[Durable remission of T-cell prolymphocytic leukemia with CLEC16A::IL2 after allogeneic hematopoietic stem cell transplantation].

A 64-year-old woman presented with fine motor impairment in both hands. MRI revealed a contrast-enhanced lesion in the medulla oblongata. Lymphoid cells with abnormal blebs were observed and a CD4+/CD8+ double positive (DP) T cell population was detected by flow cytometry (FCM) in the bone marrow (BM) and the peripheral blood (PB). CLEC16A::IL2 fusion gene was identified by whole exome sequencing with DNA prepared from DP T cells. Clonal rearrangement of the T-cell receptor gene and expression of TCL1A protein were detected. This led to a diagnosis of T-cell prolymphocytic leukemia (T-PLL) with central nervous system (CNS) infiltration. Abnormal cells in BM and PB became undetectable on microscopy and FCM, and the CNS lesion disappeared on MRI after second-line therapy with alemtuzumab. Meanwhile, the CLEC16A::IL2 fusion mRNA remained detectable in PB. Allogeneic hematopoietic stem-cell transplantation was performed, and the fusion mRNA has now been undetectable for more than 5 years since transplantation. This is the first report of a T-PLL case with a CLEC16A::IL2 fusion gene.

Impact of CD34 positive cell dose in donor graft on the outcomes after haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide - A retrospective single-center study with a Japanese cohort.

BACKGROUND: Haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with post-transplant cyclophosphamide (PTCy) is an important therapeutic option for patients lacking an HLA-matched donor. However, the significance of CD34+ cell dose in grafts has not been fully elucidated. OBJECTIVE: We aimed to explore the impact of CD34+ cell dose on outcomes after haplo-PBSCT with PTCy. STUDY DESIGN: We retrospectively investigated 111 consecutive patients who underwent haplo-PBSCT with PTCy or HLA-matched PBSCT from related donors. RESULTS: There were no statistically significant differences in 3-year overall survival (p = 0.559) or progression-free survival (p = 0.974) between haplo-PBSCT and matched PBSCT. Delayed neutrophil engraftment and a lower incidence of graft-versus-host disease were observed in haplo-PBSCT. The median dose of CD34+ cells was 4.9 × 106 /kg in 57 haplo-PBSCT and 4.5 × 106 /kg in 54 matched PBSCTs. Importantly, patients who underwent haplo-PBSCT with the administration of CD34+ cell at a dose of ≥4.0 × 106 /kg significantly had improved OS (p = 0.015) and decreased incidence of disease relapse (p = 0.001) without increasing incidence of GVHD. CONCLUSION: Our data suggest that a higher dose of CD34+ cells in haplo-PBSCT with PTCy positively impacts the outcomes without an increase of GVHD.

Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m2 ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.

Effect of Conditioning Regimens and Graft-versus-Host Disease Prophylaxis on the Outcomes of Umbilical Cord Blood Transplantation Performed with Cyclophosphamide/Total Body Irradiation-Based Regimens.

Umbilical cord blood (UCB) is a valuable alternative donor source for allogeneic hematopoietic stem cell transplantation. Various conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens aimed at improving the outcomes of umbilical cord blood transplantation (UCBT) have been explored; however, the differences in their effects remain unclear. This study was conducted to elucidate the differences in the effects of conditioning and GVHD prophylaxis regimens on UCBT outcomes by disease type in a nationwide, retrospective study. We retrospectively analyzed the effects of conditioning and GVHD prophylaxis regimens on the outcomes of UCBT performed with cyclophosphamide (Cy)/total body irradiation (TBI)-based regimens in patients with acute myeloid leukemia (AML; n = 1126), acute lymphoblastic leukemia (ALL; n = 620), myelodysplastic syndrome (MDS; n = 170), and lymphoma (n = 128). Multivariate analysis for overall survival (OS) demonstrated the benefit of adding high-dose cytarabine to the Cy/TBI regimen for the AML group (relative risk [RR], .76; P = .003) and lymphoma group (RR, .54; P = .02), but not for the ALL and MDS groups. In the ALL group, adding etoposide to the Cy/TBI regimen was associated with a lower OS (RR, 1.45; P = .03). For GVHD prophylaxis, a tacrolimus/methotrexate regimen was associated with a lower OS compared with a cyclosporine/methotrexate regimen in the AML group (RR, 1.26; P = .01); this difference was not observed in the other groups. These differences in OS according to the conditioning and GVHD prophylaxis regimen were attributable mainly to differences in relapse risk. Our data show that the effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes differed according to disease type. UCBT outcomes could be improved by selecting optimal conditioning regimens and GVHD prophylaxis for each disease type.

Identification of a DBA/2 Mouse Sub-strain as a Model for Pseudoxanthoma Elasticum-Like Tissue Calcification.

Ectopic calcification in the cardiovascular system adversely affects life prognosis. DBA/2 mice experience calcification owing to low expression of Abcc6 as observed in pseudoxanthoma elasticum (PXE) patients; however, little is known about its characteristics as a calcification model. In this study, we explore the suitability of a DBA/2 sub-strain as a PXE-like tissue calcification model, and the effect of a bisphosphonate which prevents calcification of soft tissues in hypercalcemic models was evaluated. The incidence of calcification of the heart was compared among several sub-strains and between both sexes of DBA/2 mice. mRNA expression of calcification-related genes was compared with DBA/2 sub-strains and other mouse strains. In addition, progression of calcification and calciprotein particle formation in serum were examined. Among several sub-strains of DBA/2 mice, male DBA/2CrSlc mice showed the most remarkable cardiac calcification. In DBA/2CrSlc mice, expression of the anti-calcifying genes Abcc6, Enpp1 and Spp1 was lower than that in C57BL/6J, and expression of Enpp1 and Spp1 was lower compared with other sub-strains. Calcification was accompanied by accelerated formation of calciprotein particle, which was prevented by daily treatment with bisphosphonate. A model suitable for ectopic calcification was identified by choosing a sub-strain of DBA/2 mice, in which genetic characteristics would contribute to extended calcification.

Safety of romiplostim administered immediately after cord-blood transplantation: a phase 1 trial.

Graft failure and delayed hematopoietic recovery are the major limitations of cord-blood transplantation (CBT). Romiplostim, a thrombopoietin-receptor agonist, promotes megakaryopoiesis and multilineage hematopoiesis in aplastic anemia. The decreased number of hematopoietic stem cells in the early phase after CBT and aplastic anemia share certain characteristics. Therefore, we hypothesized that romiplostim administration immediately after CBT may promote multilineage hematopoietic recovery. We investigated the safety and preliminary efficacy of administering romiplostim a day after CBT. This phase 1 dose-escalation study included six adults with hematologic malignancies in remission. Romiplostim was administered subcutaneously within 7 days after single-unit CBT, initially at doses of 5 µg/kg or 10 µg/kg in three patients, then once a week for 14 weeks or until platelet recovery. The maximum dose was 20 µg/kg. The median number of romiplostim administrations was 6 (range, 3-15). Romiplostim-related adverse events included bone pain (3/6) and injection site reaction (1/6). Non-hematological grade ≥ 3 toxicities were observed in four patients; febrile neutropenia was the most common (4/6). All patients achieved neutrophil engraftment and the median time was 14 days (range, 12-32). Platelet counts ≥ 50 × 109 /L were recorded in all patients except for one who died on day 48; the median time was 34 days (range, 29-98). No relapse, thrombosis, or bone marrow fibrosis was observed during a median follow-up of 34 months. Romiplostim may be safely administered in the early phase of CBT. Further phase 2 trial is warranted for its efficacy evaluation. Trial registration number: UMIN000033799, August 18, 2018.

Repeated immunosuppressive rabbit antithymocyte globulin therapy for adult patients with relapsed or refractory aplastic anemia.

OBJECTIVES: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A is the standard treatment for aplastic anemia (AA). However, the efficacy of repeated IST with rabbit ATG (rATG) as salvage therapy remains unclear in patients with relapsed or refractory AA. METHODS: We retrospectively evaluated the efficacy and safety of IST2 with rATG (IST2-rATG) in 19 consecutive patients with relapsed or refractory AA who received first-line IST with rATG in two centers between 2009 and 2020. RESULTS: The overall 6-month response rate of the patients was 58%. The response rates were similar between patients with relapsed and refractory AA. The presence of glycophosphatidylinositol-deficient blood cells was associated with a better response to IST2-rATG. Despite retreatment with the same rATG, serum disease and severe allergic reactions were not observed. CONCLUSION: IST2-rATG is effective and safe for the treatment of adult patients with relapsed and refractory AA after receiving first-line IST with rATG.

Adverse impact of delay of platelet recovery after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma and multiple myeloma.

BACKGROUND AIMS: The prognostic impact of platelet recovery after autologous hematopoietic cell transplantation (AHCT) on clinical outcomes remains to be elucidated. We aimed to clarify the impact of platelet recovery on clinical outcomes, risk factors of delayed platelet recovery and the necessary dose of CD34+ cells for prompt platelet recovery in each patient. METHODS: Using a nationwide Japanese registry database, we retrospectively analyzed clinical outcomes of 5222 patients with aggressive non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). RESULTS: At a landmark of 28 days after AHCT, a delay of platelet recovery was observed in 1102 patients (21.1%). Prompt platelet recovery was significantly associated with superior overall survival (hazard ratio [HR] 0.32, P < 0.001), progression-free survival (HR 0.48, P < 0.001) and decreased risks of disease progression (HR 0.66, P < 0.001) and non-relapse/non-progression mortality (HR 0.19, P < 0.001). The adverse impacts of a delay of platelet recovery seemed to be more apparent in NHL. In addition to the dose of CD34+ cells/kg, disease status, performance status and the hematopoietic cell transplant-specific comorbidity index in both diseases were associated with platelet recovery. We then stratified the patients into three risk groups according to these factors. For the purpose of achieving 70% platelet recovery by 28 days in NHL, the low-, intermediate- and high-risk groups needed more than 2.0, 3.0 and 4.0 × 106 CD34+ cells/kg, respectively. In MM, the low-risk group needed approximately 1.5 × 106 CD34+ cells/kg, whereas the intermediate- and high-risk groups required 2.0 and 2.5 × 106 CD34+ cells/kg to achieve about 80% platelet recovery by 28 days. CONCLUSIONS: A delay of platelet recovery after AHCT was associated with inferior survival outcomes.

[Waldenström macroglobulinemia complicated by peripheral neuropathy due to neural infiltration].

A 51-year-old man with the chief complaint of glove- and stocking-type dysesthesia for >3 years was diagnosed with Waldenström's macroglobulinemia (WM) based on IgM-type M-proteinemia, bone marrow infiltration of plasmacytoid B cells, multiple lymphadenopathies, and splenomegaly. A nerve conduction examination suggested demyelinating neuropathy. Serum anti-myelin-associated glycoprotein antibody was negative. Sural nerve biopsy showed myelin thinning, suggesting demyelination. Axonal damage and tumor cell infiltration in the intrafascicular epineurium were also observed. After chemotherapies with rituximab and bendamustine, M-proteinemia and lymphadenopathies disappeared. However, abnormalities in the nerve conduction examination and dysesthesia were only slightly alleviated. As articles describing patients with WM with peripheral nerve infiltration are limited, we report this case with a literature review.

[Hematopoietic recovery by ASXL1-mutated clones after immune suppressive therapy in a patient with severe aplastic anemia].

Sequencing technology has identified aplastic anemia (AA) not only as an autoimmune bone marrow failure syndrome, but also as a clonal hematopoietic disease. Here, we present a case in which an ASXL1-mutated clone was predominantly expanded during the treatment of AA. A 58-year-old man with chronic glomerulonephritis on maintenance hemodialysis presented with pancytopenia. The findings of bone marrow biopsy indicated a hypoplastic bone marrow. Magnetic resonant imaging showed fatty changes in the bone marrow. The patient was eventually diagnosed with severe AA. He was treated with anti-human thymocyte globulin, cyclosporine, granulocyte colony-stimulating factor, and the thrombopoietin receptor agonist (TPO-RA) eltrombopag. After switching to another TPO-RA, romiplostim, the neutrophil, reticulocyte, and platelet counts gradually improved, and blood transfusion was not needed 1 year after treatment. Mutational analyses revealed that reconstituted hematopoietic cells originated from the ASXL1-mutated clone. Nevertheless, the patient's blood cell counts remained normal 2 years after treatment.

[Lymphoplasmacytic lymphoma accompanied by severe myelofibrosis].

A 61-year-old female was referred to our hospital because of pancytopenia and febrile neutropenia. On admission, computed tomography showed mild hepatosplenomegaly and intra-abdominal abscess formation in the right pelvic region; however, no lymphadenopathy was found. Bone marrow (BM) examination showed severe fibrosis by silver staining. Several small- to medium-sized lymphocytes with a constriction in the nuclei were observed, exhibiting CD3 (-), CD10 (-), CD20 (+), BCL-2 (+-), and CD138 (+-). Genetic testing revealed that BM cells were positive for MYD88 mutation and positive for IgH rearrangement, whereas neither JAK2 nor CALR mutation was positive. A diagnosis of BM infiltration of lymphoplasmacytic lymphoma (LPL) was made. Rituximab monotherapy was administered once a week for four times. BM examination 4 weeks after the end of treatment showed that lymphoma cells had disappeared and that myelofibrosis had been almost gone. The MYD88 mutation of BM turned out to be negative at that moment.

Cardiac Tamponade as a Recurrence of Angioimmunoblastic T-Cell Lymphoma with the Detection of a p.Gly17Val RHOA Mutation in the Pericardial Effusion.

Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.

Triple-negative Thrombocythemia and Subsequent Acute Lymphoblastic Leukemia with Additional Somatic Mutations.

Triple-negative essential thrombocythemia (ET) is a condition in which mutations in JAK2, CALR and MPL are all negative. Transformation to acute myeloid leukemia may occur during the course of ET, while B-acute lymphoblastic leukemia B-(ALL) is rare. We experienced a case diagnosed as B-ALL during the course of triple-negative ET. Notably, cytoreduction was required for the excessive increase in blood cells during the bone marrow recovery period after chemotherapies. Whole exome sequencing identified 17 somatic mutations: 9 were identified in both ET and B-ALL samples, while 8 were specific to B-ALL, suggesting that these 8 might have caused the transformation.

[Acute myeloid leukemia harboring NUP98::DDX10].

NUP98::DDX10 is a rare fusion gene associated with acute myeloid leukemia (AML), for which the prognosis and indication for allogeneic hematopoietic stem cell transplantation are unknown. A 48-year-old woman was diagnosed with AML harboring NUP98::DDX10. The results of quantitative RT-PCR of the fusion mRNA as a minimal residual disease (MRD) marker guided the treatment. In August 2019, the patient achieved hematological remission following standard remission induction therapy with idarubicin and cytarabine. After four cycles of consolidation therapies, MRD was detected, and she underwent allogeneic stem cell transplantation in May 2020. As MRD persisted in June, the immunosuppressant was stopped and three cycles of azacitidine were administered. Despite this, a hematological relapse occurred in January 2021 that was resistant to high-dose cytarabine and an investigational agent. She died as a result of the disease's progression. Thus, a second thought should be given to the timing of transplantation, the bridging, and the intervention for relapse after transplantation. The cases must be accumulated.

High-P-T impedance measurements using a laser-heated diamond anvil cell.

The electrical conductivity (EC) of minerals found on Earth and throughout the solar system is a fundamental transport property that is used to understand various dynamical phenomena in planetary interiors. High-pressure and high-temperature (P-T) EC measurements are also an important tool for observing phase transitions. Impedance measurements can accurately measure the EC of a nonmetallic sample. In previous measurements under static conditions using a laser-heated diamond-anvil cell (LHDAC), only direct current resistance is measured, but this method overestimates the bulk sample resistance. Moreover, the previous methodology could only be applied to nontransparent samples in an LHDAC using infrared lasers, limiting the range of measurable composition. To the best of our knowledge, no in situ high-P-T EC measurements of transparent materials have been reported using LHDAC techniques. We developed a novel impedance measurement technique under high-P-T conditions in an LHDAC that applies to transparent samples. As a validation, we measured the EC of Mg0.9Fe0.1SiO3 bridgmanite up to 51 GPa and 2000 K and found that the results are consistent with those of previous studies. We also measured the EC values of sodium chloride to compare with those of previous studies, as well as those of cubic boron nitride and zirconia cement to quantify how well they insulate under high P-T conditions. This is the first report of the impedance and EC measurements of transparent minerals in an LHDAC, which allows the measurement of Fe-poor/-free materials, including the major constituents of the interiors of gas giants and icy planets, under extreme conditions.

Administration of brentuximab vedotin to a Hodgkin lymphoma patient with liver dysfunction due to vanishing bile duct syndrome resulting in a partial response without any severe adverse events.

Vanishing bile duct syndrome (VBDS) is a rare hepatic disorder which leads to liver failure as a result of progressive destruction of the intrahepatic bile ducts. There are no treatment modalities for VBDS itself and severe hepatic dysfunction restricts the treatment of underlying diseases. We safely treated a case of classic Hodgkin lymphoma (HL) with VBDS using brentuximab vedotin (BV). The patient was treated with 5 cycles of reduced BV and a partial metabolic response was obtained. Moreover, a standard dose of BV for another 5 cycles was accomplished with minimal adverse events. Our experience indicates that BV could be a treatment option for classic HL with VBDS.

Salvage Cord Blood Transplantation Using a Short-term Reduced-intensity Conditioning Regimen for Graft Failure.

Objective Graft failure (GF) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). A standardized conditioning regimen and an appropriate graft source of salvage HSCT for GF have not yet been established. Some case series have shown good hematopoietic recoveries after salvage HSCT using a short-term reduced-intensity preparative regimen consisting of fludarabine (30-90 mg/m2), cyclophosphamide (2 g/m2), and total-body irradiation (2 Gy). However, the dose of fludarabine has varied in these reports based on the clinical condition of the patients, resulting in very limited experiences with each dose of fludarabine. Methods We retrospectively analyzed 10 patients who developed GF after allogeneic HSCT and underwent salvage cord blood transplantation (CBT) using the above-mentioned conditioning regimen with a fixed dose (90 mg/m2) of fludarabine. Results Eight patients (80.0%) achieved neutrophil engraftment within 30 days from salvage HSCT with a median of 21 (range, 17-23) days. The 1-year overall survival (OS) rate after the salvage HSCT was 50.0%, and the median OS was 281 (range, 23-1,638) days. Cumulative incidences of non-relapse mortality and relapse at 1 year were 50.0% and 10.0%, respectively. Conclusion CBT using this short-term reduced-intensity conditioning regimen may be a promising salvage therapy for GF.

[IgG-variant Bing-Neel syndrome diagnosed by detecting MYD88 L265P mutation in the cerebrospinal fluid cells].

Bing-Neel syndrome (BNS), which presents with a variety of neurological complications, is a rare manifestation of the lymphoplasmacytic lymphoma (LPL) and is characterized by the infiltration of LPL cells into the central nervous system. In this study, we report the case of a patient with BNS, which was confirmed by detecting MYD88 L265P mutation in the cerebrospinal fluid (CSF) cells. A 74-year-old patient was diagnosed with IgG-variant LPL. He achieved a very good partial response to the treatment with rituximab and bendamustine (RB) and was stable for over 5 years, when presenting a slowly progressive motor deficit in the lower limbs. It was difficult to confirm BNS from morphological analysis of the CSF cells. After detecting MYD88 L265P mutation in the CSF cells, he was subsequently diagnosed with BNS and treated with RB and intrathecal chemotherapy, resulting in rapid clinical improvement. With the onset of neurological manifestation during the clinical course of LPL, the detection of MYD88 L265P mutation in the CSF cells could be helpful for the diagnosis and management of BNS.

[Acquired platelet dysfunction with severe bleeding tendency in triple-negative myelofibrosis].

A 50-year-old man demonstrated markedly increased number of white blood cells, anemia, severe splenomegaly, and bleeding tendency. Bone marrow analysis revealed remarkable hypercellularity; dysplasia in multilineage cells, including megakaryocytes; and fibrosis. He was eventually diagnosed with triple-negative myelofibrosis. A massive hematoma developed at the bone marrow biopsy site. A similar episode recurred after the second bone marrow biopsy. The von Willebrand factor and other coagulation factor activities were within normal ranges. Platelet aggregation analyses demonstrated highly impaired aggregation induced by ADP, collagen, and epinephrine. Treatment with hydroxyurea and ruxolitinib, a JAK inhibitor, was ineffective, and he eventually died on day 144 after hospitalization. Acquired platelet dysfunction uncommonly occurs in patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), without precise elucidation of the frequency and underlying mechanism. The onset of bleeding tendency in the current patient suggested that platelet dysfunction may be caused by somatic genetic events. Here, we discuss the mechanisms of acquired platelet dysfunction in MDS or MPN with a literature review.