Yuichiro Nawa

Comparison of Allogeneic Hematopoietic Cell Transplantation and Chemotherapy in Elderly Patients with Non-M3 Acute Myelogenous Leukemia in First Complete Remission

The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myelogenous leukemia (AML) in first complete remission (CR1) have mostly been evaluated in younger patients. Although favorable outcomes of allo-HCT over chemotherapy have been reported with the use of reduced-intensity conditioning (RIC) regimens in elderly patients with AML in CR1, information is still limited, especially on the effects of cytogenetic risks and donor sources. We collected data from AML patients aged 50 to 70 years who achieved CR1, and compared the outcome in 152 patients who underwent allo-HCT in CR1 (HCT group) to that in 884 patients who were treated with chemotherapy (CTx group). The cumulative incidence of relapse in the HCT group was significantly lower than that in the CTx group (22% versus 62%). Both overall survival (OS) and relapse-free survival (RFS) were significantly improved in the HCT group (OS: 62% versus 51%, P = .012), not only in the whole population, but also in the intermediate-risk group. Among patients who had a suitable related donor, the outcomes in the HCT group were significantly better than those in the CTx group. The introduction of appropriate treatment strategies that include allo-HCT may improve the outcome in elderly patients with AML in CR1.

G-CSF reduces IFN-γ and IL-4 production by T cells after allogeneic stimulation by indirectly modulating monocyte function

Despite a 10-fold increase of T cell dose, the incidence and severity of acute GVHD following allogeneic transplantation of G-CSF-mobilized PBSC is not increased compared to BMT. Experimental murine studies demonstrate that G-CSF polarizes donor T cells toward a type 2 cytokine response. To determine whether G-CSF alters T cell cytokine responses, we investigated the effects of G-CSF administration on T cell proliferative and cytokine responses to alloantigen and Con A in nonadherent PBMC (NAC) and CD3+ T cells obtained from normal individuals before and after G-CSF administration (10 μg/kg × 4 days). Although T cell proliferative and cytokine (IFN-γ and IL-4) responses to alloantigen stimulation and Con A were significantly reduced in post-G-CSF NAC, they were restored by the removal of non-T cells from post-G-CSF NAC. Furthermore, there was less T cell alloreactivity in MLR in the presence of autologous post-G-CSF monocytes than in the presence of pre-G-CSF monocytes. This alteration was not replicated in vitro by culturing PBMC with G-CSF. These results suggest that G-CSF administration suppresses T cell proliferative and cytokine (IFN-γ and IL-4) responses to allogeneic stimulation by indirectly modulating monocyte function. Bone Marrow Transplantation (2000) 25, 1035–1040.

A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission

Various prospective trials have been performed to assess the roles of allogeneic hematopoietic cell transplantation (allo-HCT) and chemotherapy in patients with acute myeloid leukemia (AML) in first complete remission (CR1). However, the results have not always been consistent, and there has been a limited evaluation of quality of life (QOL) in these postremission strategies. We performed a Markov decision analysis that enabled us to compare survival outcomes with a QOL evaluation using a database of 2029 adult AML patients who achieved CR1. The Markov decision model compared 2 strategies: allo-HCT or chemotherapy in CR1. Patients who had intermediate- or unfavorable-risk AML had a longer life expectancy when they received allo-HCT in CR1 than patients treated with chemotherapy alone. Likewise, patients who had a suitable related donor who received allo-HCT in CR1 had a longer life expectancy. The life expectancy was shortened to a greater degree by adjustment for QOL in the allo-HCT group. Nevertheless, QOL-adjusted life expectancies in most of the subgroups remained longer in the allo-HCT group than in the chemotherapy group. Our results showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allo-HCT in CR1.

High-dose Chemotherapy with Hematopoietic Stem Cell Transplantation is Effective for Nasal and Nasal-type CD56+ Natural Killer Cell Lymphomas

CD56+ natural killer (NK) cell lymphomas occur frequently in the nasal and nasopharyngeal regions and carry a poor prognosis. We have studied seven cases with NK-cell lymphomas. These lymphomas showed the following immunophenotype: CD56+, CD2+, sCD3 and Epstein-Barr virus-encoded small RNAs (EBERs)+. Six patients had localized (stage I or II) disease involving the nasopharyngeal region, while one had stage III disease. One patient with stage I disease achieved a complete remission (CR) after treatment with involved-field irradiation, but subsequently relapsed and died. The remaining six patients received combination chemotherapy as primary treatment: five patients with localized stage I or II disease and one patient with advanced stage III disease. Responses to initial chemotherapy were generally poor. These six patients received a variety of salvage chemotherapy regimens, but never achieved a CR. Subsequently, four of six patients showed a highly aggressive clinical course and died of disseminated disease within 1 year from the diagnosis. Three of six patients received high-dose chemotherapy supported by syngeneic, autologous or allogeneic peripheral blood stem cell transplantation. Two of the three transplant patients achieved a CR and are now surviving in continuous CR. Our clinical experience suggests that myeloablative high-dose chemotherapy and bone marrow rescue by hematopoietic stem cell transplantation may be an effective salvage treatment modality for refractory NK-cell lymphomas and could be considered as a part of the initial therapy for these patients.

Additional translocation (8;21)(q22;q22) in a patient with Philadelphia-positive chronic myelogenous leukaemia in the blastic phase

We report a case of Philadelphia‐positive chronic myelogenous leukaemia in blastic phase with the additional translocation (8;21)(q22;q22), which is frequent in acute myeloid leukaemia but not in chronic myelogenous leukaemia. The t(8;21) was not detected in the chronic phase, and was the only additional chromosomal anomaly in the blastic clone. Reverse transcription‐polymerase chain reaction revealed the AML1/ETO fusion transcript in the cells of blastic phase but not in those of chronic phase. Regarding t(9;22), the breakpoint on chromosome 22 occurred in the μ‐BCR region of the BCR gene, resulting in hybrid BCR/ABL mRNA with an e19a2 junction. Our findings provided molecular evidence that t(8;21) can occur as an additional genetic change in Philadelphia‐positive chronic myelogenous leukaemia.

Bone marrow transplantation from unrelated donors for patients with adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATLL) is a highly aggressive haematological malignancy. More than 40 cases of ATLL treated by allogeneic bone marrow transplantation (BMT) from sibling donors have been reported, while there have been only a few cases of unrelated BMT for treatment of this disease. We began performing allogeneic BMT from unrelated donors in 1999 to improve the outcome of ATLL patients with no suitable sibling donors. Eight ATLL patients underwent unrelated BMT; five received the conventional conditioning regimen consisting of cyclophosphamide and total body irradiation, while three received a reduced-intensity preparative regimen. Two patients died due to encephalopathy of unknown aetiology on days 10 and 35, and one patient died due to progression of ATLL 25 months after BMT. Five patients are currently alive and disease-free at a median of 20 months after BMT. Proviral human T-lymphotropic virus type-I (HTLV-I) DNA load in peripheral blood mononuclear cells (PBMCs) was assessed in four cases before and after BMT. HTLV-I proviral DNA load was reduced significantly after transplantation. Unrelated BMT is feasible for treatment of ATLL. Further studies in a larger number of cases are required to determine the optimal conditioning regimen and stem cell source.

Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation

CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical entity which is the prototype of the putative NK cell lymphomas. A 16-year-old Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose chemotherapy supported with syngeneic peripheral blood stem cell transplantation (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional chemotherapy before transplantation, resulting in a partial response. PBSC were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She achieved complete remission and is now surviving in continuous complete remission for more than 30 months after syngeneic PBSCT. Thus, marrow-ablative chemotherapy facilitated by autologous or allogeneic PBSCT should be considered as part of the primary therapy for poor prognosis NK cell lymphomas.

The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T‐cell lymphoma

Natural killer (NK)/T‐cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T‐cell lymphoma. Nineteen untreated patients with extranodal NK/T‐cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P = 0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I–II and nine (47%) were stages III–IV. Using PET/CT, eight patients (42%) were in stages I–II and 11 (58%) were in stages III–IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T‐cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

Myelodysplastic syndrome with translocation (8; 21): a distinct myelodysplastic syndrome entity or M2-acute myeloid leukemia with extensive myeloid maturation?

Abstract We report a case of refractory anemia with excess of blasts in transformation with the translocation (8; 21), which is frequent in acute myeloid leukemia (AML) but not in myelodysplastic syndromes (MDS). Bone marrow blasts were 1.6% and an extensive myeloid differentiation was noted. Fluorescence in situ hybridization analysis revealed the presence of 21q22 translocations in mature neutrophils, indicating that clonogenic blast progenitors could actively undergo terminal differentiation to mature end cells in vivo. We consider that t(8; 21)+ MDS may represent a rare clinical manifestation of M2-AML, in which blast progenitors have an extensive differentiation potential to mature neutrophils without maturation arrests.

Familial occurrence of chronic neutrophilic leukaemia

A father and son who both developed chronic neutrophilic leukaemia (CNL) are reported. The father, aged 63, had been exposed to radioactive fallout after the atomic bomb attack on Hiroshima; he presented with hepatosplenomegaly and neutrophilic leucocytosis, and died of intracerebral haemorrhage 1 month after diagnosis. 4 years later his son, then aged 44, presented with neutrophilic leucocytosis. Leukaemic transformation to acute myelogenous leukaemia (AML‐M1) occurred, and he died of refractory leukaemia 4 months after the diagnosis of CNL. This is the first report of this rare disease occurring in family members; genetic effect due to radioactive poisoning was suspected in the development of CNL in these two cases.