Mitsutaka Nishimoto

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.

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.

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.

Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin

Treatment for steroid-refractory acute graft-versus-host disease (GVHD) has not been established yet. In this article, we report a single-center experience with rabbit antithymocyte globulin (ATG) for the treatment of steroid-refractory acute GVHD. We retrospectively analyzed 11 consecutive patients between December 2009 and December 2013. ATG was given at an initial dose of 1.0 mg/kg for all but one patient with gradual dose escalation while assessing responses. The overall improvement at day 28 was 55% after a median of two treatments (range: 1-5), and a median dose of 3 mg/kg (range: 1.0-11.75 mg/kg) of ATG. Patients with skin (100%, 3/3) and gut (83%, 5/6) responded favorably, whereas the cases with liver involvement showed poor responses (25%, 1/4). The overall survival and transplant-related mortality at 1 year were 55% and 45%, respectively. There were no patients who had developed a post-transplant lymphoproliferative disorder. We suggest that response-guided ATG therapy could be an option for patients with steroid-refractory GVHD, without increasing the incidence of opportunistic infections.

Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease

There is no established second-line treatment for steroid-resistant acute graft-versus-host disease (GVHD). We prospectively assessed the safety and efficacy of intra-arterial steroid infusions (IASIs) for steroid-resistant acute gastrointestinal (GI) GVHD and compared the outcomes with those of historical controls at our institution. Nineteen consecutive, allogeneic hematopoietic stem cell transplantation subjects aged 31-67 years (median 52) were enrolled between October, 2008, and November, 2012. Acute GVHD was confirmed by biopsy in all cases. The enrolled patients were treated with infusions of methylprednisolone into the mesenteric arteries and/or gastroduodenal and left gastric arteries. Fourteen consecutive patients who developed steroid-resistant acute GI GVHD between 2001 and 2008 were used as controls. For the primary endpoint at day 28, the overall and complete responses in the IASI group trended higher (79% vs. 42%, p = 0.066) and were significantly higher (63% vs. 21%, p = 0.033) than those in the control group. Although not statistically significant, owing to the small population, the crude day-180-nonrelapse mortality rate was about 20% lower and the day-180-overall-survival rate tended to be higher than the control (11% vs. 29%, p = 0.222; 79% vs. 50%, p = 0.109, respectively). There were no serious IASI-related complications. Our results suggest that IASI can safely provide excellent efficacy for refractory acute GI GVHD without increasing infection-related complications and may improve prognosis.

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.

Diagnostic value of serum ferritin and the risk factors and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation

Abstract To examine the diagnostic value of serum ferritin, the associated risk factors, and cytokine profiles of hemophagocytic syndrome (HPS) following allogeneic hematopoietic cell transplantation (allo-HCT), we retrospectively analyzed data from patients undergoing allo-HCT between 2006 and 2012. Of 223 eligible patients, 18 patients developed HPS. A serum ferritin level above 30,000 μg/l was highly specific for the detection of HPS (specificity, 93%). The one-year survival rate for HPS was significantly lower than that of non-HPS patients (37.5% vs. 72.9%, respectively, Log-rank p < .01). In multivariable Cox models, antigen mismatches in human leukocyte antigen (HLA) in both graft-versus-host (GVH) and host-versus-graft (HVG) directions were significantly associated with the incidence of HPS. We found a significant elevation of Th1 cytokine (IFN-γ), Th2 cytokines (IL-10), and chemokines (MCP-1 and IP-10), at the onset of HPS. Our results suggest that allo-reactivity, derived from HLA-mismatch, and possibly causing a cytokine storm, may be associated with HPS development.

Lung function score including a parameter of small airway disease as a highly predictive indicator of survival after allogeneic hematopoietic cell transplantation

Some studies on the predictive value of determining pulmonary function prior to allogeneic hematopoietic cell transplantation (allo‐HCT) have shown a significant association between pulmonary function test (PFT) parameters and pulmonary complications, and mortality. However, the percentage of patients showing abnormalities in pretransplant PFT parameters is low. We comprehensively evaluated the effect of pretransplant PFT parameters, including a marker of small airway disease (ratio of the airflow rate of 50% vital capacity to the airflow rate of 25% vital capacity ( V˙ 50/ V˙ 25), on outcomes in 206 evaluable patients who underwent allo‐HCT at our institute. Notable among the significant parameters in a univariable analysis, V˙ 50/ V˙ 25 was the most powerful indicator of survival following allo‐HCT (delta‐Akaike information criterion [∆AIC] = 12.47, ∆χ2 = 14.47; P = 0.0001). Additionally, a pretransplant lung function score (pLFS) established by applying three parameters with superior predictive values including V˙ 50/ V˙ 25 represented a better discriminating variable for the prediction of survival. Our data demonstrate that a pLFS incorporating a parameter of small airway disease, rather than the parameters of central airway obstruction, may be useful for predicting patient survival following allo‐HCT.

Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review.

Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51‐year‐old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis.