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Severe acute GvHD following administration of ipilimumab for early relapse of AML after haploidentical stem cell transplantation

Bone Marrow Transplantation volume 52, pages 1047–1048 (2017)Cite this article

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Relapse of AML after allogeneic stem cell transplantation (HSCT) is associated with a dismal prognosis and the best therapeutic strategy remains to be established. Treatments usually include chemotherapeutic agents and immunological interventions (donor lymphocyte infusion or second HSCT).1, 2 Several immune mechanisms may explain relapse after HSCT, such as a partial loss of chromosome 6 (HLA locus), and might explain the absence of a GvL effect and subsequent extramedullary AML relapse in tissues with reduced immune surveillance.3 Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is a member of the Ig superfamily important in regulation of peripheral tolerance.4 Expressed by conventional T cells upon activation, it competes with co-stimulatory receptor CD28 for the B7 ligands CD80 and CD86 on Ag-presenting cells and acts as an important negative regulator of Ag-specific T-cell response. CTLA-4 is critical for peripheral self-tolerance and tolerance to tumor Ags. CTLA-4 constitutive expression on leukemic cells was previously reported and in vitro use of anti-CTLA-4 agents induced robust apoptosis of AML cell lines.5, 6 Therefore, blocking this immune checkpoint to promote a GvL effect represents an appealing strategy in patients with AML relapse after HSCT. Unfortunately, available data on immune checkpoint blockade-targeting drugs after transplant are scarce. Two studies suggested that ipilimumab, a blocking anti-CTLA-4 human Ab, could be an interesting approach in patients with post-transplant relapse.7, 8 Using a dose of 10 mg/kg, Davids et al.7 described an overall response of 32%. Diagnoses included 12 patients with (43%) AML; the median time from transplantation to treatment was 675 days and no patient was treated within 3 months after transplant. Fifteen (54%) patients received a graft from a matched related donor and no haploidentical transplantation was included. Eight patients (29%) had GvHD before ipilimumab infusion. Observed immune-related adverse events after infusion were colitis, diarrhea, immune thrombocytopenic purpura and pneumonitis (including 1 grade IV pneumonitis). Only 4/28 patients developed GvHD after ipilimumab including three with liver chronic GvHD and one with gut grade II acute GvHD. They resolved with glucocorticoids. With a median follow-up of 15 months, 1-year overall survival was 49%.We report here the case of a 26-year-old Caucasian male with no prior medical history, diagnosed with AML-M5 in May 2016. The clinical examination was normal at diagnosis. Blood count showed 222 × 109/L leukocytes with 95% of leukemic cells, 126 × 109/L platelets and 114 g/L hemoglobin. Cytogenetics revealed an adverse karyotype (46, XY, t(10;11)(p11;q23)).9, 10, 11 Next-generation sequencing showed a clonal (6%) KRAS mutation. A 7+3 first induction course (daunorubicin 90 mg/m2/day 3 days and cytarabine 200 mg/m2/day 7 days) was started in the intensive care unit the day after admission. On day 32, the blood cell count was normal and a bone marrow aspirate showed cytological remission. Then, the patient underwent a first consolidation therapy with high-dose cytarabine (18 g/m2). During aplasia, he complained of testicular pain with an infiltrative lesion on ultrasound and the blood count concomitantly revealed circulating blasts. Skin lesions appeared on his chest and a skin biopsy was consistent with an extramedullary localization of AML. We performed salvage chemotherapy with gemtuzumab ozogamicin (GO) (9 mg/m2 on a single day, on 1 July). Fifteen days later, a bone marrow aspirate showed profound aplasia without any blast cells. However, skin lesions persisted. An haploidentical allogeneic transplantation was performed 21 days later with a reduced intensity regimen including fludarabine (30 mg/m2/day from d-6 to d-2), cyclophosphamide (14.5 mg/kg/day from d-6 to d-5) and TBI (2 Gy on d-1). We chose a reduced conditioning regimen to minimize the risk of veno-occlusive disease because GO was administered 15 days earlier. The donor was the patient’s father who donated G-CSF-mobilized peripheral blood cells containing 9.48 × 106 CD34+cells/kg of recipient. Day 0 was the day of transplant. GvHD prophylaxis consisted of cyclosporine (3 mg/kg/day from d+5), mycophenolate mofetil (15 mg/kg/day from d+5 to d+35) and cyclophosphamide (50 mg/kg/day d+3, d+4) as previously described.12 Skin lesions disappeared by d+2 and the patient left hospital on d+30 with complete hematologic reconstitution, and >95% donor chimerism performed on d+28 on total peripheral blood cells. A grade II skin GvHD was diagnosed on d+31. Methylprednisolone 2 mg/kg/day was immediately started with a complete response after 7 days. Simultaneously, on d+33, specific diffuse skin lesions rapidly progressed with a non-infectious fever. The biopsy was again consistent with an extramedullary localization of AML. Cyclosporine and MMF were both stopped on day 33 with no effect on disease progression and no reactivation of GvHD during the following days. On the basis of this dismal evolution with a relatively conserved performance status, our patient underwent at d+63 after transplant an off-label 10 mg/kg infusion of ipilimumab. At that time, the absolute lymphocyte count was 1.36 × 109/L. The immediate tolerance was excellent. No effect on extramedullary disease was observed with a continuous progressive disease. On day 5 after infusion, a stage 1 skin GvHD was diagnosed. On day 9, the skin rash progressed to stage 3 (grade II) and treatment with methylprednisolone 2 mg/kg/day was started without effect. On day 15, the acute GvHD progressed to stage 4 for skin (generalized erythroderma with bullous formation), stage 2 for gastro-intestinal tract (diarrhea 1000–1500 ml per day without infectious cause) and stage 2 for liver (maximum bilirubin 4 mg/dl). A workup for viral etiology (EBV, hepatitis B,C,E, CMV, adenovirus and HHV6) was negative. The abdominal ultrasound was normal. Despite this acute grade IV GvHD, the disease progressed and the patient developed leukemic meningitis. Considering the extreme alteration of performance status and the progression of the disease, no liver biopsy was performed and the patient was given the best supportive care until death on day 19 after ipilimumab injection.To our knowledge, this is the first case of severe acute GvHD following an anti-CTLA-4 Ab administered shortly after haploidentical transplantation. Severe GvHD reports were reported with other immune checkpoint inhibitors using the PD1 pathways.13, 14, 15 These reports included a fatal GvHD using pembrolizumab in a patient with relapse of Hodgkin’s lymphoma after genoidentical bone marrow transplantation and a fatal steroid refractory acute GvHD 2 years after HSCT for the same disease with an unrelated donor after treatment with nivolumab. Herbaux et al.15 reported 2 (17%) grade III or IV GvHD after post-transplant nivolumab infusion. All these patients had a prior history of GvHD after transplantation. No data are available with immune checkpoint inhibitory drugs used earlier, within 3 months after HSCT, a period with the highest risk of acute GvHD. Furthermore, we report no beneficial effect of ipilimumab on tumor burden in our patient. Finally, even if immune checkpoint inhibitors might be useful for treating relapse after HSCT, our case suggests that their use should be carefully discussed in the case of a haploidentical donor and early relapse, given the risk of severe acute GvHD.

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Authors and Affiliations

  1. Department of Hematology and Cell Therapy, University Hospital, Bordeaux, France

    F-X Gros, T Cazaubiel, E Forcade, T Leguay, R Tabrizi, L Clement, P-Y Dumas, A Pigneux, S Vigouroux & N Milpied

  2. Laboratory of Hematology, University Hospital, Bordeaux, France

    N Lechevalier & A Bidet

  3. Department of Pharmacy, University Hospital, Bordeaux, France

    V Servant

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Gros, FX., Cazaubiel, T., Forcade, E. et al. Severe acute GvHD following administration of ipilimumab for early relapse of AML after haploidentical stem cell transplantation. Bone Marrow Transplant 52, 1047–1048 (2017). https://doi.org/10.1038/bmt.2017.78

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