Long-Term Follow-Up of Corticosteroid Refractory Acute GVHD Treated with an Inolimomab-Based Algorithm: a Single Center Experience

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

S Girerd1, M Renaud2, J Guilhot3, C Giraud1,5, R Larchee1, I Jollet4 and F Guilhot1,3

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.

Bone Marrow Transplantation (2013) 48, 1243–1248; doi:10.1038/bmt.2013.16; published online 18 March 2013 Keywords: corticosteroid refractory acute GVHD; IL-2 receptor antagonist; Inolimomab; chronic GVHD

INTRODUCTION management of partial response (PR) leads to sustained high dose Allogeneic hematopoietic SCT (HSCT) is an effective treatment corticosteroids, which may account for increased infectious procedure for various malignant and nonmalignant hematologic complications. Secondly, frequent aGVHD relapses after 23 disorders. Over the past few years, alternatives to myeloablative induction phase increase TRM. HSCT have been successfully developed with reduced-intensity We retrospectively describe the long-term follow-up (median conditioning procedures and diversification of HSCT sources 4.9 years for live patients) outcome of a monocentric cohort of allowing for an increased number of indications (B25 000 33 consecutive patients with corticosteroid refractory aGVHD allogeneic HSCT per year worldwide) and a lower transplant who were treated by an Inolimomab-based algorithm between related mortality (TRM).1 Nevertheless, acute GVHD (aGVHD), 2002 and 2008. These 33 patients received an additional relay mostly corticosteroid refractory forms (10–50% of aGVHD), treatment to decrease the relapse risk of aGVHD, and a predefined contribute to an important morbidity and mortality, and thus treatment in case of PR. We also report the OS and the occurrence remain a major challenge.2 To date, there is no consensus for the of chronic GVHD (cGVHD) in this cohort. 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 MATERIALS AND METHODS respond (partial and complete responses (CR)) to ATG.2–5 New Patients therapies have been developed such as mAbs targeting the IL-2 Between October 2002 and January 2008, at CHU (Center Hospitalier receptor (Inolimomab, Daclizumab and Basilixumab), as well as the Universitaire) of Poitiers, 161 consecutive patients were treated by TNFor CD52.6–20 The murine Ab Inolimomab recognizes the allogeneic HSCT with a majority of unrelated donors (67%). Among these a-subunit of the IL-2 receptor (CD25) and could be an efficient 161 patients, 93 (58%) developed grade X2 aGVHD and 33 patients (20%) treatment for corticosteroid refractory aGVHD by blocking the developed a corticosteroid refractory aGVHD. No patient died during initial action of IL-2, and by inhibiting the proliferation of activated treatment before Inolimomab, and all corticosteroid refractory forms were T lymphocytes.6,7,13,21 However, treatment with recent monoclonal treated by our Inolimomab-based algorithm. Most of these 33 patients had been transplanted for hematologic anti-IL-2 receptor Abs (in association with an anti-TNF AB or 14,15,17,22 malignancies (Table 1). The median age was 44 years (range 17–65) and not) are associated with a high infectious risk. the mean time between diagnosis and allogeneic HSCT was 689 days Beyond response to therapy, two majors problems remain. First, (range 110–5554 days). Six patients were allografted with HLA identical

1Department of Haematology and Oncology, Centre Hospitalier de Poitiers, Poitiers, France; 2Department of Haematology and Cellular Therapy, Centre Hospitalier Bretonneau, Tours, France; 3Inserm CIC 0802, Centre Hospitalier de Poitiers, Poitiers, France; 4HLA Laboratory, Etablissement Franc¸ais du Sang de Poitiers, Poitiers, France and 5Laboratoire therapie cellulaire EFS-CA, site de Poitiers, Poitiers, France. Correspondence: Professor F Guilhot, Inserm CIC 0802, Centre Hospitalier de Poitiers, 2 rue de la miletrie, Poitiers 86021, France. E-mail: [email protected] Received 9 November 2011; revised 19 July 2012; accepted 29 December 2012; published online 18 March 2013 Acute GVHD S Girerd et al 1244 ≥ Table 1. Clinical characteristics, conditioning regimen and type of aGVHD grade 2 or grade1>5days Maintenance regimen phase of Inolimomab graft of 33 patients treated for corticosteroid refractory acute GVHD (3times/week) with Inolimomab Steroid 2 mg/kg/day N 33 Sex ratio (male/female) 1.5 CR at D10-D15 Success after 7days Failure « steroid Median age (range) 44 years (17–65) resistance » Time diagnosis/HSCT 689 days (110–5554) Failure ATG ↓ steroid to 1mg/kg/d Induction phase Diagnoses by Inolimomab ALL/AML 9/6 (0.3 mg/kg/d) MDS 2 +MMF Partial response CLL/NHL 12 Persistence of Relapse of (PR) at D10-D15 complete aGVHD MM 2 response (CR) Medullary aplasia 1 « steroid MPS 1 dependence » Substitution ciclosporin/tacrolimus

GVHD prevention N (%) Abbreviations: aGVHD = acute GVHD; CR = complete response; PR = partial Ciclosporin þ MMF 14 (42.5) response; MMF = Mycophenolate Mofetil; ATG = anti-thymocyte globulin Ciclosporin þ MTX 18 (54.5) Ciclosporin alone 1 (3) Figure 1. Treatment algorithm of aGVHD and response criteria to steroids and Inolimomab. Donor source HLA identical sibling 6 (18) During the ‘induction phase’, Inolimomab was administered once daily HLA-matched unrelated 11 (33.5) at 0.3 mg/kg per day (i.v.) after systematic antiallergic premedication HLA-mismatched unrelated 7 (21) (Dexchlorpheńiramine, 1 injection i.v.).29 All patients received Inolimomab Cord blood 9 (27.5) 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 Stem cell source evolution of aGVHD during the Inolimomab tapering if MMF was not Single cord blood 7 (21.5) included in the conditioning regimen GVHD prophylaxis. When Double cord blood 2 (6) Inolimomab treatment was started, original prophylaxis of aGVHD was PBSC 16 (48.5) continued, and methylprednisolone was decreased to 1 mg/kg per day BM 8 (24) once aGVHD was under control. Response to Inolimomab was evaluated Reduced-intensity conditioning regimen 13 (40) between D10 and D15 of the therapy. In case of CR, Inolimomab infusions ATG in conditioning regimen 8 (24) 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 Abbreviations: HSCT ¼ hematopoietic SCT; MDS ¼ myelodysplasic syndrome; depending on the persistence of the response. This maintenance NHL ¼ non-hodgkin’s lymphoma; MM ¼ multiple myeloma; MPS ¼ myelo- treatment could be shortened or even canceled in case of severe proliferative syndrome; MMF ¼ Mycophenolate Mofetil; ATG ¼ antithymocyte infectious complications in order to reduce immunosuppression. globulin. 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. 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) Response criteria or CsA alone. Thirteen patients received a reduced conditioning regimen, CR was defined as a complete resolution of all signs of aGVHD; PR as a and ATG was used for 8 patients in case of HLA mismatch or in case of reduction of aGVHD to a less severe grading. Failure to Inolimomab was some reduced conditioning regimen. 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 Diagnosis of GVHD therapeutic choice of our Inolimomab-based algorithm. Then, the response The diagnosis of aGVHD was primarily based on clinical findings according to our protocol was evaluated at D28 and D56.32–34 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 X3 with digestive and liver stagesp1) and a ‘visceral Infections form’ (digestive stageX2 and/or hepatic stageX2). Corticosteroid During ‘induction phase’ of Inolimomab and as long as corticosteroid treatment (methylprednisolone, i.v., 2 mg/kg per day, in divided doses) therapy was higher than 1 mg/kg per day, patients were under laminar 2,26,27 was started immediately after diagnosis of grade X2 aGVHD. airflow isolation to prevent from opportunistic fungal infections. They were Corticosteroid refractory aGVHD was defined as the association of discharged from the hospital only when Inolimomab was on maintenance corticosteroid resistance and corticosteroid dependence. Corticosteroid regimen phase. During induction phase and until the stop of Inolimomab, resistance was defined as the progression of aGVHD in the first 72 h opportunistic infections were screened by systematic daily bacterial blood of corticosteroid therapy or a lack of improvement after 7 days of cultures, by weekly fecal cultures and by CMV and Aspergillosis Antigenemia 9,28 corticosteroid therapy. The relapse of aGVHD during the corticosteroid twice a week.2 Blood monitoring for other infectious agents (Human Herpes decrease above 1 mg/kg per day defined corticosteroid dependence. The Virus-6, EBV Toxoplasma gondii and JC Virus) were supervised according to diagnosis of cGVHD was made according to the Seattle criteria. serological recipient/donor status, clinical or biological signs.

Treatment plan Statistical analysis During this period, 33 patients developed corticosteroid refractory aGVHD. Analyses were performed as of 1st November 2010. Survival curves and All patients received Inolimomab (Leukotac, EUSA Pharma, Limonest, cumulative incidence were generated using the method of Kaplan–Meier and France). The indication of treatment by Inolimomab was approved by the compared using the log-rank test between groups. A multivariate analysis was French agency AFSSAPS for each patient. All the patients gave their performed using the Cox proportional Hazards model. The variables consent for data collection before transplantation. According to the French considered for inclusion within the multivariate analysis were: patient Regulations, all the patients were informed of the compassionate status of characteristic’s (ageo40 years vsX40 years, gender and acute leukemia vs Inolimomab. Figure 1 describes the management of refractory aGVHD. lymphoid hemopathy), conditioning regimen (standard vs reduced or

Bone Marrow Transplantation (2013) 1243 – 1248 & 2013 Macmillan Publishers Limited Acute GVHD S Girerd et al 1245 addition of ATG vs no ATG), origin of graft (identical sibling vs unrelated), HLA 27 patients (82%). At M6, CR was observed for 26 patients (79%) compatibility (HLA identical related vs HLA-matched unrelated vs HLA without resort to a different systemic treatment since our mismatched unrelated), source of stem cells (BM vs PBSC vs cord blood), Inolimomab-based algorithm. 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). 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 RESULTS 15.5% (95%CI:6.7–33.3%) and 29.7% (95%CI:16.6–49.6%) at 1 and Among the 33 patients with corticosteroid refractory aGVHD, 3 years, respectively. 7 patients (21%) had grade 2 aGVHD and 26 patients (79%) had Sixteen patients died between D36 and D1213 post allograft grade 3 or 4 aGVHD (Table 2). Seven patients developed an including 10 deaths related to HSCT. Causes of death were ‘isolated skin form’ and 26 patients developed a ‘visceral form’. refractory aGVHD for two patients (D79 and D36), relapse of initial The median time between the introduction of high disease for six patients, sepsis with documented infection for two dose corticosteroids and the start of Inolimomab was 15 days patients, multiorgan failure without documented infection for two (range 3–36 days). In case of corticosteroid resistance, this mean patients, obliterant bronchiolitis for two patients, one AML of period was shorter (7 days, range 3–14 days) than in case of donor origin and one death caused by air embolism. corticosteroid dependence (24 days, range 15–36 days). Prognostic factors of OS and TRM Response to therapy The results of univariate analysis showed that the two significant The median duration of ‘induction phase’ with Inolimomab was prognostic factors influencing OS were a CR to Inolimomab 17 days (range 10–40 days). The median duration of ‘maintenance (Po0.01) and the age of patient under 40 years (Po0.05) treatment’ was 20 days (range 0–73 days), and has been canceled (Figure 3). Characteristics of the graft (origin of graft, HLA in four cases because of immunosuppressive treatment complica- compatibility and source of stem cells) have no impact on OS tions. No acute infusion related side effects were observed. with the limitations of a small sample. There is no difference in OS Seventeen patients (52%) achieved a CR (sustained 1 month for among patients with corticosteroid resistant or corticosteroid 16 patients), 14 patients (42%) a PR and 2 patients (6%) failed to dependent aGVHD before Inolimomab (Figure 4). After multi- respond. CR was observed more frequently for ‘isolated skin form’ variate analysis with a Cox model, a CR to Inolimomab remained (86%) than for ‘visceral form’ of aGVHD (41%). In case of PR, the unique prognostic factor on OS with a hazard risk of 0.243 Tacrolimus was added and a CR was subsequently obtained for (P ¼ 0.016, 95% CI ¼ 0.077–0.77059). 12 patients in the month following its introduction. Two factors influenced TRM at 2 years: response to Inolimomab The evaluation of the treatment response at D28 showed CR in (Po0.001) and age of patient under 40 years (Po0.05). A trend 24 cases (73%), PR in 6 cases (18%). At D56, CR was observed for for an influence of extensive cGVHD on TRM (P ¼ 0.0525) was observed.

Table 2. Distribution of acute GVHD at the start of treatment with Infectious complications Inolimomab in the cohort of 33 patients with a corticosteroid refractory form Systematic blood culture during Inolimomab induction was positive for eight patients (Table 3). During the long-term Site Stage follow-up, we noticed severe bacterial infection (n ¼ 5), Clostridium difﬁcile colitis (n ¼ 4) and pulmonary infection (n ¼ 4). 0 (%) 1 (%) 2 (%) 3 (%) 4 (%) Primarily CMV reactivation occurred in eight patients (D31–D50) and EBV reactivation in two patients (D63, D128). Eight patients Skin 13 (40) 7 (21) 4 (12) 8 (24) 1 (3) were affected by BK virus with hemorrhagic cystitis associated Liver 26 (79) 3 (9) 0 1 (3) 3 (9) with acute renal failure for two of those patients. Three episodes Gut 6 (18) 2 (6) 9 (27) 11 (34) 5 (15) of zoster and one of viral retinitis appeared after tardive reactivation of GVHD. Grade

12 3 4Chronic GVHD Thirty patients were evaluable for cGVHD. Twenty-eight patients Overall grade 0 7 (21) 19 (58) 7 (21) developed a cGVHD, which was limited in nine patients (32%) and

100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 Proportion of TRM Proportion surviving 20 20 10 10 0 0 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120 Months from HSCT Months from HSCT Figure 2. 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 ¼ 54.5% (95% CI ¼ 36.3–69.6%) and TRM ¼ 29.7% (95% CI ¼ 16.6–49.6%).

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 1243 – 1248 Acute GVHD S Girerd et al 1246 Response to inolimomab Age 100 100 CR ≥40 years 90 90 PR <40 years 80 80 70 70 60 60 50 50 40 40 30 30 Proportion of TRM

Proportion surviving 20 20 P = 0.008 P = 0.038 10 10 0 0 0 1224364860728496108120 0 12 24 36 48 60 72 84 96 108 120 Months from HSCT Months from HSCT Figure 3. Kaplan–Meier OS curves of the two signiﬁcant prognostic factors: response to Inolimomab (left, Po0.01) and age of patient (right, Po0.05).

100 R Table 3. Occurrence of infections after allogeneic HSCT for 33 90 D patients treated with Inolimomab for corticosteroid refractory acute 80 GVHD 70 60 oD100 4D100 50 Viral reactivation 17 5 40 CMV 8 (D31–D50) 0 30 EBV 1 (D63) 1 (D128) Proportion surviving BK virus (cystitis) 8 (D20–D100) 0 20 VZV (zoster) 0 3 (D150–D680) 10 Viral retinitis 0 1 (D434) 0 Systematic blood culture 90 0 12 24 36 48 60 72 84 96 108 120 Staphylococcus epidermidis 7 Months from HSCT Pseudomonas aeruginosa 1 Figure 4. Kaplan–Meier OS curve of a non signiﬁcant factor: initial Candida albicans 1 response to corticosteroids (P ¼ 0.684). Bacterial cystitis 5 0 Severe bacterial infection 05 Candida glabrata 1 (D1213) extensive in 19 patients (68%). cGVHD was more frequent in Enterococcus 1 (D449) patients with a PR (Table 4). Klebsiella pneumoniae 1 (D130) Concerning the 19 patients with extensive cGVHD, eight Salmonella 1 (D126) Streptococcus pneumoniae 1 (D230) patients (42%) are still alive, six of them are currently treated with immunosuppressive treatment (four patients with corticos- Pulmonary infection 04 teroids p10 mg per day, one patient with corticosteroids and Pneumocystis 1 (D210) Sirolimus and one patient with MMF). Concerning the social Aspergillus 1 (D430) impact of allogeneic HSCT and refractory aGVHD, 12 of the 14 alive Unknown bacteria 2 Clostridium difﬁcile colitis 0 4 working age patients resumed their professional occupation.35,36

DISCUSSION Table 4. Chronic graft versus host disease and deaths according to Upfront treatment with 1–2 mg/kg per day corticosteroids for response to Inolimomab acute GVHD is well described and consensual but 20–40% of patients need a second line of treatment. Currently, treatments for CR, n ¼ 17 PR, n ¼ 14 Failure, n ¼ 2 corticosteroid refractory aGVHD are not consensual and results are a a generally disappointing. The aim of these treatments is to obtain a cGVHD 15 13 — rapid and persistent CR, which incidentally helps to decrease Extensive 8 11 — immunosuppressive treatments and reduce infectious hazard. In Limited 7 2 — order to obtain this response, we think that a relay treatment of Death 4102 induction phase and immediate management of PR are essential. Relapse related 4 2 0 We report here for the first time a unique algorithm of HSCT related 0 8 2 corticosteroid refractory aGVHD management with Inolimomab Abbreviations: CR ¼ complete response; PR ¼ partial response; cGVHD ¼ and MMF as induction treatment, relayed by an Inolimomab chronic GVHD; HSCT ¼ hematopoietic SCT. aOne patient with PR and the tapering and a continuation of MMF as relay treatment. In case of two patients with failure to Inolimomab were not evaluable for cGVHD. PR, the calcineurin inhibitor was substituted as an immunosuppressive escalation. Our study has the advantages to be exhaustive, homogeneous and monocentric, particularly thanks Comparison with some previous studies about IL-2 receptor to the use of a predefined unique therapeutic algorithm for Abs is difficult because of advances made in the knowledge consecutively treated patients. The lower TRM and the long-term concerning HSCT since 1990s (reduced conditioning regimen with follow-up allows us to analyze cGVHD in case of corticosteroid older patients, antiviral and antifungal treatments).11,14–17,19,20,37 refractory aGVHD, which is not well-known. Nevertheless, we found similarities about initial induction phase.

Bone Marrow Transplantation (2013) 1243 – 1248 & 2013 Macmillan Publishers Limited Acute GVHD S Girerd et al 1247 Indeed, we noticed no acute infusion related side effects, and a management of corticosteroid refractory aGVHD should not be better response in case of skin refractory aGVHD. Initial responses limited to the choice of an induction treatment. It must be after induction phase are similar to those found in the literature: associated with strict infection prevention and monitoring around 75% for skin forms and 33% for visceral forms. We also protocols, and a predefined management in the case of PR to found two known prognostic factors associated with OS, which obtain a rapid CR, which is a favorable prognostic factor for are initial response to mAbs and age. mortality after hematopoietic SCT. 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 CONFLICT OF INTEREST aGVHD, and proposes an endpoint for clinical trials at D28 after The authors declare no conflict of interest. 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 ACKNOWLEDGEMENTS late results, especially in visceral forms of aGVHD. Indeed, the majority of PRs after Inolimomab induction become complete We thank Dr Emmanuel GYAN (Department of Hematology and Cellular Therapy, Hoˆpital Bretonneau, Tours) and Dr Re´gis PEFFAULT de la TOUR (Hematology-BMT, after the replacement of CsA by Tacrolimus. Two reasons explain Hoˆpital Saint Louis, Paris) for their critical reading of the manuscript. 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Bone Marrow Transplant 2007; 40: 481–486. of patients surviving corticosteroid refractory aGVHD could go 15 Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E et al. back to work.35,39 Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005; 130: 568–574. Our study confirms the efficacy of treatment by Inolimomab in 16 Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Do¨rken B, Arnold R. Basiliximab is case of corticosteroid refractory aGVHD. A French multicentric well tolerated and effective in the treatment of steroid-refractory acute graft- study (INO-0107) is currently open to compare Inolimomab versus-host disease after allogeneic stem cell transplantation. Bone Marrow with ATG in corticosteroid refractory aGVHD. In our opinion, Transplant 2002; 30: 899–903.

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