Safety of ASP0113, a cytomegalovirus DNA vaccine, in recipients undergoing allogeneic hematopoietic cell transplantation: an open-label phase 2 trial.

Cytomegalovirus (CMV) infection/reactivation is a serious complication after hematopoietic cell transplantation (HCT). The DNA vaccine ASP0113 contains two plasmids encoding CMV antigens (glycoprotein B and tegument phosphoprotein 65) that stimulate humoral and cellular immunity. Between June 2013 and February 2014, Astellas conducted a phase 2, open-label, uncontrolled, three-center trial to investigate the safety and tolerability of ASP0113 in Japanese patients undergoing HCT for hematologic disorders. Ten patients aged 22-61 years were enrolled; nine received at least one dose of ASP0113. Six patients received all five doses of ASP0113 5 mg at intervals before and after HCT. Pre-emptive antiviral therapy was allowed. One patient died following relapse of primary disease. All patients had serious adverse events deemed unrelated to ASP0113. CMV viremia (assessed by CMV antigenemia) occurred in seven patients, who then received anti-CMV therapy. No patients developed CMV end-organ disease. Adverse events associated with ASP0113 injection included pyrexia (three patients), skin reactions [injection site pain, injection site tenderness, and erythema (two patients each); and rash, injection site erythema, injection site induration, and injection site swelling (one patient each)], and hyperuricemia (one patient). ASP0113 was well tolerated in Japanese HCT recipients. Further studies should evaluate its efficacy and safety. ClinicalTrials.gov Identifier: NCT01903928.

Hodgkin-like peripheral T-cell lymphoma (PTCL) with preserved Hodgkin-like lesions at autopsy: a case report with an interesting clinical course.

The presence of the so-called Hodgkin and Reed-Sternberg (H-RS) like cells may occur in T-cell non-Hodgkin lymphoma. Reported herein is the autopsy case of Hodgkin-like peripheral T-cell lymphoma (PTCL) in a 77-year-old male with gradual submandibular lymph node enlargement. The first biopsy showed Hodgkin-like PTCL, initially misdiagnosed as classical Hodgkin lymphoma. Although he was treated with a regimen of ABVD, his disease recurred with cervical lymph node enlargement. A second biopsy showed angioimmunoblastic T-cell lymphoma (AITL) and H-RS like cells became obscure. Despite treatment with the CHOP regimen, he died. An autopsy confirmed that only Hodgkin-like lesions preserved while the AITL component had disappeared. This clinical course is very interesting in that only the Hodgkin-like lesions were systematically exacerbated and became the main cause of death. There are no reports of Hodgkin-like PTCL following AITL and finally preserved Hodgkin-like lesions in autopsy.

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission.

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5-73.4) and 66.4 % (95 % CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3-240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.

Uncommon case of chronic myeloid leukemia with multiple myeloma.

We describe a 72-year-old woman who was diagnosed with asymptomatic multiple myeloma (MM) while being treated for Philadelphia (Ph)-positive chronic myeloid leukemia (CML) with imatinib mesylate (400 mg/day). The diagnosis of CML was based on the presence of the Ph chromosome and chimeric BCR-ABL messenger RNA. Three months after starting imatinib mesylate treatment, the patient achieved a complete cytogenetic response. However, bone marrow analysis at that time demonstrated plasmacytosis, and paraprotein (IgG, kappa-type) was also detected. Hypercalcemia, renal failure, anemia, and bone lesions were not observed, which suggested that asymptomatic MM had developed. The coexistence of CML and MM is an extremely uncommon event that has only been reported in 12 cases. We discuss the relationship between CML and MM.

Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in Japan: a retrospective analysis of 1,057 cases from Kyushu Lymphoma Study Group.

We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone.

Phase I/II study of tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma.

The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2-4 cycles of vincristine-adriamycin-dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m(2)) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3-6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.

Prognostic impact of immunohistochemical biomarkers in diffuse large B-cell lymphoma in the rituximab era.

We evaluated the usefulness of prognostic markers in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) +/- rituximab (R-CHOP) in Japan. We studied 730 patients with DLBCL; 451 received CHOP and 279 R-CHOP. We analyzed biopsy samples immunohistochemically for markers of germinal center B cells (CD10, Bcl-6), postgerminal center B cells (Multiple myeloma-1), and apoptosis (Bcl-2). The median follow-up period for surviving patients was 56.4 months for the CHOP group and 25.2 months for the R-CHOP group. DLBCL were categorized as germinal center B (GCB) subtype (352/730; 48.2%) or non-GCB subtype (378/730; 51.8%). In the CHOP group, the high expression of CD10 (P = 0.022) or Bcl-6 (P = 0.021), or GCB subtype (P = 0.05) was associated with better overall survival, whereas the high expression of Bcl-2 (P = 0.001) or MUM1 (P = 0.011), or non-GCB subtype (P = 0.05) was associated with worse overall survival. In the R-CHOP group, however, these biomarkers except Bcl-6 were not significant prognostic factors. The patients with non-GCB subtype showed improved survival in the R-CHOP group (P = 0.756). The International Prognostic Index was a useful clinical marker of survival in the CHOP group (P < 0.001) and also in the R-CHOP group (P < 0.001). Results of improved survival with rituximab addition indicate that the relevance of previously recognized prognostic factors should be re-evaluated.

[Successful treatment with intensive immunosuppressive therapy and mechanical ventilation for idiopathic pneumonia syndrome following allogeneic bone marrow transplantation].

A 45-year-old man with acute myelogenous leukemia (WHO classification, AML with multilineage dysplasia) received allogeneic bone marrow transplantation from an HLA-identical brother in first remission. He became febrile on day 7, and pulmonary failure and multi-organ failure developed subsequently, requiring mechanical ventilation. Chest X-ray and CT scan demonstrated diffuse interstitial shadows, suggesting the development of idiopathic pneumonia syndrome. Administration of methylprednisolone and tacrolimus was effective, but respiratory failure exacerbated along with a decrease in the dose of steroids. Lung biopsy revealed organizing pneumonia with CMV pneumonia. Methylprednisolone and mycophenolate mofetil were instituted, which led to an improvement of lung injury. Intensive immunosuppressive therapy with mechanical ventilation should be considered for the treatment of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.

[Bacillus cereus sepsis and subarachnoid hemorrhage following consolidation chemotherapy for acute myelogenous leukemia].

A 64-year-old man with acute myelogenous leukemia (FAB classification, M7) in remission received consolidation chemotherapy with mitoxantrone/cytosine arabinoside. WBC counts decreased to 0/microl on day 14, and fever (39.3 degrees C) and epigastralgia developed on day 15. Cefozopran was instituted for febrile neutropenia; however, on day 16, he was found to be in cardiac arrest. CT scan on day 16 revealed subarachnoid hemorrhage. Gram-positive rods were isolated from blood cultures on day 15, and were later identified as B.cereus. He recovered transiently, but eventually died on day 19. Postmortem examination demonstrated many colonies of B. cereus in the cerebrum, cerebellum, lung, and liver. Hepatocyte necrosis was also observed in the liver. Bacterial aneurysms or septic emboli were not identified in the arachnoid vessels, but necrosis of cerebral vessels was prominent, which was considered to be the cause of subarachnoid hemorrhage. Fatal subarachnoid hemorrhage has been reported to be associated with B. cereus sepsis, which developed at nadir following chemotherapy for leukemia patients. Because of the aggressive clinical course of B. cereus sepsis, including the risk for subarachnoid hemorrhage, early treatment with effective antibiotics for B. cereus sepsis would be important in the management of leukemia patients after chemotherapy.

Identification of four novel mutations in F5 associated with congenital factor V deficiency.

Coagulation factor V (FV) deficiency is a rare bleeding disorder characterized by low coagulant and antigen levels of FV with bleeding symptoms ranging from mild to severe. Only a limited number of mutations have been reported because of the large size of the factor V gene (F5) as well as the low prevalence. In this study, we have identified four novel mutations in F5 in five unrelated patients with congenital FV deficiency. All the patients, including two with undetectable FV activity, were asymptomatic and were found to have prolonged prothrombin time and activated partial thromboplastin time during preoperative screening or routine examinations. All four mutations found in this study are either missense or in-frame deletion. This is in contrast with previous reports of a high frequency of mutations introducing premature termination codons in inherited FV deficiency. Missense mutations of F5 might produce a mild phenotype and are not frequently diagnosed. Although FV deficiency is a very rare disorder with a predicted incidence of one in 1 million, this study suggests that the numbers of F5 mutations, especially missense mutations, are higher than estimated.

Leukemic transformation of Langerhans cell sarcoma.

A 57-year-old man became aware of left supraclavicular lymph node swelling, which was subsequently diagnosed as Langerhans cell sarcoma, based on a positive immunophenotype for CD1a, S-100 protein, and langerin, and histologically bizarre pleomorphism. The tumor became leukemic 3 months later. Despite intensive chemotherapy, he died of disease progression 7 months after the initial diagnosis. Tumor cells in the leukemic phase expressed CD5, CD7, CD13, CD33, CD34, CD68, and CD123. These findings suggested leukemic transformation from Langerhans cell sarcoma. Leukemic transformation may be a clinical manifestation of advanced Langerhans cell sarcoma, and should be differentiated from acute myelogenous leukemia.

The consequences of tacrolimus blood concentrations during the four weeks following marrow transplantation from an unrelated donor: a single-center experience.

In our institute, tacrolimus was started at a dose of 0.03 mg/kg/day and adjusted to maintain a blood concentration between 10 and 20 ng/mL combined with short term methotrexate after bone marrow transplantation from an unrelated donor. Dose adjustment was performed strictly, in order to prevent grade II-IV acute graft-versus-host disease (GVHD)while avoiding renal toxicity of tacrolimus. Then, in this study, we retrospectively evaluated the tacrolimus blood concentration during the first 4 weeks after transplantation. The mean tacrolimus concentration of the eligible 52 patients was 17.41+/-4.84(range, 9.5-33.4)ng/mL in the 1st week after transplantation, but declined to 13.7+/- 4.0(range, 8.1-25.6)ng/mL in the 2nd week. The dose of tacrolimus was decreased as follows: 0.022+/-0.005 mg/ kg/day(range 0.011-0.039)in the 1st week, and 0.018+/-0.007 mg/kg/day(range 0.004-0.040)in the 2nd week. The incidence of grade II-IV GVHD was 63.0% and grade III-IV was 13.9%. The individual variations of tacrolimus blood concentration did not affect the incidence of grade II-IV acute GVHD, as far as the concentration being maintained in the range of 14.82+/-4.22 ng/mL during the first 4 weeks after transplantation. In addition, the variations of tacrolimus concentration didn?t associate statistically with renal toxicity.

[The unification of hematopoietic stem cell transplantation registry in Japan and establishment of the TRUMP system].

There are four registries of hematopoietic cell transplant in Japan; the Japan Society for Hematopoietic Cell Transplantation (JSHCT), Japanese Society of Pediatric Hematology, Japan Marrow Donor Program and Japan Cord Blood Bank Network, each playing an important role in society by reporting the number and outcomes of transplantations and contributing new findings obtained from studies on individual topics. However, there have been a number of difficulties with analyzing data in overlapping registries and multiple databases at centers affiliated with each of the four registry organizations. JSHCT was pivotal in orchestrating the computerization and unification of hematopoietic stem cell transplant registries for the purpose of resolving these issues and providing a more accurate awareness of hematopoietic stem cell transplantations performed in Japan. JSHCT played a central role in developing the "Transplant Registry Unified Management Program (TRUMP)" to enable transplant institutes to manage patient information with emphasis on convenience to institutes, safety of patient information, and quality of data management. While enhancing domestic registries, the program seeks to coordinate with other hematopoietic cell transplant registries around the world to contribute to the development of registries throughout Asia.

Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System.

There are 4 registries of hematopoietic cell transplantation in Japan; the Japan Society for Hematopoietic Cell Transplantation (JSHCT), Japanese Society of Pediatric Hematology, Japan Marrow Donor Program, and Japan Cord Blood Bank Network; each play an important role in society by reporting the number and outcomes of transplantations and contributing new findings obtained from studies on individual topics. However, there have been a number of issues with the difficulty of analyzing data in overlapping registries and multiple databases at centers affiliated with each of the 4 registry organizations. JSHCT was pivotal in orchestrating the computerization and unification of hematopoietic stem cell transplantation registries for the purpose of resolving these issues and providing a more accurate awareness of hematopoietic stem cell transplantations being performed in Japan. JSHCT played a central role in developing the "Transplant Registry Unified Management Program (TRUMP)" to enable transplantation institutes to manage patient information with emphases on convenience to institutes, safety of patient information, and quality of data management. While enhancing domestic registries, the program seeks to coordinate with other hematopoietic cell transplantation registries around the world to contribute to the development of registries throughout Asia.

Toxoplasmosis encephalitis following severe graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group.

Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.

Repeated relapses of acute myelogenous leukemia in the isolated extramedullary sites following allogeneic bone marrow transplantations.

Isolated extramedullary (EM) relapses of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been reported to be rare, and are usually followed by bone marrow relapses. We report a 49-year-old man with AML with the unfavorable chromosome abnormality 7q-, who was treated by allo-HSCT. Fifteen months after allo-HSCT, the patient initially developed a relapse only in his inguinal lymph nodes, and then bone marrow relapse became evident one month after the EM relapse. Subsequently, the patient received chemotherapy and a second allo-HSCT from another donor, but he suffered another relapse in different EM sites including the skin and central nervous system with a persistently normal marrow. This case is characterized by repeated relapses in isolated EM sites after allo-HSCT and suggests that the anti-leukemic effects of chemotherapy and/or graft-versus-leukemia effects in the EM sites might not be so uniformly effective as that in the marrow. Accordingly, we should be aware that AML relapses can occur repeatedly only in isolated EM sites post allo-HSCT, resulting in treatment failure and a poor prognosis.

Local cytomegalovirus infection in patients with diarrhea following allogeneic stem cell transplantation.

To evaluate local cytomegalovirus (CMV) infection in patients who developed diarrhea after allogeneic hematopoietic stem cell transplantation (HSCT), histologic and molecular analysis was carried out with intestinal biopsy samples. from 17 transplant recipients. A CMV-specific intranuclear inclusion body indicating intestinal CMV disease was documented in 2 biopsy samples. CMV DNA was detected by quantitative polymerase chain reaction in 8 of 23 (34.8%) samples, including 2 samples diagnosed with intestinal CMV disease. Of 15 patients without histologic confirmation of intestinal CMV disease, pre-emptive therapy was carried out for 8 patients based on positive antigenemia, and for 2 patients on positive CMV DNA, respectively. Intestinal CMV disease was successfully treated with antiviral therapy for 2 patients and prevented with pre-emptive therapy based on either positive antigenemia or positive CMV DNA for 10 patients. Endoscopic examinations with histologic and molecular analysis may be important in the early treatment and the prevention of intestinal CMV disease in patients with diarrhea after allogeneic stem cell transplantation.

Successful stem cell transplantation without cryopreservation from a microchimeric haploidentical sibling for refractory acute myeloid leukemia complicated with critical thrombophlebitis and cellulitis.

We describe the case of a 38-year-old male patient who had acute myeloid leukemia and developed prolonged neutropenia after induction chemotherapy. He developed thrombotic complications at multiple sites. Thrombophlebitis of the hemorrhoidal plexus became exacerbated and developed into critical cellulitis. Because the patient had no human leukocyte antigen-identical sibling, we considered an alternative donor. Because of the necessity for early neutrophil recovery to resolve the critical infection, we proceeded with allogeneic peripheral blood stem cell transplantation (PBSCT) from a microchimeric haploidentical sibling donor. We infused peripheral blood mononuclear cells directly into the patient without cryopreservation and thawing procedures. We aimed for the contaminating granulocytes to act as a granulocyte transfusion. Actually, the neutrophils increased to 1.6 x 10(9)/L on day 1, when the patient showed a temporary resolution of infection. Engraftment was achieved shortly after neutropenic nadir, and acute graft-versus-host disease (GVHD) has been well controlled. Although the patient experiences extensive chronic GVHD, he has been well as an outpatient with a 90% Karnofsky performance status score. The leukemia has been in complete remission for more than 1 year. These findings suggest the clinical utility of a salvage therapy with allogeneic PBSCT from a microchimeric haploidentical donor to treat refractory leukemia concurrent with life-threatening infection.

Allogeneic bone marrow transplantation from unrelated human T-cell leukemia virus-I-negative donors for adult T-cell leukemia/lymphoma: retrospective analysis of data from the Japan Marrow Donor Program.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-matched related donor has been suggested to improve the poor prognosis of adult T-cell leukemia/lymphoma (ATLL). However, the infusion of HTLV-I-infected cells from HTLV-I-positive related donors could lead to the development of donor-derived ATLL under immunosuppressive conditions. Although most ATLL patients lack a suitable HLA-matched related donor and require an HTLV-I-negative unrelated donor, little information is currently available regarding the outcome of unrelated bone marrow transplantation (UBMT) for ATLL. To evaluate the role of UBMT in treating ATLL, we retrospectively analyzed data from 33 patients with ATLL treated by UBMT through the Japan Marrow Donor Program (JMDP). Overall survival (OS), progression-free survival, and cumulative incidence of disease progression and progression-free mortality at 1 year after UBMT were 49.5%, 49.2%, 18.6%, and 32.3%, respectively. Multivariate analysis identified recipient age as an independent prognostic factor for OS (P = .044). Patients age >or=50 years who showed nonremission at transplantation tended to have higher rates of treatment-related mortality. Our observations suggest that UBMT could represent a feasible treatment option for ATLL patients and warrant further investigation based on these risk factors.

Late relapse of acute myelogenous leukemia followed by epstein-barr virus-associated lymphoproliferative disease 11 years after allogeneic bone marrow transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following myeloablative conditioning represents the treatment of choice for patients with chemotherapy-resistant leukemia. We describe a 49-year-old man with advanced, refractory acute myelogenous leukemia (AML) that was treated successfully by allogeneic bone marrow transplantation from a sibling donor with HLA mismatched at 1 locus. However, the patient developed a quiescent form of chronic graft-versus-host disease (GVHD) 7 years after transplantation, requiring long-term immunosuppressive therapy. AML relapse was documented 11 years after transplantation. Subsequently, Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD) was also diagnosed. Immune reconstitution after allo-HSCT might have been impaired by the persistent chronic GVHD and the prolonged administration of immunosuppressive agents. As a result, immune surveillance against remaining quiescent leukemic cells as well as viral infection may have been defective, leading to the relapse of leukemia and EBV-associated PTLD.