Fludarabine

We present a case of a 49-year-old man previously diagnosed with chronic myelogenous leukemia. His bone marrow biopsy showed a complex triple translocation involving chromosomes 9, 12, and 22. He received imatinib mesylate but failed to go into cytogenetic remission. For this reason, he underwent an allogeneic peripheral blood stem cell transplantation from his HLA-matched brother after conditioning with fludarabine (120 mg/m^sup 2^) and intravenous busulfan (12.8 mg/kg). After the transplant, the patient showed a stable mixed donor cell chimerism that ranged between 80% and 90%, despite early withdrawal of immunosuppression with tacrolimus. He achieved a cytogenetic complete response but remained positive for Bcr-Abl molecular detection. Since he did not develop any signs of graft-versus-host disease (GVHD), the patient was then infused with 2 doses of donor lymphocyte infusions (1 × 10^sup 8^ T cells/kg) at 6-week intervals. One week after the second infusion, he developed a limited skin rash, fever, and mouth vesicles and ulcers, suggestive of herpesvirus infection. These findings were accompanied by significantly increased liver function tests, as follows: aspartate aminotransferase, 342 U/L; alanine aminotransferase, 742 U/L; alkaline phosphatase, 188 U/ L; and total bilirubin, 2.8 mg/dL (48 µmol/L). Viral serologies were negative. A liver biopsy was performed.

The interlobular bile ducts showed swollen epithelial cells with dyspolarity of nuclei (Figure 1, A). The portal areas showed a mixed cell infiltrate with lymphocytes, plasma cells, and eosinophils (Figure 1, A and B). The bile duct showed sparse lymphocyte infiltration (Figure 1, B). Scattered periportal apoptotic hepatocytes were surrounded by microinflammation and were seen undergoing variable stages of cell death. Hepatocytes depicted in Figure 2, A, displayed coagulative necrosis, while those in Figure 2, B, showed karyorrhexis. In addition, there was a cholestatic hepatocyte undergoing feathery degeneration (Figure 2, A). A mixed infiltrate showed spillage into adjacent hepatocyte parenchyma (Figure 3, A). Pronounced lobular hepatocyte disarray and sinusoidal lymphocytic inflammation were also evident (Figure 3, B).

What is your diagnosis?

Pathologie Diagnosis: Hepatitic Variant of GVHD of Liver Following Donor Lymphocyte Infusion

Donor lymphocyte infusion (DLI) is an effective method of treatment of patients who have relapsed after allogeneic bone marrow transplantation. In patients in the chronic phase of chronic myelogenous leukemia who have relapsed after transplant and have received DLI, it is believed that up to 70% will successfully attain cytogenetic and molecular complete response. Therefore, curative therapy is achieved through a graft-versus-leukemia effect after DLI. The development of GVHD may result in significant morbidity and mortality. The mortality rate from GVHD-related complications may be as high as 50%.1-7

Typical liver GVHD is characterized by bile duct damage, portal lymphocytic infiltrate, and centrilobular necrosis. Other features include marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, many acidophilic bodies scattered throughout the lobule, and vacuolization of the biliary epithelial cells with exocytosis.8,9 According to Akpek et al/ there are 2 subtypes of GVHD of the liver. The first subtype displays features consistent with classic GVHD. This subtype is characterized by bile duct epithelial injury, portal lymphocytic infiltration, and preserved hepatocellular structure devoid of significant lobular inflammation. The second subtype shows features consistent with a hepatitic variant of GVHD. In this subtype, the predominant finding is lobular hepatitis, with relatively mild bile duct injury.7

Our case displayed an underlying, albeit unrelated, fatty liver disease without steatohepatitis. Features indicative of acute GVHD include a low-grade portal inflammation with mixed cell infiltrate and lymphocytic ductulitis (Figure 3, A). In our case, bile duct injury was subtle (Figure 1), which made the diagnosis of classic acute GVHD difficult. Other findings included moderate lobular inflammation (Figure 3, B), hepatocyte unrest, apoptosis, and mild cholestasis (Figure 2, A and B). The differential diagnosis of an infectious process was eliminated through a negative viral serology and negative immunohistochemical workup for cytomegalovirus, human herpesvirus 1, and human herpesvirus 2 antigens.

The onset for occurrence of acute GVHD is within 90 days posttransplant, while chronic GVHD can occur even later than a year posttransplant. Its occurrence is more frequent in patients who have previously developed acute GVHD and in patients receiving peripheral blood stem cell transplants, in comparison to those undergoing bone marrow transplantation. Although the date for allogeneic peripheral stem cell transplantation was remote in our patient, a history of recent DLI provides a new immunological trigger for the development of acute GVHD.

The presence of lobular hepatitis in the hepatitic variant of GVHD correlates with a marked, greater than 10-fold elevation of serum aminotransferases. It is postulated that the hepatitis may be a result of direct cytotoxicity through the release of preformed Fas ligand by infiltrating donor T cells, causing recipient tissue damage.7,10

Graft-versus-host disease of the liver after DLI can be a difficult diagnosis owing to the subtle manifestation of bile duct damage. However, a recent history of DLI and certain clinical features, including markedly elevated liver function tests, the presence of skin rash, mucosal ulcers, and low-grade fever (in the absence of positive viral serology), should lead one to the diagnosis. Since early treatment with high-dose immunosuppressive therapy could effectively halt progression to cholestatic liver damage or a fatal outcome, early diagnosis of GVHD is a crucial factor in determining prognosis.5,8

References

1. Ma SY, Au WY, lie AK, et al. Liver graft-versus-host disease after donor lymphocyte infusion for relapses of hematologie malignancies post allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;34:57-61.

2. Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation.J CUn Oncol. 2002;20:405-412.

3. de Lima M, Bonamino M, Vasconcelos Z, et al. Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease. Bone Marrow Transplant. 2001:27:73-78.

4. Alyea E, Weller E, Schlossman R, et al. T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood. 2001:98: 934-939.

5. lmoto S, Murayama T, Comyo H, et al. Long-term molecular remission induced by donor lymphocyte infusions for recurrent acute myeloblastic leukemia after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2000;26: 809-810.

6. Novitzky N, Rubinstein R, Hnllett IM, et al. Bone marrow transplantation depleted of T cells followed by repletion with incremental doses of donor lymphocytes for relapsing patients with chronic myeloid leukemia: a therapeutic strategy. Transplantation. 2000;69:1358-1363.

7. Akpek G, Boitnott JK, Lee LA, et al. Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion. Blood !serial online]. 2002:100:3903-3907. Available at: http://www.bloodiournal.org/cgi/content/full/100/12/3903.

8. Strasser Sl, Shulman HM, Flowers ME, et al. Chronic graft-versus-host dis ease of the liver: presentation as an acute hepatitis. Hepatology. 2000;32:1265-1271.

9. Fujii N, Takenaka K, Shinagawa K, et al. Hepatic graft-versus-host disease presenting as an acute hepatitis after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant. 2001;27:1007-1010.

10. Wasem C, Frutschi C, Arnold D, et al. Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease. J lmmunol. 2001; 167:2936-2941.

Shou-Jin Wu, MD; Damiano Rondelli, MD; Grace Guzman, MD

Accepted for publication February 1, 2005.

From the Departments of Pathology (Drs Wu and Cuzman) and Hematology/Oncology (Dr Rondelli), University of Illinois at Chicago.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Shou-Jin Wu, MD, Department of Pathology, MC 847, University of Illinois at Chicago, College of Medicine, 1819 Polk St, Chicago, IL 60612-7335 (e-mail: shwu@uic.edu).

Reprints not available from the authors.

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