Masayuki Hino

Clinical Factors Predicting the Response of Acute Graft-versus-Host Disease to Corticosteroid Therapy: An Analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation

Systemic corticosteroid therapy is recommended as a first-line treatment for acute graft-versus-host disease (GVHD). We performed a retrospective study to identify the factors affecting the response of grade II to IV acute GVHD to systemic corticosteroid therapy using the Japanese national registry data for patients who received first allogeneic hematopoietic cell transplantation with bone marrow (BM) (nxa0=xa01955), peripheral blood stem cells (PBSCs) (nxa0=xa0642), or umbilical cord blood (UCB) (nxa0=xa0839). Of 3436 patients, 2190 (63.7%) showed improvement of acute GVHD to first-line therapy with corticosteroids. Various factors were identified to predict corticosteroid response. Interestingly, UCB (versus HLA-matched related BM) transplantation was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement. HLA-matched related PBSC transplantation was not significantly different from HLA-matched related BM transplantation. Patients without improvement from corticosteroid therapy had a 2.5-times higher nonrelapse mortality and a .6-times lower overall survival rate. The present study demonstrated, for the first time, a higher probability of improvement in grade II to IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. A prospective study is warranted.

Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine

The prognosis of patients after allogeneic hematopoietic stem cell transplantation (HSCT) is still not satisfactory because, while treatment-related mortalities have decreased, relapse after HSCT remains a major concern. The effectiveness of allogeneic HSCT for hematological malignancies is the result of immunologic rejection of recipient leukemia cells by donor T cells, known as the graft-versus-leukemia (GVL) effect.1 It is thus obviously important to be able to exploit the GVL effect while minimizing graft-versus-host disease (GVHD). A targeted anti-leukemic immunotherapy, such as use of a leukemia vaccine,2 is a promising strategy to boost the GVL effect. n nWilms tumor1 (WT1) protein is one of the best targets for leukemia vaccines. Overexpression of the wild-type WT1 gene has been detected in all types of human leukemia.3, 4, 5 We performed a phase I clinical study of immunotherapy targeting the WT1 protein in patients with leukemia, and were able to show that WT1 vaccination was safe and could induce WT1-specific cytotoxic T lymphocyte (CTL).6 Furthermore, reduction of minimal residual disease and long-lasting complete remission (CR) was observed in some leukemia patients who were given the WT1 vaccine.7 n nThis report presents the results of phase I clinical study of WT1 vaccination for HLA-A*2402-positivie post-HSCT patients who were at high risk of relapse (HSCT in non-CR and 2nd HSCT for post-transplant relapse) or had already relapsed. The HLA-A*2402-restricted modified 9-mer WT1 peptide (amino acids 235–243 CYTWNQMNL)8 was emulsified with Montanide ISA51 adjuvant. Patients were intradermally injected with 1.0u2009mg (three patients: UPNs 1, 4 and 6) or 3.0u2009mg (other six patients) of WT1 peptide four times weekly. When no adverse effects and no obvious disease progression were observed after the fourth injection, further WT1 vaccinations at 2-week intervals were administered. n nNine patients (five with acute myeloid leukemia (AML), one each with acute lymphoblastic leukemia, chronic myelomonocytic leukemia, multiple myeloma and T-cell lymphoblastic lymphoma) were enrolled in this study (Supplementary Tables 1 and 2). Local inflammatory response was observed at the vaccine injection sites of all patients. One patient (UPN5) suffered mild hypoxia (PaO2 65u2009mmu2009Hg at room air) and restrictive pulmonary dysfunction (FEV1.0 40%) 65 days after the start of WT1 vaccination (day 199 after HSCT; Figure 1a). He was diagnosed with bronchioleitis obliterans (BO), which was a symptom of chronic GVHD. The patient recovered soon after administration of inhaled steroids. While early and sudden discontinuation of prednisolone and tacrolimus (day 103 after HSCT) were considered to be the reason for development of BO, the possibility of an association between BO and WT1 vaccination cannot be entirely ruled out. In other eight patients, no severe toxicities related to WT1 vaccine were observed (Table1). n n n nFigure 1 n nClinical course of patients who attained CR after the start of WT1 peptide vaccination. (a) Clinical course of UPN5 who achieved CR after administration of WT1 vaccine but stopped vaccination because of the development of bronchioleitis obliterans. ( ... n n n n n nTable 1 n nPatient outcomes n n n nThree AML patients (UPN1–3), who had undergone HSCT in non-CR, started WT1 vaccine in CR (Supplementary Tables 1 and 2). They started WT1 vaccination on post-HSCT days 141, 76 and 93 and have remained in CR for 1038, 973 and 662 days, respectively (as of 8 April 2013; Table1), suggesting the potential of WT1 vaccination as a maintenance therapy after HSCT. n nSix patients started WT1 vaccination in non-CR and two of them became CR after WT1 vaccination. One B-ALL patient (UPN4) with MLL-AF4 underwent bone marrow transplantation from an HLA-matched unrelated donor during the first CR. On post-HSCT day 111, MLL-AF4 and WT1 mRNA in peripheral blood (PB) had increased to 16u2009000 and 15u2009000 copies/μg RNA, indicating that the disease had relapsed. Tacrolimus and prednisolone doses were tapered off to induce GVL effects. The expression levels of MLL-AF4 and WT1 mRNA in PB had decreased to 2700 and 190 copies/μg RNA by day 132, and WT1 vaccination was started on day 133. MLL-AF4 mRNA had become undetectable by day 146, and had never appeared until post-HSCT day 1312 (day 1179 after the start of WT1 vaccination as of 8 April 2013; Figure 1b). n nSkin tumors appeared in UPN5 (AML-M5) on post-HSCT day 103 and was diagnosed by biopsy as leukemia relapse. Tacrolimus was discontinued on day103, and WT1 vaccination was started on day 130. Cutaneous tumors had regressed 2 weeks after the start of WT1 vaccination, but vaccination was terminated after the second injection because of the development of BO as described earlier (Figure 1a). This patient has been remained in CR until post-HSCT day 972 (day 842 after the start of WT1 vaccination at 8 April 2013). While the exact contribution of the vaccination effect to the disease remission in addition to the GVL effect was unclear, the fact that both of these two patients still have remained in CR until now is encouraging to continue this trial. In the following phase II trials, the enumeration of WT1-specific CTLs should be performed more frequently after the start of vaccination to clarify the relationship between the effect of WT1 peptide vaccination and leukemia regression. n nWT1 (a natural 9-mer WT1 peptide) HLA-A*2402 tetramer assays could be performed with peripheral blood mononuclear cell in seven of the nine patients to determine whether WT1235 peptide-specific CD8+ T cells had increased after WT1 vaccination. The gates for WT1 tetramer+ cells were drawn as <0.1% of CD8+ T cells were included in the tetramer-positive gate in multiple healthy individuals (Supplementary Figure 1A). WT1235 tetramer+ cells increased after the start of vaccination in three (UPNs1, 2 and 4) of the four patients who have remained in CR (Figure 1b and Supplementary Figure 1B). In the cases with progressive disease, continuous increase in the frequencies of WT1235 tetramer+ cells was not observed (Supplementary Figure 1B). n nOur results suggest that WT1 vaccination should be started when the leukemia burden is minimal. The timing of the start of WT1 vaccination may be also important. For the cases with good outcomes, WT1 vaccination was started 76–140 days after transplantation (UPNs1–5), and at later times (days 299–1815) for PD cases (UPNs 6–9). A lymphopenic environment a few months after transplantation may be favorable for rapid and extensive expansion of tumor antigen-specific CTLs. n nIn summary, this report suggests that WT1 vaccine can be safely administrated for post-HSCT patients with hematological malignancies and has potential as a maintenance therapy. Clinical benefit of WT1 vaccination for post-HSCT patients will be evaluated in the subsequent phase II trials.

PBSC collection from family donors in Japan: a prospective survey

Severe adverse events (SAE) and late hematological malignancies have been reported after PBSC donation. No prospective data on incidence and risk factors have been available for family donors so far. The Japan Society for Hematopoietic Cell Transplantation (JSHCT) introduced therefore in 2000 a mandatory registration system. It defined standards for donor eligibility and asked harvest centers to report any SAE immediately. All donors were examined at day 30 and were to be contacted once each year for a period of 5 years. Acute SAEs within day 30 were reported from 47/3264 donations (1.44%) with 14 events considered as unexpected and severe (0.58%). No donor died within 30 days. Late SAEs were reported from 39/1708 donors (2.3%). The incidence of acute SAEs was significantly higher among donors not matching the JSHCT standards (P=0.0023). Late hematological malignancies in PBSC donors were not different compared with a retrospective cohort of BM donors (N:1/1708 vs N:2/5921; P=0.53). In conclusion, acute and late SAEs do occur in PBSC donors at relatively low frequency but risk factors can be defined.

Dasatinib maintenance therapy after allogeneic hematopoietic stem cell transplantation for an isolated central nervous system blast crisis in chronic myelogenous leukemia.

A 22-year-old male with Ph-positive chronic myelogenous leukemia (CML) was started on treatment with imatinib. After 12 months of therapy, he achieved a complete cytogenetic response (CCyR). Although the CCyR persisted in his bone marrow, he developed an isolated CML blast crisis in his central nervous system (CNS) after 29 months of therapy. He underwent allogeneic hematopoietic stem cell transplantation (HSCT) following combination therapy with dasatinib, intrathecal chemotherapy and cranial irradiation. Subsequently, 168 days after allogeneic HSCT, he was started on dasatinib maintenance therapy to prevent a CNS relapse. Thirty-eight months after allogeneic HSCT, he has sustained a complete molecular response in both bone marrow and CNS. We believe dasatinib has the potential to prevent CNS relapse if used for maintenance therapy after allogeneic HSCT.

Fatal BK virus pneumonia following stem cell transplantation

We report the case of a 39‐year‐old male patient who died of severe BK virus (BKV) pneumonia 168 days after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After suffering from BKV‐associated late‐onset hemorrhagic cystitis (HC) with long‐term sustained BKV viremia, he died of rapidly progressive pneumonia. On autopsy, numerous viral intranuclear inclusions were seen in his lungs and bladder. An immunohistochemical examination of his lungs was positive for simian virus 40. Based on these pathological results and the high sustained BKV viral load in his blood, we reached a diagnosis of BKV pneumonia. Viral infection can occasionally become life threatening among HSCT recipients. It is widely known that BKV can cause late‐onset HC, but BKV‐associated pneumonia is rare. Because of its rapid progression and poor prognosis, it is difficult to make an antemortem diagnosis of BKV pneumonia. A treatment strategy for BKV pneumonia also needs to be formulated. Similar to other viral pathogens, BKV can cause pneumonia and the clinician should therefore be aware of it in immunocompromised patients.

Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation

BackgroundThere has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation.MethodWe retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%).ResultsEngraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively.ConclusionGraft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.

Comparison of outcomes between autologous and allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphomas with central review of pathology

Comparison of outcomes between autologous and allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphomas with central review of pathology

Immunoglobulin Prophylaxis Against Cytomegalovirus Infection in Patients at High Risk of Infection Following Allogeneic Hematopoietic Cell Transplantation

Reports on the efficacy of intravenous immunoglobulin (IVIG) prophylaxis against cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (HCT) have often sparked controversy. In addition, we are not aware of any study that has examined whether prophylaxis with IVIG affects the incidence of CMV infection in high-risk patients--those who are elderly or have received human leukocyte antigen (HLA) mismatched HCT. In the present open-label, phase II study, we addressed this question. We enrolled 106 patients in the study. The cumulative incidences of CMV infection at 100 days after HCT were similar in the intervention and the control groups (68% and 64%, P=.89; 89% and 87%, P=.79, respectively, for patients 55 years or older and those who received HLA-mismatched HCT). In those who received HLA-mismatched HCT, 1-year overall survival after HCT was 46% in the intervention group and 40% in the control group (P=.31); for age≥55 years, the corresponding values were 46% and 40% (P=.27). Our data showed that prophylaxis with regular polyvalent IVIG did not affect the incidence of CMV infections or survival among older patients or those who receive HLA-mismatched HCT.

Reduced-intensity conditioning by fludarabine/busulfan without additional irradiation or T-cell depletion leads to low non-relapse mortality in unrelated bone marrow transplantation.

In reduced intensity, allogeneic stem cell transplantation from unrelated donors (u-RIST), graft-versus-host disease (GVHD), graft failure, and non-relapse mortality (NRM) are persistent problems. Although anti-thymocyte globulin, alemtuzumab, and total body irradiation (TBI) have been explored as conditioning modalities for u-RIST, the necessity for T-cell depletion or TBI to prevent GVHD or facilitate engraftment in u-RIST has not been determined. We here report the use of u-RIST with bone marrow grafting, following a simple conditioning regimen of 180 mg/m2 fludarabine and 8 mg/kg of oral or intravenous busulfan without TBI or T-cell depletion. The study population was exclusively Japanese patients with a history of prior chemotherapy. We retrospectively analyzed 31 consecutive patients (median age 53 years). Twenty-five patients (81%) were transplanted from HLA-A, -B, and -DRB1 allele-matched donors. In all patients, neutrophil engraftment was achieved. The cumulative incidence of grade II–IV acute GVHD was 42%. However, 77% of patients with acute GVHD improved with, and could be managed by, initial, systemic, high-dose steroid treatment alone. Two-year overall and event-free survival was 62 and 53%, respectively. The NRM of 10% at 2 years was relatively low. Our results suggest that u-RIST without TBI or T-cell depletion may improve the prognosis after u-RIST in certain patient populations.

Risk factors affecting cardiac left-ventricular hypertrophy and systolic and diastolic function in the chronic phase of allogeneic hematopoietic cell transplantation

Chronic impairment of cardiac function can be an important health risk and impair the quality of life, and may even be life-threatening for long-term survivors of allogeneic hematopoietic cell transplantation (HCT). However, risk factors for and/or the underlying mechanism of cardiac dysfunction in the chronic phase of HCT are still not fully understood. We retrospectively investigated factors affecting cardiac function and left-ventricular hypertrophy (LVH) in the chronic phase of HCT. Sixty-three recipients who survived for >1 year after receiving HCT were evaluated using echocardiography. Based on simple linear regression models, high-dose TBI-based conditioning was significantly associated with a decrease in left-ventricular ejection fraction and the early peak flow velocity/atrial peak flow velocity ratio, following HCT (coefficient=−5.550, P=0.02 and coefficient=−0.268, P=0.02, respectively). These associations remained significant with the use of multiple linear regression models. Additionally, the serum ferritin (s-ferritin) level before HCT was found to be a significant risk factor for LVH on multivariable logistic analysis (P=0.03). In conclusion, our study demonstrated that a myeloablative regimen, especially one that involved high-dose TBI, impaired cardiac function, and that a high s-ferritin level might be associated with the development of LVH in the chronic phase of HCT.