Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7–34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops. Bone Marrow Transplantation (2001) 27, 15–20.
Adult T cell leukemia/lymphoma (ATL) is a T cell neoplasm characterized by lymph node swelling, hepatosplenomegaly, skin lesions, hypercalcemia and abnormal peripheral blood lymphocytes.1 Human T-lymphotropic virus type I (HTLV-I) is the cause of ATL.234 It has a very poor prognosis5678 because patients are usually highly immunocompromised leading to frequent severe infections,9 and tumor cells are usually resistant to conventional chemotherapeutic agents.101112 As there have been only a few reports of allogeneic bone marrow transplantation (allo-BMT) for ATL,131415 the outcome and any beneficial effect of allo-BMT are not yet well established. To assess the efficacy of allogeneic stem cell transplantation (allo-SCT) for ATL, we reviewed 10 cases Japanese ATL patients who had received allo-SCT. Here we report an improved survival of ATL by allo-SCT.
Patients and methods
Ten patients with ATL (8 acute, 1 lymphoma and 1 chronic type) received an allo-SCT at nine hospitals during the period from March 1995 to February 1999. The median age at the time of diagnosis of ATL was 43 (range 33–51 years). There was no common protocol for allo-SCT among the hospitals in this study. Clinical data were collected from the medical records of each patient and were reviewed retrospectively. Clinical characteristics of ATL patients are shown in Tables 1 and 2.
Diagnosis and classification of clinical subtypes of ATL
The diagnosis of ATL was made according to the following criteria: (1) HTLV-I antibody positive in the serum; (2) presence in peripheral blood of abnormal lymphocytes with convoluted or lobulated nuclei, or histologic findings compatible with ATL in the biopsied lymph nodes; (3) tumor cells with mature CD4+ T cell phenotype; and (4) clonal integration of HTLV-I proviruses in the DNA of tumor cells determined by Southern blot method. Clinical subtypes of ATL were classified according to the criteria of the Japanese Lymphoma Study Group.9
Definition of therapeutic response
Response to induction chemotherapy was divided into three categories: complete remission (CR), partial remission (PR) and no response (NR). Responses were defined as follows. CR constituted resolution of all malignant phenotypes (including the disappearance of circulating leukemic cells) for at least 4 weeks. PR was reduced by at least 50% of measurable disease indices for at least 4 weeks without the development of new lesions. NR was reduction of less than 50% in the indices, or further disease progression.
Measurement of HTLV-I proviral DNA
We measured the HTLV-I proviral DNA in peripheral blood mononuclear cells (PBMC) from two typical patients (patients 6 and 8) before and after allo-SCT by real-time PCR amplification of HTLV-I pX DNA, using LightCycler System (Roche Molecular Biochemicals, Mannheim, Germany) according to the manufacturer's instruction manual.16 In brief, about 50 ng of DNA from the patient's PBMC was used for PCR amplification of HTLV-I pX DNA with a reference DNA of human β-globin gene which defines one copy per haploid DNA in human cells in the LightCycler System. The relative copy number of HTLV-I proviral DNA was calculated by the following formula: copy number of HTLV-I pX per 1000 PBMC = [(copy number of HTLV-I pX)/(copy number of β-globin/2)] × 1000.
The leukemia-free survival period from the time of transplantation was analyzed according to the method of Kaplan and Meier.17
Chemotherapy before allo-SCT resulted in CR in four patients, PR in five and NR in one (Table 2). Eight patients received an allo-BMT, one a peripheral blood stem cell transplant (PBSCT) and one PBSCT combined with BMT. The median period from diagnosis of ATL to allo-SCT was 8.0 months (range 3.5–20.1). Nine patients were grafted from HLA-identical siblings and one from an unrelated HLA-identical donor. Three of the 10 donors had anti-HTLV-I antibodies, but all were healthy carriers.
Preconditioning regimens for SCT varied from patient to patient although all patients received total body irradiation (TBI = 10–13.2 Gy). Preparative regimens for allo-SCT for each patient are shown in Table 3. Cyclophosphamide (CY) was given to six patients, melphalan (L-PAM) to two, cytosine-arabinoside (CA) to four and etoposide (ETO) to four, in various combinations. Regimen-related toxicity (RRT) was mild, or absent. Only two patients suffered from RRT (grade II nausea and vomiting in one and grade III stomatitis in the other).
Engraftment was achieved in all patients with a neutrophil recovery (>5 × 105/l) median time of 14 days (range 11–17) and a platelet recovery median time (>5 × 107/l) of 26 days (range 18–31) (Table 3). CR was achieved in all patients and complications after allo-SCT were similar to those seen after allo-SCT for other hematological malignancies. Hemorrhagic cystitis due to adenovirus type 11 infection developed in two patients. Two patients suffered from bacterial septicemia (one from complicated bacterial meningitis), and CMV antigenemia was detected in two patients. One patient was diagnosed as having thrombotic microangiopathy (TMA), which proved fatal. Veno-occlusive disease was not observed in this series. Monoclonal integration of HTLV-I proviral DNA was detected by Southern blotting in all but one of the patients at the time of diagnosis of ATL, but was not detected in any of the seven patients examined after allo-SCT treatment. Three patients were not eligible for Southern blot analysis due to early relapse and death after allo-SCT (two relapsed and one died relatively early after transplant) (Table 3).
Two cases of the allo-SCT patients were followed up by quantitation of HTLV-I proviral DNA (Table 4). Patient 6 showed 98% reduction of HTLV-I proviral DNA at 3 months after the allo-SCT and kept the lowered level of 86–90% reduction. Patient 8 showed 99% reduction at 6 months after the allo-SCT and remained at the lower level of 94–97% reduction. Patient 6 developed acute and chronic GVHD as well as TMA, and eventually died of GI bleeding. Patient 8 developed grade II acute GVHD but survived longer than 19.5 months. He is currently free of disease. The viral load of these two patients was successfully kept lower than the average HTLV-I proviral DNA in healthy HTLV-I carriers (64.9 ± 73.9/1000 PBMC of healthy carriers) (92 cases).
Cyclosporin A (CsA) and short course methotrexate were given to nine patients for GVHD prophylaxis and tacrolimus (FK-506) to one. Six patients subsequently developed acute GVHD (grade I in one, grade II in three, grade III in one, grade IV in one), and four patients chronic GVHD (limited in one, extensive in three) (Table 5).
The median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7–34.4+). Two of three patients who showed no clinical manifestations of acute or chronic GVHD relapsed 3.7 and 4.0 months after allo-SCT. Four patients died. The causes of death were renal insufficiency after relapse, interstitial pneumonitis, gastrointestinal bleeding probably due to TMA, and grade IV acute GVHD. The patients with renal insufficiency and pneumonitis had received their allo-SCTs from donors who were HTLV-I carriers. Six patients are alive 11.8, 19.5, 28.7, 31.5, 32.7 and 34.4 months after the transplant, and their Karnofsky scores are 80% to 100%. Although one patient relapsed 3.7 months after the transplant, five are free of disease at a median of 31.5+ months (Table 6, Figure 1).
CR rate and median survival of patients with acute or lymphoma-type ATL have been reported to be only 25–40% and 3 to 9 months, respectively.5678 Patients with these aggressive types of ATL usually die of tumor progression because ATL cells are resistant to chemotherapy, not only in the refractory stage but also at the time of onset.11 In fact, the overexpression of P-glycoprotein, the protein product of the multiple drug resistance gene family, and multidrug-resistance protein are known to be associated with drug resistance in ATL.101112 Immunotherapy for ATL targeting cell surface components such as CD25 have shown substantial effects, but it has not been confirmed that these results are better than those after conventional chemotherapy.18 To overcome drug resistance, high-dose chemotherapy and autologous SCT (auto-SCT) have been performed in ATL. Tsukasaki et al19 reported poor results with auto-SCT in ATL because of high relapse rates and transplant-related complications.
Borg et al15 reported an ATL patient in whom HTLV-I provirus in the peripheral blood became undetectable by PCR after BMT. Furthermore, Kawa et al20 reported eradication of HTLV-I from the peripheral blood of an HTLV-I carrier with congenital pure red cell aplasia who had received an allo-BMT from an HTLV-I negative sibling. They emphasized that allo-BMT could be a new strategy for eradicating lymphocytes carrying HTLV-I.
In this study, the median leukemia-free survival after allo-SCT for ATL was 17.5+ months. Surprisingly, only two patients relapsed (patients 1 and 10) and the other eight remained in remission during the follow-up period. In fact, none of the seven patients with acute and/or chronic GVHD relapsed. These results strongly suggest the existence of a graft-versus-leukemia (GVL) reaction after allo-SCT for ATL.
In addition to the disappearance of the monoclonal integration on Southern blot analysis, we also recognized a marked decrease in the relative copy number of HTLV-I provirus in PBMC after allo-SCT compared to before allo-SCT. These findings suggest that non-clonal carrier lymphocytes or a very minute clonal population of ATL persist after allo-SCT. In this context, we have serially examined the HTLV-I provirus loads in patients with ATL who have received an allo-SCT to ascertain whether the provirus eventually decreases or disappears, after allo-SCT, as Kawa et al20 reported.
Another issue of concern is what will be the outcome in patients receiving an allo-SCT from HTLV-I-positive donors. Two of three patients who receive an allo-SCT from an HTLV-I-positive donor died of renal insufficiency after relapse and interstitial pneumonitis. However, one case (patient 4) had a good clinical outcome, surviving longer than 31.5 months (Table 6). A long follow-up period will be needed to resolve this issue.
Patients with ATL are immunocompromised even at the time of disease onset and often develop fatal or severe complications from infectious diseases.9 Four patients are reported to have died of infectious diseases within 4 months of auto-SCT.19 In earlier reports of allo-SCT for ATL, two patients died of infectious complications after SCT without disease relapse.1314 In our study, infectious complications were seen in five out of 10 patients and all but one (patient 7) recovered after appropriate treatment. These results may show that infectious complications in ATL after allo-SCT are more easily controllable than are those in patients undergoing conventional chemotherapy or receiving auto-SCT.
The lower relapse rate of ATL after allo-SCT in this study is encouraging. A further large-scale prospective study is needed to ascertain accurately the efficacy of allo-SCT for ATL, and to define the indications for allo-SCT, prognostic value of HTLV-I proviral load, complications after allo-SCT and leukemia-free survival.
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We would like to thank Dr I Sanada (Institute for Clinical Research, Kumamoto National Hospital), Dr E Ohtsuka (Second Department of Internal Medcine, Oita Medical University), Dr E Ohno (Department of Hematology, Oita Prefectural Hospital), Dr Y Nawa (Division of Internal Medicine and Hematology, Ehime Prefectural Central Hospital), Dr H Taji (Department of Hematology and Chemotherapy, Aichi Cancer Center) and Dr Y Atsuta (Division of Hematology, Japanese Red Cross Nagoya First Hospital) for providing information on ATL patients who received allo-SCT.
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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 27, 15–20 (2001) doi:10.1038/sj.bmt.1702731
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