Isolated cardiac valve involvement in smoldering adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by infection with the Human T-cell Lymphotropic Virus Type 1 (HTLV-1). Cardiac involvement in patients with ATLL is infrequent, and when it happens it is usually seen in aggressive ATLL subtypes. However, ATLL presenting as isolated cardiac valve involvement is extremely rare. To date, only three histologically proven cases of ATLL with isolated cardiac valve involvement have been reported. Herein, we describe a 61-year-old Peruvian man who presented heart failure symptoms secondary to progressive cardiac valve infiltration. The patient underwent mitral valve replacement with a mechanical prosthesis. Histopathological evaluation of the resected valve revealed leaflet thickening with a nodular appearance due to fibrous tissue containing atypical T-lymphocytes with Foxp3 expression, infiltrating all layers of the resected valve. Interestingly, tumor cells were distributed around an incidental venous malformation (i.e., cavernous hemangioma). Postoperative evaluation demonstrated positive serology for HTLV-1, and a diagnosis of ATLL was established. Postoperative positron emission tomography/computed tomography did not show lesions outside the heart and cell blood counts were within normal range with low level of circulating CD4+ CD25+ lymphoma cell counts (7%); therefore, patient's disease was considered as smoldering ATLL and a "watch and wait" strategy was pursued. Currently, the patient is alive with no progression of disease after 18 months from diagnosis. Isolated cardiac valve involvement by ATLL should be considered in the differential diagnosis of HTLV-1 carriers with progressive heart failure, even when systemic lymphoma involvement is absent or not apparent.

[A Case of T-Cell Lymphoma Treated by Emergency Surgery Due to Bleeding of Jejunal Lesion].

A 78-year-old man was aware of lightheadedness and darkness at a routine outpatient visit, and his blood pressure was declined at 87/51 mmHg. Contrast-enhanced CT scan showed an extravascular leakage image at jejunum. We diagnosed as small intestinal hemorrhage. Because he was in hemorrhagic shock, emergency surgery was performed. A tumor was found coincident with the bleeding site, and partial resection of the small intestine including enlarged lymph nodes was performed. Based on the pathological findings of T-cell origin and positive for serum anti-HTLV-1 antibody, he was suspected as adult T-cell leukemia/lymphoma(ATLL). Endoscopic examination of the upper and lower gastrointestinal tracts, bone marrow examination, and PET-CT scan were performed, but no other lesions were found. We report a case of the T-cell lymphoma with suspected solitary ATLL of the jejunum.

Mediastinal debulking for a T-cell leukaemia/lymphoma presenting with cardiac tamponade.

Anterior mediastinal masses are relatively uncommon and include a wide variety of lesions. Lymphomas account for 25% of anterior mediastinal masses. Lymphomas and other haematological malignancies are associated with pericardial effusion. There are also cases where a cardiac tamponade occurred. The aim of the case reported herein is to discuss the surgical approach and particularly the mediastinal debulking as an adjunct to systematic treatment for haematological diseases presenting as an anterior mediastinal mass responsible for a cardiac tamponade.

[Bowel Perforation in a Patient with Adult T-Cell Leukemia/Lymphoma].

Adult T-cell leukemia/lymphoma(ATLL)can infiltrate throughout various organs and frequently involves the gastrointestinal tract. However, bowel perforation in ATLL patients is rare. Herein, we present a case of ATLL with bowel perforation. A 75-year-old man presented with bowel distension. Computed tomography showed a large mass of the cecum. Edema and stenosis of the ascending colon was seen on colonoscopy, and tumor on the anal side of the stenosis was also found. After admission, the patient complained of abdominal pain with a peritoneal irritation sign. Free air was seen around a large mass of the cecum on computed tomography and an emergency operation was performed under the diagnosis of bowel perforation. Microscopic examination revealed bowel infiltration of ATLL. Gastrointestinal perforation can be caused by ATLL itself and is associated with a poor prognosis. The standard treatment for ATLL is chemotherapy but emergency surgery is necessary in case of perforation. It is important to observe the patient with ATLL carefully.

A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma.

BACKGROUND: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan. MATERIALS AND METHODS: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. RESULTS: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively. CONCLUSION: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority.

Breakthrough fungemia due to Candida fermentati with fks1p mutation under micafungin treatment in a cord blood transplant recipient.

The prophylactic use of antifungal drugs in allogeneic hematopoietic cell transplant recipients has revealed that the rate of non-albicans candidemia has increased. We herein report the case of a patient with adult T-cell leukemia who developed candidemia due to Candida fermentati during micafungin treatment after cord blood transplantation. The isolate was identified on day 47 by sequencing of the internal transcribed spacer region of the ribosomal RNA gene. The sequencing of the hot spot region of fks1p of isolate revealed naturally occurring amino acid substitutions, which conferred reduced echinocandin susceptibility. This case highlights that breakthrough candidemia due to C. fermentati occurred in a patient receiving micafungin treatment.

Primary Cardiac T-Cell Lymphoma Localized in the Mitral Valve.

Primary cardiac lymphoma is a rare cardiac tumor, and usually originates from B cells and involves the right side of the heart. We present an extremely rare case of primary cardiac T-cell lymphoma involving the mitral valve alone. A 58-year-old woman who was positive for human T-cell leukemia virus 1 underwent mitral valve replacement because of severe mitral regurgitation. The postoperative pathologic diagnosis of the mitral valve was T-cell lymphoma. Further evaluation revealed no malignancy, except for the mitral valve. To the best of our knowledge, this is the first case of primary cardiac T-cell lymphoma localized in the mitral valve.

Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP.

Adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis. Experience with allo-SCT for ATL appears encouraging but is limited to Japanese series. This retrospective analysis of the EBMT registry revealed 21 HTLV-I seropositive ATL including 7 acute and 12 lymphoma subtypes. Four patients received auto-SCT and rapidly died from ATL. Out of 17 allo-SCT (4 myeloablative, 13 reduced intensity), 6 are still alive (4 were in CR1 at SCT). Eleven patients died within 2 years, eight from relapse/progression and three from transplant toxicity. Six of seven informative patients who lived >12 months had chronic GVHD. Overall these results indicate that allo-SCT but not auto-SCT may salvage a subset of ATL patients, supporting the existence of graft vs ATL effect also in non-Japanese patients.

HTLV-1 bZIP factor-specific CD4 T cell responses in adult T cell leukemia/lymphoma patients after allogeneic hematopoietic stem cell transplantation.

We document human T lymphotropic virus type 1 (HTLV-1) bZIP factor (HBZ)-specific CD4 T cell responses in an adult T cell leukemia/lymphoma (ATL) patient after allogeneic hematopoietic stem cell transplantation (HCT) and identified a novel HLA-DRB1*15:01-restricted HBZ-derived naturally presented minimum epitope sequence, RRRAEKKAADVA (HBZ114-125). This peptide was also presented on HLA-DRB1*15:02, recognized by CD4 T cells. Notably, HBZ-specific CD4 T cell responses were only observed in ATL patients after allogeneic HCT (4 of 9 patients) and not in nontransplanted ATL patients (0 of 10 patients) or in asymptomatic HTLV-1 carriers (0 of 10 carriers). In addition, in one acute-type patient, HBZ-specific CD4 T cell responses were absent in complete remission before HCT, but they became detectable after allogeneic HCT. We surmise that HTLV-1 transmission from mothers to infants through breast milk in early life induces tolerance to HBZ and results in insufficient HBZ-specific T cell responses in HTLV-1 asymptomatic carriers or ATL patients. In contrast, after allogeneic HCT, the reconstituted immune system from donor-derived cells can recognize virus protein HBZ as foreign, and HBZ-specific immune responses are provoked that contribute to the graft-versus-HTLV-1 effect.

Impact of graft-versus-host disease on allogeneic hematopoietic cell transplantation for adult T cell leukemia-lymphoma focusing on preconditioning regimens: nationwide retrospective study.

Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used.

Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience.

Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT.

[Two cases of adult T-Cell leukemia/lymphoma with main lesion in stomach treated by VCAP-AMP-VECP regimen].

We report two cases of adult T-cell leukemia/lymphoma(ATLL)having their main lesions in the stomach. Case 1 was a 74-year-old man, complaining of left upper abdominal mass and pain. Upper gastrointestinal endoscopy revealed an ulcerous lesion in the stomach. Histological analysis and southern blotting for HTLV-1 pro-viral DNA led us to our diagnosis of ATLL. There were no apparent lesions in the bone marrow and other organs. He died of tumor lysis and multi-organ failure shortly after treatment with the VCAP-AMP-VECP regimen. Case 2 was a 68-year-old man complaining of abdominal bloating and pain. Upper gastrointestinal endoscopy disclosed an irregularity of the gastric mucosa. A biopsy sample was diagnosed pathohistologically as non-Hodgkin's lymphoma. We conducted total gastrectomy. Based on the results from the histological study and southern blotting for HTLV-1 p ro-viral DNA in the resected specimen, a diagnosis of ATLL was made. We treated him with a VCAP-AMP-VECP regimen, but multiple bone metastases and pathologic fracture occurred, proving that the disease was progressive. ATLL having a main lesion in the stomach is rare, and requires an accumulation of cases analyzed with careful diagnostic approach to establish a standard therapy for it.

Allogeneic HSCT for ATL: a good start.

In this issue of Blood, Ishida and colleagues report the latest update on their nationwide retrospective study of allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia in Japan.

Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study.

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study of ATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL.

How I treat adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I. ATL carries a bad prognosis because of intrinsic chemoresistance and severe immunosuppression. In acute ATL, Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis, but long-term survival is poor when these patients are managed with a watchful-waiting policy or with chemotherapy. Recently, a worldwide meta-analysis revealed that the combination of zidovudine and IFN-α is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. ATL lymphoma patients still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine/IFN. To prevent relapse, clinical trials assessing consolidative targeted therapies such as arsenic/IFN combination or novel monoclonal antibodies are needed. Finally, allogeneic BM transplantation should be considered in suitable patients.

Hematopoietic SCT for adult T-cell leukemia/lymphoma: a review.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus type 1. The aggressive forms of the disease carry a poor prognosis with standard therapies. The role of high-dose treatment with blood and marrow transplantation has, therefore, been examined mainly by Japanese groups in the form of retrospective studies. In this study, we review the literature, discuss some of the challenges facing successful transplantation approaches and stress the need for more innovative studies including in the Western hemisphere.

Clinical trials for human T-cell lymphotropic virus type I-associated peripheral T-cell lymphoma in Japan.

The most common subtype of T-/natural killer (NK) cell lymphoma in Japan is adult T-cell leukemia-lymphoma (ATL), which is associated with the human T-cell lymphotropic virus type I (HTLV-1). The investigators in Japan have conducted several clinical trials on multi-agent chemotherapy and stem cell transplantation for patients with ATL. They have also initiated several new clinical trials with a number of agents: an anti-CCR4 antibody, KW-0761; forodesine, a purine nucleoside phosphorylase inhibitor; and lenalidomide, an immunomodulatory agent. Clinical trials with pralatrexate, a folate analog, and denileukin diftitox, an immunoconjugate, are under discussion for patients with ATL and peripheral T-cell lymphoma (PTCL).