¹Second Department of Internal Medicine, Oita Medical University, Oita, Japan

²Blood Transfusion Center, Oita Medical University, Oita, Japan

³Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan

⁴Department of Virology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan

Correspondence to: Dr M Ogata, Second Department of Internal Medicine, Oita Medical University, Hasama-machi, Oita 879-5593, Japan

We report a 51-year-old male with adult T cell leukemia (ATL) who received a BMT from an HLA-identical unrelated donor. The ATL proved refractory to chemotherapy, and he underwent BMT conditioned with CY/TBI. Complications of encephalitis of unknown origin were successfully treated with steroid therapy and the patient has been in CR for 16 months after BMT. Human T cell leukemia virus type 1 proviral DNA loads were reduced to undetectable levels in PBMC sampled 12 months after BMT. This encouraging result suggests that BMT from an unrelated donor should be considered for ATL even if the disease is refractory to chemotherapy.

Bone Marrow Transplantation (2002) 30, 699-701. doi:10.1038/sj.bmt.1703702

adult T cell leukemia; unrelated donor transplant; HTLV-1; encephalitis

Adult T cell leukemia (ATL) is a peripheral CD4⁺ T cell malignancy endemic to southwestern Japan and the Caribbean basin, and human T cell leukemia virus type 1 (HTLV-1) plays a causative role in its development. The prognosis of ATL is extremely poor, with the median duration of overall survival being less than 1 year. Intensified chemotherapy and/or autologous stem cell transplantation have not yet improved this prognosis.^1,2 Although some successful cases of allogeneic stem cell transplantation (allo-SCT) have been reported,^3,4,5 HLA-matched and HTLV-1 seronegative siblings are available to only a small number of patients.

We report a successful BMT from an unrelated donor in a patient with ATL refractory to various combination chemotherapy modalities. The patient has remained in CR for 16 months after BMT, with no detectable HTLV-1 infected cells. This case suggests that unrelated BMT can be used to successfully maintain long-term remission and cure even in this high-risk setting.

Case report

A 51-year-old Japanese male was initially referred to our hospital due to leukocytosis in March 1998. Systemic lymphadenopathy and splenomegaly were noted. The WBC count was 32.6 ´ 10⁹/l. Differential count revealed 45% multilobulated abnormal lymphocytic cells positive for CD3, CD4 and CD25. Serum LDH was 815 IU/l (normal 420 IU/l), and calcium levels were normal. Antibody for HTLV-1 was positive, and monoclonal integration of HTLV-1 proviral DNA in PBMC was demonstrated using Southern blot analysis. A diagnosis of chronic type ATL was made according to the criteria of the Lymphoma Study Group.⁶ The patient was followed without receiving chemotherapy. Abnormal lymphocytes in the peripheral blood decreased gradually during follow-up and had disappeared by July 1998, and subcutaneous nodules subsequently appeared on his chest and left thigh in December 1998. Biopsy of a chest nodule revealed T cell involvement, and he was treated with oral low-dose etoposide and localized irradiation to the nodules, resulting in a decrease in size. In March 2000, however, the patient presented with complaints of fever and general fatigue. Systemic lymphadenopathy and splenomegaly were noted. Laboratory data revealed leukocytosis (56.4 ´ 10⁹/l) with 75% abnormal lymphocytic cells displaying multilobulated nuclei. Serum LDH was 715 IU/l, and calcium levels were elevated to 4.24 mmol/l. Based on these findings, progression to acute type ATL was diagnosed. Chemotherapy with cyclophosphamide, pirarubicin, etoposide, and prednisolone was initiated, and hypercalcemia was treated using rehydration and intravenous sodium pamidronate. However, response to the chemotherapy was minimal. Although various combinations of chemotherapy were given, ATL cells in the peripheral blood rapidly re-increased during the intervals between chemotherapies (Figure 1). To control hypercalcemia, administration of combination chemotherapy and sodium pamidronate was required every 2 weeks. Due to repeated chemotherapies, ANC sometimes decreased to less than 0.1 ´ 10⁹/l despite G-CSF support, and his general condition deteriorated. As the patient had no HLA-matched siblings, a search for a donor was started with the Japan Marrow Donor Program, and a donor whose HLA-A, B, and DR were phenotypically identical to those of the patient was identified.

The BMT conditioning regimen comprised CY 60 mg/kg once daily i.v. for 2 days (total dose 120 mg/kg) followed by TBI 4 Gy for 3 days. In September 2000, the patient received BM containing 3.08 ´ 10⁸/kg donor nucleated cells. GVHD prophylaxis was with CsA starting at 3 mg/kg/day i.v. from day -1 according to the standard protocol at this institution, together with MTX 0.2 mg/kg i.v. on day +1 and 0.14 mg/kg on days +3 and +6. An ANC >0.5 ´ 10⁹/l was reached on day +18, and untransfused platelets of 50 ´ 10⁹/l on day +36. Acute grade I GVHD (skin) was controlled using oral prednisolone. Analysis of chimeric status using short tandem repeat microsatellite markers for the determination of engraftment revealed donor origin at 2 months after BMT.

On day +70, amnesia, ataxia and tremor developed, and these symptoms rapidly progressed. Cerebrospinal fluid (CSF) examination revealed increased mononuclear cells and protein (148 mg/dl). CSF examination failed to identify abnormal cells, levels of myelin basic protein were normal, and PCR was negative for human herpesvirus-6. Intrathecal antibody against HTLV-1 was positive according to particle aggulutination assay. No DNA for HTLV-1, herpes simplex, or VZV was detected in samples from peripheral blood. Electroencephalography yielded slightly abnormal results, but CT and MRI displayed no abnormalities. Although the cause of the encephalitis could not be determined, steroid pulse therapy (starting with 500 mg/body i.v. methylprednisolone for 3 days, then tapering) was initiated and both neurological symptoms and CSF findings dramatically improved.

Extensive chronic GVHD developed 4 months after BMT with skin erythema and resolved with prednisolone and CsA. At the time of writing, 16 months after BMT, the patient remains in CR. Chronic GVHD was well controlled by 50 mg/day of CsA and 5 mg/day of prednisolone, and a Karnofsky score of 90% was achieved.

We measured HTLV-1 proviral load in PBMC from the patient before and after BMT using real-time PCR amplification of HTLV-1 pX DNA, as previously described.⁵ Relative HTLV-1 proviral load was calculated according to the formula: copies of HTLV-1 pX/1000 PBMC = [(copies of HTLV-1 pX)/(copies of -globin/2)] ´ 1000. The mean HTLV-1 proviral load for healthy HTLV-1 carriers is reported as 64.9 ± 73.9/1000 PBMC.⁵ The relative HTLV-1 provirusal load was reduced from 4151.1/1000 PBMC at 1 month before BMT to undetectable levels (<1/1000 PBMC) in the samples taken 3, 6 and 12 months after BMT.

Discussion

Intensification of chemotherapy for ATL has improved response rates, but has improved survival in only a few trials.^1,7 Although high-dose therapy and autologous stem cell transplantation have been shown to improve prognoses in other poor-risk aggressive lymphomas, outcomes for ATL remain poor due to high relapse rates and complications.² Utsunomiya et al⁵ recently reported promising results for allo-SCT in patients with ATL. However, HLA-matched siblings are seldom available to these patients. Furthermore, about two-thirds of siblings of patients with ATL are HTLV-1 carriers.⁸ Immunocompromised hosts are reportedly at risk of developing ATL by transfusion-induced HTLV-1 infection.⁹ BMT from an HTLV-1 positive donor may carry the risk of promoting the development of ATL due to the new HTLV-1 load on the recipient. To benefit from allo-SCT, most ATL patients therefore require an unrelated donor. The experience of using unrelated donors in the treatment of ATL is, however, limited. To our knowledge, only one patient is reported to have received a BMT from an unrelated donor when the patient was in CR.⁵

When this patient developed acute type ATL, he displayed a number of poor prognostic factors,¹⁰ including poor performance status, high LDH values, age 40 years, increased number of total involved lesions and hypercalcemia. In fact, the ATL cell count rapidly re-increased during the intervals between chemotherapies, leading to hypercalcemia, and administration of combination chemotherapy together with sodium pamidronate was required every 2 weeks to control the hypercalcemia. The HTLV-1 viral load was extremely high prior to BMT. Despite this high-risk scenario, the patient has remained in CR as of 16 months after BMT, with no detectable HTLV-1-infected cells. This promising result strongly suggests that allo-SCT represents a highly useful modality for patients with ATL, and allogeneic BMT should be considered if HLA-identical unrelated donors are available.

Recovery of the patient was complicated by encephalitis of unknown origin. Interestingly, Ljungman et al¹¹ also reported a case of ATL after allogeneic BMT who developed life-threatening encephalitis, and discussed the possibility of HTLV-1 directly affecting the central nervous system (CNS).¹¹ CSF examination in both cases demonstrated increased mononuclear cell counts, but normal findings on brain CT and MRI. Although the causes of encephalitis in these two cases remain unclear, it should be noted that the high cellular immune response of virus-specific T cells to HTLV-1 contributes to the inflammatory process within CNS lesions in HTLV-1-associated myelopathy.¹² The fact that CSF Ab was detected against HTLV-1, and that steroid therapy proved highly effective in treating the present case, raises the possibility that the CNS is attacked by lymphocytes derived from the graft through a response against HTLV-1 Ag. The responsiveness of graft-derived lymphocytes against HTLV-1 Ag may not only support the graft-versus-leukemia effect, but also implies the existence of HTLV-1-associated inflammatory disorders in allo-SCT. Encephalitis, therefore, should be seriously considered as a potential complication in allo-SCT for ATL.

Although allo-SCT has been suggested as improving the prognosis of ATL, a small number of ATL patients are fortunate enough to have suitable HLA-identical and HTLV-1 seronegative donors in the family. The encouraging result from our case suggests that BMT or stem cell transplantation from an unrelated donor should be considered for ATL even if the disease is refractory to chemotherapy.

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2 Tsukasaki K, Maeda T, Arimura K et al. Poor outcome of autologous stem cell transplantation for adult T cell leukemia/lymphoma: a case report and review of the literature. Bone Marrow Transplant 1999; 23: 87-89. Article MEDLINE

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5 Utsunomiya A, Miyazaki Y, Takatsuka Y et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 15-20.

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9 Chen YC, Wang CH, Su IJ et al. Infection of human T-cell leukemia virus type I and development of human T-cell leukemia lymphoma in patients with hematologic neoplasms: a possible linkage to blood transfusion. Blood 1989; 74: 388-394. MEDLINE

10 Lymphoma Study Group. Major prognostic factors of patients with adult T-cell leukemia-lymphoma: a cooperative study. Leuk Res 1991; 15: 81-90.

11 Ljungman P, Lawler M, Asjo B et al. Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia. Br J Haematol 1994; 88: 403-405. MEDLINE

12 Nagai M, Jacobson S. Immunopathogenesis of human T cell lymphotropic virus type I-associated myelopathy. Curr Opin Neurol 2001; 14: 381-386. Article MEDLINE

Figure 1 Schematic representation of clinical course after patient evolved to acute ATL. Ab-lymph indicates abnormal lymphocytes. A = cyclophosphamide, pirarubicin, etoposide, prednisolone, pamidronate disodium; B = cyclophosphamide, pirarubicin, vincristine, prednisolone, pamidronate disodium; C = cyclophosphamide, methotrexate, vindesine, prednisolone, pamidronate disodium; D = cyclophosphamide, doxorubicin, etoposide, prednisolone, pamidronate disodium; E = cyclophosphamide, doxorubicin, vindesine, prednisolone, pamidronate disodium; F = cyclophosphamide, pirarubicin, vindesine, prednisolone, pamidronate disodium.