Jun Ooi

Cytomegalovirus infection following unrelated cord blood transplantation for adult patients : a single institute experience in Japan

Summary. Cytomegalovirus (CMV) infection in 28 adult patients after cord blood transplantation (CBT) from unrelated donors was compared with that after bone marrow transplantation from HLA (human leucocyte antigen)‐matched related (R‐BMT) and unrelated (U‐BMT) donors. Positive CMV antigenaemia was seen in 19 (79%) of 24 CMV‐seropositive patients at a median of 42 d (range 29–85 d) after CBT, but in zero of four CMV‐seronegative patients. This did not differ significantly from values observed after R‐BMT and U‐BMT (66%, P = 0·22, and 60%, P = 0·15 respectively). Based on the antigenaemia results, 16 patients (67%) received pre‐emptive ganciclovir therapy from a median of 47 d (range 36–67 d) after CBT. This proportion was higher than that observed after R‐BMT (28%, P = 0·0048), but did not differ from that after U‐BMT (50%, P = 0·21). In addition, the probability of requiring more than two courses of ganciclovir therapy after CBT (21%) was higher than after R‐BMT and U‐BMT (0%, P = 0·015 and 0·039 respectively). One patient (5%) developed CMV disease after U‐BMT, whereas no patients developed CMV disease after CBT or R‐BMT. The CMV serostatus, use of a steroid and HLA disparity affected the probability of requiring ganciclovir therapy after CBT (P = 0·024, 0·032 and 0·017 respectively). These results suggest that recovery of CMV‐specific immunity after CBT is delayed when compared with BMT.

Transient hematopoietic stem cell rescue using umbilical cord blood for a lethally irradiated nuclear accident victim.

We performed stem cell rescue and allogeneic skin transplantation on a lethally neutron-irradiated nuclear accident victim. HLA-DRB1 mismatched unrelated umbilical cord blood cells (2.08 × 107/kg recipient body weight) were transplanted to an 8–10 Gy equivalent neutron-irradiated patient because of a lack of a suitable bone marrow or peripheral blood donor. Pre-transplant conditioning consisted of anti-thymocyte γ-globulin alone, and GVHD prophylaxis was a combination of cyclosporine (CYA) and methylprednisolone (mPSL). Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoietin (TPO) were concurrently administered after transplantation. The absolute neutrophil count reached 0.5 × 109/l on day 15, the reticulocyte count rose above 1% on day 23, and the platelet count was over 50 × 109/l on day 27, respectively. Cytogenetic studies of blood and marrow showed donor/recipient mixed chimerism. Rapid autologous hematopoietic recovery was recognized after withdrawal of CYA and mPSL. Repeated pathological examinations of the skin revealed no evidence of acute GVHD. Eighty-two days after the irradiation, skin transplantation was performed to treat radiation burns. Almost 90% of the transplanted skin engrafted. Immunological examination after autologous hematopoietic recovery revealed an almost normal T cell count. However, immune functions were severely impaired. The patient died from infectious complication 210 days after the accident.Bone Marrow Transplantation (2002) 29, 197–204. doi:10.1038/sj.bmt.1703356

A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukaemia in complete remission

Summary.  We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft‐versus‐host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease‐free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT.

Unrelated Cord Blood Transplantation after Myeloablative Conditioning in Adults with Acute Myelogenous Leukemia

We analyzed the disease-specific outcomes of adult acute myelogenous leukemia (AML) patients treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and February 2008, 77 adult patients with AML were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning. The median age was 45 years, the median weight was 55 kg, the median number of nucleated cells was 2.44 x 10(7)/kg, and the median number of CD34-positive cells was 1.00 x 10(5)/kg. All patients received a single and HLA mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 50 and platelet recovery at day 200 was 94.8% and 91.7%, respectively. A higher CD34-positive cell dose was associated with faster hematopoietic recovery. The cumulative incidence of grade III to IV acute graft-versus-host disease (aGVHD) and extensive-type chronic GVHD (cGVHD) was 25.1% and 28.6%, respectively. With a median follow-up of 78 months, the probability of event-free survival (EFS) at 5 years was 62.8%. The 5-year cumulative incidence of treatment related-mortality (TRM) and relapse was 9.7%, 25.8%, respectively. In multivariate analyses, the risk factor identified for event free survival (EFS) was disease status and cytogenetics. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with AML.

Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation

Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication that significantly reduces a patient’s quality of life. We retrospectively analysed the incidence of and risk factors for BO in allo-SCT recipients. In 2087 patients who underwent allo-SCT between January 1994 and June 2005 and survived >90 days after transplantation, 57 patients developed BO with a 5-year cumulative incidence of 2.8%. The median time interval from transplantation to BO diagnosis was 335 days (range 83–907 days). The 5-year cumulative incidence of BO was 1.62% in bone marrow transplantation (BMT) from related donors, 3.83% in peripheral blood stem cell transplantation (PBSCT) from related donors (R-PBSCT), 2.91% in BMT from unrelated donors and 2.65% in unrelated cord blood transplantation. The incidence of BO after R-PBSCT was significantly higher than that after any other type of allo-SCT (p = 0.02). R-PBSCT (p = 0.019) and preceding chronic graft-versus-host disease (GVHD) (p < 0.001) were BO-associated risk factors. Overall 5-year survival of patients with BO from the time of diagnosis was 45.4%, significantly less than those without (77.5% from day 335, p < 0.001). R-PBSCT recipients with existent chronic GVHD have a high risk of developing BO, and need extensive care and repeated pulmonary function tests.

Varicella-zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan

Summary. Varicella‐zoster virus (VZV) infection was studied in 40 adult patients who underwent cord blood transplantation (CBT) from unrelated donors. Twenty‐five patients developed VZV reactivation at a median of 5 months after CBT (range 1·7–26 months). The cumulative incidence of VZV reactivation after CBT was 80% at 30 months. Twenty‐two patients developed localized herpes zoster. The remaining three patients developed atypical non‐localized herpes zoster, which was associated with visceral dissemination in one patient. All the patients responded well to antiviral therapy. Unexpectedly, the absence of grade II–IV acute graft‐versus‐host disease (GVHD) was associated with a higher rate of VZV reactivation after CBT (100% versus 55%, P = 0·01). These results suggest that recovery of VZV‐specific immune responses after CBT is delayed even in patients without severe acute GVHD.

Allogeneic stem cell transplantation for hepatosplenic gammadelta T-cell lymphoma.

Hepatosplenic gammadelta T-cell lymphoma (HSTCL) was first described by Farcet et al. in 1990 [1]. Most cases of HSCTL occur in young men. Patients typically present with hepatosplenomegaly and bone marrow infiltration with resultant cytopenias but comparatively little lymphadenopathy. The prognosis of HSCTL is poor with reported median survivals of 8 – 16 months and few instances of longterm disease free survival with conventional chemotherapy [2,3]. Recently, a limited number of cases treated with allogeneic SCT for HSTCL have been reported [2 – 15]. We previously reported a patient of HSTCL successfully treated with allogeneic bone marrow transplantation (BMT) from an HLAidentical sibling [6]. In this report, we provide an update of this patient with 7-years follow-up and review the literature for allogeneic SCT for HSTCL. A 23-year-old Japanese male was admitted to our hospital in June 1999 with abdominal distension, malaise, and night sweats. As previously described, the patient was diagnosed with hepatosplenic gamma/delta T-cell lymphoma and treated with intensive B-NHL86 protocol chemotherapy. After the two courses of chemotherapy, he achieved complete remission (CR). Thereafter, he received allogeneic BMT in August 1999 from an HLAidentically matched younger sister. The conditioning regimen consisted of four fractionated 12-Gy total body irradiation (TBI) on Day 79 and Day 78 and high-dose etoposide (60 mg/kg), which was administered as 24-h continuous intravenous infusion on Day 74. Graft-versus-host disease (GVHD) prophylaxis consisted of intravenous cyclosporine and short-term methotrexate. He had evidence of grade II acute GVHD of the skin and gut, which required no steroid treatment. Chimerism evaluation assessed by fluorescent in situ hybridization (FISH) using a mixture of X and Y chromosome-specific probes revealed complete donor chimerism of bone marrow cells on Day þ28. Because of high risk of disease relapse after transplantation, cyclosporine was tapered rapidly and finished on Day þ70. Thereafter, mild chronic GVHD of the liver and skin developed at 4 months after BMT, requiring treatment with oral cyclosporine for 8 months. At 5 years post-BMT, bone marrow examination revealed complete donor chimerism by sex mismatched FISH. Seven years after BMT, the patient is alive and free of disease. Treatment modalities for HSTCL have considerable heterogeneity [3], including splenectomy, corticosteroids, purine analogue, anthracycline containing regimens such as CHOP (cyclophosphamide, hydroxydaunomycin, vincristine and prednisone) or CHOP-like regimen, second or third generation aggressive lymphoma regimen such as IEV (ifosphamide, epirubicin and etoposide) or modified MACOP-B (methotrexate, etoposide instead of adriamycin, cyclophosphamide, vincristine, predonisone and bleomycin), alemtuzumab and autologous and allogeneic stem cell transplantation. However, such treatments have limited efficacy and the vast majority of patients will die from progressive disease. Although allogeneic SCT, which is the only potentially curative therapy, has been attempted to treat

Unrelated cord blood transplantation for adult patients with myelodysplastic syndrome-related secondary acute myeloid leukaemia

Seven adult patients with myelodysplastic syndrome (MDS)‐related secondary acute myeloid leukaemia (AML) were treated with total body irradiation (TBI), cytosine arabinoside (Ara‐C) and cyclophosphamide (CY), followed by unrelated human leucocyte antigen (HLA)‐mismatched cord blood transplantation (CBT). Granulocyte colony‐stimulating factor (G‐CSF) was infused continuously from 12 h before until the end of Ara‐C therapy to enhance the antileukaemia effect of Ara‐C. Five patients are alive and free of disease at 7–31 months after transplantation. These preliminary results suggest that adult MDS‐related secondary AML patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Cord blood transplantation in adults

Umbilical cord blood has several advantages of immediate availability, no risk to donors, a lower risk for acute and chronic GVHD despite major human leukocyte Ag (HLA) disparity, and a lower risk of transmitting infections. As a result of the early successes with pediatric cord blood transplantation (CBT), cord blood from unrelated donors have been increasingly used as an alternative stem cell source for adult patients with hematological malignancies. Recent single-institute and registry-based studies suggest that CBT is a safe, feasible and effective strategy for adult patients without suitable related or unrelated BM donors. In this review, we focus on recent results of myeloablative CBT in adults.

Human herpesvirus 6 variant B infection in adult patients after unrelated cord blood transplantation.

Human herpesvirus 6 var1iant B (HHV-6B) infection was studied in 23 adult patients who underwent cord blood transplantation (CBT). HHV-6B DNA was detected by quantitative polymerase chain reaction analysis after CBT in the sera from 15 patients (65%) at day 14 or 15 (week 2), from 16 patients (70%) at day 21 or 22 (week 3), and from 3 patients (13%) at day 28 or 29 (week 4). HHV-6B DNAemia was found in none of the 20 patients examined at day 7 or 8 (week 1). The overall incidence of HHV-6B DNAemia reached 87% (20 of 23 patients). This incidence was much higher than after unrelated bone marrow transplantation (19%, P < .0001). In CBT patients, positive HHV-6B DNAemia at week 3 was significantly associated with early skin rash (88% versus 14%, P < .005) and grade II–IV acute graft-versus-host disease (aGVHD) (69% versus 14%, P < .05). In contrast, positive HHV-6B DNAemia at week 2 was associated with neither skin rash nor aGVHD. Prospective large-scale studies are needed to determine the role of HHV-6 infection in CBT patients.