Ann Hematol (2005) 84: 755–757 DOI 10.1007/s00277-005-1076-7
ORIGINA L ARTI CLE
Karin Mellgren . Anders Fasth . Robert Saalman . Michael Olausson . Jonas Abrahamsson
Liver transplantation after stem cell transplantation with the same living donor in a monozygotic twin with acute myeloid leukemia Received: 13 October 2004 / Accepted: 16 June 2005 / Published online: 7 July 2005 # Springer-Verlag 2005
Abstract Two monozygotic twins from a Swedish, nonconsanguine family—with concordant acute myeloid leukemia and similar morphological and cytogenetic changes, but with additional changes in one twin, suggestive of clonal evolution—are described. Twin I relapsed 4 months after completion of treatment, while twin II was still on treatment and was transplanted with stem cells from the human leukocyte antigen-identical father. An early relapse after transplantation was treated with donor lymphocyte infusions, but twin I relapsed again and died 8 months after stem cell transplantation (SCT). On relapse of twin I, treatment of twin II was reconsidered and consolidation was intensified with SCT in CR1 with peripheral blood stem cells from the father. Due to irreversible liver failure caused by severe venoocclusive disease, a living, related liver transplantation from the father was performed on day +84 post-SCT. Minimal immunosuppression was required, and graft rejection did not occur. The patient was in complete remission 29 months after SCT and 25 months after liver transplantation. Keywords Stem cell transplantation . Venoocclusive disease . Liver transplantation . Acute myeloid leukemia . Pediatric cancer
Introduction The etiology of childhood leukemia is currently being investigated through large-scale epidemiological studies. Studies of twin pairs with leukemia have shown a common clonal origin, with an important role of chromosomal translocations during early gestation [1]. The concordance of leukemia in twins varies from 50% in infant cases to 5– 10% in older childhood cases [1]. Postnatal latency may vary considerably, as postnatal events are necessary in addition to early prenatal chromosomal events. In acute myeloid leukemia (AML), only a few cases of familial predisposition have been reported [2–5]. Venoocclusive disease (VOD) is a serious and potentially fatal complication of stem cell transplantation (SCT). Several risk factors have been identified, including age and liver status just before SCT. The first report on liver transplantation for VOD was published in 1990 [6]. A limited number of liver transplantations after SCT have been published [7, 8], and only a few involved living, related liver transplants [9, 10]. We report on a patient with irreversible liver failure due to VOD post-SCT, where left liver segments from the human leukocyte antigen (HLA)identical father were successfully transplanted.
Case report K. Mellgren (*) . A. Fasth . J. Abrahamsson Department of Pediatric Oncology and Immunology, The Queen Silvia Children’s Hospital, Gothenburg, Sweden e-mail:
[email protected] Tel.: +46-31-3436655 Fax: +46-31-215486 R. Saalman Department of Pediatric Gastroenterology, The Queen Silvia Children’s Hospital, Gothenburg, Sweden M. Olausson Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
Monozygotic twin I A 1-year-old girl was diagnosed with AML (FAB M1) with central nervous system (CNS) involvement in March 2002. Cytogenetic investigations revealed a complex karyotype (49,XX,del(7)(q),+8,9qh+,del(12)(p),+19,+22[25]). She started treatment according to the Nordic protocol (NOPHO-93) [11] and was in complete remission after the first course of chemotherapy. In accordance with the protocol, she received high-dose, cytarabine-based consolidation without SCT in CR1. In December 2002, 4 months after completion of therapy, twin I experienced a combined bone marrow and CNS
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relapse. A second remission was achieved after one FLAG [fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF)] course. In February 2003, she underwent SCT with peripheral blood stem cells (PBSCs) (cell dose 8.3×106 CD34+ cells kg−1) from her HLA-identical father (identical at HLA-A, HLA-B, and HLA-DR, with high-resolution testing) after conditioning with busulfan, 2.55 mg kg−1, given orally, twice daily, for 4 days [the dose was adjusted to achieve an area under the curve (AUC) value of 9,000–11,000 ng ml−1 h] and cyclophosphamide, 60 mg kg−1, given intravenously, once daily, for 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus for 3 months, tapered over 6 weeks, and three doses of methotrexate, 10 mg m−2, given intravenously, on days 1, 3, and 6 after transplantation. Ursodeoxycholic acid was given as a VOD prophylaxis for 90 days post-SCT. Engraftment was rapid and no sign of GvHD was observed during the initial posttransplant period. In June 2003, twin I experienced another bone marrow relapse but achieved remission after treatment with cytarabine, 100 mg m−2, and etoposide, 100 mg m−2, for 5 days, followed by two donor lymphocyte infusions (DLIs) at doses of 20×106 and 200×106 CD3+ cells kg−1 given at 6week intervals. After the second DLI, she developed gradeIV liver GvHD, and a liver biopsy showed “vanishing bile duct syndrome”. Despite GvHD treatment with steroids, tacrolimus, and mycophenylate mophetil, she developed severe liver failure. In October 2003, a third bone marrow relapse occurred; she died 2 months later. Monozygotic twin II Twin II was diagnosed with AML (FAB M1) 3 months after her sister, in July 2002. Leukemia cell morphology was the same in both twins, and cytogenetic investigations showed almost identical aberrations, although twin II had additional changes suggestive of clonal evolution (46–49, XX,del(7)(q),+8,del(12)(p),+19,+2118/40–45,XX,−6,del(7) (q),+8,del(12)(p),−16,+19,−20,+21,+226/46,XX1). Twin II was treated using the same protocol used on her sister. During aplasia after induction treatment, she developed septicemia with Pseudomonas aeruginosa and liver dysfunction, with increased bilirubin and ascites but without meeting the diagnostic criteria for a VOD. She subsequently suffered from vomiting and abdominal pain due to a subtotal occlusion of the proximal jejunum. Repeated biopsies showed inflammatory infiltrates. She required total parenteral nutrition for several months. In December 2002, on the first relapse of her twin sister, twin II’s treatment was reconsidered and consolidation was intensified by SCT in CR1. After conditioning with busulfan, 3.03 mg kg−1, given orally, twice daily, for 4 days (the dose was adjusted to achieve an AUC value of 9,000– 11,000 ng ml−1 h) and cyclophosphamide, 60 mg kg−1, given intravenously, daily, for 2 days, she received PBSCs from her HLA-identical father at a dose of 5.3×106 kg−1 in January 2003. GvHD prophylaxis was the same as that for her sister (tacrolimus and three doses of methotrexate).
Engraftment was rapid and no sign of GvHD was observed during the posttransplant period. Ursodeoxycholic acid was given as a VOD prophylaxis. On day +15, twin II developed severe VOD with ascites, elevated bilirubin (57 μmol l−1), decreased AT III serum levels, and a weight gain of 10%. Treatment with defibrotide (starting dose 40 mg kg−1 day−1, accidentally increased to 200 mg kg−1 day−1 for a short period) was initiated on day +18, and a peritoneal drain was placed. On day +70, bilirubin levels increased to 91 μmol l−1 and a weight gain of 20% was observed. A biopsy revealed VOD features, including severe, irreversible impairment of venous circulation. Because of the severe liver failure, liver segments 2+3 from the father were transplanted on day +84 after SCT, in April 2003. Prednisolone, 5 mg kg−1 day−1, given orally, rapidly tapered over the next week, was given as graft rejection prophylaxis. Tacrolimus was withdrawn 4 months after SCT and 4 weeks after liver transplantation. Repeated liver biopsies did not show any signs of rejection. The patient experienced several episodes of cholangitis, and P. aeruginosa was isolated from blood cultures. Since the surgical revision of a posttransplant extrahepatic biliary stricture in October 2003, she has been in excellent clinical condition. At 29 months after SCT and 25 months after liver transplantation, she remains in complete remission with normal liver function.
Discussion In this report, we describe monozygous twins presenting concordantly with AML, with similar morphological and cytogenetic changes. In childhood leukemia, chromosome translocations may arise before birth, as shown by studies of Guthrie cards [1, 12]. In the leukemia of our two patients, the cells presented a complex karyotype with deletions and trisomy of various chromosomes. Interestingly, they had almost identical karyotypes, and the twin diagnosed later had additional changes suggestive of clonal evolution. Concordance of leukemia in twins is explained by the initiation of leukemia in one twin in utero, which is spread via intraplacental anastomoses to the other twin [1, 13, 14]. Selected cases of patients who received solid organ transplants after an SCT have been published [7, 10, 15]. In the few patients where the solid organ and the stem cells originated from the same donor, interruption of immunosuppression was possible [7, 10, 16, 17]. Development of stable graft tolerance, following withdrawal of immunosuppressive medication after transplantation with a cadaveric liver through family donor SCT, was reported in one case [18]. Our patient underwent SCT because of an AML with a high risk of an early relapse, as revealed by an early relapse of leukemia in her monozygotic twin. Prolonged immunosuppression in this setting is undesirable since the graftversus-leukemia (GvL) effect is necessary for the treatment of the leukemia. Using liver segments from the same stem cell donor enabled liver transplantation without the need for additional immunosuppression.
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Young age, liver dysfunction, and busulfan dose are all risk factors for VOD. The dose of busulfan was adjusted according to concentrations obtained, with a target value of 9,000–11,000 ng ml−1 h. This target value has been tested in a limited sampling model for patients treated with busulfan given orally, twice daily [19]. Twin II required higher doses than her twin sister maybe because of slow gastric absorption. The combination of a higher total dose of busulfan and the preexisting liver dysfunction in twin II might explain why only one of them developed VOD. Defibrotide levels were accidentally increased to levels well above that recommended (200 mg kg−1 day−1). No signs of major toxicity such as bleeding were observed though. Our case demonstrates that, for patients developing irreversible liver failure after SCT, living, related liver transplantation from the stem cell donor is a feasible and effective method of treatment. Long-term follow-up for patients after a double transplant is lacking, however, and late effects are unknown.
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