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- Case Report
An 11-month-old boy with acute lymphoblastic leukemia (ALL) underwent umbilical cord blood transplantation (CBT) from an unrelated donor after a first complete remission. Despite the prophylactic use of low molecular weight heparin, prostaglandin E1 and ursodeoxycholic acid, hepatic veno-occlusive disease (VOD) occurred on the 29th day after CBT. Furthermore, neither defibrotide nor antithrombin-III improved the hepatic coma and coagulopathy due to the hepatic VOD. On the 42nd day after CBT, he underwent living related liver transplantation (LRLT) with a left lateral segment graft from his father. He received tacrolimus for the prevention of rejection and graft-vs.-host disease (GVHD) and also received aggressive antifungal and antiviral prophylaxis. Although he showed signs of acute rejection on postoperative days 5 and 10, the postoperative course was uneventful in general. At present, 17 months after LRLT, the patient shows stable liver function and no signs of either GVHD or a relapse of ALL. In conclusion, LRLT can be seen as a feasible option for the treatment of a hepatic VOD after CBT, though aggressive prophylaxis for infection and the anticipation of acute rejection are of importance.
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- Case Report
On 29 October 1999, an 11-month-old boy who had leukocytosis and tumors on both his auricles and his mandibule was diagnosed as acute lymphoblastic leukemia (ALL) of subtype L1 according to French-American-British (FAB) classification. Rearrangement of the mixed lineage leukemia gene (MLL) and chimeric MLL-AF 9 mRNA of leukemic cells were detected using Southern blot analysis and the reverse transcriptase-polymerase chain reaction (RT-PCR) method, respectively. From 2 November 1999, the patient underwent induction chemotherapy including vincristine (VCR), cyclophosphamide (CY), doxorubicin, dexamethasone (DEX), etoposide (VP-16), and cytarabine (Ara-C). After the first complete remission, he was treated with an additional 3 courses of consolidation chemotherapy, which consisted of VCR, CY, Ara-C, l-asparaginase, DEX, prednisolone, mitoxantrone, pirarubicin, VP-16 and methotrexate (MTX). Bone-marrow puncture showed no relapse of ALL after the consolidation chemotherapy. Then, CBT was scheduled because patients with infant ALL bearing an MLL rearrangement are at high risk for early relapse in general. Conditioning regimens including high-dose CY (120 mg/kg in total dose), busulfan (BUS) (280 mg/m2 in total dose) and total body irradiation (TBI) (12 Gy in total dose) were performed 6 days before CBT.
On 23 March 2000, the patient underwent CBT from an unrelated female donor, who was a perfect match according to HLA typing. The total count of transfused cells was 5.65 × 107/kg, including 1.6 × 106/kg of CD34-positive cells. Twenty-eight days after CBT, bone-marrow puncture revealed good engraftment of allogeneic stem cells. For prophylaxis against hepatic VOD, low molecular weight heparin (LMWH) (70 IU/kg/day), prostaglandin E1 (PGE1, 50 μg/day) and ursodeoxycholic acid (UDCA) (100 mg/day) were given, starting 6 days before CBT. MTX and tacrolimus were also administered for prophylaxis against graft-vs.-host disease (GVHD).
However, the patient developed fever, hepatomegaly, and weight gain (21.3%) due to ascites 29 days after CBT. T-Bil began to rise to 2.1 mg/dL, and both aspartate transaminase (AST) and alanine aminotransferase (ALT) were over 1000 IU/L. PT and activated partial thromboplastin time (APTT) were also prolonged. Plasminogen activator inhibitor-1 (PAI-1) was 891 ng/mL, which was highly elevated compared to 20 ng/mL before start of the conditioning regimens. The patient was then diagnosed as hepatic VOD.
Either DF (300 mg/day) or antithrombin-III (AT-III) (500 U/day) in addition to PGE1 and LMWH did not improve liver function. Furthermore, the patient showed hepatic encephalopathy despite continuous hemodiafiltration and plasma exchange. He was transferred to our hospital and underwent LRLT using a left lateral segment graft from his 23-year-old father, whose blood type was O, on the 42nd day after CBT. The recipient's blood type changed from A to B after CBT. The histology of the excised liver was compatible with hepatic VOD as shown in Figure 1 (17).
Figure 1. The histology of the excised liver demonstrated: (i): congestion, hemorrhage, and dropout of the hepatocytes in the centrilobular lesion; (ii) macrovesicular steatosis in the residual hepatocytes, and (iii) relatively intact portal areas, all of which were compatible with hepatic VOD.
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A summary of the postoperative course of LRLT is shown in Figure 2. The patient did not have any postoperative surgical complications. Tacrolimus was continuously administered from CBT. On postoperative day 5 (POD 5) and on POD 10, acute rejection was highly suspected because of the elevation of transaminases and bilirubin (AST 235 IU/L, ALT 404 IU/L, T-Bil 3.7 mg/dL, D-Bil 2.0 mg/dL on POD 5), although the absolute count of CD3+ cells and the CD4+/CD8+ ratio decreased on POD 9 (Figure 3B). Methylprednisolone was injected intravenously for 3 days, both from POD 5 and from POD 10, respectively, and liver dysfunction subsequently improved. As prophylaxis against fungal and cytomegalovirus (CMV) infection, intravenous administration of amphotericin B and ganciclovir was performed in the pre- and postoperative periods for 13 days and for 19 days, respectively. Platelet transfusion was required until POD 21 due to thrombocytopenia. PAI-1 decreased rapidly after LRLT and protein C returned to normal (Figure 3A). The patient was discharged on POD 31.
Figure 2. Postoperative course in the patient undergoing LRLT for hepatic VOD. Liver dysfunction on POD5 and POD10 improved after steroid pulse therapy, respectively.
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Figure 3. (A) Changes of plasma levels of PAI-1 and protein C in the patient undergoing LRLT for hepatic VOD. The level of PAI-1 decreased rapidly after LRLT, and the level of protein C returned to normal. (B) Changes of the CD3+ cell count and the CD4+/CD8+ ratio in the patient in the patient undergoing LRLT for hepatic VOD. Both the CD3+ cell count and the CD4+/CD8+ ratio decreased on POD 9 despite the clinical evidence of acute rejection on POD5 and POD 10.
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On POD 64 (105 days after CBT), a bone-marrow puncture showed good engraftment of allogeneic stem cells according to Y-chromosome fluorescence in situ hybridization, and RT-PCR showed no signs of relapse of the ALL with MLL-AF 9.
At present, 17 months after LRLT, the patient shows stable liver function and no signs of either GVHD or a relapse of ALL.
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- Case Report
Hepatic VOD is characterized by jaundice, painful hepatomegaly, and weight gain due to ascites. The pathophysiology of hepatic VOD is thought to start with a widespread injury of zone 3 structures, which are very sensitive to toxic damage, followed by subendothelial edema and subsequent collagenization. High-dose chemotherapy and TBI are presumably the primary causes of hepatic VOD.
Recently, the clinical criteria developed by both the Seattle and Baltimore groups have been widely used for the diagnosis of hepatic VOD instead of the histological evidence of venular occlusion (1–3,17). In this particular patient's case, the clinical findings included all of the Seattle and Baltimore criteria for hepatic VOD except for early onset. Because of late onset of symptoms in this case, PAI-1 was useful to rule out acute GVHD (16).
As prophylaxis against hepatic VOD, UDCA, LMWH and PGE1 have been favorably reported (18–20), while conservative treatments of hepatic VOD include rt-PA, DF, AT-III and PGE1 (6,7,21). In this case, we tried all of the above – except for rt-PA – and all failed.
As a possible permanent solution, liver transplantation (LTx) has been applied in 12 cases of severe hepatic VOD after HCT (Table 1) (8–16). All patients except for one were adults. HCT was performed from related donors in seven, from unrelated donors in two and from autologous donors in two. Prophylaxis against hepatic VOD was performed in five, and conservative treatments were performed in eight. Onset of VOD ranged from 2 to 40 days after HCT. LTx was performed from 22 to 79 days after HCT.
Table 1. : Data of patients before LTx in previous reports and our case
|Authora||Age||Sex||Original diseaseb||Type of HCTc||Conditioning regimensd||Prophylaxis for VODe||Pre-LTx treatment for VODf||Onset of VOD||LTx after HCT|
|Nimer8||34y||F||MDS||R-BMT||BUS + CPA||None||None||10d||40d|
|Rapoport9||34y||F||CML||R-BMT||BUS + CPA||None||rt-PA|| 5d||35d|
|Dowlati10||43y||M||NHL||A-PBSCT||VP-16 + CPA +BCNU||Pentoxifylline +PGE2||None|| 2d||22d|
|Schlitt11||38y||M||AML||R-BMT||BUS + CPA||None||PGE2 + Hep||13d||23|
|Hagglund12||32y||F||CML||U-BMT||CPA + TBI||Hep||rt-PA||10d||39d|
|31y||F||ALL||R-BMT||BUS + CPA||None||rt-PA||14d||25d|
|33y||M||CML||R-BMT||BUS + CPA||None||None||16d||36d|
|Bunin13||2 month||F||SAA||U-BMT||Ara-C + CPA + TBI||None||rt-PA + Hep|| 7d||33d|
|Norris14||25y||M||ALL||A-BMT||BUS + CPA||None||rt-PA + Hep|| 3 week||32d|
|Rosen15||35y||M||AML||BMT||CPA + TBI||UDCA||None||10d||43d|
|Salat16||39y||F||AML||R-BMT||BUS + CPA||Hep||PGE2||40d||79d|
|47y||M||CML||R-BMT||BUS + CPA||Hep||rt-PA||20d||41d|
|Our cases||11 month||M||ALL||U-CBT||BUS + CPA + TBI||UDCA + PGE1 +LMWH||DF + AT-III + PGE1 +LMWH||29d||42d|
Postoperative data from the reported cases are summarized in Table 2. One patient underwent LRLT. Three patients received grafts from ABO-blood-type-incompatible donors. Four patients (33.3%) had acute rejection. Two patients (16.7%) had acute GVHD – one liver-derived and the other hemopoietic stem cell-derived. Three patients (25%) had CMV disease, and one patient (8.3%) had fatal fungal infection. Nine out of 12 patients died postoperatively, mainly due to infections or multi-organ failures.
Table 2. : Data of patients after LTx in previous reports and our case
|Authora||Type of LTxb||ABO compatibilityc||ACRe||Acute GVHDf||CMV disease||Fungal infection||Outcome||Cause of death||Follow-up periodh|
|Nimer8||OLT||C||None||None||None||None||Dead||relapse of MDS||14 month|
|Dowlati10||OLT||*d||Yes||None||None||None||Dead||ARDS due to re-LTx||70d|
|Schlitt11||OLT||ID||None||Yesg||Yes||None||Alive|| ||40 month|
|Hagglund12||OLT||IC||None||Yes||*||*||Dead||pneumonia due to BM engraftment insuffciency||30d|
| ||OLT||ID||Yes||None||Yes||None||Dead||chr. liver graft failure due to CMV hepatitis||213 d|
| ||OLT||C||*||*||*||*||Dead||cerebral edema||3d|
|Bunin13||LRLT||IC||None||None||Yes||None||Alive|| ||9 month|
|Norris14||OLT||IC||Yes||None||None||None||Dead||pneumocystis pneumonia due to chr. rejection||6 month|
|Rosen15||OLT||*||None||*||*||*||Alive|| ||5 month|
|Salat16||OLT||*||*||*||*||Yes||Dead||intracerebral hemorrhage due to aspergillosis||62d|
| ||OLT||*||*||*||*||*||Dead||BM engraftment insufficiency||60d|
|Our case||LRLT||C||Yes||None||None||None||Alive|| ||17montha|
The indications for LTx in cases of hepatic VOD after HCT should be strictly adhered to if the original disease is malignant. The indications have been cited in some reports as follows: (i) absence of relapse of the original disease, (ii) good prognosis for the original disease after HCT, (ii) evidence of bone marrow engraftment, (iv) absence of acute GVHD, (v) absence of active infection, and (vi) absence of severe failure in other organs (8,9,13,15).
When this patient developed hepatic VOD after CBT, and conservative therapy attempts failed, LTx became necessary. Even though the patient's original disease was malignant and the prognosis for infant ALL with an MLL rearrangement is poor (22), we decided to perform an LRLT for this patient because unpublished data suggested that infants over 6 months of age (who have ALL with the MLL rearrangement) actually have a significant chance of survival. According to a committee of the Japanese Ministry of Health and Welfare in 1999, the estimated event free survival (EFS) is 66.3% in patients of ALL with MLL rearrangement whose age at occurrence was more than 6 months, compared to 15.9% in those whose age at occurrence was less than 6 months. Also, no residual leukemia was proven by RT-PCR just before the CBT in our case.
In conclusion, LRLT can be seen as a feasible option for the treatment of hepatic VOD after CBT, though aggressive prophylaxis for infection and the anticipation of acute rejection are of importance.