Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Causes of macrocytic anemia among 628 patients: mean corpuscular volumes of 114 and 130 fL as critical markers for categorization.

There have been no studies on the distribution of causes of macrocytic anemia with respect to mean corpuscular volume (MCV) cutoff values. We retrospectively investigated the causes of macrocytic anemia (MCV ≥100 fL) among 628 patients who visited the outpatient hematology clinic in Tohoku University Hospital. To ensure data validity, we also analyzed data from 307 patients in eight other hospitals in the Tohoku district. The leading causes of macrocytic anemia (number of patients, %) were myelodysplastic syndromes (121, 19.3 %), suspected bone marrow failure syndromes (BMF; 74, 11.8 %), aplastic anemia (51, 8.1 %), plasma cell dyscrasia (45, 7.2 %), and vitamin B12 deficiency (40, 6.4 %) in Tohoku University Hospital. We made three primary findings as follows. First, the most common cause of macrocytic anemia is BMF. Second, lymphoid and solid malignancies are also common causes of macrocytosis. Third, macrocytic anemia may be classified into three groups: Group 1 (megaloblastic anemia and medications), which can exceed MCV 130 fL; Group 2 (alcoholism/liver disease, BMF, myeloid malignancy, and hemolytic anemia), which can exceed MCV 114 fL; and Group 3 (lymphoid malignancy, chronic renal failure, hypothyroidism, and solid tumors), which does not exceed MCV 114 fL. These conclusions were supported by the results from eight other hospitals.

A retrospective analysis of bortezomib therapy for Japanese patients with relapsed or refractory multiple myeloma: beta2-microglobulin associated with time to progression.

Bortezomib is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM), but only a few clinical studies for Japanese patients who were treated with bortezomib have been reported. We retrospectively analyzed 40 patients with relapsed or refractory MM who have received bortezomib at three collaborating centers in Miyagi prefecture in Japan. All the patients have been received bortezomib in combination with dexamethasone. Responses were determined using International Myeloma Working Group uniform response criteria. The overall response was observed in 30 patients (75%), including very good partial response in 8 patients (20%), and partial response in 22 patients (55%). The median time to disease progression was 8.7 months, and the median overall survival has not been reached. The factors affecting time to disease progression were International Staging System stage, serum beta2-microglobulin level, and number of treatment cycles. The most common grade 3 and 4 adverse events were thrombocytopenia (50%), peripheral neuropathy (25%), leukopenia (25%), and herpes zoster infection (25%). Thus, bortezomib is well tolerated and effective for Japanese patients with relapsed or refractory MM. Our results suggest that serum beta2-microglobulin level may be a marker of prognosis on bortezomib therapy for patients with relapsed or refractory MM although further studies are needed.

Successful treatment of advanced extranodal NK/T cell lymphoma with unrelated cord blood transplantation.

Nasal natural killer (NK)/T cell lymphoma is a rare entity of non-Hodgkin's lymphoma which mostly occurs in East Asian countries. The advanced disease above clinical stage III is often refractory to the radiation and chemotherapies, remission is transient even if achieved, and median survival is about 12 months. Thus the prognosis of advanced NK/T cell lymphoma is generally poor, however, the promising results of allogeneic hematopoietic stem cell transplantation for advanced NK/T cell lymphoma have been recently reported. In most of these cases, stem cell sources were human leukocyte antigen (HLA) matched donors and alternative sources were seldom used. We report here a case of a 36-year-old woman who was diagnosed as having an extranodal NK/T cell lymphoma, nasal type. The patient achieved a complete remission after 2 cycles of chemotherapy including Carboplatin, Etoposide, Ifosfamide, and Dexamethasone, but 3-months later relapsed during the search for HLA-matched unrelated donors. She received unrelated cord blood transplantation (CBT) in the second remission achieved by a regimen containing L-asparaginase. The conditioning regimen was 12 Gy of total body irradiation, high-dose cytarabin and cyclophosphamide. FK506 and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. GVHD involving the intestine and the oral mucosa was observed, but improved without additional immunosuppressive therapies. The patient remains in remission 33 months after CBT. Cord blood thus could be an appropriate stem cell source for patients with advanced NK/T lymphoma who have no HLA matched donors.

Dose modification of imatinib by monitoring the level of BCR-ABL transcript in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a hematological malignancy that is characterized by the chromosome anomaly, t(9;22)(q34;q11). By this chromosomal translocation, a novel activated tyrosine kinase, BCR-ABL chimeric protein, is generated, and the protein is causative of the disease. Recently, Imatinib mesylate targeting to a BCR-ABL chimeric protein has been developed, and shown to achieve complete remission at a high rate. Patients are currently required to receive a fixed dose, 400 mg daily; however, it is possible that some of patients can maintain their remission with reduced doses of imatinib. In this study, we determined levels of BCR-ABL transcript in CML patients by real-time quantitative polymerase chain reaction analysis, and explored the possibility of individualization of therapeutic doses of imatinib. Thirty-five CML patients, including 17 newly diagnosed patients, 16 patients pre-treated with interferon-alpha, and 2 relapsed patients after allogeneic transplantation, were treated with imatinib. Complete cytogenetic response was achieved in 31 (89%) patients. Major molecular response (MMR) was achieved in 21 (60%). Complete molecular response (CMR) was achieved in 7 (20%). Imatinib was discontinued in 2 patients, one patient with MMR due to noncompliance and other patient sustaining CMR, but both patients relapsed 7 and 13 months later, respectively. The doses of imatinib were reduced in 7 patients due to its side effects, but 4 out of the 7 patients have sustained MMR, and 2 of them have sustained CMR for more than 23 months. These results indicate that some patients are able to maintain MMR with low-dose imatinib.

CD26, together with cell surface adenosine deaminase, is selectively expressed on ALK-positive, but not on ALK-negative, anaplastic large cell lymphoma and Hodgkin's lymphoma.

CD26/dipeptidyl peptidase IV is a cell surface antigen with multiple biological functions. Although its involvement in tumor biology has been suggested, the significance of its expression in malignant lymphoma has not been clarified in detail. This study examined the expression of CD26 and cell surface adenosine deaminase (ADA) in 42 cases of Hodgkin's lymphoma (HL) and T-cell lymphoma by immunohistochemistry on frozen sections. CD26 was expressed in three of 14 cases of HL, in four of eight cases of anaplastic large cell lymphoma (ALCL), in two of nine cases of peripheral T-cell lymphoma, in one of six cases of lymphoblastic lymphoma and in none of three cases of adult T-cell lymphoma/leukemia. Expression of cell surface ADA was fully correlated with the expression of CD26 and expression of CD26/ADA in ALCL and HL was also completely correlated with the expression of p80 and epithelial membrane antigen. Of 10 CD26-positive patients, seven had fever and elevated CRP at initial diagnosis and over a median follow-up of 61 months (range, 7 - 152 months) only three survived. This study suggested that CD26 is selectively expressed on ALK-positive, but not on ALK-negative, ALCL and HL. This is also the first report to demonstrate that ADA is coexpressed with CD26 on the cell surface of malignant neoplasms in vivo.

Increased expression of insulin-like growth factor i is associated with Ara-C resistance in leukemia.

Resistance to cytosine arabinoside (Ara-C) is a major problem in the treatment of patients with acute myeloid leukemia (AML). In order to investigate the mechanisms involved in Ara-C resistance, the gene expression profile of Ara-C-resistant K562 human myeloid leukemia cells (K562/AC cells) was compared to that of Ara-C-sensitive K562 cells (K562 cells) by using a cDNA microarray platform. Correspondence analysis demonstrated that insulin-like growth factor I (IGF-I) gene was upregulated in K562/AC cells. The biological significance of IGF-I overexpression was further examined in vitro. When K562 cells were incubated with IGF-I ligand, they were protected from apoptosis induced by Ara-C. In contrast, a significant inhibition of growth and increase of apoptosis of K562/AC cells were induced by IGF-I receptor neutralizing antibody, or suramin, a nonspecific growth factor antagonist. Moreover, from the analysis of 27 AML patients, we have shown that IGF-I expression levels are higher in patients at refractory stage, after Ara-C combined chemotherapy, than those in patients at diagnosis. These results suggest that the inhibition of IGF-I and its downstream pathway is a valuable therapeutic approach to overcome Ara-C resistance in AML.

Primary effusion lymphoma of the pericardial cavity carrying t(1;22)(q21;q11) and t(14;17)(q32;q23).

We report a case of primary effusion lymphoma (PEL) in a 75-year-old woman without human immunodeficiency virus or hepatitis C virus, which presented as fever, chest pain, and pericardial effusion. The lymphoma cells were positive for CD20 and CD79a, and were negative for CD3 and CD10. Genomic human herpes virus 8 (HHV-8) and Epstein-Barr virus were not detected in the lymphoma cells. Cytogenetic analysis showed complex abnormalities by the G-banding technique, and spectral karyotyping (SKY) analysis provided more detailed characterization of the chromosomal aberrations, including t(1;22)(q21;q11) and t(14;17)(q32;q23). We did not detect C-MYC gene rearrangement or BCL-2 expression. She was treated successfully with six courses of the CHOP regimen. The present case demonstrated a rare category of PEL that is not associated with HHV-8 or C-MYC gene rearrangement. In addition, SKY analysis disclosed cryptic chromosomal abnormalities involving 1q21 and 17q23.

Imatinib mesylate in conjunction with allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome positive leukemias: report of 4 cases.

We described here four patients diagnosed with Philadelphia chromosome positive (Ph+) leukemia, consisting of chronic myeloid leukemia (CML) (n=2) and Ph+ acute lymphoblastic leukemia (ALL) (n=2). All patients were treated with imatinib mesylate (300-400 mg/day) for the treatment of relapsed CML after allogeneic hematopoietic stem cell transplantation (SCT) (n=2), relapsed Ph+ ALL after SCT (n=1), and Ph+ ALL preceding SCT (n=1). Significant clinical and molecular responses were observed in all patients and three of them achieved sustained molecular remission. Imatinib was well tolerated and did not induce noticeable graft versus host disease although one patient presented severe skin rash (Grade III). Notably, serum cyclosporine A concentration increased after the initiation of imatinib treatment, probably through competitive inhibition of P450 3A4 isoenzyme. Our data suggest that imatinib in conjunction with SCT for the Ph+ leukemia may be a promising treatment strategy.

A case of familial thrombocytosis: possible role of altered thrombopoietin production.

Familial thrombocytosis (FT) is an inherited disorder with clinical presentations similar to essential thrombocytosis (ET). In several pedigrees, overproduction of thrombopoietin (TPO) has been shown to be responsible for the disease. We report herein three cases of thrombocytosis in three successive generations. All cases had increased serum TPO levels. Sequence analysis of TPO gene and transmembrane domain of c-MPL, known as the TPO receptor, revealed no mutations. Platelet c-MPL expression was similar or slightly increased as compared to normal volunteers. These data suggest that altered regulation of the TPO gene might be involved in the pathogenesis of FT.

Fludarabine- and cyclophosphamide-based nonmyeloablative conditioning regimen for transplantation of chronic granulomatous disease: possible correlation with prolonged pure red cell aplasia.

An 18-year-old patient with chronic granulomatous disease who had had at least 2 episodes of life-threatening Aspergillus pneumonia was treated with nonmyeloablative allogeneic stem cell transplantation (NSCT) from an HLA-identical and major ABO-incompatible sibling. The conditioning regimen consisted of cyclophosphamide at a dose of 60 mg/kg (days -5, -4) and fludarabine at a dose of 30 mg/m2 (days -5, -4, -3, -2, -1). Full donor T-cell engraftment was attained on day 28, and full myeloid engraftment was established by day 150 after tacrolimus withdrawal. The bacteriocidal activity of neutrophils, as indicated by flow cytometry with the use of a dichlorofluorescein diacetate oxidation assay, remained low until 150 days after transplantation, but no infection was detected, a finding that suggests mixed chimerism of granulocytes controlled infection. Graft-versus-host disease and severe regimen-related toxicity (grade 3 or greater) were not observed. This patient developed prolonged pure red cell aplasia, possibly caused by persistent antidonor isohemagglutinin produced by the residual host B-cells. The aplasia resolved with the combination of erythropoietin, double filtration plasmapheresis, and rituximab. In the setting of major ABO-incompatible NSCT, a fludarabine- and cyclophosphamide-based conditioning regimen may lead to prolonged PRCA.