Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are among the most clinically relevant molecular abnormalities in acute myeloid leukemia (AML); however, the therapeutic significance of rare non-canonical FLT3 mutations involving the juxtamembrane domain (JMD) remains poorly defined. We report a 34-year-old woman with acute monocytic leukemia harboring a rare FLT3-JMD missense mutation (V579A) who experienced early relapse following standard induction and consolidation chemotherapy. Targeted next-generation sequencing revealed the presence of FLT3 V579A along with a concurrent truncating ARID1A mutation. Salvage therapy with the type I FLT3 inhibitor gilteritinib induced rapid hematologic remission within three weeks, allowing successful bridging to haploidentical allogeneic hematopoietic stem cell transplantation. Three months after transplantation, the patient relapsed, and genomic analysis demonstrated loss of the FLT3-mutated clone with the emergence and expansion of TP53-mutated independent clones, indicating clonal evolution and an apparent shift away from FLT3-dependent disease biology. This case suggests that AML harboring rare FLT3-JMD point mutations may exhibit transient dependence on FLT3 signaling and may respond to FLT3 inhibition despite the absence of canonical FLT3 alterations. These findings highlight the potential value of extended molecular profiling and longitudinal genomic assessment to identify potential therapeutic targets and mechanisms of resistance in relapsed AML.

PURPOSE:Physical function frequently declines after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the influence of disease status and general condition at the time of transplantation on longitudinal functional changes remains unclear. METHODS:This retrospective study included 135 adult patients with hematological malignancies who underwent their first allo-HSCT and completed physical function assessments before transplantation and at discharge. Handgrip strength and 6-min walk distance (6MWD) were evaluated. Patients were stratified according to disease status (complete remission [CR] vs. non-CR) and general condition (performance status [PS]). RESULTS:Both handgrip strength and 6MWD decreased significantly after transplantation in all groups. No significant differences in functional changes were observed between the CR and non-CR groups. In contrast, patients with poor PS at transplantation tended to show a greater decline in 6MWD than those with good PS. Multiple regression analysis identified PS at transplantation, age, sex, and change in the hemoglobin level as significant factors associated with changes in 6MWD. CONCLUSION:Pre-transplant PS was associated with a greater post-transplant decline in endurance capacity, regardless of disease status. PS may serve as a practical clinical indicator for identifying patients at higher risk of physical function deterioration and guiding early targeted rehabilitation interventions.

Cytomegalovirus (CMV) reactivation remains a major complication after hematopoietic cell transplantation (HCT), particularly in high-risk settings. Although the antigenemia (AG) assay has long been the standard CMV monitoring tool in Japan, quantitative PCR (qPCR) offers improved sensitivity and is now widely adopted. We analyzed a total of 1878 samples from 231 HCT recipients who underwent CMV monitoring at multiple centers. We evaluated the correlation between AG and qPCR results, determined qPCR thresholds equivalent to AG positivity, and compared actual AG-guided therapy durations with simulated qPCR-guided therapy. Among 1878 sample sets, AG and qPCR showed strong correlation (r = 0.65) and high concordance (87.6

This study retrospectively examined changes in physical functioning and quality of life (QOL) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients at their first (HSCT-1) and second (HSCT-2) transplantations. Seventeen patients who underwent HSCT-2 after relapse following HSCT-1 at our hospital between May 2013 and November 2023 and who underwent physical therapy evaluations before and after both transplantations were analyzed. Physical functioning was evaluated using handgrip strength as a measure of muscle strength, and exercise tolerance using the 6-min walk test (6MWT). QOL was assessed using the Medical Outcome Study 36-Item Short Form Health Survey (SF-36). Changes in physical functioning included handgrip strength (HSCT-1: − 9.3

Here, we report a rare case of relapsed adult T-cell leukemia-lymphoma (ATL) with evidence of clonal relapse 26 years after initial diagnosis. The patient had been diagnosed with an aggressive form of lymphoma-type ATL 26 years prior and did not receive further ATL treatment for approximately 26 years after achieving complete remission. We used nested PCR to identify the amplification of ATL clone-specific accumulation sites in DNA from hematoxylin and eosin-stained specimens from the patient. Furthermore, the sequence of amplicons obtained from peripheral blood mononuclear cells and lymphoma cells from the previously diagnosed ATL were identical, indicating that a human T-cell leukemia virus-type 1 (HTLV-1)-infected clone identical to the one that recently caused ATL was present in the original lymphoma tissue. Although we were unable to identify this clone as the cause of the previous ATL, the peripheral leukemia cells revealed an ATL clone that was present in the tumor cells of a lymph node diagnosed 26 years earlier. To our knowledge, this is the first report demonstrating survival of HTLV-1-infected clones for a quarter of a century in a patient with recurrent ATL.

Essential thrombocythemia (ET) cases without canonical JAK2, CALR, or MPL mutations, that is, triple-negative (TN) ET, have been found in 10%-20% of ET cases. Owing to the limited number of TN ET cases, its clinical significance remains unclear. This study evaluated TN ET's clinical characteristics and identified novel driver mutations. Among 119 patients with ET, 20 (16.8%) had no canonical JAK2/CALR/MPL mutations. Patients with TN ET tended to be younger and had lower white blood cell counts and lactate dehydrogenase values. We identified putative driver mutations in 7 (35%): MPL S204P, MPL L265F, JAK2 R683G, and JAK2 T875N were previously reported as candidate driver mutations in ET. Moreover, we identified a THPO splicing site mutation, MPL*636Wext*12, and MPL E237K. Four of the seven identified driver mutations were germline. Functional studies on MPL*636Wext*12 and MPL E237K revealed that they are gain-of-function mutants that increase MPL signaling and confer thrombopoietin hypersensitivity with very low efficiency. Patients with TN ET tended to be younger, although this was thought to be due to the inclusion of germline mutations, hereditary thrombocytosis. Accumulating the genetic and clinical characteristics of noncanonical mutations may help future clinical interventions in TN ET and hereditary thrombocytosis.

A correction to this paper has been published: https://doi.org/10.1007/s12185-021-03125-7

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.

We retrospectively analyzed 38 patients with AML who received azacitidine (AZA) to treat disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with objective response (OR) (n = 20) after AZA had significantly higher 2-year overall survival (OS) (45.0% vs 5.6%; p = 0.004) than progressive disease. The 2-year OS was significantly higher in the retransplant group (n = 23) than in the nonretransplant group (n = 15) (34.8% vs 13.3%; p = 0.034). We analyzed 167 patients who underwent the second allo-HSCT to clarify the impact of pretransplant AZA after the second allo-HSCT. Patients in the AZA group (n = 21) had significantly higher 2-year disease-free survival (DFS) (32.7% vs 14.5%; p = 0.012) and OS (38.1% vs 17.5%; p = 0.044) than those in the SOC group (n = 146). Our data demonstrate that AZA is an effective and well-tolerated bridging therapy to the second allo-HSCT.

Schizophyllum commune, a basidiomycete fungus, is a quite rare cause of invasive sinusitis for which no standard treatment has yet been established. We report herein a 59-year-old woman who developed S. commune rhinosinusitis after remission induction chemotherapy for her acute myeloid leukemia. No causative microorganisms were identified in the sinus lavage fluid culture, whereas nucleotide sequencing of the internal transcribed spacer region using endoscopic sinus biopsy specimen could confirm the pathogen as S. commune. Liposomal amphotericin B and voriconazole (VRCZ) treatment ameliorated both her clinical symptoms and laboratory findings. The patient was successfully treated with allogeneic stem cell transplantation, under continuous VRCZ administration, without aggravation of S. commune sinusitis. Molecular diagnosis and prompt intervention with suitable antifungal drugs may be crucial to manage this rare infectious complication.

A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABLIns35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABLIns35bp , leading to the initial increase in the proportion of BCR-ABLIns35bp . Thereafter, both native BCR-ABL and BCR-ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL+ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABLIns35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABLIns35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.

Adult T-cell leukemia/lymphoma (ATLL), which is a peripheral T-cell lymphoma related to human T-lymphotropic virus type I (HTLV-1), is known as a poor prognostic disease and its median age of onset is late 60s. Allogeneic hematopoietic stem cell transplantation is considered a treatment modality to contribute prolonging the survival in some population of patients. Although cord blood transplantation (CBT) widely practiced for hematological malignancies, a Japanese registry data suggested that 1 yr and 2 yrs overall survival (OS) after CBT in ATLL patients was only about 30% and 20%, respectively (Kato K, et al. 2014 BBMT). On the other hand, promising results were reported in the patients who were received CBT during their disease was controlled (Fukushima T, et al. 2013 IJH). Since it would be considered that CBT with non-TBI regimens, especially using reduced intensity conditioning (RIC), have a potential of engraftment failure compared to TBI regimen, it is less common conditioning regimen for CBT. Here we report a safety and an efficacy of CBT with non-TBI-RIC regimen using fludarabine (Flu) and melphalan (Mel) in 34 ATLL patients. We analyzed days from the beginning of systemic chemotherapy to transplantation, engraftment of neutrophil (EN), overall survival (OS), incidence of GVHD, non-relapse mortality (NRM) and disease-mortality (DRM), respectively. OS was defined as survival days from transplantation. OS were analyzed with logrank test. Cumulative incidence of EN and GVHD was considered with early death and NRM was considered with DRM as a competing risk. Incidence of GVHD, EN, NRM, and DRM was analyzed with Gray's method. Statistical significance defined P<0.05. Statistical analysis was carried out using the EZR. Thirty-four patients (18 male, 16 female) were consecutively undergone CBT with non-TBI-RIC regimen using Flu 125 mg/m2 and Mel 140 mg/m2 between January, 2014 and August, 2018 at our institute where is located in HTLV-1-endemic area. Twenty-eight patients used tacrolimus 0.02 mg /kg/day (TAC) and methotrexate (MTX) 5 mg/m2 / day at day 1, 3, 6 after transplantation, 5 patients TAC and mycophenolate mofetil (MMF) 750-2000 mg/day and one patient TAC alone as a GVHD prophylaxis. Median age at CBT was 61 years (44-70) and 30 patients were diagnosed as acute type ATLL whereas 4 lymphoma type. Sixteen patients were status in CR and 18 non-CR at CBT. Median duration of observation was 839.5 days (370-1890) and median time to CBT from the beginning of systemic chemotherapy was 113 days (61-416). Cumulative incidence of EN was 91.2 % and median time to EN was 20 days (14-68). OS at 2 years after transplantation (2 yr OS) was 43.9 %. 2 yr OS in CR patients was 68.2 % whereas 22.2 % in non-CR. There is no statistical significance about OS in age, gender, and incidence of GVHD. Cumulative incidence of NRM at day 100 and DRM at 1 year after CBT was 26.5 % and 26.5 %, respectively. CBT with non-TBI-RIC regimen using Flu/Mel was safe based on the result of feasible incidence of EN and NRM after CBT. Since 43.9 % of 2 yr OS was relatively high rate compared to previous report of Japanese registry data, CBT with non-TBI-RIC regimen using Flu/Mel can be a promising treatment strategy for ATLL. Figure Disclosures Nakano: Novartis: Honoraria.

The reported incidence of engraftment syndrome (ES) varies widely due to differences in the diagnostic criteria used [1–3] and the presence of underlying diseases. In most cases, the symptoms of ES...

Rationale: Metastatic littoral cell angioma (LCA) is extremely rare. No standard therapeutic strategy has been established, and the impact of chemotherapy has not yet been evaluated. Patient concerns: A 61-year-old woman was admitted because of bicytopenia. She had a splenectomy for LCA of the spleen 10 years earlier. Bone marrow aspiration was normal, and a computed tomography (CT) scan showed hepatomegaly with multiple liver tumors. Diagnoses: Liver biopsy samples showed macrophage-like cell infiltration in the hepatic sinusoids. Metastatic LCA was diagnosed based on immunohistochemistry, imaging tests, and the clinical course. Interventions: Immunosuppressive agents, such as prednisolone and cyclosporine, were ineffective. Next, cytotoxic agents, such as etoposide, paclitaxel, and vincristine, were administered. Outcomes: Cytotoxic agents showed a prominent effect against LCA. CT showed improvement of the hepatomegaly, and fluorodeoxyglucose (FDG) uptake decreased markedly at a follow-up FDG-positron emission tomography (PET) scan. Lessons: Chemotherapeutic treatment based on hemophagocytic syndrome or angiosarcoma might have anti-tumor activity against metastatic LCA. Analysis of the molecular characteristics of this tumor is needed to develop better treatment options.

Treatment with tyrosine kinase inhibitors (TKI) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional PCR monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABL(Ins35bp)) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABL(Ins35bp) was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABL(Ins35bp) became undetectable in 3 patients who attained complete molecular response (CMR), whereas in the remaining all 34 patients, BCR-ABL(Ins35bp) was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR-ABL(Ins35bp) was persisted, although BCR-ABL(Ins35bp) does not definitively mark TKI resistance. Therefore, quantification of BCR-ABL(Ins35bp) is useful for evaluating functional MRD and determining the effectiveness of TKI with accuracy.