Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced-intensity conditioning allogeneic stem cell transplantation.

Reduced-intensity conditioning allogeneic stem cell transplantation (RIC allo-SCT) is associated with less toxicity and is used for older patients. We retrospectively studied the predictive value of two risk assessment scores, which were the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score, for assessing the outcome of RIC allo-SCT. Seventy-eight patients underwent transplantation between 2005 and 2013 at a single institution. RIC was performed with fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of patients with an HCT-CI >3 was significantly worse than that of patients with an HCT-CI 0-3 (31.6% vs. 59.6%, P = 0.020). Also, the 3-year overall survival of patients with a PAM score >24 was significantly worse than that of those with a PAM score ≤24 (29.2% vs. 61.4%, P = 0.005). The present findings suggest that changing the cut-off values of these risk assessment scores can improve prediction of outcomes in patients receiving RIC allo-SCT with this conditioning regimen and we need validation by large-scale study with other regimens.

Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen.

Human herpesvirus-6 (HHV-6) encephalopathy is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although reactivation of HHV-6 is often observed after allo-HSCT, encephalopathy only affects a few patients with HHV-6 reactivation. Human leukocyte antigen (HLA) class I is expressed by most somatic cells, and a relationship between some class I alleles and neurological diseases has been reported. The HHV-6 load at two, three, and four weeks after allo-HSCT was examined. HHV-6 encephalopathy was diagnosed from symptoms, results of cerebrospinal fluid examination, and magnetic resonance imaging findings. The relation between HHV-6 reactivation or encephalopathy and the HLA class I status of the recipients was investigated. In 130 patients, 147 allo-HSCT transplantation procedures were carried out. HHV-6 reactivation and encephalopathy occurred in 56 and nine procedures, respectively. HLA mismatch (p = 0.008) and unrelated donor (p = 0.001) were associated with HHV-6 reactivation, but not with HHV-6 encephalopathy. HHV-6 encephalopathy was more frequent in patients with HLA-B*40:06 (p = 0.027). In addition, HLA-A*26:01 and HLA-B*40:06 were found to be associated with each other (p = 0.089), while HLA-B*40:06 and HLA-C*08:01 showed a significant association (p < 0.001). The HLA class I alleles of recipients may be associated with the occurrence of HHV-6 encephalopathy after allo-HSCT.

Validation of the European Group for Blood and Marrow Transplantation (EBMT) risk score in patients receiving allogeneic hematopoietic stem cell transplantation at a single center in Japan.

We validated the European Group for Blood and Marrow Transplantation (EBMT) risk score in 273 consecutive adult patients receiving allogeneic hematopoietic stem cell transplantation between 2000 and 2010 at our center. The patients were divided into four groups according to the EBMT risk score: low risk (LR, score 0-2), intermediate risk-1 (IR-1, score 3), intermediate risk-2 (IR-2, score 4), and high risk (HR, score 5-7). The five-yr overall survival of the LR (n = 65), IR-1 (n = 67), IR-2 (n = 70), and HR (n = 71) groups was 72%, 57%, 41%, and 25%, respectively (p < 0.001). The five-yr transplant-related mortality rates were 16%, 30%, 25%, and 36%, respectively (p = 0.07). The five-yr cumulative incidence of relapse was 20%, 18%, 37%, and 41%, respectively (p < 0.001). In the subgroup analysis, the prognostic value of the EBMT risk score was confirmed in patients undergoing myeloablative conditioning (MAC), but not in those undergoing reduced-intensity conditioning (RIC). The results suggest that the EBMT risk score is a useful tool to predict transplant outcome for patients undergoing MAC, but not for those undergoing RIC and may be beneficial for stratifying patients in clinical studies.

[Immune-mediated encephalomyelitis following varicella-zoster virus infection after allogeneic stem cell transplantation].

A 40-year-old Japanese man with acute myeloid leukemia received allogeneic bone marrow transplantation. On day 101, varicella-zoster virus (VZV) infection occurred, but was improved by administration of acyclovir and immunoglobulin. On day 119, he complained of numbness and double vision, and he was admitted due to exacerbation of the symptoms. The findings of cerebrospinal fluid and magnetic resonance image examination were consistent with the diagnosis of immune-mediated encephalomyelitis (IMEM). Intravenous immunoglobulin therapy was effective and his neurological findings dramatically improved without recurrence. IMEM is a rare non-infectious inflammatory demyelinating disease that can occur after transplantation. We herein describe a case report with a review of the associated literature.

[Immunophenotypic analysis of hematogones in patients with hematological malignancies].

We studied immunophenotypic analysis of hematogones by flow cytometry. A total of 102 specimens from 93 patients with acute leukemia (52 specimens), myelodysplastic syndromes (4), or malignant lymphoma (46) were analyzed between April and August, 2011. Hematogones were detected in 55 specimens and highly identified in patients with acute myeloid leukemia in remission and B cell lymphoma. Stage 1 (CD34(+)CD20(-)) and stage 2/3 (CD34(-)CD20(+)) were detected in 9.9% and 52.7%, respectively. In addition, the intermediate type (CD34(+)CD20(+)) was identified in 37.4%. All specimens of stage 3 in bright CD45 expression were positive for CD5 and included CD5(+)CD23(-)CD11c(-), 11.1%, CD5(+)CD23(+)CD11c(-), 85.2%, and CD5(+)CD23(+)CD11c(+), 3.7%. These findings suggest that hematogones with unreported immunophenotypes may exist and the appearance of hematogones in hematologic malignancies may be relatively frequent.

[Extramedullary relapse of acute lymphoblastic leukemia in the breast after unrelated allogeneic bone marrow transplantation].

A 28-year-old female presented with an isolated extramedullary relapse in the breast following an unrelated allogeneic bone marrow transplantation(UBMT)for acute lymphoblastic leukemia. She complained of a tumor in her right breast with hematological complete remission 23 months after her first UBMT. The extramedullary lesion resolved with chemotherapy, and she then received a second UBMT. Although there had been no relapse of leukemia in the bone marrow and extramedullary sites, she died from a herpes simplex virus infection in the central nervous system. Extramedullary relapses in the so-called 'sanctuary'sites after hematopoietic stem cell transplantation are unusual, and breast recurrences are even more rare. A treatment strategy for unusual sites of relapse after BMT should be established.

Long-term outcome of human herpesvirus-6 encephalitis after allogeneic stem cell transplantation.

Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.

Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes.

We analyzed 338 adult patients with acute myeloid leukemia (AML) with t(8;21) and inv(16) undergoing stem cell transplantation (SCT) who were registered in the Japan Society for Hematopoietic Cell Transplantation database. At 3 years, overall survival (OS) of patients with t(8;21) and inv(16) was 50% and 72%, respectively (P= .002). Although no difference was observed when restricted to allogeneic SCT in first complete remission (CR; 84% and 74%), OS of patients with t(8;21) and inv(16) undergoing allogeneic SCT in second or third CR (45% and 86% at 3 years; P= .008) was different. OS was not different between patients in first CR who received allogeneic SCT and those who received autologous SCT for both t(8;21) AML (84% vs 77%; P= .49) and inv(16) AML (74% vs 59%; P= .86). Patients with inv(16) not in CR did better after allogeneic SCT than those with t(8;21) (70% and 18%; P= .03). Patients with t(8;21) and inv(16) should be managed differently as to the application of SCT. SCT in first CR is not necessarily recommended for inv(16). For t(8;21) patients in first CR, a prospective trial is needed to clarify the significance of autologous SCT and allogeneic SCT over chemotherapy.

[Relationship between early lymphocyte recovery and prognosis after allogeneic hematopoietic stem cell transplantation for acute leukemia in remission].

To assess the relationship between early lymphocyte recovery and outcomes after allogeneic hematopoietic stem cell transplantation (SCT) for acute leukemia in remission, 79 adult patients (AML: 48, ALL: 31) who received transplantation between January 2000 and November 2009 were retrospectively analyzed. The median lymphocyte count on day 30 after SCT (LC30) was 465/µl (range, 10∼2640). On comparison of clinical outcomes between patients with low (LC30<400/µl) and high (LC30≥400/µl) counts, the 5-year overall survival (OS) was significantly better in high LC30 group than in low LC30 group (81.6 vs. 52.6%, p=0.014), but the cumulative relapse rate (RR) and non-relapse mortality (NRM) at 5 years did not differ between the two groups. On multivariate analysis, low LC 30 (HR, 2.44; 95% CI, 1.02∼5.88; p=0.046) and grade II∼IV acute graft-versus-host disease (HR, 2.41; 95% CI, 0.99∼5.90, p=0.0053) were significantly associated with worse OS. However, LC30 was not a risk factor for RR or NRM. These findings suggest that LC30 may be one of the outcome predictors for patients receiving SCT.

[Successful selection of chemotherapy based on cell surface antigens in a patient with mixed phenotype acute leukemia].

A 47-year-old man was admitted to our hospital in June 2009 because of fatigue and blast cells in peripheral blood. Bone marrow examination showed that 67% leukemic cells were positive for myeloperoxidase (MPO) and negative for esterase stain. Flow cytometric analysis (FCM) revealed the expressions of CD2, cyCD3, CD5, TdT, CD13 on the blasts. Chromosome analysis of the bone marrow cells demonstrated 46, XY in 18 of the 20 analyzed cells, 46,XY,t(1;11)(q21;p15) in 1 of the 20 analyzed cells, and 47,XY,+11 in 1 of the 20 analyzed cells. The patient was diagnosed as having mixed phenotype acute leukemia, T/myeloid, NOS, according to the WHO classification. He received induction chemotherapy for ALL, but could not achieve complete remission (CR). After initial treatment, residual leukemic cells with CD13, CD33 and MPO were detected by FCM; therefore, he received re-induction chemotherapy for AML, and achieved CR. Acute leukemia of ambiguous lineage is a relatively rare subtype in acute leukemia and standard chemotherapy has not been established. It was suggested that the selection of chemotherapy based on the results of FCM was successful in our patient.

[Second transplantation for graft failure after allogeneic hematopoietic stem cell transplantation--a retrospective survey by Kanto Study Group for Cell Therapy].

We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

[Successful treatment with reduced-intensity stem cell transplantation for primary myelofibrosis].

A 60-year-old man was found to have anemia and leukocytosis from a health examination, and diagnosed with primary myelofibrosis (PMF). He was treated with low-dose melphalan but required frequent transfusions of red blood cells, and his splenomegaly enlarged. He received reduced-intensity stem cell transplantation (RIST)from an HLA-identical unrelated donor. The recovery of hematopoiesis was delayed due to the small number of transplanted cells (0.4 x 10(8)/kg). Splenomegaly and myelofibrosis gradually improved, and transfusion was not necessary 6 months later. He died of pneumonia about 1 year after transplantation. However, this case suggests that RIST is an effective treatment for PMF with giant splenomegaly.

[Air-leak syndrome in patients with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation].

We reported 5 patients who developed air-leak syndrome (ALS) including pneumothorax, pneumomediastinum and subcutaneous emphysema after allogeneic stem cell transplantation (SCT). The underlying diseases were AML (n=2), ALL (n=1), MDS (n=1), and CML (n=1). All patients received allogeneic SCT from related donors including 2 donors with HLA mismatch. Total body irradiation was performed as a conditioning regimen in all patients. Late-onset noninfectious pulmonary complications (LONIPC) were detected in all patients before the development of ALS. The interval from diagnosis of LONIPC to onset of ALS was 10-360 days (median, 20 days). Four of 5 patients were treated with corticosteroid for chronic graft-versus-host disease and/or LONIPC. To date, three patients have died of respiratory failure. The others are currently alive and one of these surviving patients is receiving home oxygen treatment. Physicians should be aware of this rare complication following LONIPC, because treatment of ALS is difficult in some patients.

Allogeneic hematopoietic stem cell transplantation after surgical resection of pulmonary aspergillosis in 5 patients with acute leukemia.

We report five patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT) following surgical resection of pulmonary aspergillosis. The patients were three men and two women with a median age of 40 (range, 32 approximately 60). The diagnosis, based on CT imaging, Aspergillus antigen, culture, and histopathology of resected lung specimens, included two proven and three possible pulmonary aspergillosis. Median duration from surgery to HSCT was 2.5 months (range, 1.0 approximately 20). Pre-transplant restrictive-type lung dysfunction was observed in four patients. Antifungal prophylaxis after HSCT was attempted with voriconazole in three patients, amphotericin-B in one patient, and micafungin in one patient. No patients experienced a relapse of pulmonary aspergillosis, although three patients died after HSCT. The causes of death included leukemia relapse in two and hemophagocytic syndrome in one. These results suggest that pre-transplant surgical resection with post-transplant prophylactic antifungal agents seems to be an effective strategy to prevent the relapse of pulmonary aspergillosis in patients with residual disease in the lung before allogeneic HSCT.

[Myocardial infiltration and formation of multiple granulocytic sarcoma of acute myeloid leukemia after cord blood transplantation].

A 57-year-old woman was diagnosed with acute myeloid leukemia (AML, M5a) with MLL rearrangement in August 2006. Cord blood transplantation (CBT) conditioned with a reduced-intensity regimen was carried out during second complete remission in March 2007. Marrow study on day 28 confirmed complete chimera and disappearance of minimal residual disease by RT-PCR. She complained of left chest pain around day 120. CT scan on day 127 showed left pleural effusion, tumors of the upper mediastinum and spleen, and pericardial effusion. She suddenly died of cardiogenic shock on day 129. Postmortem examination revealed systemic granulocytic sarcomas and infiltration of leukemic cells into the right atrium and epicardium without recurrence of leukemia in blood and marrow.

[Allogeneic hematopoietic stem cell transplantation from HLA one-locus-mismatched related donors].

Fourteen patients who received allogeneic hematopoietic stem cell transplantation (HSCT) from a serologically HLA one mismatched related donor (MMRD) between November 1987 and July 2003, were compared with HSCT from matched sibling donor (MSD) (n=142) or matched unrelated donor (MUD) (n=78). Cumulative incidence of acute graft-versus-host disease (GVHD) in patients with MMRD was significantly higher than in those with MSD, but was not different from that in those with MUD. There was no difference in the incidence of extensive type chronic GVHD in HSCT according to donor type. Overall survival (OS) at 5-years in patients with MMRD, MSD and MUD was 42.8%, 55.6% and 44.3%, respectively. The presence of acute GVHD and disease status at HSCT were identified as risk factors for overall survival by multivariate analysis. Acute GVHD was a risk factor for prognosis in patients with MSD and MUD, but not in those with MMRD. It was confirmed that the therapeutic results could be obtained in HSCT from MMRD as well as MUD.

Central nervous system relapse of leukemia after allogeneic hematopoietic stem cell transplantation.

Little information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P = .029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P = .042), the history of CNS invasion before HSCT (RR = 5.62, 95% CI = 2.62-12.0, P = 9.2 x 10(-6)), and the prophylactic intrathecal chemotherapy after HSCT (RR = 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients.

Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy.

The clinical significance of minimal residual disease (MRD) is uncertain in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) treated with imatinib-combined chemotherapy. Here we report the results of prospective MRD monitoring in 100 adult patients. Three hundred and sixty-seven follow-up bone marrow samples, collected at predefined time points during a uniform treatment protocol, were analysed for BCR-ABL1 transcripts by quantitative reverse transcription polymerase chain reaction. Ninety-seven patients (97%) achieved complete remission (CR), and the relapse-free survival (RFS) rate was 46% at 3 years. Negative MRD at the end of induction therapy was not associated with longer RFS or a lower relapse rate (P = 0.800 and P = 0.964 respectively). Twenty-nine patients showed MRD elevation during haematological CR. Of these, 10 of the 16 who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) in first CR were alive without relapse at a median of 2.9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. These results demonstrate that, in Ph+ ALL patients treated with imatinib-combined chemotherapy, rapid molecular response is not associated with a favourable prognosis, and that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect.

Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy.

To identify factors associated with relapse-free survival (RFS), 80 patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia, enrolled in a phase II study of imatinib-combined chemotherapy, were analyzed. The median follow-up of surviving patients was 26.7 months (maximum, 52.5 months). Twenty-eight out of 77 patients who had achieved CR relapsed. The probability of RFS was 50.5% at 2 years. Multivariate analysis revealed that the presence of secondary chromosome aberrations in addition to t(9;22) at diagnosis constitute an independent predictive value for RFS (p=0.027), and increase the risk of treatment failure by 2.8-fold.

[Thyrotoxicosis after cord blood transplantation for acute myelogenous leukemia].

We describe a 44-year-old man with acute myelogenous leukemia who developed thyrotoxicosis after unrelated cord blood transplantation. He complained of fever, general fatigue, tremor and tachycardia on day 63. On examination of thyroid function, free triiodothyronine (23.67 pg/ml) and free thyroxine (5.71 ng/dl) were increased, and thyroid-stimulating hormone (<0.03 microU/ml) was decreased. Antithyroid receptor antibody, antithyroid peroxidase antibody and antithyroglobulin antibody were all negative. The patient was diagnosed as having thyrotoxicosis. His symptoms improved and thyroid function returned to the normal levels within 2 weeks. Thyrotoxicosis is a rare complication, but we should be aware that it may cause idiopathic fever after stem cell transplantation.