Akira Tomonari

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.

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.

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.

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.

Unrelated cord blood transplantation after myeloablative conditioning in adults with ALL.

We analyzed the disease-specific outcomes of adult ALL treated with cord blood transplantation (CBT) after myeloablative conditioning. Between October 2000 and November 2007, 27 adult patients with ALL were treated with unrelated CBT. All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. The median age was 36 years, the median weight was 57 kg and the median number of nucleated cells was 2.47 × 107/kg. All patients received a single and HLA-mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 30 and platelet recovery at day 200 was 92.6 and 92.3%, respectively. With a median follow-up of 47 months, the probability of EFS at 5 years was 57.2%. The 5-year cumulative incidence of TRM and relapse was 3.7 and 27.4%, respectively. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with ALL.

Impact of ABO incompatibility on engraftment and transfusion requirement after unrelated cord blood transplantation: a single institute experience in Japan.

The impact of ABO incompatibility between donor and recipient on engraftment and transfusion requirement was studied in 95 adults who underwent unrelated cord blood transplantation (CBT). The patients included 27 ABO-identical, 29 minor, 21 major and 18 bidirectional ABO-incompatible recipients. Neutrophil engraftment did not differ between ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients (hazard ratio (HR) 1.17, P=0.48). Cumulative incidence of platelet engraftment in ABO-identical/minor ABO-incompatible recipients was higher than in major/bidirectional ABO-incompatible recipients (HR 1.88, P=0.013). In addition, fewer platelet transfusions were required during the first 60 days after CBT in ABO-identical/minor ABO-incompatible recipients (HR 0.80, P=0.040). RBC engraftment did not differ between the two groups (HR 1.25, P=0.33). However, fewer RBC transfusions were required in ABO-identical/minor ABO-incompatible recipients than in major/bidirectional ABO-incompatible recipients (HR 0.74, P<0.005). No patients developed pure red-cell aplasia after CBT. These results indicate that ABO incompatibility affected platelet engraftment and transfusion requirement of RBC and platelet in CBT recipients. Further studies including larger patient numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of CBT.

Cardiovascular toxicity of cryopreserved cord blood cell infusion.

Although infusion of cryopreserved bone marrow or peripheral blood stem cell is associated with a variety of symptoms, there have been no reports detailing the data of infusion-related toxicities of cryopreserved cord blood (CB) units. We prospectively evaluated the incidence and significance of infusion-related toxicities in 34 adult patients undergoing unrelated CB transplantation. Cryopreserved CB units were thawed and immediately infused, unfiltered, through a central intravenous catheter without further manipulation. Heart rate, blood pressure, oxygen saturation and clinical symptoms were recorded during and after infusion. Twenty-four percent of patients experienced non-cardiovascular toxicities related to infusion. The incidence of systolic and diastolic hypertension and bradycardia was 58, 64 and 32%, respectively. Although three patients (9%) with severe systolic hypertension after the infusion required treatment with antihypertensive agents, no patients experienced life-threatening side effects or needed discontinuation of CB unit infusion. Patient or transplant characteristics had no effect on the hypertension and bradycardia related to the infusion of CB. These data suggest that infusion of cryopreserved CB without further manipulation after thawing is safe and well tolerated. However, cardiovascular toxicities including hypertension and bradycardia were frequently observed.