Case Report Refractory Chronic GVHD Emerging After Splenectomy in a Marrow Transplant Recipient with Accelerated Phase CML

Bone Marrow Transplantation (2003) 32, 333–335 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Case report Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML

CA Rodrigues, FA Fermino, Y Vasconcelos and JSR de Oliveira

Hospital Sa˜o Paulo, Sa˜o Paulo, Brazil

Summary: between splenectomy and worsening of GVHD.5–8 We report a case in which this association clearly occurred. We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G- Case report CSF associated with progressive splenomegaly and RBC/ platelet transfusion dependency were present from day 39-year-old female patient presented with fatigue and +60 after BMT. MRD assessed by FISH and RT-PCR abdominal fullness.Massive splenomegaly was found and multiplex for BCR-ABL rearrangement was negative, and WBC showed marked leukocytosis (160 Â 109/l) with left- complete chimerism was documented by VNTR on days shifted myeloid series and basophilia.Bone marrow +100, +180, +360 and 2 years after BMT. Splenect- aspiration and Ph1 chromosome positivity confirmed the omy was performed on day +225 and pancytopenia diagnosis of CML.She was admitted for HLA identical resolved but chronic extensive graft-versus-host disease sibling donor BMT, and the conditioning regimen consisted developed, with hepatic cholestasis, diffuse scleroderma of busulphan (16 mg/kg)/cyclophosphamide (120 mg/kg).9 and sicca-like syndrome. She was sequentially and GVHD prophylaxis consisted of short-term methotrexate progressively treated with different immunosuppressive plus cyclosporine (CyS).10 Engraftment occurred on day therapy combinations with no clear benefit. On day +940, +28.On day +60, a routine CBC showed pancytopenia she presented with infection over the previously present (WBC 2.2 Â 109/l with ANC 0.602 Â 109/l, hemoglobin ulcers on both limbs, which culminated in septic shock of 7.2 g/dl and platelet count of 23 Â 109/l) associated with and death on day +1041. We conclude that, although progressive splenomegaly.Bone marrow aspiration and splenectomy may reverse poor graft function after biopsy revealed a normocellular marrow.Over the next allogeneic BMT, hyposplenism may trigger or worsen 5 months, she had eight febrile neutropenic episodes chronic extensive GVHD leading to increased morbidity requiring hospital admission and treatment with broad- and mortality. spectrum antibiotics.Daily subcutaneous 5 mg/kg G-CSF Bone Marrow Transplantation (2003) 32, 333–335. infusions were given for 14 days with no improvement.She doi:10.1038/sj.bmt.1704122 received a total of 19 U of RBC and 75 random units Keywords: BMT; chronic GVHD; splenectomy of platelets.G-Band karyotyping was normal.MRD searched by FISH and RT-PCR multiplex for BCR-ABL rearrangements were negative and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 Allogeneic BMT is a therapeutic option for many years after BMT.We concluded that the patient was hematologic malignancies and the only curative available entirely donor on chimerism studies and had evidence of treatment for CML to date.Graft-versus-host disease hypersplenism. (GVHD) remains one of the major complications and has As she remained pancytopenic and transfusion depen- a high mortality rate.Splenectomy has been undertaken to dent for more than 7 months after BMT, splenectomy was reverse poor graft function because of hypersplenism after performed on day +225.The spleen had no morphological allogeneic BMT, with satisfactory results.1–3 Previous or cytogenetic evidence of tumor.Pancytopenia and studies indicate that surgical or functional postallogeneic dependency on transfusion resolved after splenectomy. BMT hyposplenism may be associated with a higher Edema and rash in both forearms and hands were seen incidence of chronic extensive GVHD.4 However there on day +260 and evolved into a diffuse scleroderma are conflicting data in the literature about the relationship (Figure 1).As part of the extensive c-GVHD, a sicca-like syndrome and liver cholestasis were diagnosed at that time. She was sequentially treated with CyS plus prednisone and weekly high-dose immunoglobulin infusions.CyS was Correspondence: Dr JSR Oliveira, Division of Hematology, Universi- dade Federal de Sa˜ o Paulo, R.Botucatu, 740 30 andar Sa ˜ o Paulo, discontinued on day +921 because of acute renal failure. SP 04023 900, Brazil On day +486, she developed Herpes Zoster lesions on the Received 1 November 2002; accepted 3 February 2003 trunk that progressed to local ulceration with secondary Chronic extensive GVHD after splenectomy in BMT for CML CA Rodrigues et al 334 complications were required.On day +1034, she had a Staphylococcus aureus systemic infection with worsening of the limb ulceration, culminating in septic shock and death on day +1041.

Discussion

We describe a patient who underwent allogeneic BMT for CML in accelerated phase and developed a severe and persistent pancytopenia in the post transplant period associated with splenomegaly and hypersplenism.Splenect- omy was performed and the pancytopenia resolved, but a progressive de novo chronic extensive GVHD emerged after the surgery.All immunosuppressive measures adopted failed to change the course of the chronic GVHD which had a fatal outcome. Post transplant hypersplenism was first described in 1992 and should be considered in patients presenting with pancytopenia and splenomegaly after allogeneic BMT.It has been associated with splenic hypervascularity, and expanded vascular capacity and proliferation of infused stem cells in the spleen, possibly related to physical impediment of flow.3 Splenectomy has been shown to Figure 1 Sclero-like lesions. resolve pancytopenia in 11 previously reported cases, with no associated comorbidity.1–3 Accordingly, in the present case, splenectomy successfully resolved the pancytopenia. There is controversy in the literature regarding the relationship between splenectomy and chronic GVHD. Ringde´ n et al5 have shown an increased incidence of acute GVHD and higher death rate in patients splenectomized before BMT.The same European group confirmed later that splenectomy was an important risk factor for acute and chronic GVHD on bivariate analysis and in only chronic GVHD on multivariate analysis.6 Michallet et al7 evaluated 157 patients who underwent BMT from an HLA- identical sibling and found that splenectomy was the most important factor determining GVHD severity on multi- variate analysis.However, a more recent retrospective analysis to evaluate the role of splenectomy on BMT outcome showed no significant influence of splenectomy on acute or chronic GVHD, although it was associated with an increased risk for all grades of acute GVHD, but this was not statistically significant.8 The exact mechanism of the influence of splenectomy on GVHD incidence and severity is not known.The most likely hypothesis is that the spleen functions as a ‘filter’ for activated T cells by the activity of HLA-DR and CD1a- positive cells (dendritic cells).11 Donor-derived alloreactive T cells, post-thymic activated CD4+ T cells and T cells Figure 2 Limb ulcerations. immunoreactive to minor HLA antigens, which are extremely important in the pathogenesis of chronic GVHD, could then possibly be ‘cleared’ by the spleen.By this mechanism, the spleen may also play a role in modulating infection and concomitant ulceration of both limbs the activation of different helper T-cell subsets (Th1 vs Th2) (Figure 2).She underwent hyperbaric oxygen therapy with minimizing the effects of cytokines secreted by Th2 cells some recovery.The generalized scleroderma evolved to (IL-4, IL-5, IL-10), which predominate in chronic affect the trunk and limbs.A year post transplant, PUVA GVHD.12 The other two hypotheses include the role of therapy associated with daily MMF (2 g), thalidomide the spleen in the modulation of infections,13 and its (600 mg) and prednisone (80 mg) were sequentially and production of an immunosuppressive peptide in animal progressively initiated.Several admissions for infectious studies, never found in human studies.14 Infection was

Bone Marrow Transplantation Chronic extensive GVHD after splenectomy in BMT for CML CA Rodrigues et al 335 constantly present in this case: before splenectomy because of cytomegalovirus serology in recipients and donors – acute of severe neutropenia and after splenectomy because of graft-versus-host disease, and splenectomy. Transplantation severe chronic GVHD, despite a normal neutrophil count. 1990; 49: 1100–1105. We believe that infection was also an important risk factor 7 Michallet M, Corront B, Bosson JL et al.Role of splenectomy in the development of chronic GVHD in this case. in incidence and severity of acute graft-versus-host disease: a Bone Marrow Transplant It is also important to emphasize that the patient multicenter study of 157 patients. 1991; 8: 13–17. remained in continuous complete remission during the 8 Kalhs P, Schwarzinger I, Anderson G et al.A retrospective whole post transplant period and that a chronic GVHD- analysis of the long-term effect of splenectomy on late associated GVL effect may have had an important role. infections, graft-versus-host disease, relapse, and survival after We conclude that, although splenectomy may reverse allogeneic marrow transplantation for CML. Blood 1995; 86: poor graft function after allogeneic BMT, surgical hypo- 2028–2032. splenia may trigger or worsen chronic extensive GVHD 9 Santos GW, Tutschka PJ, Brookmeyer R et al.Marrow leading to an increase in morbidity and mortality. transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Eng J Med 1983; 309: 1347–1353. References 10 Storb R, Deeg HJ, Whitehead J et al.Marrow transplantation for leukemia and aplastic anemia: two controlled trials of a 1 Richard C, Romon I, Perez-Encinas M et al.Splenectomy for combination of methotrexate and cyclosporine vs cyclosporine poor graft function after allogeneic BMT in patients with alone for prophylaxis of acute graft-vs-host disease. Transplant chronic myeloid leukemia. Leukemia 1996; 10: 1615–1618. Proc 1987; 19: 2608. 2 von Bueltzingsloewen A, Bordigoni P, Dorvaux Y et al. 11 Korngold R, Sprent J.Lethal GVHD across minor histo- Splenectomy may reverse pancytopenia occurring after allo- compatibility barriers: nature of the effector cells and role of geneic BMT. Bone Marrow Transplant 1994; 14: 339–340. the H-2 complex. Immunol Rev 1983; 71: 5–29. 3 Grigg AP, Berean K, Shore T, Phillips GL.Pancytopenia due 12 Rus V, Svetic A, Nguyen P et al.Kinetics of Th1 and Th2 to hypersplenism after allogeneic BMT. Bone Marrow Trans- cytokine production during the early course of acute and plant 1992; 10: 177–179. chronic murine graft-versus-host disease. J Immunol 1995; 155: 4 Cuthbert RJ, Iqbal A, Gates A et al.Functional hyposplenism 2396–2406. following allogeneic BMT. J Clin Pathol 1995; 48: 257–259. 13 Baumgartner JD, Glauser MP, Burgoblack AL et al.Severe 5 Ringden O, Nilsson B.Death by graft-versus-host disease cytomegalovirus infections in multiply transfused, splenecto- associated with HLA mismatch, high recipient age, low marrow mized trauma patients. Lancet 1982; 2: 63–66. cell dose, and splenectomy. Transplantation 1985; 40: 39–44. 14 Garcia-Girarlt E, Morales VH, Lasalvia E et al.Suppression of 6 Bostrom L, Ringden O, Jacobsen N et al.A European graft-versus-host reaction by a spleen extract. J Immunol 1972; multicenter study of chronic graft-versus-host disease.The role 109: 878–880.

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