Cost-effectiveness of the sequential application of tyrosine kinase inhibitors (TKIs) is an important issue in chronic myelogenous leukemia (CML). Similarly, although overall survival (OS) has tremendously improved, the treatment of multiple myeloma (MM), including 12 new drugs, typically costs more than $100,000 per year. This price should not be judged in isolation but rather evaluated in the context of clinical benefit, which can be assessed by cost-effectiveness analyses such as the total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Physicians change drugs several times to prolong individual patient survival over the course of their therapy, which means there are variations in treatment choices and treatment sequence. To achieve a clinical response by each treatment is very important, and the overall response rate and OS are key pieces of information to assess this. The additional treatment goal is sustained minimal residual disease (MRD) negativity. In Japan, medical costs for MM are mostly covered by public health insurance. Modifications in treatment patterns for CML and MM drugs and medical costs for patients are important issues; how to cure the disease or prolong the therapy-free interval with lower costs is an urgent requirement. Total medical costs have remained stable since 2010, but there are important issues to consider in the use of generic drugs, Phase 2 approval of new drugs, and decreasing costs of other care, particularly for hospitalization that includes treatment costs other than that of CML and MM drugs. We must aim for treatment-free remission and a clinical cure in the future. We can stop treatment with a 2-year sustained molecular response (MR)4.5 in CML and MRD negative (<10-5) in MM with full informed consent and careful watch by the BCR-ABL international scale and next-generation flow.
This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.
Currently, the humanized anti-C5 monoclonal antibody, eculizumab, is widely used for treating paroxysmal nocturnal hemoglobinuria (PNH) due to its effects on suppression of intravascular hemolysis and resulting improvement in quality of life. However, in some cases, this treatment is refractory or is associated with meningococcal meningitis. No region-specific analyses have been published, and currently, information on region specificity and genetic factors is limited. We present here the results of a retrospective study involving eight patients with PNH who were treated with eculizumab in our hospital in Wakayama, Japan. The median age of these patients was 77 (range 23-88) years. Six patients had a complication of aplastic anemia, four patients had a history of thrombosis, and two experienced hemolytic episodes. Before initiating eculizumab treatment, the median serum LDH level was 1,192 IU/l (range 755-1,525 IU/l). Serum LDH levels normalized in five patients within a month of initiating therapy and PNH-related symptoms disappeared. C5 gene mutations were identified in the three patients who did not respond to eculizumab.
Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy caused by the human T-cell lymphotropic virus, type I and it has an extremely poor prognosis. A 66-year-old man with severe hepatic damage, massive pleural effusion and ATL cell infiltration-induced ascites was referred to our department. Reduced-intensity cytotoxic chemotherapy was attempted, but could not continue due to persistent hyperbilirubinemia. Laboratory results also showed elevated lactate dehydrogenase (LDH) and serum albumin levels were profoundly decreased. A humanized monoclonal antibody against chemokine receptor type 4 (CCR4), mogamulizumab (Moga), was thereby challenged and it successfully resolved the hepatic damage. Finally, a standard dose of chemotherapy could be administered, and it induced a complete remission. The patient is still in remission more than three years after the final dosage of standard chemotherapy. These results indicate that Moga, whose pharmacokinetics are not significantly influenced by hepatic function or serum albumin, could be a promising treatment option for patients with ATL complicated by severe hepatic damage due to infiltration of ATL cells.
A 7-month-old male infant with severe hemophilia A who received on-demand therapy with recombinant factor VIII (rFVIII) vomited because of acute intracranial bleeding. With rFVIII treatment for suppressing bleeding, there was development of high-titer (≤673 BU/ml) inhibitors. The patient was administered bypassing agents followed by immune tolerance induction therapy (ITI) with 50 U/kg of FVIII thrice weekly. In addition, he was treated with weekly and thrice weekly prophylaxis with 50 U/kg of activated prothrombin complex concentrate (aPCC). Despite ITI and aPCC prophylaxis treatments, it was difficult to control the hemorrhage, and the annualized bleeding ratio (ABR) remained high (5-13 bleeding episodes per year). We started emicizumab 2 weeks after completing the administration of aPCC. Weekly subdermal injections of 1.5 mg/kg emicizumab after loading dramatically decreased ABR (one bleeding episode per year), although biweekly injections of 3 mg/kg emicizumab for several months were associated with one joint hemorrhage. Compared to regular aPCC administration, our observations suggest that weekly emicizumab treatments can improve the ABR in a hemophilia patient with inhibitors and improve the quality of life of patient without limitations in terms of school events.
Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation. The gastrointestinal tract is a major target organ of GVHD, and disruption of the barrier function of the intestinal mucosa leads to an influx of danger signals derived from intestinal microbiota, which may further exaggerate GVHD. We have shown that the recombinant human R-spondin1 protects intestinal stem cells against GVHD, improves intestinal dysbiosis, and ameliorates GVHD. However, the endogenous R-spondin-producing cells in the small intestine remained to be studied in greater detail. This study clarified that R-spondin3 is the predominant R-spondin protein produced in the mouse small intestine. We also found that R-spondin3 is predominantly produced by lymphatic endothelial cells. Furthermore, we found that GVHD targets lymphatic endothelial cells in the small intestine, leading to decreased R-spondin3 production. GVHD-induced reduction of endogenous R-spondin3 could delay intestinal epithelial regeneration, possibly resulting in GVHD deterioration.
Since induced pluripotent stem (iPS) cell-derived blood products can be produced from any individual, they are expected to complement current transfusion products. However, a main problem is how to produce 10 U platelet preparations. Therefore, we established an immortalized megakaryocyte cell line (imMKCL) from iPS cells. We also found that turbulent flow was an essential physical factor for platelet generation in vivo. This knowledge enabled us to obtain 100 billion functional platelets from imMKCL using an 8 L bioreactor. We propose that the enhanced platelet production in the bioreactor occurs due to the turbulent flow that promoted the release of stress-induced cytokines.
Dysregulation of pre-mRNA splicing and transcription is a key step in gene expression control in patients with leukemia. Herein, we discuss the occurrence of frequent overlap of mutations affecting epigenetic regulation and pre-mRNA splicing in patients with leukemia, which together promote leukemogenesis through coordinated effects on the epigenome and pre-mRNA splicing. In particular, we have determined an important pathogenic role of cross-talk between altered epigenetic state and pre-mRNA splicing, provided functional evidence that mutations in pre-mRNA splicing factors drive leukemia development, and uncovered spliceosomal changes as a novel mediator of IDH2 mutant leukemogenesis. By isolating specific pre-mRNA splicing events that functionally contribute to IDH2/SRSF2 double-mutant leukemogenesis, we found that loss of the Integrator complex plays an important role in leukemia development. Our studies provided new evidence that defects in the Integrator complex remarkably affect several gene expression programs associated with hematopoietic differentiation and signaling pathways via transcriptional pause-release dysregulation, blockade of myeloid differentiation, and promotion of leukemogenesis in the Idh2 mutant background in vivo. Moreover, our results revealed important translational implications, given the substantial efforts to pharmacologically inhibit mutant IDH1/2 and splicing factors.
Splicing factor 3b subunit 1 (SF3B1) is the most commonly mutated RNA splicing factor identified in myelodysplastic syndrome (MDS), chronic lymphocytic leukemia, and uveal melanoma. The mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing events with a positive CRISPR screen to prioritize alterations that functionally promote oncogenesis. Our results indicated that diverse, recurrent SF3B1 mutations converge on the repression of bromodomain containing 9 (BRD9), a core component of the recently described non-canonical barrier-to-autointegration factor complex (ncBAF). Mutant SF3B1 recognizes intronic sequences within BRD9 as exons, thereby permitting inclusion of aberrant sequence (i.e., poison exon) that will result in the degradation of BRD9 mRNA. BRD9 depletion results in significant loss of ncBAF at CCCTC-binding factor (CTCF)-binding loci but has no impact on the localization of canonical BAF. These actions resulted in disturbed myeloid/erythroid differentiation and promoted the development of MDS and melanoma. Of note, correcting BRD9 mis-splicing in SF3B1-mutant cells with antisense oligonucleotides (ASOs), by targeting the poison exon with CRISPR-directed mutagenesis, or via the use of spliceosomal inhibitors are all potential therapeutic options. Our results implicate disruption of ncBAF as a critical factor promoting the development of the diverse array of cancers that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.
Hematopoietic stem cells (HSCs) are maintained in steady state in the bone marrow (BM); these cells are capable of continuous self-renewal and have the potential for multilineage-differentiation into all blood cell lineages. The BM has long been considered as an immune-privilege organ with little immunological reactions. However, recent findings have revealed that immunological/hematopoietic challenges such as infection or inflammation induce broad spectrum of immune and inflammatory responses in BM. While these responses play a beneficial role to boost immune activation and blood production, chronic challenge might lead to BM pathology and dysregulation, including hematopoietic aplasia or neoplasia. We will introduce recent findings focused on hematopoietic activation induced by existing outside of our body or co-existing with us, and discuss to what degree and how function of HSCs and progenitors is regulated and altered by bacterial insult.
Recent advances in genomic analysis technology have revolutionized precision medicine, especially with respect to the diagnosis, prognosis, and treatment of pediatric cancers. Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; genetic abnormalities associated with ALL are useful for the diagnosis and risk stratification in patients with ALL. Thus, genomic medicine (clinical sequencing) in pediatric ALL at diagnosis would help in the improvement of prognostic prediction and risk stratification. Recently, integrated genetic analysis using next generation sequencing technology revealed the full genetic landscape of pediatric ALL. These studies disclosed that in addition to fusion genes, aberrations of cell proliferation pathways and epigenetic regulations are also involved in the pathogenesis of pediatric ALL. Therefore, the realization of genomic medicine is an urgent necessity for improving the outcomes of pediatric patients diagnosed with ALL.
In Japan, acute myeloid leukemia (AML) accounts for approximately 25% of all pediatric leukemias, with approximately 150 cases of newly diagnosed AML occurring annually. Approximately 10% of patients have primary induction failure and 30% of patients, who initially achieve remission in primary treatments, subsequently relapse. Novel treatment modalities need to be developed to further improve the prognosis of pediatric AML patients. AML is a heterogeneous genetic disease characterized by changes in the genome of hematopoietic progenitor cells. Recent studies that have made progress in research related to the pathogenesis of AML have suggested that genotype-specific treatment strategies are associated with increased efficacy. Potential new therapeutic alternatives for pediatric AML include: tyrosine kinase inhibitors, monoclonal or bispecific T-cell engager antibodies, chimeric antigen receptor T-cell therapy, and metabolic agents. This review highlights the current landscape of novel therapeutic approaches for childhood AML, including the results of both preclinical and clinical trials, as well as introducing the results of several preceding adult clinical studies, which could potentially be translated into pediatric AML patients.
Several novel therapeutics that employ immunological mechanisms have been introduced in recent years for the treatment of hematological malignancies. To date, very few drugs have been introduced for acute lymphoblastic leukemia (ALL). Nonetheless, three novel agents have been approved recently in the US, Europe, Australia, and Japan: blinatumomab, which kills CD19-positive leukemia cells via cytotoxic activity of the patient's autologous T cells; inotuzumab ozogamicin, which delivers the anti-cancer antibiotic calicheamicin via CD22 internalization after antibody binding; and tisagenlecleucel, which uses patient's T cells via anti-CD19 chimeric antigen receptors. Aggressive multi-agent chemotherapy followed by allogeneic hematopoietic cell transplantation has been the only curative strategy for relapsed or refractory ALL. However, treatment strategies for such patients are about to change dramatically. In this article, I review the clinical development of the new therapeutics and discuss their roles in modern therapy for ALL in children and adolescents. An approach for treatment selection has not yet been established. Therefore, it is important to understand the advantages and disadvantages of each treatment for choosing a treatment strategy for each individual.
Genetic predisposition is a major cause of childhood cancer. Multiple cancer-predisposing syndromes have been identified, including Li-Fraumeni syndrome (LFS), neurofibromatosis type 1, APC-related adenomatous polyposis, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, ataxia telangiectasia, RUNX1 deficiency, Fanconi anemia, Bloom syndrome, and PTEN hamartoma tumor syndrome. LFS is a prototypical genetically predisposing condition. Accordingly, individualized therapy, surveillance, risk reduction, and family counseling are needed when a patient is diagnosed with LFS. More ethically important problems are encountered in a pediatric LFS patient, including the identification of patients requiring screening, the age at screening, the process of obtaining informed consent from children, and the responsibility of following a pediatric patient with a genetic predisposition. Therefore, it is crucial to determine whether planned genetic testing has direct benefits for pediatric patients. In this context, TP53 testing may be justified in a pediatric cancer patient with suspected LFS, given the importance of decisions such as the use of radiotherapy and the screening of family members as hematopoietic stem cell transplantation donors, the surveillance of subsequent cancers, and counseling for family members. In this review article, I have discussed these issues and indicated some consensus among various clinicians, including adult hematologists.
The RUNX1 gene is a critical transcription factor for the generation and maintenance of hematopoietic stem cells. RUNX1 is also one of the most frequently mutated gene in sporadic leukemias. Heterozygous loss-of-function mutations of the RUNX1 gene in the germline cause a rare autosomal dominant disorder called familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML). Besides the preexisting platelet disorder in FPD/AML patients, AML also develops in 20-60% of affected individuals. Since its discovery by the Gilliland group in 1999, RUNX1 mutation in the germline has been extensively investigated in the field. The past two decades of research have taught us three important lessons: 1) patients with FPD/AML display atypical symptoms and they have a widened clinical spectrum of FPD, such as eczema and syndromic thrombocytopenia, 2) the elucidation of variant of uncertain significance (VUS) of RUNX1 have revealed their role in epigenetic functions and involvement in the Fanconi anemia DNA repair pathway, and 3) non-coding mutations of RUNX1 also causes FPD/AML. In three distinct familial cases, an enhancer for RUNX1, eR1, was either lost or disconnected from the promoter through genetic deletion or chromosomal translocation abnormalities. This experience, with congenital mutations of RUNX1, will be very useful for future research for a series of other leukemia-causing germline mutations that have been recently identified.