Development of immunity against hepatitis B virus after donor lymphocyte infusion in a peripheral blood stem cell transplantation recipient with chronic hepatitis B

Hepatitis B virus (HBV) infection is one of the main concerns in blood and marrow transplantation (BMT) patients for possible breakthrough hepatitis. Active recipient immunization against HBV was found to be ineffective and many studies had showed that the adoptive transfer of immunity against hepatitis B virus would be possible by BMT with unknown duration and mechanism. A 46-year-old female patient with chronic hepatitis B had persistent detectable HBV DNA and positive serum hepatitis B e antigen (HBeAg), even while on long-term lamivudine and adefovir therapy. She received allogeneic matched unrelated donor peripheral blood stem cell transplantation (allo-MUD-PBSCT) for her refractory acute myeloid leukemia (AML). The HBV DNA became undetectable and she developed HBeAg seroconversion after PBSCT. Her hepatitis B surface antigen (HBsAg) remained positive, which disappeared later, along with the development of antibody to HBsAg after one shot of donor lymphocyte infusion (DLI) as a boost against her AML. In summary, BMT from an immunized donor would probably bring adoptive immunity against HBV. This adoptive immunity might be further enhanced by the subsequent DLI.     

Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation.

CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical entity which is the prototype of the putative NK cell lymphomas. A 16-year-old Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose chemotherapy supported with syngeneic peripheral blood stem cell transplantation (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional chemotherapy before transplantation, resulting in a partial response. PBSC were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She achieved complete remission and is now surviving in continuous complete remission for more than 30 months after syngeneic PBSCT. Thus, marrow-ablative chemotherapy facilitated by autologous or allogeneic PBSCT should be considered as part of the primary therapy for poor prognosis NK cell lymphomas.     

A case of a long-time survivor with chronic active Epstein-Barr virus infection

Epstein-Barr virus (EBV) is associated with hypersensitivity to mosquito bites (HMB) and fatal EBV-associated hemophagocytic syndrome (HPS). The prognosis of patients with chronic active EBV infection (CAEBV) is very poor. We report a rare case of an adult woman patient with a 28-yr history of HMB, who developed EBV-HPS. EBV genome was detected in the serum and peripheral blood lymphocytes. Clonal proliferation of EBV was demonstrated by Southern blot analysis using an EBV genome terminal-repeat probe. This is a very rare case of a long-term survivor with CAEBV. The patient was initially treated with immunochemotherapy and achieved complete remission. However, the patient immediately relapsed and underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. Peripheral blood cell recovered well, and EBV genome disappeared from the peripheral blood. Allogeneic BMT may be effective in eradicating EBV-HPS. Unfortunately, the patient died of graft vs. host disease on the 92nd day after BMT.     

A pilot study of cytoreductive chemotherapy combined with infusion of additional peripheral blood stem cells reserved at time of harvest for transplantation in case of relapsed hematologic malignancies after allogeneic peripheral blood stem cell transplant

Reharvesting leukocytes from donors for a donor leukocyte infusion (DLI) is inconvenient and occasionally impossible in case of unrelated donors. It is well known that the effect of a growth factor-primed DLI is comparable to that of a nonprimed DLI. In total, 42 patients with hematologic malignancies and a high risk of relapse were allocated, on an intent-to-treat basis, a peripheral blood stem cell transplantation (PBSCT) from HLA-matched sibling donors, and then at the time of harvest, additional peripheral blood stem cells (PBSCs) were also reserved for a therapeutic primed DLI in case of relapse. In all, 12 patients who relapsed after allogeneic PBSCT were treated with mainly cytarabine-based chemotherapy followed by a cryopreserved PBSC infusion. The median dose of CD3+ and CD34+ cells for the primed DLIs was 1.43 x 10(8)/kg and 4.75 x 10(6)/kg, respectively. Six of the 12 relapsed patients exhibited a complete response after the primed DLI, plus their 1-year survival rate was 33%. The new development or progression of graft-versus-host disease after a primed DLI was observed in 50% of the patients. Overall, the survival at 1 year was 16.7%. Accordingly, the induction of a graft-versus-leukemia effect through a primed DLI, using additional PBSCs reserved at the original time of harvest, would appear to be feasible for patients with relapsed hematologic malignancies. Furthermore, this approach is also more convenient for donors.     

Successful clearance of hepatitis B virus after allogeneic stem cell transplantation: beneficial combination of adoptive immunity transfer and lamivudine

We report a 38-yr-old male with acute lymphocytic leukemia (ALL), whose serological tests for the hepatitis B virus (HBV) before transplantation showed a chronic carrier status, and a liver biopsy specimen revealed chronic liver injury because of HBV. The patient underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his sibling who was hepatitis B surface antibody (HBsAb) positive. He had received lamivudine treatment for the prophylaxis of HBV reactivation during cytotoxic chemotherapy, and lamivudine administration continued after transplantation. Successful engraftment was documented 3 wk after PBSCT, and clearance of the hepatitis B surface antigen (HBsAg) was observed 2 months after PBSCT. Liver function tests transiently showed a mild elevation of aminotransferases on day 25, although this returned to normal after the dose escalation of the immunosuppressive agent. We presume that the combination of adoptive immunity transfer by bone marrow transplantation (BMT) from an HBsAb-positive donor and antiviral drugs such as lamivudine is beneficial in clearing HBV in chronic carriers.     

Successful antiviral treatment for fulminant reactivated hepatitis B after autologous stem cell transplantation and prophylaxis during subsequent allogeneic stem cell transplantation

The risk of severe hepatic damage due to reactivation of hepatitis B virus (HBV) infection after intensive myelosuppressive chemotherapy is well known. Two of the most evolved nucleotide analogues showing good activity against the hepatitis B virus are lamivudine and famciclovir. We report the successful therapeutic use of lamivudine and famciclovir for fulminant reactivated hepatitis B after autologous peripheral blood stem cell transplantation (PBSCT) and the subsequent prophylactic use of lamivudine during allogeneic blood stem cell transplantation (alloSCT) for chronic lymphocytic leukemia (CLL) in a 40-year-old patient. Antiviral therapy was well tolerated and no hematotoxicity occurred. Our observation warrants further investigation of antiviral therapy with famciclovir and lamivudine in HBV carriers receiving intensive myelosuppressive chemotherapy.     

A case report of thrombotic thrombocytopenic purpura and severe acute renal failure post non-myeloablative allogeneic peripheral blood stem cell transplantation treated with plasma exchange and hemodialysis

A 59-year-old-woman received related non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) subsequent to autologous PBSCT in our hospital five years after she was diagnosed as oligo-secretory myeloma. She was admitted to our hospital because of vomiting and grayish diarrhea 4 months after non-myeloablative allogeneic PBSCT (mini-alloPBSCT). Although her initial symptoms improved after admission, she gradually showed thrombocytopenia, anemia, and oliguria during the 2 weeks after admission. Our diagnosis was thrombotic thrombocytopenic purpura (TTP) and acute renal failure (ARF) secondary to mini-alloPBSCT. After cessation of cyclosporine administration, we began to treat her with plasma exchange (PE) and hemodialysis. During the three and a half months after we started PE, the TTP gradually improved. Although PE had been reported to be ineffective for TTP post bone marrow transplantation, we could finally discontinue PE. In contrast, since her anuria continued, she was managed with hemodialysis. One month after PE was started, her activity of von Willebrand factor-cleaving protease was 41% (normal range, >50%) and the ultrasonographic investigation of both kidneys was normal. She could be discharged after four and a half months hospitalization and lived well as an outpatient for a further two months. She died shortly after readmission from multiple organ failure without the relapse of TTP. The patient's clinical course would suggest that TTP post mini-alloPBSCT could be treated with PE in some cases, despite the development of dialysis-requiring severe ARF being a poor prognostic factor.     

Diverse Clinical Applications Using Advantages of Allogeneic Peripheral Blood Stem Cell Transplantation

The diverse clinical applications of allogeneic peripheral blood stem cells based on use of their advantages are summarized. It is apparent that more stem cells and T-lymphocytes can be harvested by mobilization treatment with cytokines from healthy donors in allogeneic peripheral blood stem cell transplantation (PBSCT) than in bone marrow transplantation. It is also clear that a stronger graft-versus-tumor effect can be induced with allogeneic PBSCT than with bone marrow transplantation. One merit of allogeneic PBSCT is that it allows clinicians to design diverse clinical applications. It would appear that allogeneic PBSCT may be preferable in special clinical settings, such as advanced hematological malignancies, situations requiring a strong graft-versus-tumor effect, nonmyeloablative stem cell transplantation, and situations requiring a megadose of stem cells. Cytokine-primed peripheral blood stem cells can also be used for adoptive immunotherapy, such as a nonprimed donor lymphocyte infusion.     

Successful treatment with allogeneic peripheral blood stem cell transplantation and granulocyte transfusion for severe aplastic anemia with sinusitis

A 43-year-old woman with severe aplastic anemia (SAA) received anti-thymocyte globulin and cyclosporin A (CyA) and achieved hematological remission. Although she had maintained hematological remission, the disease relapsed 10 months after arbitrary discontinuance of maintenance therapy with CyA. Resumption of CyA therapy was not effective, and her condition became complicated with progressive sinusitis with bone destruction, which was refractory to antibiotics, antifungal agents, granulocyte colony-stimulating factor, and surgical drainage. Because of the necessity for early neutrophil recovery (to resolve the infection), we proceeded with a combination therapy using allogeneic peripheral blood stem cell transplantation (PBSCT) promptly followed by granulocyte transfusion (GTX) from the same human leukocyte antigen-identical donor rather than carrying out a second immunosuppressive therapy. The patient showed temporal resolution of infection on the second day after a single GTX. Although the patient had pneumonia on day 11, it was resolved promptly after engraftment on day 16. This report suggests the clinical utility of a salvage therapy with allogeneic PBSCT followed by GTX in a particular case of recurrent SAA with refractory infections.     

Bortezomib plus dexamethasone treatment followed by reduced-intensity allogeneic stem cell transplantation for multiple myeloma refractory to high-dose chemotherapy with autologous transplantation

We present two long-term survivors after allogeneic transplantation with reduced-intensity conditioning regimen following relapse after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). The first case was a 47-year-old male with IgG MM treated with 2 courses of high-dose melphalan along with ASCT and thalidomide, resulting in a minimal response. He then received 2 courses of bortezomib plus dexamethasone (BD) regimen, which was discontinued due to peripheral neuropathy. Allogeneic peripheral stem cell transplantation (PBSCT) from a sibling donor was performed after pretreatment with fludarabin (125 mg/m(2)) and melphalan (100 mg/m(2)). Engraftment was observed on day 11 and monoclonal IgG had disappeared 5 months after transplantation. The patient has been in complete remission for more than two and a half years with moderate chronic graft-versus-host disease (GVHD). The second case was a 51-year-old male who relapsed after ASCT for IgA MM. After 3 courses of BD treatment, irradiation to lumbar plasmacytoma, and thalidomide therapy, he received allogeneic PBSCT from a related donor after the same reduced intensity conditioning as performed in case 1. A complete response was observed 6 months after PBSCT. The patient has remained relapse-free for two years without GVHD. BD treatment followed by allogeneic stem cell transplantation with reduced intensity conditioning is supposed to be one of the most powerful strategies for patients showing relapse after ASCT.     

Successful treatment of progressive NK cell lymphoma with allogeneic peripheral stem cell transplantation followed by early cyclosporine tapering and donor leukocyte infusions

We describe a patient with progressive natural killer (NK) cell lymphoma who was treated successfully with allogeneic peripheral blood stem cell transplantation (allo-PBSCT) followed by early cyclosporine (CsA) tapering and donor leukocyte infusion (DLI). Because the disease showed early resistance to conventional chemoradiotherapy, we performed high-dose chemotherapy followed by allo-PBSCT. After achieving hematologic engraftment, the patient underwent early tapering of CsA and DLI in an attempt to induce a graft-versus-lymphoma effect. Although the disease was in a progressive state at the time of transplantation, complete remission was obtained after allo-PBSCT. As of this report, the patient has been well for more than 2 years.     

Reduced risk of persisting cytomegalovirus pp65 antigenemia and cytomegalovirus interstitial pneumonia following allogeneic PBSCT

In order to evaluate the risk of cytomegalovirus (CMV) associated disease after allogeneic stem cell transplantation (SCT), 158 consecutive patients at risk for infection were analyzed. BMT was performed in 101 patients and peripheral blood stem cell transplantation (PBSCT) in 57 patients. CMV antigenemia was found in 57 cases (56%) after BMT and 27 cases (47%) after PBSCT, respectively. CMV antigenemia resistant to a 14-day course of GCV was found in 26 patients (26%) after BMT but in only four patients (7%) after PBSCT (P < 0.01). Eighteen patients (11%) developed CMV disease, 14 post BMT and four post PBSCT. Lethal CMV-related interstitial pneumonia (CMV-IP) occurred in 13 cases of whom 12 patients were bone marrow recipients (P = 0.04). The subgroup of seronegative patients with a CMV seropositive donor had a significantly lower risk of developing CMV antigenemia, GCV-resistant CMV antigenemia (P < 0.01) and CMV-related disease (P = 0.01). In conclusion, the incidence of persistent CMV antigenemia and CMV-IP was significantly reduced when allogeneic transplantation was performed with peripheral blood stem cells instead of bone marrow. These findings suggest that our previous in vitro data on improved immune reconstitution after allogeneic PBSCT as compared to allogeneic BMT have clinical relevance.     

Successful non-myeloablative stem cell transplantation for a heavily transfused woman with severe aplastic anemia complicated by heart failure.

A 30-year-old Japanese woman weighing 35 kg with severe hemochromatosis due to multiple transfusions was referred to our clinic for treatment of severe aplastic anemia (SAA). The patient had heart failure with an ejection fraction of 36% requiring diuretics and a severe liver dysfunction with an indocyanine green clearance rate of 18%, as well as other transfusion-related complications such as chronic hepatitis due to hepatitis C virus and diabetes mellitus. She was treated with a non-myeloablative preparative regimen that included fludarabine monophosphate (Flu, 120 mg/m(2)), cyclophosphamide (CY, 1200 mg/m(2)) and antithymocyte globulin (ATG, 15 mg/kg) followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from her HLA-matched sister. The regimen was well tolerated, and engraftment rapidly occurred without any therapy-related complications. Chimerism analysis on day 14 after transplant showed reconstitution with 100% donor cells. She no longer needed transfusion after day 23 and has been well in 90% Karnofsky status at 4 months post transplant. The clinical course of this patient indicates that this preparative regimen enables SAA patients with severe organ failure to safely undergo allogeneic stem cell transplantation.     

A possible role for lamivudine as prophylaxis against hepatitis B reactivation in carriers of hepatitis B who undergo chemotherapy and autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

Hepatitis B virus (HBV) reactivation, a well-known complication in immunosuppressed patients, can give rise to acute hepatitis and even fatal fulminant hepatitis. Three Japanese males with non-Hodgkin's lymphoma (NHL) who were carriers of HBV received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). To prevent HBV reactivation, all received oral lamivudine (150 mg/day), a nucleoside analogue, at the start of chemotherapy. All were treated at full-dose intensity, including corticosteroids, without modification of treatment regimens. All three patients completed the total course of chemotherapy and PBSCT, with no signs of HBV reactivation. Peripheral blood stem cell (PBSC) harvests and hematological recoveries after transplantation were not affected by lamivudine, which was continued for at least 16 weeks after transplantation. HBV-DNA and DNA polymerase levels remained negative/normal after discontinuation of lamivudine. Lamivudine effectively inhibits HBV replication and has few serious adverse effects, particularly those related to hematopoiesis. Thus, prophylactic use of lamivudine from initiation of chemotherapy deserves consideration in the treatment of HBV carriers who require immunosuppressive chemotherapy, and may prevent HBV reactivation.     

Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency.

Wild-type strains of Epstein-Barr virus (EBV) can be distinguished on the basis of variations in the molecular weight of virus-encoded, growth transformation-associated proteins. This approach was used to study the persistence of EBV in two seropositive recipients of allogeneic bone marrow transplants. The first patient received marrow from her EBV-seronegative brother, became EBV seronegative after grafting, and remained so for greater than 1200 days. Subsequently, she became infected with a new EBV strain that differed from her pretransplant strain but was indistinguishable from the virus isolated from her husband. The second patient received marrow from his EBV-seropositive brother. This patient showed only a transient decrease in IgG antibodies to EBV capsid antigen. His pretransplant strain differed from the virus of his donor. On days 252 and 915 after transplantation, lymphoblastoid cell lines were grown from the peripheral blood of the patient and were found to carry exclusively the virus of the donor. These results suggest that the latently EBV-infected host cells reside in a cellular compartment that can be destroyed by graft-versus-host reactivity, irradiation, or cytotoxic drugs. Hemopoietic tissue is the most likely candidate.     

Successful second allogeneic peripheral blood stem cell transplantation and donor lymphocyte infusion in patients with relapsed acute leukemia using the same donors as for the initial allogeneic bone marrow transplantation

We report the successful treatment of two acute lympho- blastic leukemia (ALL) patients who relapsed following allogeneic bone marrow transplantation (allo-BMT) with allogeneic peripheral blood sem cell transplantation(allo-PBSCT) and donor lymphocyte infusion (DLI) from the same HLA-identical related donors as those used for the first allo-BMT. The patients relapsed on days 154 and 351 from the initial allo-BMT, respectively. Since conventional reinduction chemotherapy failed, allo-PBSCT was undertaken while the patients were still myelosuppressed immediately after reinduction chemotherapy. To induce and/or enhance GVL effects following allo-PBSCT, we performed rapid tapering of CsA and added DLI. After allo-PBSCT and DLI, the patients maintained their complete remission at 55 and 48 months post allo-PBSCT, respectively. From these findings, allo-PBSCT and DLI may be a useful treatment strategy for acute leukemia relapsing after allo-BMT.     

Persistent aplasia after chemotherapy for acute myeloid leukaemia treated with stem cell transplantation from a matched unrelated donor after dose-reduced conditioning

Persistent aplasia is a rare complication with poor prognosis after intensive chemotherapy for acute leukaemia. A 59-year-old man with acute myeloid leukaemia (AML), was treated after 186 d of chemotherapy-induced persistent aplasia with an allogeneic peripheral blood stem cell transplantation (PBSCT) from a matched unrelated donor (MUD) after dose-reduced conditioning. The patient remains in complete haematological remission more than 8.5 months after haematological recovery. We believe that this is the first reported case of treatment for chemotherapy-induced persistent aplasia with MUD-PBSCT after dose-reduced conditioning, a procedure that can be successfully performed even in elderly patients.     

Membranous Nephropathy Associated with Donor Lymphocyte Infusion following Allogeneic Bone Marrow Transplantation

Nephrotic syndrome after hematopoietic stem cell transplantation (HSCT) followed by donor lymphocyte infusion (DLI) has never been described. We report the case of a myelodysplastic syndrome (MDS) patient who developed nephrotic syndrome with membranous nephropathy 18 months after allogeneic HSCT and 4 months after DLI. A 50-year-old woman with MDS underwent allogeneic bone marrow transplantation from her HLA-matched brother. MDS relapsed 55 days after transplantation, donor lymphocytes were infused as adoptive immunotherapy, and complete remission was achieved. Four months after the third DLI, the patient developed nephrotic syndrome with proteinuria up to 9 g/day. Renal biopsy revealed granular deposits of immunoglobulin G along the glomerular basement membrane, and subepithelial electron-dense deposits. A diagnosis of membranous nephropathy was made. For maintenance of the immunotherapeutic effect of DLI, minimum doses of immunosuppressive therapy for decreasing proteinuria were administered, and improvement of nephrotic syndrome and persistent complete remission of MDS were achieved.     

Cyclosporine is required to prevent severe acute GVHD following T-cell-depleted peripheral blood stem cell transplantation

Reduced immunosuppression may improve immune recovery and increase the graft-versus-leukemia effect after allogeneic stem cell transplantation. Furthermore, the requirement for post-transplant immunosuppression following extensive T-cell depletion remains unclear. We therefore evaluated the role of cyclosporine (CSA) in recipients of HLA-identical T-cell-depleted peripheral blood stem cell transplants (PBSCT), followed by donor lymphocyte infusions (DLIs) scheduled on days +45 and +100. Before day+45, successive cohorts of patients received decreasing amounts of CSA: standard-dose (SD) CSA, low-dose (LD) CSA, or no CSA until day+45. LD CSA was as effective as SD CSA in preventing acute graft-versus-host disease (GVHD). However, moderate-to-severe acute GVHD was significantly more frequent before the day +45 DLI in patients receiving no CSA (33.3 vs 12.7%, P=0.036, including the only four grade III-IV cases). As a result of higher rates of early acute GVHD, more patients in the 'no CSA' group failed to receive any DLI (30.7 vs 7.1%, P=0.01). Overall, there was no difference in the incidence of acute GVHD, as patients receiving CSA developed more GVHD after DLI. Similarly, no significant differences were found in chronic GVHD, transplant-related mortality, or survival. These results define a role for CSA in preventing GVHD at low T-cell doses following PBSCT.