Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic ...cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.
Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for refractory hematological malignancies. However, there are many treatment-related complications, including ...organ disorders, graft-versus-host disease (GVHD), and infectious diseases. Furthermore, there are many unclear points regarding central nervous system (CNS) complications, and the prognosis in patients with CNS complications is extremely poor. We herein report a 49-year-old woman who developed CNS-GVHD after a second transplantation for therapy-related myelodysplastic syndrome. CNS-GVHD in this case was refractory to all treatments, including steroids, and progressed. We also present a review of the literature about the symptoms, diagnosis, and treatment of CNS-GVHD.
Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr ...virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient's death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.
Background: Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is ...needed. Methods: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 106 CD34-positive cells/kg (range: 0.3-47.4 × 106 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 106 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed. Results: The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 72.3% vs. n = 11 44.0% in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 106/μL; range: 1.60-47.4 × 106 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment. Conclusion: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.
We evaluated the impact of
FLT3
-ITD,
NPM1
mutations, and double mutant
CEBPa
(
dmCEBPa
) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid ...leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16–65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed
FLT3
-ITD,
NPM1
mutations and
CEBPa
using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with
dmCEBPa
. Patients with
FLT3
-ITD had significantly worse OS after relapse than those without (19% vs 41%,
p
= 0.002), while OS was comparable between patients with and without
NPM1
mutations (37% vs 34%,
p
= 0.309). Patients with dm
CEBPa
had improved OS than those without (61% vs 32%,
p
= 0.006). By multivariate analysis,
FLT3
-ITD was independently associated with worse OS after relapse hazard ratio (HR) 1.99, 95% CI 1.27–3.12,
p
= 0.003, and
dmCEBPa
with improved OS (HR 0.40, 95% CI 0.17–0.93,
p
= 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.
In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)–positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication ...(FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation–positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut–positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival OS, 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival RFS P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut–positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.
•The ELN guideline classifying FLT3-ITD low allele ratio with NPM1 mutation as having a favorable prognosis is questionable.•Performing allo-HSCT during CR1 irrespective of the FLT3-ITD allele ratio and NPM1 mut status significantly improves outcome.
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Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) ...is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the
telomerase reverse transcriptase
and cryptic DKC patients with
RTEL1
mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.
Aim
The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara‐C), and melphalan (MEL) is widely used before auto‐peripheral blood stem cell transplantation (auto‐PBSCT) for ...malignant lymphoma in Japan. The MEAM regimen generally consists of 200–400 mg/m2 for 4 days, but we decided to increase the dosage of Ara‐C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high‐dose Ara‐C MEAM therapy.
Methods
The high‐dose Ara‐C MEAM protocol consisted of MCNU 300 mg/m2 on day –7, ETP 200 mg/m2 on days –6, –5, –4, –3 and Ara‐C 2 g/m2 on day –4 –3, and MEL 140 mg/m2 on day –2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020.
Results
All patients got engraftment and there were no cases of treatment‐related mortality. In all cases, the 3‐year overall survival (OS) and progression‐free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty‐one cases of diffuse large B‐cell lymphoma recurrence, for which there is proven usefulness of auto‐PBSCT, showed good results after transplantation, with the 3‐year OS and PFS after transplantation being 100% and 74.3%, respectively.
Conclusion
The safety and efficacy of high‐dose Ara‐C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.
We retrospectively analyzed malignant lymphoma in patients who underwent auto‐peripheral blood stem cell transplantation, with high‐dose cytarabine MEAM therapy as the conditioning regimen. In all cases, the 3‐year overall survival after transplantation was 80.6% and the 3‐year progression‐free survival after transplantation was 65.7%. There were no cases of treatment‐related mortality with this therapy, and this one tended to be more effective than ICE and BU/CY/VP‐16 therapies.
The prognostic significance of
FLT3
-tyrosine kinase domain (TKD) mutations remains unknown. To investigate the prognostic impact of
FLT3
-TKD, 676 de novo acute myeloid leukemia (AML), we ...retrospectively analyzed cases and conducted a review of the literature. Of the 676 de novo AML cases, 34 (5.0%) were
FLT3
-TKD-positive; both
FLT3
-TKD and
FLT3
-ITD were noted in only two cases (0.3%). Although no significant differences in relapse-free survival (RFS) were noted,
FLT3
-TKD-positive cases showed better prognoses than
FLT3
-ITD-positive cases (
FLT3
-TKD versus
FLT3
-ITD,
p
= 0.152). For overall survival (OS), although
FLT3
-TKD-positive cases showed prognoses similar to those for
FLT3
-WT cases, their prognoses were significantly better than those of
FLT3
-ITD-positive cases (
FLT3
-TKD versus
FLT3
-ITD,
p
= 0.032). Moreover, the 5-year OS for
FLT3
-TKD-positive cases was 46.1%, indicating that this as an intermediate prognosis group. Although no reports from Asia have indicated a frequency of
FLT3
-TKD-positive cases > 10%, several reports from Europe and the United States have indicated frequencies > 10%. This suggests the possibility that
FLT3
-TKD-positive cases are less common in Asia than in Europe and the United States. We anticipate that in the future, the appearance of targeting agents, such as FLT3 inhibitors, will improve the prognosis of
FLT3
-TKD-positive AML relative to that of
FLT3
-WT AML.
Background: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, ...early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. Methods: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. Results: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. Conclusion: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.
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