Publications by authors named "Hisayuki Yokoyama"

60 Publications

Dasatinib-based Two-step Induction for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood Adv 2021 Sep 13. Epub 2021 Sep 13.

Kanazawa University, Kanazawa, Japan.

The standard treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, approximately 40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities and relapse before HSCT, and older age. We evaluated dasatinib-based two-step induction with the primary endpoint of 3-year event-free survival (EFS) in this study. The first induction (IND1) was dasatinib plus prednisolone to achieve CR and the second (IND2) was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD)-negativity. Patients who achieved CR and had an appropriate donor were recommended to undergo HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate. Prophylactic dasatinib after HSCT was assigned to patients with positive pre-transplant MRD. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD-negativity after IND2. Non-relapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight (74.4%) patients underwent HSCT in CR1 and 44 (75.9%) were negative with pre-transplant MRD. At a median follow-up of 4.0 years, the 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based two-step induction was demonstrated to improve the 3-year EFS. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004607DOI Listing
September 2021

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

Int J Clin Oncol 2021 Aug 7. Epub 2021 Aug 7.

NHO Nagoya Medical Center, Nagoya, Japan.

Background: Until recently, no effective targeted therapies for FLT3-mutated (FLT3 relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3 R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001).

Methods: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC.

Results: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%).

Conclusion: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-021-02006-7DOI Listing
August 2021

Salvage Cord Blood Transplantation for Sustained Remission of Acute Megakaryoblastic Leukemia That Relapsed Early after Myeloablative Transplantation.

Intern Med 2021 Sep 5;60(18):3015-3019. Epub 2021 Apr 5.

Department of Hematology, Tohoku University Hospital, Japan.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia accompanied by an aggressive clinical course and dismal prognosis. We herein report a case of AMKL preceded by mediastinal germ cell tumor that relapsed early after allogeneic hematopoietic stem cell transplantation with myeloablative conditioning but was successfully treated using salvage cord blood transplantation (CBT) with reduced-intensity conditioning. Although several serious complications developed, sustained remission with a favorable general condition was ultimately achieved. Although an optimal therapeutic strategy remains to be established, the graft-versus-leukemia effect of CBT may be promising, even for the treatment of refractory AMKL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6796-20DOI Listing
September 2021

Second direct-acting antiviral therapy for hepatitis C virus infection after umbilical cord blood transplantation: A case report.

J Infect Chemother 2021 Aug 12;27(8):1230-1233. Epub 2021 Feb 12.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Hepatitis C virus (HCV) infection has an adverse impact on outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). It is recommended that HSCT candidates infected with HCV receive the treatment prior to transplantation. Although the recent approval of direct-acting antivirals (DAAs) has led to great advances in the treatment of HCV infection, little information is available on the efficacy and safety of DAA therapy in patients receiving allogeneic HSCT. Herein, we report the clinical course of an umbilical cord blood (UCB) recipient treated with DAAs for HCV infection. The patient achieved HCV RNA negativity with glecaprevir and pibrentasvir after consolidation therapy for acute myeloid leukemia (AML), and underwent transplantation before confirming sustained virological response (SVR) at 12 weeks. The HCV viral load became detectable on day +28 after transplantation and second HCV treatment with sofosbuvir, velpatasvir, and ribavirin was required. It is important to confirm SVR prior to transplantation, but it is often difficult. If early transplantation is required, close monitoring of HCV RNA after transplantation is needed. Further investigation is required to clarify the optimal management of HCV infection for allogeneic HSCT recipients in the DAA era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jiac.2021.02.002DOI Listing
August 2021

Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation.

Bone Marrow Transplant 2021 06 8;56(6):1352-1363. Epub 2021 Jan 8.

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01203-8DOI Listing
June 2021

Primary adrenal extranodal NK/T-cell lymphoma: A case report and literature review.

Leuk Res Rep 2020 28;14:100223. Epub 2020 Sep 28.

Department of Hematology, Tohoku University Hospital, Sendai, Japan.

A 37-year-old man was admitted to our department following the detection of bulky tumors in his bilateral adrenal glands. A biopsy resulted in the diagnosis of extranodal NK/T cell lymphoma, nasal type (ENKL). After debulking by chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHCT) was performed. Relapses in the liver and adrenal glands were identified 2 months post alloHCT, for which temporary administration of l-asparaginase resulted in complete metabolic response. However, multiple relapses in the central nervous system and lethal lymphomatous meningitis successively developed. Primary adrenal ENKL could tend to present as bulky lesion and follow an aggressive clinical course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lrr.2020.100223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527573PMC
September 2020

Low-dose lenalidomide and dexamethasone therapy after melphalan-prednisolone induction in elderly patients with newly diagnosed multiple myeloma.

Ann Hematol 2020 Oct 31;99(10):2351-2356. Epub 2020 Aug 31.

Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-857, Japan.

Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2-9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42-83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21-33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04240-xDOI Listing
October 2020

A novel case of γδ T cell leukemia with recurrent genetic abnormalities accompanied by agranulocytosis.

Ann Hematol 2021 Oct 31;100(10):2665-2668. Epub 2020 Aug 31.

Department of Hematology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04241-wDOI Listing
October 2021

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Cancer Sci 2020 Sep 17;111(9):3367-3378. Epub 2020 Jul 17.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469806PMC
September 2020

Sustained remission of giant pancreatic plasmacytoma with daratumumab.

Ann Hematol 2021 Oct 18;100(10):2633-2634. Epub 2020 Jun 18.

Department of Hematology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04145-9DOI Listing
October 2021

Favorable Effect of Cytomegalovirus Reactivation on Outcomes in Cord Blood Transplant and Its Differences Among Disease Risk or Type.

Biol Blood Marrow Transplant 2020 07 18;26(7):1363-1370. Epub 2020 Apr 18.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

The effects of cytomegalovirus (CMV) reactivation on cord blood transplant (CBT) are unclear. We assessed the effect of CMV reactivation in adult single-unit CBT without in vivo T cell depletion. Of 3147 eligible cases, 2052 were acute myeloid leukemia (AML), 643 acute lymphoblastic leukemia (ALL), and 452 myelodysplastic syndrome (MDS). CMV reactivation up to 100 days after CBT was associated with better overall survival (OS) compared with no reactivation cases (57.3% versus 52.6% at 3 years after CBT), whereas nonrelapse mortality (NRM) was increased in ALL (16.2% versus 8.9%) and standard disease risk (17.1% versus 10.6%, P = .014) by CMV reactivation. On multivariate analysis, CMV reactivation had favorable effects on relapse in MDS (hazard ratio [HR], .55; P = .044) and high disease risk (HR, .77; P = .047). In NRM, only standard-risk cases showed adverse effects of CMV reactivation (HR, 1.56; P = .026). OS was significantly improved with CMV reactivation in a subgroup of patients with AML (HR, .84; P = .044), MDS (HR, .68; P = .048), and high disease risk (HR, .81; P = .013). This favorable effect of CMV reactivation on OS in AML and high disease risk cases was maintained even after considering the effect of grades II to IV acute graft-versus-host disease. Thus, CMV reactivation might have beneficial or adverse effects on relapse, NRM, and OS, depending on the disease type or disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.04.002DOI Listing
July 2020

Optimal treatment strategy with nilotinib for patients with newly diagnosed chronic-phase chronic myeloid leukemia based on early achievement of deep molecular response (MR ): The phase 2, multicenter N-Road study.

Cancer Med 2020 06 6;9(11):3742-3751. Epub 2020 Apr 6.

Division of Hematology and Oncology, Japanese Red Cross Society, Narita Red Cross Hospital, Narita, Japan.

For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR achievement. The primary study endpoint was achievement of MR by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR . The MR rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286457PMC
June 2020

Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome.

Bone Marrow Transplant 2020 07 16;55(7):1399-1409. Epub 2020 Mar 16.

Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0859-8DOI Listing
July 2020

Successful Treatment of Life-threatening Bleeding Caused by Acquired Factor X Deficiency Associated with Respiratory Infection.

Intern Med 2020 May 5;59(10):1303-1308. Epub 2020 Feb 5.

Department of Hematology and Rheumatology, Tohoku University Hospital, Japan.

Acquired factor X deficiency (AFXD) is a very rare coagulation disorder. A 40-year-old man with no comorbidities suffering from a fever, malaise, and severe hemorrhagic symptoms, including massive hematuria, was emergently admitted. His platelet count was normal, but his prothrombin time and activated partial thromboplastin time were markedly prolonged, which was thought to be due to autoantibody against a coagulation factor in the common pathway. Despite severe massive hematuria resulting in transient renal failure, he was successfully treated with urgent immunosuppressive therapy. Computed tomography revealed bronchopneumonia, which improved with antibiotic administration. AFXD without evidence of amyloidosis was subsequently diagnosed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.4142-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303456PMC
May 2020

Successful treatment of methotrexate-associated classical Hodgkin lymphoma with brentuximab vedotin-combined chemotherapy: a case series.

Int J Hematol 2020 May 18;111(5):667-672. Epub 2020 Jan 18.

Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.

Methotrexate (MTX)-associated classical Hodgkin lymphoma (CHL) is unlikely to regress following discontinuation of MTX, and its treatment usually requires chemotherapy. Standard chemotherapy for CHL is the ABVD regimen, which contains pneumotoxic bleomycin. This can be problematic in MTX-CHL patients suffering from an autoimmune disease (AID), such as rheumatoid arthritis (RA), as they frequently have pulmonary complications. However, brentuximab vedotin (BV)-containing chemotherapy without bleomycin (A + AVD regimen) was recently reported to show favorable efficacy for CHL, and could therefore be beneficial in MTX-CHL. We treated three cases of MTX-CHL using the A + AVD regimen. All were female and had received MTX for more than 15 years. Underlying AIDs in these patients were RA in two patients, and overlap syndrome with systemic lupus erythematosus and dermatomyositis in one patient. The A + AVD regimen resulted in a complete response in all patients. Peripheral neuropathy developed in two patients, necessitating reduction of the BV dose. All three patients experienced hematological toxicity necessitating dose reduction; however, no severe adverse effects, including infection or pulmonary complication, were documented. RA was well-controlled without additional immunosuppressants. The A + AVD regimen is a promising chemotherapy for MTX-CHL with favorable efficacy and tolerable toxicity profiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02822-zDOI Listing
May 2020

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11.

Blood Adv 2020 01;4(1):66-75

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960455PMC
January 2020

High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura.

Int J Hematol 2020 Mar 2;111(3):388-395. Epub 2020 Jan 2.

Department of Hematology, National Hospital Organization Hiroshimanishi Medical Center, Otake, Japan.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18-80 years with platelet counts of < 20 × 10/l, or < 50 × 10/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7-77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02808-6DOI Listing
March 2020

Clinical course of autologous recovery with chromosomal abnormalities after allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2020 06 9;55(6):1023-1028. Epub 2019 Dec 9.

Department of Hematology, Oita University Hospital, Oita, Japan.

After primary graft failure following allogeneic hematopoietic stem cell transplantation, some patients experience autologous recovery of hematopoiesis without salvage transplantation. However, clinicians occasionally encounter unusual chromosomal abnormalities in recipient cells, not related to the original underlying diseases. In this study, through a survey based on data from the nationwide registry at the Japan Society for Hematopoietic Cell Transplantation, 42 patients were identified as having chromosomal abnormalities after autologous recovery. The complex chromosomal abnormalities were not consistent and randomly changed at each testing. Of the 42 patients, seven experienced disappearance of chromosome abnormalities without any treatment, and the probability was estimated as 17.4% (95% CI: 7.5-30.7%) at the 5-year observation. On the other hand, two patients developed hematologic malignancy at 1447 and 6202 days. Ten patients were alive without relapse or development of hematologic disorders, even though chromosomal abnormalities were continuously detected at a median of 3192 (103-4710) days. In conclusion, chromosomal abnormalities can persist for more than 10 years, and may eventually contribute to hematologic malignancy development in a small fraction of cases. Although oncogenic effects of the chromosomal abnormalities are still unclear, these findings may provide supporting evidence for late occurrence of secondary malignant neoplasms after cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-019-0765-0DOI Listing
June 2020

Impact of HLA Allele Mismatch at HLA-A, -B, -C, and -DRB1 in Single Cord Blood Transplantation.

Biol Blood Marrow Transplant 2020 03 9;26(3):519-528. Epub 2019 Nov 9.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The impact of allele-level HLA mismatch on outcomes of cord blood transplantation has not been well established. We retrospectively analyzed the effects of HLA allele matching at HLA-A, -B, -C, and -DRB1 in cord blood transplantation for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome. In multivariate analysis, overall survival (OS) significantly deteriorated in the 4-allele or higher mismatch in pediatric cases (hazard ratio, 1.8 for 4/8 match [reference, 6/8 match] and 2.85 for 3-1/8 match) and the 5-allele or higher mismatch in adult cases (hazard ratio, 1.23 for 3-0/8 match). Incidence of grade Ⅲ to Ⅳ acute graft-versus-host disease was low in the 8/8 match and 1-allele mismatch in pediatric cases (hazard ratio, 0.19 for 8/8 match and 0.41 for 7/8 match) and the 8/8 match in adult cases (hazard ratio, 0.41 for 8/8 match). On the other hand, a higher incidence of relapse was noted in the 8/8 match in adults (hazard ratio, 1.53). The incidence of neutrophil and platelet engraftment decreased in the 3-allele or higher mismatch in adults. In subgroup analysis of graft-versus-host disease prophylaxis in adult cases, a deteriorating effect on OS of HLA 5-allele or higher mismatch was more significant in cases with calcineurin inhibitor with methotrexate than with mycophenolate mofetil. These results suggest that allele-level HLA mismatch affects the outcomes of cord blood transplantation. Information on HLA allele matching at HLA-A, -B, -C, and -DRB1 may be useful for cord blood unit selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.11.001DOI Listing
March 2020

Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML.

N Engl J Med 2019 10;381(18):1728-1740

From the Abramson Cancer Center, University of Pennsylvania (A.E.P.), and Thomas Jefferson University (M.K.) - both in Philadelphia; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Meldola (G.M.), L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna (S.P.), Ospedali Riuniti Villa Sofia-Cervello, Palermo (F.F.), and IRCCS San Raffaele Scientific Institute, Milan (F.C.) - all in Italy; University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Universitätsklinikum Giessen und Marburg, Marburg, Germany (A.N.); Memorial Sloan Kettering Cancer Center, New York (E. Berman); Hospital Universitari i Politècnic La Fe, Valencia, and Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto Carlos III, Madrid - both in Spain (P.M.); University of Maryland Greenebaum Comprehensive Cancer Center (M.R.B.) and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (M.J.L.) - both in Baltimore; University of Chicago, Chicago (R.A.L.), and Astellas Pharma, Northbrook (C.L., N. Hasabou, X.L., E. Bahceci) - both in Illinois; University of Minnesota, Minneapolis (C.U.); University of Alabama at Birmingham, Birmingham (H.P.E., A.D.S.); Hollings Cancer Center, Medical University of South Carolina, Charleston (R.S.); University of California, San Francisco, San Francisco (R.O.); National Taiwan University, Taipei City, Taiwan (W.-C.C.); Yale University School of Medicine, New Haven, CT (N.P.); Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France (C.R.); Sendai Medical Center, National Hospital Organization, Sendai (H.Y.), and University of Fukui, Fukui (N. Hosono) - both in Japan; Seoul National University (S.-S.Y.) and Asan Medical Center, University of Ulsan College of Medicine (J.-H.L.) - both in Seoul, South Korea; Wake Forest Baptist Medical Center, Winston-Salem, NC (T.P.); and Massachusetts General Hospital, Harvard Medical School, Boston (A.T.F.).

Background: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene () infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory -mutated AML.

Methods: In a phase 3 trial, we randomly assigned adults with relapsed or refractory -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.

Results: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

Conclusions: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1902688DOI Listing
October 2019

Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome.

Biol Blood Marrow Transplant 2020 01 20;26(1):139-144. Epub 2019 Sep 20.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P < .001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.09.021DOI Listing
January 2020

Flow Cytometry-Based Photodynamic Diagnosis with 5-Aminolevulinic Acid for the Detection of Minimal Residual Disease in Multiple Myeloma.

Tohoku J Exp Med 2019 09;249(1):19-28

Division of Blood Transfusion and Cell Processing, Tohoku University Hospital.

Multiple myeloma is the cancer of plasma cells. Along with the development of new and effective therapies, improved outcomes in patients with multiple myeloma have increased the interest in minimal residual disease (MRD) monitoring. However, the considerable heterogeneity of immunophenotypic and molecular markers of myeloma cells has limited its clinical application. 5-Aminolevulinic acid (ALA) is a natural compound in the heme biosynthesis pathway. Following ALA treatment, tumor cells preferentially accumulate porphyrins because of the differential activities of aerobic glycolysis, known as Warburg effect. Among various porphyrins, protoporphyrine IX is a strong photosensitizer; thus, ALA-based photodynamic diagnosis has been widely used in various solid cancers. Here, the feasibility of flow cytometry-based photodynamic detection of MRD was tested in multiple myeloma. Among various human cell lines of hematological malignancies, including K562 erythroleukemia, Jurkat T-cell leukemia, Nalm6 pre-B cell leukemia, KG1a myeloid leukemia, and U937 monocytic leukemia, human myeloma cell line, KMS18, and OPM2 abundantly expressed ALA transporters, such as SLC36A1 and SLC15A2, and 1 mM ALA treatment for 24 h resulted in nearly 100% porphyrin fluorescence expression, which could be competitively inhibited by ALA transport with gamma-aminobutyric acid. Titration studies revealed that the lowest ALA concentration required to achieve nearly 100% porphyrin fluorescence in KMS18 cells was 0.25 mM, with an incubation period of 2 h. Under these conditions, incubation of primary peripheral blood mononuclear cells resulted in only 1.8 % of the cells exhibiting porphyrin fluorescence. Therefore, flow cytometry-based photodynamic diagnosis is a promising approach for detecting MRD in multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1620/tjem.249.19DOI Listing
September 2019

Effects of HLA mismatch on cytomegalovirus reactivation in cord blood transplantation.

Bone Marrow Transplant 2019 07 6;54(7):1004-1012. Epub 2018 Nov 6.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

Although human leukocyte antigen (HLA) mismatch is often thought to be associated with a high incidence of cytomegalovirus (CMV) reactivation, it is not clear whether this process is mediated by HLA mismatch or other factors, such as acute graft-versus-host disease (aGVHD). Here we focused on cord blood transplantation (CBT) and examined the effects of HLA mismatch on the incidence of CMV reactivation while minimizing the effects of aGVHD. In a multivariate analysis considering aGVHD as a time-dependent covariate, a significant effect on the incidence of CMV reactivation was noted for HLA disparity (hazard ratio [HR]: 0.54 for 8/8 match compared with 3-allele mismatch) and development of aGVHD (HR: 1.26). Next, in an analysis excluding cases that developed aGVHD, the incidences of CMV reactivation for 8/8 match and 1-allele mismatch were low compared with those for other mismatches. These findings were supported by the multivariate analysis (HR: 0.49 for 8/8 match and 0.64 for 1-allele mismatch compared with 3-allele mismatch). Together, these results suggested that HLA mismatch was involved in CMV reactivation and was associated with high morbidity of opportunistic infection after CBT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0369-0DOI Listing
July 2019

Rapid diagnosis of mixed phenotype acute leukemia after identifying a blood histogram abnormality.

Pract Lab Med 2018 Nov 12;12:e00101. Epub 2018 May 12.

Department of Clinical Laboratory, Tohoku Medical and Pharmaceutical University Hospital, Japan.

A 38-year-old woman was suffering from back, right arm, and ankle joint pain, and visited our emergency department. Upon admission, the white blood cell (WBC) count was high (11,700/µL), and low numbers of red blood cells (2.21 × 10/µL) and platelets (PLTs) (42,000/µL) were observed. A PLT histogram showed an abnormally shaped peak at around 20-30 fL, suggesting the presence of giant PLTs or PLT aggregation. The WBC histogram showed abnormal elevation at 35 fL and around 100 fL, suggesting abnormal cells including nucleated red blood cells. A peripheral blood smear was prepared, and morphology was examined. As a result, blasts (4%) including many orthochromatic erythroblasts (48/100 WBCs) were observed. Acute leukemia was suspected, and the patient was transferred the next day to a hospital with a hematology department. Bone marrow aspiration revealed that 99% of cells were blasts positive for B lymphoid lineage markers and myeloperoxidase. The patient was diagnosed with mixed phenotype lineage acute leukemia, treated immediately, and achieved remission. Thus, careful observation of histogram abnormalities of an automatic blood cell analyzer is important for rapid diagnosis of acute leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plabm.2018.e00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041423PMC
November 2018

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

Clin Lymphoma Myeloma Leuk 2018 05 15;18(5):353-360.e1. Epub 2018 Mar 15.

Department of Hematology, Ogaki Municipal Hospital, Gifu, Japan.

Introduction: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective.

Patients And Methods: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed.

Results: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ T-cell and CD4 regulatory T-cell (CD25CD127) counts before discontinuation correlated significantly with successful therapy discontinuation.

Conclusion: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2018.03.004DOI Listing
May 2018

Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum.

Int J Hematol 2017 May 7;105(5):606-613. Epub 2017 Feb 7.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

It has been suggested that use of recombinant soluble thrombomodulin (rTM) is superior to conventional drugs in treatment of disseminated intravascular coagulation (DIC) complicating acute leukemia. However, its safety and efficacy have not been fully examined in prospective studies. Here, we performed a multicenter prospective study to examine outcomes of rTM treatment for DIC in patients with acute leukemia. Of 33 patients registered in this study, 13 had acute myeloid leukemia (AML), three had acute lymphoblastic leukemia (ALL), and 17 had acute promyelocytic leukemia (APL). The cumulative rates of DIC resolution at day 7 and day 35 were 56 and 81% in AML/ALL and 53 and 77% in APL, respectively. The median time from the initiation of rTM to DIC resolution was 4 days in AML/ALL and 6 days in APL patients. Adverse events related to hemorrhage occurred in two AML/ALL patients (13%) and three APL patients (18%). Of these, one AML/ALL patient died with intracranial hemorrhage, and two APL patients died with intracranial hemorrhage and pulmonary hemorrhage. These results suggest that rTM may improve the survival of acute leukemia patients with DIC by inhibiting early death related to hemorrhagic events, as reported previously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-017-2190-8DOI Listing
May 2017

Impact of Human Leukocyte Antigen Allele Mismatch in Unrelated Bone Marrow Transplantation with Reduced-Intensity Conditioning Regimen.

Biol Blood Marrow Transplant 2017 Feb 11;23(2):300-309. Epub 2016 Nov 11.

Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan; Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.

The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8-allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR],  1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2016.11.009DOI Listing
February 2017
-->