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The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.

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BACKGROUND AND OBJECTIVES: Intensity-modulated radiation therapy (IMRT) helps achieve good radiation dose conformity and precise dose evaluation. We conducted a single-centre prospective study to assess the safety and feasibility of total body irradiation with IMRT (IMRT-TBI) using helical tomotherapy in allogeneic haematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: Thirty-nine adult patients with haematological malignancy (acute lymphoblastic leukaemia [n = 21], chronic myeloid leukaemia [n = 6], mixed phenotype acute leukaemia [n = 5], acute myeloid leukaemia [n = 4], and malignant lymphoma [n = 3]) who received 12 Gy IMRT-TBI were enrolled with a median follow-up of 934.5 (range, 617-1254) d. At the time of transplantation, 33 patients (85%) achieved complete remission. The conditioning regimen used IMRT-TBI (12 Gy in 6 fractions twice daily, for 3 d) and cyclophosphamide (60 mg/kg/d, for 2 d), seven patients were combined with cytarabine, and five with etoposide. We set dose constraints for the lungs, kidneys and lens as the organs at risk. RESULTS: The mean doses for the lungs and kidneys were 7.50 and 9.11 Gy, respectively. The mean maximum dose for the lens (right/left) was 5.75/5.87 Gy. The 2-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 69, 64, 18 and 18%, respectively. Thirty-six patients developed early adverse events (AEs) (including four patients with Grade 3/4 toxicities), most of which were reversible oral mucositis and may partially have been related to IMRT-TBI. However, the incidence of toxicity was comparable to conventional TBI-based conditioning transplantation. None of the patients developed primary graft failure, or Grade III-IV acute graft-versus-host disease (GVHD). In late complications, chronic kidney disease was observed in six patients, a lower incidence compared to conventional TBI-based conditioning transplantation. No radiation pneumonitis or cataracts were observed in any of the patients. CONCLUSIONS: IMRT-TBI is safe and feasible for haematological malignancies with acceptable clinical outcomes.KEY MESSAGESIMRT-TBI-helical tomotherapy aids in accurate dose calculation and conformity.It could be used without any considerable increase in the rate of TBI-related AEs.Allo-HSCT with IMRT-TBI may be an alternative to conventional TBI for clinical use.

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Sarcopenia is a prognostic factor for cancer. Because creatinine is formed from creatine phosphate in muscle tissue, urinary creatinine excretion (UCE) serves as an index of muscle volume. However, as of yet, there are no studies assessing the clinical impact of UCE or weight- adjusted urinary creatinine excretion (WA-UCE) on allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We analyzed the association between pre-transplant WA-UCE and transplant outcomes among 164 adult patients with acute myeloid leukemia in complete remission who underwent their first allo-HSCT at our center. The patients were classified into a high (n = 106) and a low WA-UCE group (n = 58) for predicting overall survival (OS) based on the receiver operating characteristics curve. On multivariate analysis, low WA-UCE was associated with poor OS, progression-free survival and a high incidence of non-relapse mortality. WA-UCE has the potential to be an objective biomarker for predicting transplant outcomes, especially the incidence of infection-related death.

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A 60-year-old woman with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent unrelated bone marrow transplantation from a human leukocyte antigen (HLA) 8/8 allele-matched male donor. Neutrophil engraftment was achieved on day 29. Fluorescence in situ hybridization of sex chromosomes demonstrated complete donor chimerism. The red blood cell and platelet transfusion dependence continued, and the neutrophil count decreased gradually. Despite prolonged administration of broad-spectrum antibiotics for febrile neutropenia, blood cultures on days 46 and 58 returned positive for Stenotrophomonas maltophilia (SM). Contrast-enhanced computed tomography revealed multiple nodules of septic emboli in the lungs and kidneys, suggesting a disseminated SM infection. Antibiotic therapy was conducted based on antimicrobial susceptibility testing. However, the blood cell count failed to normalize and a secondary graft failure was diagnosed. A HLA-haploidentical peripheral-blood stem-cell transplantation from the patient's son was performed on day 134 after the initial transplantation. Neutrophil engraftment was achieved on day 11. Red blood cells and platelets were also engrafted. After the resolution of the SM bacteremia, the patient was discharged on day 63. The prognosis of the SM bacteremia with neutropenia is poor. Antibiotic treatment based on antimicrobial susceptibility testing and a second transplant from an HLA-haploidentical donor likely contributed to the successful outcome in this patient.

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A 22-year-old man with a history of mediastinal germ cell tumor, which was diagnosed at age 20 and remained disease-free after chemotherapy, was diagnosed with acute myeloid leukemia (AML) M2 in January 2020. Karyotype analysis of bone marrow (BM) specimen at diagnosis detected 47,XXY, inv (16) in all cells. Following induction treatment, he achieved complete remission with a remarkable decrease in the minimal residual disease marker. Although considered related to therapy, the AML had a prognostically favorable karyotype, and the initial treatment response was very good. He had no human leukocyte antigen-matched sibling donor candidate. Thus, allogeneic hematopoietic stem cell transplantation was not scheduled at the first complete remission. After three cycles of consolidation therapy, he remained disease-free for over one year. Karyotype analysis of BM during remission revealed that all analyzed cells harbored 47,XXY, and Klinefelter syndrome (KS) was diagnosed. Although the patient experienced an adjustment disorder on KS diagnosis, he had overcome the difficulty with the assistance of psycho-oncologists, clinical psychologists, and genetic counselors. Herein, we report this rare case of KS that manifested after AML diagnosis following mediastinal germ cell tumor treatment.

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Variants of the t (8;21) (q22;q22) involving chromosome 8, 21, and other chromosomes account for about 3% of all t (8;21) (q22;q22) in patients with acute myeloid leukemia (AML). However, the prognosis of AML with variant t (8;21) remains unknown due to the scarcity of reported cases. Herein we report a case of AML with t (6;21;8) (p23;q22;q22). Fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. This is the first report on a variant of t (8;21) involving the breakpoint 6p23. After induction chemotherapy, our patient achieved complete remission and has been stable for four years.

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Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

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Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27-72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at high risk of developing invasive pneumococcal disease (IPD) with substantial morbidity and mortality. Pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) are the primary prevention strategy. The difference between the Japanese and international guidelines is limited except when to start PCV13. However, Japanese data regarding the incidence of IPD after allo-HSCT that include vaccination status are limited. Therefore, we aimed to study the clinical characteristics of patients with IPD following allo-HSCT, focusing on unvaccinated patients. We retrospectively reviewed allo-HSCT recipients between April 2005 and December 2018 at Komagome Hospital. Among 1,091 recipients, 11 (1008/100,000 recipients) developed 13 episodes of IPD. The median period from the first allo-HSCT to the first IPD episode was 686 days (10-3040 days). Ten patients developed IPD before vaccination, and seven of these unvaccinated patients with late-onset IPD were ineligible for vaccination based on domestic guidelines. Although appropriate treatments resulted in a good short-term prognosis, most episodes of IPD developed in unvaccinated allo-HSCT recipients. Our data support the promotion of better adherence to the current guidelines and the importance of pneumococcal vaccination even years after allo-HSCT to protect against late-onset IPD.

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Cytomegalovirus (CMV) reactivation in cord blood transplantation (CBT) may result in the proliferation and maturation of natural killer (NK) cells. Similarly, a mismatch of the killer cell immunoglobulin-like receptor (KIR)-ligand induces NK cell activation. Therefore, if CMV reactivation occurs in the presence of KIR-ligand mismatch, it might improve CBT outcomes. We assessed the difference in the effect of CMV reactivation in the presence of KIR-ligand mismatch on disease relapse in the graft-versus-host direction. A total of 2840 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were analyzed. Among those with a HLA-Bw4/A3/A11 (KIR3DL-ligand) mismatch, CMV reactivation up to 100 days following CBT had a favorable impact on relapse (18.9% vs. 32.9%, P = 0.0149). However, this effect was not observed in cases without the KIR3DL-ligand mismatch or in those with or without a HLA-C1/C2 (KIR2DL-ligand) mismatch. The multivariate analysis suggested that CMV reactivation had a favorable effect on relapse only in cases with a KIR3DL-ligand mismatch (hazard ratio 0.54, P = 0.032). Moreover, the interaction effect between CMV reactivation and KIR3DL-ligand mismatch on relapse was significant (P = 0.039). Thus, our study reveals the association between KIR-ligand mismatches and CMV reactivation, which will enhance CBT outcomes.

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Although measurable residual disease (MRD) at the time of allogeneic hematopoietic cell transplantation (allo-HCT) has been reported to be an important prognostic factor for Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) during first complete remission (CR1), the prognostic impact of MRD is unclear during second CR (CR2). To clarify the impact of MRD for both CR1 and CR2, we analyzed data from a registry database including 1625 adult patients with Ph+ ALL who underwent first allo-HCT during either CR1 or CR2 between 2002 and 2017. Adjusted overall and leukemia-free survival rates at 4 years were 71% and 64%, respectively, for patients undergoing allo-HCT during CR1 with MRD-, 55% and 43% during CR1 with MRD+, 51% and 49% during CR2 with MRD-, and 38% and 29% during CR2 with MRD+. Although survival rates were significantly better among patients with CR1 MRD- than among patients with CR2 MRD-, no significant difference was observed in survival rate between patients with CR1 MRD+ and CR2 MRD-. Relapse rates after 4 years were 16% in patients with CR1 MRD-, 29% in CR1 MRD+, 21% in patients with CR2 MRD-, and 46% in patients with CR2 MRD+. No significant difference was identified in relapse rate between patients with CR1 MRD- and CR2 MRD-. CR2 MRD- was not a significant risk factor for relapse in multivariate analysis (hazard ratio, 1.26; 95% confidence interval, 0.69-2.29; P = .45 vs CR1 MRD-). MRD at time of allo-HCT was an important risk factor in patients with Ph+ ALL during both CR1 and CR2.

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Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation. Although salvage cord blood transplantation (CBT) is a curative therapy for GF, the optimal immunosuppression after salvage CBT remains unknown. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage CBT using immunosuppressants, including calcineurin (CNI) alone (n = 177); CNI plus methotrexate (CNI+MTX, n = 150); and CNI plus mycophenolate mofetil (CNI+MMF, n = 161). The CNI+MMF group, in comparison with the CNI+MTX and CNI alone groups, demonstrated better neutrophil recovery at 30 days (62.7 vs. 42.7 vs. 53.1%, P < 0.001); better overall survival (OS) at 12 months (48.4 vs. 33.5 vs. 28.3%, P < 0.001); and lower non-relapse mortality (NRM) at 12 months (35.2 vs. 53.9 vs. 56.5%, P < 0.001). On multivariate analysis, CNI+MMF had the best neutrophil recovery (hazard ratio (HR), 1.71; P < 0.001) and OS (HR, 0.64; P = 0.002) and the lowest NRM (HR, 0.53; P < 0.001). Hemorrhage was relatively less frequent in the CNI+MMF group. CNI+MMF can be a promising immunosuppressant regimen after salvage CBT for GF, with better engraftment and survival outcomes, compared with CNI alone and CNI+MTX.

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Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8+/CMV pp65 tetramer+ cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson's index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2-4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.

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Total body irradiation using intensity-modulated radiation therapy total body irradiation (IMRT-TBI) by helical tomotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) allows for precise evaluation and adjustment of radiation dosage. We conducted a single-center pilot study to evaluate the safety of IMRT-TBI for allo-HSCT recipients. Patients with hematological malignancies in remission who were scheduled for allo-HSCT with TBI-based myeloablative conditioning were eligible. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were engraftment rate, overall survival, relapse rate, non-relapse mortality, and the incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively). Between July 2018 and November 2018, ten patients were recruited with a median observation duration of 571 days after allo-HSCT (range, 496-614). D80% for planning target volume (PTV) in all patients was 12.01 Gy. Average D80% values for lungs, kidneys and lenses (right/left) were 7.50, 9.03 and 4.41/4.03 Gy, respectively. Any early AEs (within 100 days of allo-HSCT) were reported in all patients. Eight patients experienced oral mucositis and gastrointestinal symptoms. One patient experienced Bearman criteria grade 3 regimen-related toxicity (kidney and liver). All cases achieved neutrophil engraftment. There was no grade III-IV aGVHD or late AE. One patient died of sinusoidal obstruction syndrome 67 days after allo-HSCT. The remaining nine patients were alive and disease-free at final follow-up. Thus, IMRT-TBI was well tolerated in terms of early AEs in adult patients who underwent allo-HSCT; this warrants further study with longer observation times to monitor late AEs and efficacy.

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There are few reports on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia (B-ALL) harboring t(1;19)(q23;p13.3). We used nationwide registry data of Japan for 2003-2016 to evaluate transplant outcomes and clarified prognostic factors among adult allo-HSCT recipients with B-ALL harboring t(1;19)(q23;p13.3) (n = 125). Compared with cytogenetically normal (CN) B-ALL patients (n = 1057), their 3-year overall survival (OS) rates were comparable (55.4% for t(1;19) and 54.4% for CN; P = 0.76). Considering only patients in first complete hematological remission (CR1), the 3-year OS rates remained comparable (70.5% for t(1;19) and 67.8% for CN; P = 0.86). For t(1;19) patients in CR1, minimal residual disease (MRD) at transplantation was associated with relatively worse outcomes. The 3-year OS rates were 43.6% for patients with MRD and 77.4% for those without it (P = 0.016). The 3-year relapse rates were 54.5% for patients with MRD and 12.8% for those without it (P < 0.001). Multivariate analyses revealed that MRD at transplantation was a significant risk factor for OS and relapse. In the high-intensity chemotherapy era, t(1;19)(q23;p13.3) did not have a poorer posttransplant prognosis than the normal karyotype. However, even for patients in CR1, MRD at transplantation was associated with comparatively worse OS and higher relapse rates.

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A 70-year-old man was admitted to our hospital due to fever, lymphadenopathy, and leukocytosis. White blood cell count was 22,700/µl with 92% blastoid cells. Bone marrow examination revealed abnormal lymphoid cell expansion. Abnormal cells expressed surface CD5 (dim), CD10, CD19, CD20, CD23 (dim) antigens, and kappa immunoglobulin light chains. Cytogenetic analysis of bone marrow cells at the time of diagnosis showed t (11:14) (q13;q32), t (14;18) (q32;q21), and t (8;14;18) (q24;q32;q21). Fluorescence in situ hybridization analyses of bone marrow identified translocations of IGH/MYC, IGH/BCL2, and IGH/CCND1. The patient was diagnosed with aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocation and was treated with various chemotherapies including R-CHOP, R-ESHAP, DA-EPOCH-R, R-hyper-CVAD, and radiotherapy. However, the lymphoma recurred after every chemotherapy session. Finally, he died after 6 months after first admission. Double-hit lymphoma/triple-hit lymphoma has previously been reported to present with an aggressive clinical course. In the present case, co-existence of IGH/CCND1, IGH/MYC, and IGH/BCL2 is very rare. Further clinical and biological investigations are necessary to establish an optimal treatment strategy.

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The de novo myeloid sarcoma (MS) type of acute promyelocytic leukemia (APL) is rare, and clinical features may differ from extramedullary diseases in advanced APL. Many cases occur as a spinal tumor, and some occur in the absence of bone-marrow diseases or coagulation abnormalities. Fluorescence in situ hybridization analysis of MS tissue is useful for accurate diagnosis, even in preserved tissue.

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A 34-year-old man, working at a park in Tokyo, Japan, was repeatedly bitten by mosquitoes while cutting grass. He was hospitalized with sudden fever, fatigue, and weakness. He was eventually diagnosed with dengue virus infection, detected using reverse transcription polymerase chain reaction for the genome and by the presence of nonstructural protein 1 in his peripheral blood. Symptomatic treatments such as acetaminophen for the fever were not effective. Moreover, peripheral blood examination showed drastically decreased white blood cells and platelets, as well as marked elevations of ferritin and soluble interleukin 2 receptor. Furthermore, bone marrow examination revealed increased macrophages with hemophagocytosis. Dengue infection with hemophagocytic lymphohistiocytosis (HLH) was ultimately diagnosed. Half-dose steroid pulse therapy for three days dramatically reduced his temperature, thereby ameliorating physical symptoms and restoring normal peripheral blood data. He was discharged 12 days after admission. Dengue infection with HLH is rare and this is the first report, to our knowledge, of domestic dengue infection with HLH in Japan. Early steroid therapy may be effective in such cases.

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