Aggressive natural killer cell leukemia: Therapeutic potential of l-asparaginase and allogeneic hematopoietic stem cell transplantation

We conducted a retrospective JapanKorea multicenter study to better elucidate the clinicopathologic features and therapeutic modalities for aggressive natural killer cell leukemia (ANKL). A total of 34 patients were analyzed. The median age of the patients was 40 years. Among the patients in the study, four had a history of EpsteinBarr virus-related disorders. Three types of ANKL cells were categorized according to their morphological features. Leukemic cells were below 20% in both peripheral blood and bone marrow of 11 patients. The clinical characteristics and prognoses of these 11 patients did not differ significantly from those of the others. As an initial therapy, l-asparaginase chemotherapy resulted in a better response. A total of six patients received allogeneic hematopoietic stem cell transplantation (HSCT) and two received autologous HSCT, with all in non-complete remission (CR). After HSCT, four with allogeneic and one with autologous HSCT reached CR. Median survival of all patients was 51 days. Median survival for the patients with and without HSCT were 266 and 36 days, respectively. A total of two patients with allogeneic HSCT were alive and in CR. All patients without HSCT died of ANKL. The use of l-asparaginase was indicated as a factor for longer survival (HR 0.33, 95% confidence interval; 0.130.83, P = 0.02). Early diagnosis of ANKL, l-asparaginase-based chemotherapy and allogeneic HSCT might lead to improved patient outcomes.ArticleCANCER SCIENCE. 103(6):1079-1083 (2012)journal articl

Long-Term Outcome after Bone Marrow Transplantation for Aplastic Anemia Using Cyclophosphamide and Total Lymphoid Irradiation as Conditioning Regimen

AbstractWe retrospectively studied 49 patients in a single institute to evaluate the long-term outcome of total lymphoid irradiation (TLI) conditioning for allogeneic stem cell transplantation (allo-SCT) to treat aplastic anemia (AA). Most of the patients had received transfusions and had undergone previous treatment, with 33 receiving related transplants and 16 receiving unrelated transplants. Conditioning consisted of cyclophosphamide (Cy; 200 mg/kg) plus TLI (750 cGy) for related transplantation and Cy plus total body irradiation (TBI; 500 cGy) and TLI (500 cGy) for unrelated transplantation. Antithymocyte globulin (ATG) was added for 6 of the unrelated transplantations. Graft-versus-host-disease (GVHD) prophylaxis consisted mainly of cyclosporine (CSA) and methotrexate (MTX). Graft failure developed in 2 patients (4.1%). With a median follow-up of 7 years, overall survival (OS) was 81% and was not statistically significantly different between the patients receiving related transplants and those receiving unrelated transplants. In multivariate analyses, a history of previous treatment with ATG was the sole factor associated with a worse survival rate, and the interval from diagnosis to treatment was not prognostic. The incidence of acute (grade II to IV) GVHD (aGVHD) was 23%, and that of chronic GVHD (cGVHD) was 29%. Female-to-male transplantation was the sole factor associated with chronic GVHD. B cell lymphoproliferative disorder developed only after the ATG-containing conditioning. No other secondary malignancies developed after long-term follow-up. Our findings suggest that TLI conditioning is feasible and effective for patients with AA

Peripheral Blood as a Preferable Source of Stem Cells for Salvage Transplantation in Patients with Graft Failure after Cord Blood Transplantation: A Retrospective Analysis of the Registry Data of the Japanese Society for Hematopoietic Cell Transplantation

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT

Changing trends in prognostic factors for patients with multiple myeloma after autologous stem cell transplantation during the immunomodulator drug/proteasome inhibitor era

We evaluated the clinical significance of prognostic factors including the International Staging System (ISS) and modified European Group for Blood and Marrow Transplantation response criteria in 1650 Japanese patients with multiple myeloma (MM) who underwent upfront single autologous stem cell transplantation (ASCT). We categorized patients into two treatment cohorts: pre-novel agent era (1995-2006) and novel agent era (2008-2011). The combined percentage of pre-ASCT complete response and very good partial response cases (463 of 988, 47%) significantly increased during the novel agent era compared with the pre-novel agent era (164 of 527, 31%; P < 0.0001). The 2-year overall survival (OS) rate of 87% during the novel agent era was a significant improvement relative to that of 82% during the pre-novel agent era (P = 0.019). Although significant differences in OS were found among ISS stages during the pre-novel agent era, no significant difference was observed between ISS I and II (P = 0.107) during the novel agent era. The factors independently associated with a superior OS were female gender (P = 0.002), a good performance status (P = 0.024), lower ISS (P < 0.001), pre-ASCT response at least partial response (P < 0.001) and ASCT during the novel agent era (P = 0.017). These results indicate that the response rate and OS were significantly improved, and the ISS could not clearly stratify the prognoses of Japanese patients with MM who underwent upfront single ASCT during the novel agent era. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malig- nancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epi- genetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.Aggressiivinen NK-soluleukemia (ANKL) on elimistön luonnolliseen puolustusjärjestelmään kuuluvien luonnollisten tappajasolujen eli natural killer (NK) –solujen verisyöpä eli leukemia. ANKL:aan sairastuneet potilaat säilyvät käytössä olevilla solunsalpaaja- ja kantasolusiirtohoidoilla elossa keskimäärin vain joitakin kuukausia. Erityisesti aasialaisväestössä esiintyvän ANKL:n lisäksi NK-soluisiin syöpiin kuuluu Suomessakin harvinaisina tavattavia NK/T-soluisia lymfoomia. ANKL:n taustalla olevia hankittuja geenimuutoksia eli mutaatioita ei ole aiemmin selvitetty laajamittaisesti. Tutkimuksessa selvitimme ANKL:n tautimekanismeja kartoittamalla 14 potilaan syöpäsolujen geenimuutokset perimän proteiineja koodaavien geenien osalta ja tutkimalla pahanlaatuisten NK-solujen herkkyyttä yli 400 lääkeaineelle. Löysimme ANKL-potilaiden soluista geenimuutoksia etenkin STAT3- ja DDX3X-geeneissä, joita kumpiakin oli yli viidenneksellä potilaista. STAT3-mutaatioita on aiemmin todettu suurten granulaaristen lymfosyyttien (LGL) leukemiassa, sekä useissa muissakin T- ja NK-soluista lähtöisin olevissa syövissä. STAT3-mutaatiot ANKL:ssa viittaavat osin yhteisiin tautimekanismeihin näiden sukulaistautien kanssa. Kun yhdistimme ANKL-potilaiden geenitietoa aiemmin julkaistujen NK//T-solulymfoomapotilaista tuotettujen aineistojen kanssa, havaitsimme NK-soluisille syöville yhteisiä JAK-STAT-signalointigeenien monistumia. Etsimme myös potentiaalisia lääkeaineita NK-soluisten syöpien hoitoon testaamalla pahanlaatuisten NK-solujen herkkyyttä yli 400 lääkeaineelle. Havaitsimme NK-solujen olevan poikkeuksellisen herkkiä JAK-tyrosiinikinaasin ja BCL-perheen solukuolemaa säätelevien proteiinien estäjille. JAK-estäjillä pyritään hiljentämään samaa JAK-STAT-signalointireittiä, josta löysimme geneettisiä muutoksia ANKL-potilailla. Myeloproliferatiivisten sairauksien ja nivelreuman hoidossa käytettävillä JAK-estäjillä voitaisiin mahdollisesti tehostaa NK-soluisten syöpien hoitoa hyödyntämällä kyseisen solutyypin voimakasta riippuvuutta JAK-STAT-signaloinnin aktiivisuudesta. Tutkimuksemme valottaa geenitason muutoksia aiemmin tautimekanismeiltaan tuntemattomassa ANKL:ssa. Lääkeherkkyysseulonnan avulla pystyimme tunnistamaan potentiaalisia lääkeaineita ajatellen hoitokokeiluja harvinaisessa ANKL:ssa, jossa kliinisiä lääketutkimuksia pystytään harvoin toteuttamaan

Correction. "The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms" Leukemia. 2022 Jul;36(7):1720-1748

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms

Progress in the treatment of NK-cell lymphoma/leukemia

Natural killer (NK)/T cell lymphoma includes two major subtypes of disease, specifically extranodal NK/T cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL). Both are strongly associated with Epstein-Barr virus and are prevalent in East Asia and Latin America. Except for that of limited-stage ENKL, the prognosis of both diseases was poor in the previous decade. The advent of non-anthracycline-based chemoradiotherapy has contributed to an improvement in ENKL prognosis, but there is still room for further treatment progress. Recently, the high efficacy of PD-1 antibody was reported in relapsed or refractory ENKL patients. This was later supported by the finding that PD-L1/PD-L2 genetic alterations are frequently observed in ENKL and ANKL patients. Due to the rarity of the disease, a standard treatment for ANKL remains to be established. Currently, allogeneic stem cell transplantation is the only curative treatment, and this is even applicable to chemo-resistant ANKL patients. In this review, we focus on recent treatment approaches for NK/T cell lymphomas including novel agents