizes the α-subunit of the IL-2 receptor (CD25) and could be an efficient treatment for corticosteroid refractory aGVHD by blocking the action of IL-2, and by inhibiting the proliferation of activated T lymphocytes.6, 7, 13, 21 However, treatment with recent monoclonal anti-IL-2 receptor Abs (in association with an anti-TNF AB or not) are associated with a high infectious risk.14, 15, 17, 22 Beyond response to therapy, two majors problems remain. First, management of partial response (PR) leads to sustained high dose corticosteroids, which may account for increased infectious complications. Secondly, frequent aGVHD relapses after induction phase increase TRM.23

We retrospectively describe the long-term follow-up (median 4.9 years for live patients) outcome of a monocentric cohort of 33 consecutive patients with corticosteroid refractory aGVHD who were treated by an Inolimomab-based algorithm between 2002 and 2008. These 33 patients received an additional relay treatment to decrease the relapse risk of aGVHD, and a predefined treatment in case of PR. We also report the OS and the occurrence of chronic GVHD (cGVHD) in this cohort.

Materials and methods

Patients

Between October 2002 and January 2008, at CHU (Center Hospitalier Universitaire) of Poitiers, 161 consecutive patients were treated by allogeneic HSCT with a majority of unrelated donors (67%). Among these 161 patients, 93 (58%) developed grade 2 aGVHD and 33 patients (20%) developed a corticosteroid refractory aGVHD. No patient died during initial treatment before Inolimomab, and all corticosteroid refractory forms were treated by our Inolimomab-based algorithm.

Most of these 33 patients had been transplanted for hematologic malignancies (Table 1). The median age was 44 years (range 17–65) and the mean time between diagnosis and allogeneic HSCT was 689 days (range 110–5554 days). Six patients were allografted with HLA identical sibling donors, 27 with matched unrelated donors (including 7 with mismatch) and 9 with unrelated cord blood. GVHD prophylaxis consisted of Cyclosporin (CsA) associated with MTX or Mycophenolate Mofetil (MMF) or CsA alone. Thirteen patients received a reduced conditioning regimen, and ATG was used for 8 patients in case of HLA mismatch or in case of some reduced conditioning regimen.

Table 1 Clinical characteristics, conditioning regimen and type of graft of 33 patients treated for corticosteroid refractory acute GVHD with Inolimomab

Diagnosis of GVHD

The diagnosis of aGVHD was primarily based on clinical findings according to the Glucksberg classification, before D100 and supported by biopsy whenever indicated.24, 25 Two forms of aGVHD were defined: an ‘isolated skin form’ (skin stage 3 with digestive and liver stages1) and a ‘visceral form’ (digestive stage2 and/or hepatic stage2). Corticosteroid treatment (methylprednisolone, i.v., 2 mg/kg per day, in divided doses) was started immediately after diagnosis of grade 2 aGVHD.2, 26, 27 Corticosteroid refractory aGVHD was defined as the association of corticosteroid resistance and corticosteroid dependence. Corticosteroid resistance was defined as the progression of aGVHD in the first 72 h of corticosteroid therapy or a lack of improvement after 7 days of corticosteroid therapy.9, 28 The relapse of aGVHD during the corticosteroid decrease above 1 mg/kg per day defined corticosteroid dependence. The diagnosis of cGVHD was made according to the Seattle criteria.

Treatment plan

During this period, 33 patients developed corticosteroid refractory aGVHD. All patients received Inolimomab (Leukotac, EUSA Pharma, Limonest, France). The indication of treatment by Inolimomab was approved by the French agency AFSSAPS for each patient. All the patients gave their consent for data collection before transplantation. According to the French Regulations, all the patients were informed of the compassionate status of Inolimomab. Figure 1 describes the management of refractory aGVHD. During the ‘induction phase’, Inolimomab was administered once daily at 0.3 mg/kg per day (i.v.) after systematic antiallergic premedication (Dexchlorphéniramine, 1 injection i.v.).29 All patients received Inolimomab for at least 10 days regardless of the response to the therapy. MMF was added when Inolimomab was started in order to prevent a subsequent evolution of aGVHD during the Inolimomab tapering if MMF was not included in the conditioning regimen GVHD prophylaxis. When Inolimomab treatment was started, original prophylaxis of aGVHD was continued, and methylprednisolone was decreased to 1 mg/kg per day once aGVHD was under control. Response to Inolimomab was evaluated between D10 and D15 of the therapy. In case of CR, Inolimomab infusions were reduced from 3 times a week to twice then to once a week at the same dose (‘maintenance regimen phase’), and tapered at a pace depending on the persistence of the response. This maintenance treatment could be shortened or even canceled in case of severe infectious complications in order to reduce immunosuppression.

Figure 1
figure1

Treatment algorithm of aGVHD and response criteria to steroids and Inolimomab.

In case of PR, Inolimomab was continued daily and CsA was substituted for Tacrolimus.30, 31 In case of failure, Inolimomab was stopped, and patients received ATG as third line treatment.

Response criteria

CR was defined as a complete resolution of all signs of aGVHD; PR as a reduction of aGVHD to a less severe grading. Failure to Inolimomab was defined by an absence of improvement or a worsening of aGVHD. First of all, the response to Inolimomab was evaluated after the induction phase with Inolimomab (best response between D10 and D15), because of the therapeutic choice of our Inolimomab-based algorithm. Then, the response to our protocol was evaluated at D28 and D56.32, 33, 34

Infections

During ‘induction phase’ of Inolimomab and as long as corticosteroid therapy was higher than 1 mg/kg per day, patients were under laminar airflow isolation to prevent from opportunistic fungal infections. They were discharged from the hospital only when Inolimomab was on maintenance regimen phase. During induction phase and until the stop of Inolimomab, opportunistic infections were screened by systematic daily bacterial blood cultures, by weekly fecal cultures and by CMV and Aspergillosis Antigenemia twice a week.2 Blood monitoring for other infectious agents (Human Herpes Virus-6, EBV Toxoplasma gondii and JC Virus) were supervised according to serological recipient/donor status, clinical or biological signs.

Statistical analysis

Analyses were performed as of 1st November 2010. Survival curves and cumulative incidence were generated using the method of Kaplan–Meier and compared using the log-rank test between groups. A multivariate analysis was performed using the Cox proportional Hazards model. The variables considered for inclusion within the multivariate analysis were: patient characteristic’s (age<40 years vs40 years, gender and acute leukemia vs lymphoid hemopathy), conditioning regimen (standard vs reduced or addition of ATG vs no ATG), origin of graft (identical sibling vs unrelated), HLA compatibility (HLA identical related vs HLA-matched unrelated vs HLA mismatched unrelated), source of stem cells (BM vs PBSC vs cord blood), grade of aGVHD (2 vs 3 and 4), initial response to corticosteroids (resistance or dependence) and response to Inolimomab (complete vs partial). The median follow-up for alive patients was 4.9 years (range 2.9–8 years).

Results

Among the 33 patients with corticosteroid refractory aGVHD, 7 patients (21%) had grade 2 aGVHD and 26 patients (79%) had grade 3 or 4 aGVHD (Table 2). Seven patients developed an ‘isolated skin form’ and 26 patients developed a ‘visceral form’.

Table 2 Distribution of acute GVHD at the start of treatment with Inolimomab in the cohort of 33 patients with a corticosteroid refractory form

The median time between the introduction of high dose corticosteroids and the start of Inolimomab was 15 days (range 3–36 days). In case of corticosteroid resistance, this mean period was shorter (7 days, range 3–14 days) than in case of corticosteroid dependence (24 days, range 15–36 days).

Response to therapy

The median duration of ‘induction phase’ with Inolimomab was 17 days (range 10–40 days). The median duration of ‘maintenance treatment’ was 20 days (range 0–73 days), and has been canceled in four cases because of immunosuppressive treatment complications. No acute infusion related side effects were observed. Seventeen patients (52%) achieved a CR (sustained 1 month for 16 patients), 14 patients (42%) a PR and 2 patients (6%) failed to respond. CR was observed more frequently for ‘isolated skin form’ (86%) than for ‘visceral form’ of aGVHD (41%). In case of PR, Tacrolimus was added and a CR was subsequently obtained for 12 patients in the month following its introduction.

The evaluation of the treatment response at D28 showed CR in 24 cases (73%), PR in 6 cases (18%). At D56, CR was observed for 27 patients (82%). At M6, CR was observed for 26 patients (79%) without resort to a different systemic treatment since our Inolimomab-based algorithm.

OS, transplant related mortality

The OS rate were 79% (95%CI:61–89%) and 54.5% (95%CI:36.3–69.6%) at 1 and 3 years, respectively (Figure 2). The TRM rate were 15.5% (95%CI:6.7–33.3%) and 29.7% (95%CI:16.6–49.6%) at 1 and 3 years, respectively.

Figure 2
figure2

Kaplan–Meier OS (left) and TRM (right) curves of corticosteroid refractory aGVHD patients treated with Inolimomab from the time of HSCT. At 3 years: OS=54.5% (95% CI=36.3–69.6%) and TRM=29.7% (95% CI=16.6–49.6%).

Sixteen patients died between D36 and D1213 post allograft including 10 deaths related to HSCT. Causes of death were refractory aGVHD for two patients (D79 and D36), relapse of initial disease for six patients, sepsis with documented infection for two patients, multiorgan failure without documented infection for two patients, obliterant bronchiolitis for two patients, one AML of donor origin and one death caused by air embolism.

Prognostic factors of OS and TRM

The results of univariate analysis showed that the two significant prognostic factors influencing OS were a CR to Inolimomab (P<0.01) and the age of patient under 40 years (P<0.05) (Figure 3). Characteristics of the graft (origin of graft, HLA compatibility and source of stem cells) have no impact on OS with the limitations of a small sample. There is no difference in OS among patients with corticosteroid resistant or corticosteroid dependent aGVHD before Inolimomab (Figure 4). After multivariate analysis with a Cox model, a CR to Inolimomab remained the unique prognostic factor on OS with a hazard risk of 0.243 (P=0.016, 95% CI=0.077–0.77059).

Figure 3
figure3

Kaplan–Meier OS curves of the two significant prognostic factors: response to Inolimomab (left, P<0.01) and age of patient (right, P<0.05).

Figure 4
figure4

Kaplan–Meier OS curve of a non significant factor: initial response to corticosteroids (P=0.684).

Two factors influenced TRM at 2 years: response to Inolimomab (P<0.001) and age of patient under 40 years (P<0.05). A trend for an influence of extensive cGVHD on TRM (P=0.0525) was observed.

Infectious complications

Systematic blood culture during Inolimomab induction was positive for eight patients (Table 3). During the long-term follow-up, we noticed severe bacterial infection (n=5), Clostridium difficile colitis (n=4) and pulmonary infection (n=4).

Table 3 Occurrence of infections after allogeneic HSCT for 33 patients treated with Inolimomab for corticosteroid refractory acute GVHD

Primarily CMV reactivation occurred in eight patients (D31–D50) and EBV reactivation in two patients (D63, D128). Eight patients were affected by BK virus with hemorrhagic cystitis associated with acute renal failure for two of those patients. Three episodes of zoster and one of viral retinitis appeared after tardive reactivation of GVHD.

Chronic GVHD

Thirty patients were evaluable for cGVHD. Twenty-eight patients developed a cGVHD, which was limited in nine patients (32%) and extensive in 19 patients (68%). cGVHD was more frequent in patients with a PR (Table 4).

Table 4 Chronic graft versus host disease and deaths according to response to Inolimomab

Concerning the 19 patients with extensive cGVHD, eight patients (42%) are still alive, six of them are currently treated with immunosuppressive treatment (four patients with corticosteroids 10 mg per day, one patient with corticosteroids and Sirolimus and one patient with MMF). Concerning the social impact of allogeneic HSCT and refractory aGVHD, 12 of the 14 alive working age patients resumed their professional occupation.35, 36

Discussion

Upfront treatment with 1–2 mg/kg per day corticosteroids for acute GVHD is well described and consensual but 20–40% of patients need a second line of treatment. Currently, treatments for corticosteroid refractory aGVHD are not consensual and results are generally disappointing. The aim of these treatments is to obtain a rapid and persistent CR, which incidentally helps to decrease immunosuppressive treatments and reduce infectious hazard. In order to obtain this response, we think that a relay treatment of induction phase and immediate management of PR are essential.

We report here for the first time a unique algorithm of corticosteroid refractory aGVHD management with Inolimomab and MMF as induction treatment, relayed by an Inolimomab tapering and a continuation of MMF as relay treatment. In case of PR, the calcineurin inhibitor was substituted as an immunosuppressive escalation. Our study has the advantages to be exhaustive, homogeneous and monocentric, particularly thanks to the use of a predefined unique therapeutic algorithm for consecutively treated patients. The lower TRM and the long-term follow-up allows us to analyze cGVHD in case of corticosteroid refractory aGVHD, which is not well-known.

Comparison with some previous studies about IL-2 receptor Abs is difficult because of advances made in the knowledge concerning HSCT since 1990s (reduced conditioning regimen with older patients, antiviral and antifungal treatments).11, 14, 15, 16, 17, 19, 20, 37 Nevertheless, we found similarities about initial induction phase. Indeed, we noticed no acute infusion related side effects, and a better response in case of skin refractory aGVHD. Initial responses after induction phase are similar to those found in the literature: around 75% for skin forms and 33% for visceral forms. We also found two known prognostic factors associated with OS, which are initial response to mAbs and age.

Our results differ from other studies in terms of OS (79% 1 year after HSCT) and TRM (15.5% 1 year after HSCT).14 These results are also confirmed after 3 years. Mac Millian et al.23 suggested the influence of a prompt response on TRM for 2 years in case of aGVHD, and proposes an endpoint for clinical trials at D28 after the beginning of corticosteroid therapy. The initial addition of MMF and the rapid replacement of CsA by Tacrolimus differ from the other studies, and are probably crucial points to obtain better late results, especially in visceral forms of aGVHD. Indeed, the majority of PRs after Inolimomab induction become complete after the replacement of CsA by Tacrolimus. Two reasons explain our choice of Tacrolimus: its probably superior action to CsA and its rapid efficacy in contrast to other molecules with longer t1/2, such as Sirolimus for example.31 Additionally, a potential effect of MMF on PR cannot be ruled out. The definition of PR is not consensual, but it allowed us in this therapeutic algorithm to adapt immediately the treatment thanks to a premature evaluation of the response. This has probably increased the rate of CRs at D28 (73%) and D56 (82%), especially in visceral forms of aGVHD where initial CRs were lower.

In cases of corticosteroid refractory aGVHD, the main cause of death is infectious. Our study shows a low-level of infection and a low TRM. Regarding the infectious risks to treatment by mAbs, studies of Perales et al.14 and Przepiorka et al.17 found a death rate from opportunistic infections with Daclizumab, respectively of 79 and 65%.14, 17 Opportunistic infections developed in 95% patients in Perales’s study. We believe that two explanations could be proposed to explain our low infectious risk. First, proactive management of infectious hazard, as well as progress in antimicrobial treatments contributed to reduce initial TRM. Second, relapses of aGVHD after Inolimomab induction were rare, allowing for a rapid corticosteroids decrease, which has an important role to reduce infections. We think that our treatment algorithm reduce this hazard of relapse especially important in others studies.20

Concerning long-term mortality, it is interesting to note that no patient with an initial CR to Inolimomab died of TRM. However, long-term TRM was higher in the group of patients with an initial PR with Inolimomab probably because of longer period to obtain CR. More intensive immunosuppressive treatments seem to be necessary, but major immunodepression can induce a higher mortality as shown in a recent study.22 A prompt immunosuppressive escalation will be more appropriate in visceral forms aGVHD for example, with an earlier substitution of calcineurin inhibitor to quickly obtain CR.

The frequency of cGVHD (especially extensive forms) is higher in our study compared with results of Hervé et al.19, 37 (Inolimomab, 58% for 1 year) or Patriarca (Infliximab, 55%) that might be explain by longer follow up and a lower 1-year TRM. Limited forms seem to be correlated with a better OS, but it is not a statistically significant correlation probably because of small populations. Inolimomab has been suspected to increase cGVHD risk by inhibiting regulatory T cells.38 In our study, risk of severe cGVHD is above all associated with response to treatment, with more than 50% of patients free of extensive cGVHD in case of CR to Inolimomab. Despite the significant social impact of cGVHD, 85% of patients surviving corticosteroid refractory aGVHD could go back to work.35, 39

Our study confirms the efficacy of treatment by Inolimomab in case of corticosteroid refractory aGVHD. A French multicentric study (INO-0107) is currently open to compare Inolimomab with ATG in corticosteroid refractory aGVHD. In our opinion, management of corticosteroid refractory aGVHD should not be limited to the choice of an induction treatment. It must be associated with strict infection prevention and monitoring protocols, and a predefined management in the case of PR to obtain a rapid CR, which is a favorable prognostic factor for mortality after hematopoietic SCT.

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Acknowledgements

We thank Dr Emmanuel GYAN (Department of Hematology and Cellular Therapy, Hôpital Bretonneau, Tours) and Dr Régis PEFFAULT de la TOUR (Hematology-BMT, Hôpital Saint Louis, Paris) for their critical reading of the manuscript. We are grateful to EUSA Pharma for computer support and to Association Pictave pour l′ Etude des Maladies du Sang (APEMSA) for financial support.

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Correspondence to F Guilhot.

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Girerd, S., Renaud, M., Guilhot, J. et al. Long-term follow-up of corticosteroid refractory acute GVHD treated with an Inolimomab-based algorithm: a single center experience. Bone Marrow Transplant 48, 1243–1248 (2013) doi:10.1038/bmt.2013.16

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Keywords

  • corticosteroid refractory acute GVHD
  • IL-2 receptor antagonist
  • Inolimomab
  • chronic GVHD

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