Nobuaki Nakano

Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia.

We retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m² fludarabine, 80 mg/m² melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34(+) cell number were 2.50 × 10⁷/kg and 0.76 × 10⁵/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.

Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone.

Background. The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status. Methods. We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control). Results. FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups. Conclusions. MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.

Effect of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia-lymphoma: cutaneous adverse reactions may predict the prognosis.

Adult T‐cell leukemia–lymphoma (ATL) is one of the most malignant lymphomas with poor prognosis. ATL cells express CC chemokine receptor 4 (CCR4) and mogamulizumab, a monoclonal antibody against CCR4 that exhibits very strong cytotoxicity for ATL cells via antibody‐dependent cellular cytotoxicity. Although its effect is dramatic in ATL, serious adverse reactions such as Stevens–Johnson syndrome have been reported. However, these eruptions can appear as therapeutic signs of mogamulizumab. We evaluated the effectiveness of mogamulizumab in five acute‐type ATL patients. Peripheral blood (PB) and lymph nodes (LN) were affected in three and four patients, respectively. In PB, complete response (CR) was obtained in all three patients and partial response (PR) was recorded in LN of one patient. In skin lesions, four of five patients manifested CR; in two, the lesions worsened after the start of mogamulizumab treatment and subsequently improved. In these lesions, CD4+8−25+ ATL cells were replaced by CD3+8+ cytotoxic T cells. Cutaneous adverse reactions (CAR) developed in two patients with CR; they did not show a relapse of ATL over the course of 9 months. Our findings suggest that mogamulizumab should be continued and surface marker evaluation should be performed even in patients whose skin lesions show aggravation, and that CAR may be a marker for a favorable prognosis.

Monobactam and aminoglycoside combination therapy against metallo-β-lactamase-producing multidrug-resistant Pseudomonas aeruginosa screened using a ‘break-point checkerboard plate’

Abstract Metallo-β-lactamase-producing multidrug-resistant Pseudomonas aeruginosa (MDR P. aeruginosa) is a cause of life-threatening infections. With parenteral colistin not available in Japan, we treated MDR P. aeruginosa sepsis with monobactam and aminoglycoside combination therapy, with screening using a ‘break-point checkerboard plate’.

Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab: HBV reactivation after mogamulizumab therapy

The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T‐cell leukemia–lymphoma (ATL) and peripheral T‐cell lymphoma, and the humanized anti‐CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose‐finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation.

Clinical significance of cutaneous adverse reaction to mogamulizumab in relapsed or refractory adult T-cell leukaemia-lymphoma

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Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

Effect of a novel anti-CCR4 monoclonal antibody (Mogamulizmab) on skin lesions of adult T-cell leukemia-lymphoma (ATL) and its adverse skin reactions (ASR)

We studied the effects of Mogamulizmab on ATL and its adverse reactions in 10 patients with ATL, among them 6 patients had skin lesions. Informed consent was obtained prior to study. Four out of 6 patients with cutaneous involvement showed complete response (CR), with 4 to 8 cycles of treatments. Of interest were two cases which appeared to have worsened in the early phase of treatment because of enlargement of cutaneous nodules or tumors. It, however, was found to be actually improving determined from histopathological examinations, i.e., more inflammatory cell infiltration and edema with less number of lymphoma cells in the skin. Eventually, these two patients showed CR. Furthermore, 2 each patients with 4 CR patients showed no recurrence with ASR, i.e., erythema and plaque, and showed reccurence without ASR. ASR were observed in 4 out of 10 patients. All these ASR fortunately subsided later. Immunohistopathological examinations revealed the infiltration of cytotoxic T-lymphocytes in the dermis. These results suggest that 1) Mogamulizmab had excellent effects (4/6) to suppress the growth of cutaneous lesions in ATL, 2) ASR might be favorable signs of the effects (2/4), and 3) ASR (4/10) were not serious. Studies of plasma and tissue levels of Mogamulizmab and T-reg cells may reveal the action mechanism of this novel anti-CCR4 agent in detail.

Pre- and posttransplant use of mogamulizumab in patients with aggressive adult T-cell leukemia-lymphoma: A statement from key opinion leaders in Japan

Recently, the anti‐CCR4 antibody mogamulizumab (Moga, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) was approved as a treatment for CCR4‐positive adult T‐cell leukemia‐lymphoma (ATL) in Japan. We use Moga before or after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in patients with aggressive ATL. A recent retrospective analysis using a database from a nationwide survey showed that the use of Moga before allo‐HSCT was associated with an increased risk of severe/steroid‐refractory acute GVHD and inferior overall survival. Meanwhile, it was reported that a number of patients with chemotherapy‐refractory ATL achieved disease control with Moga, including those who subsequently underwent allo‐HSCT. To address these issues pertaining to Moga in transplant‐eligible patients with ATL, a key opinion leader (KOL) meeting comprising hematologists and transplant physicians was conducted by Kyowa Hakko Kirin Co., Ltd. in Japan. The goal of this KOL meeting was to design a framework to guide decision‐making on the use of Moga in transplant‐eligible patients with ATL. KOLs first presented their experiences, and after a subsequent discussion, the KOLs agreed on the key scientific statement as summarized in this Expert Commentary. Our experiences suggest that a good number of patients benefited from Moga, achieving disease control that was often unattainable by conventional chemotherapies. However, as our statement is based largely on retrospective studies and real clinical practice, it requires further validation. Nevertheless, we believe that this statement should help efficiently guide decision‐making concerning Moga use in transplant‐eligible patients with ATL.

Detection of an early adult T-cell leukemia-lymphoma clone in lymph nodes with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma involvement

A 58-year-old man was admitted to our hospital with systemic lymphadenopathy and was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Although he was a human T-cell leukemia virus type I (HTLV-1) carrier, Southern blot analysis of the lymph node did not show monoclonal integration of HTLV-1 provirus deoxyribonucleic acid (DNA). He achieved complete remission after chemotherapy and subsequently, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. Fifteen months after the auto-PBSCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of TRB. He was diagnosed with chronic type adult T-cell leukemia-lymphoma (ATL), which immediately progressed to the acute type. He died of tumor progression despite intensive chemotherapy. We analyzed genomic alterations of the ALCL and ATL cells using array comparative genomic hybridization. We found that the genomic alteration pattern differed between the two diseases. T-cell receptor clonality analysis using polymerase chain reaction (PCR) showed that the T-cell clone of the ATL was present in the lymph nodes with ALCL involvement, but not in peripheral blood. This finding suggests that lymph nodes can serve as a niche for ATL development.