Chronic Graft-versus-Host Disease following Varicella-Zoster Virus Infection in Allogeneic Stem Cell Transplant Recipients

We describe 2 allogeneic stem cell transplantation patients who developed chronic graft-versus-host disease (GVHD) after dermatomal varicella-zoster virus (VZV) infection. Localized zoster did not respond to oral valaciclovir but did resolve with intravenous aciclovir. However, skin eruptions, eye/oral dryness, and liver dysfunction were observed at the healing stage of localized zoster, suggesting development of GVHD. Intensification of immunosuppressive therapy was required to control GVHD. Quantitative real-time PCR for VZV DNA was used to distinguish liver involvement by chronic GVHD from visceral dissemination of VZV in 1 patient. VZV infection may trigger chronic GVHD after allogeneic stem cell transplantation.     

Hepatic graft-versus-host disease resembling acute hepatitis: additional treatment with ursodeoxycholic acid

Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone-marrow transplantation (BMT). The disease is often refractory to immunosuppressive therapy. We present a 30-year-old Japanese male, who developed an abrupt elevation of aminotransferases, on day 135 after allogeneic BMT. A liver biopsy specimen revealed degeneration of the small bile ducts and portal fibrosis, and the diagnosis of chronic hepatic GVHD was confirmed. No manifestation of chronic GVHD was observed except liver dysfunction. The administration of prednisolone (PSL) and cyclosporin (CsA) ameliorated laboratory data to a degree, but they did not return to normal. Treatment with ursodeoxycholic acid (UDCA), subsequently added to the immunosuppressive therapy, apparently normalized the levels of biliary tract enzyme and total bilirubin. His liver function test completely returned to normal on day 260. We believe that it is worthwhile to administer UDCA as an additional treatment for not only common hepatic GVHD but also atypical cases presenting as acute hepatitis.     

Clinicopathological features in patients with hepatic graft-versus-host disease

BACKGROUND/AIMS: Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation and often results in a fatal outcome. However, hepatic manifestation of chronic GVHD accompanied by unresolved acute GVHD has not been clarified so far. The present study was intended to examine clinicopathological features in patients in which acute GVHD appeared to progress gradually into chronic GVHD. METHODOLOGY: We evaluated laboratory data, pathological features and response to immunosuppression in 11 patients whose diseases were diagnosed as hepatic GVHD, retrospectively. The patients were classified into 3 groups: acute GVHD group (n=3), non-progressive chronic GVHD group (n=5) and progressive chronic GVHD group (n=3), which means continuous liver dysfunction beyond day 100 post-transplant. RESULTS: Patients with progressive chronic GVHD showed higher peaks of aminotransferase and biliary tract enzyme levels than patients with acute GVHD and non-progressive chronic GVHD. Their biopsy specimens demonstrated severer changes in lobular parenchyma, portal area and small interlobular bile ducts. They also showed marked loss of bile ducts. Despite administration of prednisolone or dose escalation of cyclosporin A, their liver function tests did not return to normal within one year. CONCLUSIONS: In cases of liver dysfunction that emerges within 100 days after transplantation, liver biopsy appears to be important to confirm diagnosis. Patients with acute hepatic GVHD need strong immunosuppression to prevent progression to chronic GVHD.     

Successful treatment with reduced-intensity stem cell transplantation in a case of relapsed refractory central nervous system lymphoma

A 33-year-old male with refractory relapsed central nervous system lymphoma underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical sibling after reduced-intensity conditioning chemotherapy. The preparative regimen for allo-HSCT consisted of fludarabine and busulfan. Cyclosporine (CsA) and short-term methotrexate were used as prophylaxis for acute graft-versus-host disease (GVHD). Although CsA was quickly reduced to induce a graft-versus-lymphoma (GVL) effect, no symptoms of GVHD and GVL effect were evident. Donor lymphocyte infusion (DLI) was performed on day +40 following transplantation. The patient developed acute GVHD (grade III) after DLI, and lymphoma regression was observed after the occurrence of GVHD. Four months after transplantation, complete remission was achieved with extensive chronic GVHD, and the patient continues to be disease free at 15 months after transplantation.     

One-year cyclosporine prophylaxis reduces the risk of developing extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation

BACKGROUND AND OBJECTIVES: Chronic graft-versus-host disease (GVHD) remains the most common late complication of allogeneic stem cell transplantation, producing significant long-term morbidity and contributing to a substantial risk of late mortality. Chronic GVHD may be more common, more protracted and less responsive to current treatments after peripheral-blood stem cell (PBSC) transplantation than after bone marrow transplantation. The purpose of this retrospective cohort study was to determine whether the hazard of extensive chronic GVHD after allogeneic PBSC transplantation could be decreased by prolonging cyclosporine A (CsA) prophylaxis over 12 months. DESIGN AND METHODS: Fifty-seven consecutive patients with hematologic malignancies who had received a PBSC transplant from an HLA-identical sibling were evaluable for chronic GVHD. All patients began CsA tapering at day 50 but 2 different durations of immunosuppression were used: the first 36 patients were allocated to receive a 6-month course with tapering by 5% at weekly intervals (group A), while the following 21 received a 12-month course with tapering by 5% every 2 weeks (group B). RESULTS: The cumulative incidence of extensive chronic GVHD at 2 years was 69% (95% CI, 53-85%) for group A and 25% (95% CI, 3-47%) for group B with a significantly lower hazard in group B than in group A (HR=0.2; 95% CI, 0.07-0.57; p=0.0009). In multivariate analysis, the 12-month CsA tapering schedule was associated with a significantly decreased risk of extensive chronic GVHD (HR=0.2; 95% CI, 0.06-0.66; p=0.008). The hazard of transplant-related mortality, relapse and failure to survive in remission was not significantly different among the 2 groups. INTERPRETATION AND CONCLUSIONS: One-year CsA prophylaxis seems to be more effective than the standard six-month CsA regimen at preventing extensive chronic GVHD after PBSC transplant from an HLA-identical sibling. Conclusive assessment of the benefits of such prolonged immunosuppression, in terms of better quality of life and minor morbidity, requires both long-term follow-up to evaluate the rates of relapse and secondary tumors and a randomized setting.     

Central and extrapontine myelinolysis following allogeneic peripheral haematopoietic progenitor cell transplantation. Favourable outcome in a patient with chronic myeloid leukaemia

A 48-year-old-man in the first chronic phase of chronic myeloid leukaemia developed a central nervous system complication on day +57 after HLA-identical peripheral blood progenitor cell (PBPC) transplantation. The clinical picture evolved to a reversible pseudobulbar palsy requiring mechanical ventilation. MRI examination disclosed lesions typical of central and extrapontine myelinolysis (CEPM), which disappeared on a repeat examination 20 days later. The patient had received cyclosporine A (CsA) as GVHD prophylaxis and severe hyponatremia was detected 7 days after the first neurological sign. CEPM has been described in alcohol-induced liver disease, following rapidly corrected hyponatremia and associated with CsA in orthotopic liver transplantation. This is the first reported case of CEPM in PBPC transplantation, and CsA seems to have played a role in the development of this very serious complication.     

Reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells from the same donor for relapsed leukemia after bone marrow transplantation

We report the clinical courses of two cases with relapsed acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT). After reinduction chemotherapy, the patients received reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells harvested from their previous BMT donors. The conditioning regimen used consisted of fludarabine and melphalan. Graft-versus-host disease (GVHD) prophylaxis was performed with low dose cyclosporin A (CsA, 1 mg/kg/day d.i.v.) on its own. The regimen related toxicity was minimal, and stable engraftment was achieved. Since acute GVHD had not developed by day 30, CsA was stopped abruptly in both cases. After CsA withdrawal, acute GVHD developed, and subsequent chronic GVHD. One of two cases is alive without any relapse of the leukemia 40 months after the peripheral blood stem cell transplantation (PBSCT). In the other case, ALL relapsed 15 months after the PBSCT, however, complete remission was again induced concomitantly with reactivated GVHD. In both these cases, the results suggest that using PBSC as a stem cell source and abrupt cessation of GVHD prophylaxis provided a potent graft-versus-leukemia effect.     

Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease

Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an accepted treatment for both thalassemia and sickle cell disease (SCD). However, it is associated with decided risk of both transplant-related mortality (TRM) and chronic graft-versus-host disease (GVHD). We analyzed 44 patients (median age, 5 years; range, 1-20 years) given an allogeneic related cord blood transplant for either thalassemia (n = 33) or SCD (n = 11). Thirty children were given cyclosporin A (CsA) alone as GVHD prophylaxis, 10 received CsA and methotrexate (MTX), and 4 patients received other combinations of immunosuppressive drugs. The median number of nucleated cells infused was 4.0 x 10(7)/kg (range, 1.2-10 x 10(7)/kg). No patient died and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range, 4-76 months). Only one patient with SCD did not have sustained donor engraftment as compared with 7 of the 33 patients with thalassemia. Three of these 8 patients had sustained donor engraftment after BMT from the same donor. Four patients experienced grade 2 acute GVHD; only 2 of the 36 patients at risk developed limited chronic GVHD. The 2-year probability of event-free survival is 79% and 90% for patients with thalassemia and SCD, respectively. Use of MTX for GVHD prophylaxis was associated with a greater risk of treatment failure. Related CBT for hemoglobinopathies offers a good probability of success and is associated with a low risk of GVHD. Optimization of transplantation strategies could further improve these results.     

Enhancement of cyclosporin A-induced autologous graft-versus-host disease after peripheral blood stem cell transplantation by utilizing selected CD34(+) cells

Although autologous graft-versus-host disease (GVHD) can be induced by administration of cyclosporin A (CsA) after peripheral blood stem cell transplantation (PBSCT), the incidence appears to be remarkably lower compared to the incidence after bone marrow transplantation. The reduced incidence of autologous GVHD after PBSCT may be attributed to peripheral regulatory cells that are transferred with the stem cell inoculum. To determine whether transplantation of CD34-selected peripheral blood stem cells (PBSCs) leads to potentiation of autologous GVHD, five patients with malignant lymphoma were transplanted with CD34-selected PBSCs, followed by administration of CsA and interferon (IFN)-gamma. Inducibility of autologous GVHD and autocytotoxic activities of peripheral blood mononuclear cells (PBMCs) after transplantation were assessed. All patients demonstrated prompt hematologic recovery. Cytotoxic activity of PBMCs against autologous lymphocytes was detectable in four of four patients analyzed during a limited period from days 14 to 34 post-transplant. An erythematous rash compatible with GVHD, confirmed by skin biopsy, developed in three of five patients. One of the three patients developed not only skin, but also gut and liver GVHD. Transplantation of the CD34-selected stem cell graft that does not accompany transfusion of regulatory cells may potentiate the inducibility of autologous GVHD by the administration of CsA and IFN-gamma.     

Chronic Graft-versus-Host Disease of the Liver Presenting as an Acute Hepatitis following Nonmyeloablative Hematopoietic Stem Cell Transplantation

Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic disease. We observed 3 patients in whom chronic GVHD of the liver after allogeneic nonmyeloablative hematopoietic stem cell transplantation (HSCT) presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. The liver biopsies revealed predominant diffuse lobular injury and degenerative small bile ducts. Prompt administration of high-dose immunosuppressive therapy achieved a rapid improvement of liver enzymes and bilirubin levels. We conclude that a distinct syndrome of chronic hepatic GVHD presenting as an acute hepatitis should be considered as one possible explanation for hepatic dysfunction in patients who receive nonmyeloablative allogeneic HSCT.     

MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation

The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were scored. Positivity in immunostaining was quantified as the number of positive cells/high power field. Treatment with MC1288 decreased clinical signs of GVHD compared with untreated or CsA-treated rats. Histological manifestations of GVHD, expressed as mean total increment, were significantly lower (1.4 +/- 0.5) in MC1288 than in untreated (5.0 +/- 1.6) or CsA (3.5 +/- 1.0) groups. Combining MC1288 and CsA further improved histology (1.1 +/- 0.6). The expression of CD4, CD8, MHC class II, interleukin-2 receptor, nitric oxide 2, and NKR-P1A (NK cells) positivity was significantly decreased in the liver and skin of BMT rats by MC1288. MC1288 was effective in preventing clinical and histological signs and symptoms of GVHD. This novel vitamin D analog could be used as an immunomodulating agent in BMT.     

Effect of blood cyclosporine concentration on the outcome of hematopoietic stem cell transplantation from an HLA-matched sibling donor

We retrospectively evaluated the effect of the blood cyclosporine (CsA) concentration on the outcome of allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor in 171 patients who received a continuous infusion of CsA and short-course methotrexate to prevent graft-versus-host disease (GVHD). CsA was started at 3.0 mg/kg/day and the dose was adjusted to maintain the blood CsA concentration between 250 and 350 ng/ml. The actual dose of CsA averaged 1.9 mg/kg/day at the 3rd week after transplantation. The incidence of grade II-IV acute GVHD was 29.9%. Patient age and sex were identified as independent significant risk factors for acute GVHD. The CsA concentration during the 3rd week after transplantation most strongly affected the incidence of grade II-IV acute GVHD (RR 0.995 for an increase in CsA concentration by 1 ng/ml, P = 0.037) adjusted for other risk factors. The incidence of acute GVHD was significantly lower in patients with a 3rd-week CsA concentration higher than 300 ng/ml than in those with values between 200 and 300 ng/ml (20% vs. 35%, P = 0.036). We concluded that the blood CsA concentration at peri-engraftment period may be important in preventing acute GVHD.     

Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.     

Result of allogeneic bone marrow transplantation from unrelated donor

Two patients treated by unrelated bone marrow transplantation were reported. Case 1 was an eight-year-old boy with Morquio's disease received bone marrow graft from an HLA one-locus mismatched, MLC non reactive unrelated donor. The patient was prepared with conventional dose of cyclophosphamide, and thoracoabdominal irradiation. For the prophylaxis of GVHD, three drug regimen consisted of methotrexate (MTX), cyclosporine A (CsA), and prednisolone (PSL) was administered. Engraftment was prompt, and grade I of acute GVHD developed, which resolved with increased dose of PSL. Case 2 was a ten-month-old boy with juvenile chronic myelogenous leukemia received bone marrow graft from an HLA fully matched, MLC non reactive unrelated donor. Preconditioning regimen consisted of total body irradiation, VP-16, and cytosine arabinoside. MTX, CsA, and methylprednisolone were administered to prevent GVHD, but grade II of acute GVHD developed, which resolved with prolonged course of PSL. Both cases are alive and well, without chronic GVHD. In conclusion, unrelated donor bone marrow transplantation may be a useful to treat hematologic malignancies, aplastic anemia, and some inherited diseases.     

Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level

Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.     

Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation

Bone marrow from 22 histocompatible siblings was depleted of 98% of the lymphocytes using a combination of density flotation centrifugation followed by counterflow elutriation. Even with the marrow suppressive influence of methotrexate (MTX), the viability of the hematopoietic stem cells was not affected, as indicated by the normal repopulation after grafting in the evaluable patients. One patient (UPN 9) showed a primary graft failure, possibly resulting from persisting septicemia and long-term antibiotic therapy. Two patients have persistent host lymphocytes, one of whom was examined during relapse; the other remains in remission. Two patients did not receive immunosuppression after bone marrow transplantation (BMT), and acute graft-v-host disease (GVHD) developed in both. Nine patients received MTX as immunosuppression following BMT. GVHD did not develop in any of them, but fatal infections in the immediate posttransplant period developed in five patients. Eleven patients received cyclosporine (CsA) after transplantation. Beginning in week 5 after BMT, CsA was gradually replaced by MTX. Acute GVHD, substantial chronic GVHD, or fatal infections did not develop in any of these patients. Removal of 98% of the lymphocytes by counterflow centrifugation prevents development of acute GVHD, provided that immunosuppression is administered after BMT. Graft rejection was not observed, but the number of evaluable patients is limited at present.     

Liver Graft-Versus-Host Disease is associated with poor survival among allogeneic hematopoietic stem cell transplant recipients

Liver Graft-versus-host disease (GVHD) is common in patients with post-transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post-transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a “non-liver GVHD” group, which consisted of other etiologies of post-transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post-transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the “non-liver GVHD” group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time-varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non-relapse mortality, and adverse relapse-free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting.     

Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis

Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic disease in patients with skin, mouth, and eye involvement. We observed 14 patients in whom chronic GVHD of the liver presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. Onset of liver dysfunction was at 294 days (range, 74-747 days) after allogeneic hematopoietic cell transplantation and coincided with a recent cessation or taper of immunosuppressive drugs. Median peak serum alanine transaminase (ALT) was 1,640 U/L (698-2,565 U/L), and median bilirubin was 12.3 mg/dL (0.9-55.9 mg/dL). All biopsies showed characteristic features of GVHD with damaged and degenerative small bile ducts. Other features included a marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, and many acidophilic bodies scattered throughout the lobule. When high-dose immunosuppressive therapy was instituted soon after presentation, progressive improvement and eventual normalization of liver enzymes and bilirubin levels were observed. However, in cases in which the diagnosis was not made and therapy was delayed, a progressive cholestatic picture emerged with histologic evidence of loss of small bile ducts and portal fibrosis. We conclude that a distinct syndrome of chronic liver GVHD presenting as an acute hepatitis can be recognized in a patient at risk who is receiving no, or minimal, immunosuppressive medications. Liver biopsy is necessary to exclude viral causes of liver dysfunction and to confirm characteristic abnormalities of small bile ducts. Institution of high-dose immunosuppression can prevent progressive bile duct destruction and effect resolution of jaundice if given early.     

Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders

Thirty-six patients with chronic B-lymphoproliferative disorders (B-LPD) underwent reduced-intensity allogeneic transplantation (RIT) from HLA-identical related donors. Diagnoses included follicular (n=17), mantle cell (n=9) and small lymphocytic lymphoma (n=2), and chronic lymphocytic leukaemia (n=8). Median age at transplant was 51 years (range, 30-66) and time from diagnosis was 3.4 years (range, 0.3-9.5). At transplant, 28% were in CR, 36% were in PR and 36% were chemorefractory. Conditioning therapy included fludarabine and either cyclophosphamide (n=27) or melphalan (n=9). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin (CsA)/methotrexate (n=21), CsA/mycophenolate mofetil (n=13) or CsA alone (n=2). Eight patients died owing to acute GVHD (n=3), infection in association with chronic GVHD (n=4) and intra-abdominal bleeding (n=1). Treatment-related mortality was 8% at day 100, and 17 and 20% at one and two years, respectively. The cumulative incidence of grade II-IV acute GVHD was 58%, whereas limited and extensive chronic GVHD occurred in 25 and 56%, respectively. No patient has relapsed or progressed. At a median follow-up of 48 months, overall survival probability is 80% (95% CI, 67-93%). We confirm that RIT in chronic B-LPD can result in high and durable CR rates but with significant incidences of acute and chronic GVHD.     

Acute myelogenous leukemia with mediastinal and subcutaneous emphysema following chronic GVHD after allogeneic bone marrow transplantation

A 38-year-old man was diagnosed as having acute myelogenous leukemia in December 2001. He achieved a complete remission after undergoing three courses of induction chemotherapy. As the patient's prognosis was considered to be poor, he was then treated with a bone marrow transplant from his HLA 1 antigen mismatched sister in May 2002. Grade 2 skin graft-versus-host-disease (GVHD) developed on day 14 but reduced with methylprednisolone (mPSL). Prednisolone (PSL) was discontinued on day 104, and the patient was discharged on day 112. There was no evidence of clinical chronic GVHD, the serum creatinine level remained high, and cyclosporine (CsA) was gradually tapered off and discontinued on day 165. However chronic GVHD of the skin appeared on day 179, and CsA (100 mg/day) was restarted. On day 186 he was admitted to our hospital complaining of fever. A CT scan of the chest demonstrated bilateral interstitial infiltrates, which were considered as lung GVHD lesions and PSL was started, following which chronic GVHD of the skin and liver improved. The lung GVHD worsened, however, subcutaneous and mediastinal emphysema developed and the patient died on day 206. Interstitial pneumonia had progressively worsened as the manifestation of the chronic lung GVHD. We concluded that this clinical course was rare.