"Counseling on Cancer Genomic Medicine" was added to the list of roles of cancer consultation centers located in Designated Cancer Hospitals under on the Third Cancer Control Act established in 2018. Although cancer consultation centers do not make decisions on whether to conduct genetic testing, it has been revealed that a certain number of such consultations are taking place. Consultations on genetic panel testing are expected to further increase in the future. In order to accommodate this need, individual cancer consultation staff needs to provide services based on the principles of consultation and support. For example, they must have adequate knowledge on the characteristics and limitations of genetic panel testing, understand the true needs of patients and their families, enable such individuals to understand the relevant information, and collaborate with patients and their families to consider the course forward. Furthermore, in order to ensure the quality of individual support, physicians and genetic counselors are expected to contribute by participating in organization-building between genetic counselors, genomic medicine coordinators, and other experts in and outside of hospitals. It is also anticipated that networks will be formed with nearby external institutions and organization, such as Designated Core Hospitals for Cancer Genomic Medicine, Designated Core Hospitals, and Medical Cooperation Hospitals.

In June 2019, 2 comprehensive cancer genome profiling(CGP)tests were approved with reimbursement, and are now available at designated hospitals stratified to 3 layers on the basis of their roles. The reimbursement-approved CGP tests were restricted to patients with solid tumors that have progressed on standard chemotherapy, rare tumors, or tumors of unknown primary, and perform primary structure analysis of cancer genome on several hundred genes at a time using next generation sequencer. In tumor molecular board, appropriate treatments were recommended based on the interpretation made for results of CGP. Because 2 CGP tests differ functionally in terms of the sample requirements, the target gene sets, and items to be reported, results need to be evaluated carefully. Although the detection rate of genomic alterations in CGP tests is high, the number of cases lead to treatments consistent with genomic alterations is limited. Improving this ratio will be the key for Japanese precision oncology to meet the full potential of the CGP tests.

Venetoclax, a selective BCL-2 inhibitor, is prescribed clinically for acute myeloid leukemia (AML) treatment. However, it is unclear if known chromosomal or genetic abnormalities associated with AML also influence BCL-2 expression. Few studies have examined BCL-2 expression in AML-related precursor neoplasms such as primary myeloid sarcoma (MS) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In this study, we examined BCL-2 expression using immunohistochemistry in 7 patients with AML, who also carried genetic and chromosomal abnormalities typical to AML including t (8;21), t (15;17), FLT3-ITD mutation, and complex karyotype, along with 1 patient with primary MS and 3 patients with BPDCN. As a result, expression of BCL-2 was observed in all patients with AML and 1 patient with primary MS. In the patients with BPDCN, BCL-2 was highly expressed in all regions with evidence of tumor cell infiltration, such as skin, bone marrow, and lymph node. These results could be used as evidence in the support of administering venetoclax to adverse-risk patients with AML, MS, or BPDCN.

Gilteritinib fumarate (Xospata® tablets 40 mg) is a novel, highly selective, oral FMS-like tyrosine kinase 3 (FLT3) inhibitor used for the treatment of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), and it was approved in Japan in September 2018. Preclinical studies demonstrated that gilteritinib inhibited FLT3 and showed antiproliferative activity against Ba/F3 cells expressing mutated FLT3. In addition, gilteritinib inhibited tumor growth, induced tumor regression, and prolonged survival in mice xenografted with MV4-11 cells endogenously expressing FLT3-internal tandem duplication. In clinical trials conducted in the United States, Europe, and Japan, plasma concentrations after administration of gilteritinib 20 to 450 mg/day were generally dose proportional, and gilteritinib was well tolerated. Multiple clinical trials, including a global Phase III study, in patients with relapsed or refractory FLT3-mutated AML treated with gilteritinib demonstrated higher response rates of complete remission or complete remission with partial hematologic recovery and longer overall survival compared with patients treated with salvage chemotherapy. Some clinical trials are ongoing in patients with FLT3-mutated AML at various treatment stages, such as induction therapy, maintenance therapy, and treatment after hematopoietic stem cell transplantation. In conclusion, in vitro, in vivo, and clinical data indicate that gilteritinib fumarate is an effective treatment option in adult patients with relapsed or refractory FLT3-mutated AML in Japan.

Target molecules of existing anti-cancer therapeutic monoclonal antibodies (mAbs) are divided into 1) receptor-type tyrosine kinases, such as human epidermal growth factor receptor (HER) family, 2) differentiation antigens, such as CD20 (Rituxan target), 3) angiogenesis-related molecules, and 4) immune checkpoint molecules (PD-1, etc.). We have recently reported a novel therapy targeting lymphangiogenesis, but not angiogenesis, using an anti-LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1) mAb. At present, many transporters are not considered to be target molecules for the cancer therapy; however, our study strongly suggested that the inhibition of cancer metabolism by mAbs against amino acid transporters will play a significant role in future cancer therapies. Most anti-cancer therapeutic mAbs bind cell-surface molecules on viable cancer cells: therefore, it is necessary to produce mAbs recognizing epitopes on the extracellular domains of native and non-denatured proteins. We concluded that viable cancer cells or cells transfected with cDNA encoding target proteins are suitable immunogens for the production of anti-cancer therapeutic mAbs. We introduce our efforts to develop seeds for therapeutic mAbs using whole cancer cells and transfectants as the immunogen. As many target candidates in the future are multi-pass membrane proteins, such as 12-pass amino acid transporter proteins belonging to the solute carrier (SLC) family, and their possible immunogenic extracellular regions are small, the production of specific mAbs is highly difficult. In this review, we summarize the successful preparation and characterization of mAbs recognizing the extracellular domain of oncoproteins, including transporters.

A 53-year-old male presented with pancytopenia for 13 months. He had a past history of follicular lymphoma and hypopharyngeal cancer, which was treated via chemotherapy and radiotherapy. Bone marrow aspiration biopsy of the patient revealed a hypocellular marrow with 32% of hypergranular blasts without Auer bodies. There were also erythroid and megakaryocytic dysplasia in the bone marrow. Although the PML/RARA transcript was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), the G-banding karyotype analysis showed a complex karyotype without t (15;17). The PML/RARA fusion signal was identified on chromosome 15 by metaphase FISH. The patient was diagnosed of therapy-related acute promyelocytic leukemia (t-APL) with cryptic PML/RARA. He successfully attained molecular complete remission with all-trans retinoic acid (ATRA) and two courses of arsenic trioxide (ATO). He was subsequently administered nivolumab without ATRA maintenance therapy because of a progressing metastasis of a hypopharyngeal cancer to the lung. The patient had a relapse of t-APL following nine courses of nivolumab, 8 months after ending consolidation therapy with ATO. Reinduction therapy with ATRA was not effective for the relapsed t-APL that was accompanied by del (5q) and monosomy 7. Little has been previously reported on t-APL with cryptic PML/RARA. Therefore, the clinical course of this patient may provide useful insights about the characteristics of t-APL with cryptic PML/RARA.

Cancer cells harboring somatic mutations give rise to neoantigens, which are immunologically foreign in nature to be distinguished from itself, showing high immunogenicity and, thus, induce specific T-cell responses against cancer. Therefore, neoantigens are expected to be promising targets for anti-cancer immunotherapy. The general methods used to identify candidate neoantigens are as follows: (1) non-synonymous mutations are identified by whole exome and RNA sequencing; (2) neoantigens from the mutations are predicted based on in silico MHC ligand prediction algorithm; (3) specific T-cell responses toward the candidate neoantigens are verified using tumor infiltrating T cells or peripheral blood mononuclear cells. In hematological malignancy, several neoantigens have been identified as an important treatment target. In contrast with solid malignancies, the occurrence of frameshift mutations and fusion genes producing neoantigens are high. A shared neoantigen derived from frameshift mutation of nucleophosmin I, which is often observed in acute myeloid leukemia, was reported to induce specific immune responses in vitro and in vivo. We should examine neoantigens as possible target of novel immunotherapy despite several issues to be addressed for clinical application.

Novel drugs, such as proteasome inhibitors, immunomodulators, and antibody drugs, have been consistently developed, and several standard treatment regimens were approved for elderly patients with multiple myeloma who are ineligible for autologous transplantation. Meanwhile, the clinical characteristics of elderly patients are more diverse than those of younger patients in terms of various factors, such as cognitive, mental, or social functions as well as physical or organ functions. Therefore, it is difficult to implement a standard treatment regimen to all elderly patients with a one-size-fits-all approach. Furthermore, it is important to evaluate the diversity of elderly patients as objectively as possible by evaluating organ functions and frailty in accordance with geriatric assessment, which helps determine the treatment plan. In addition, it is also ideal to select the treatment after considering the factors associated with tumors, such as the presence or absence of unfavorable chromosomal abnormalities.

Molecular targeted therapies with small molecule inhibitors and antibodies have rapidly replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). We discuss the current treatment strategies for CLL with special emphasis on genomic and molecular risk factors including IGHV unmutated status, 11q deletion, and 17p deletion. Ibrutinib and venetoclax are two molecular targeted agents currently available in Japan. They are highly effective, well tolerated, and have improved overall survival. Therefore, molecular targeted therapies are preferred to chemoimmunotherapy for most patients. Ongoing studies will clarify the optimal option between combination and sequence of treatment regimens with an appropriate timing of therapeutic intervention for longer survival. We are nearing an era of chemotherapy-free CLL management.

Since the discovery of the gain-of-function mutation JAK2 V617F, significant progress has been made in clarifying the pathology and developing novel agents for myeloproliferative neoplasms, including polycythemia vera (PV). The treatment strategy for PV is to first classify patients into either high- or low-risk groups for thrombosis. All patients with PV should be treated with low-dose aspirin and phlebotomy. In addition, for high-risk PV patients, cytoreductive therapy is recommended. Although hydroxyurea (HU) is the most popular agent for PV treatment, the advantages of ruxolitinib, a JAK inhibitor, for patients who are intolerant or resistant to HU were recently reported. Furthermore, the ability of interferon-α to selectively eliminate the malignant clone and induce complete molecular response was previously demonstrated. In this article, important clinical trials associated with the treatment strategy for PV and recent advances in PV treatments are described.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by the Philadelphia chromosome, t (9;22)(q34;q11.2), which causes the generation of the BCR-ABL1 oncoprotein with constitutively active tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of CML. Optimal treatment decisions at specific time points in patients with suboptimal response minimizes the risk of disease progression and CML-related death. The expected survival for patients with CML treated with TKI is now similar to that of the general population. Given the stable clinical course over the years, treatment-free remission (i.e., functional cure) can be considered in patients with sustained deep molecular response. Second-generation TKIs achieved higher rates of deep molecular response than imatinib, which could translate to increased candidates for functional cure without TKI therapy. The third-generation TKI, ponatinib, brought a new hope to patients who failed multiple TKIs because of resistance and/or intolerance. EUTOS long-term survival (ELTS) score can guide optimal treatment selection.

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.

In acute myeloid leukemia (AML), a number of chromosomal abnormalities and gene mutations associated with onset and recurrence were discovered by the recent progress of genome analysis technology. The founding did not only have clinical application as prognostic factors and minimal residual disease markers but also contributed to novel molecular targeted drug development. Many new drugs, such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor, have been developed in Europe and the United States. In addition, the second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, which significantly improved the treatment outcome of AML. However, there is still a large disparity in drug availability between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to practical use in Japan. This paper presents an outline of the prognosis stratification and indication of allogenic hematopoietic cell transplantation for AML by gene diagnosis in Japan.

Some studies have reported the clinical significance of minimal/measurable residual disease (MRD) in considering the prognostic stratification and therapeutic intervention after complete remission in acute myeloid leukemia (AML). In the clinical setting, multicolor flow cytometry (MFC), a quantitative PCR method targeting the expression of fusion genes generated by chromosomal translocation, such as PML-RARA, RUNX1-RUNXT1, and CBFB-MYH11, as well as WT1 mRNA, was used to detect MRD in AML. In recent years, quantitative PCR, next-generation sequence, and digital-droplet PCR methods targeting genetic alterations often detected in AML have been developed to assess its clinical significance. However, besides analysis methods, many common problems persist in MRD evaluation, such as sample collection points, type of samples, and threshold setting. Although several gene mutations involved in clonal hematopoiesis have been detected in CR patients, their presence did not correlate with the prognosis, and some leukemia-specific mutations did not always persist during the clonal evolution of AML. Therefore, it is essential to combine multiple methods, such as target gene mutation, quantitative PCR, and MFC to enhance the sensitivity of measurement. Furthermore, the establishment of novel treatment strategies incorporating MRD and molecular abnormalities is warranted for better clinical outcomes of AML.

Genomics and novel molecularly targeted drugs for treating acute myelogenous leukemia (AML) are developing rapidly. To optimize the allocation of patients to the best possible treatment, we have to expedite test results of cytogenetic and molecular analyses for target mutations such as CBF and FLT3, since gene mutations are specifically associated with patient prognosis and therefore inform medical decision making. However, novel agents cannot completely eradicate AML because of the emergence of resistance to these agents; therefore, at the moment it is still necessary to combine cytotoxic treatment with novel agents. Hence, it becomes vital to understand how to stratify AML patients and subsequently treat the right patients with the right combination of cytotoxic treatments and novel agents.

Evidence of human leukemia stem cells (LSCs) in acute myeloid leukemia (AML) was first reported nearly a quarter century ago through the identification of rare engrafting cell subpopulations in patient-derived xenograft assays. Since then, studies have revealed diverse characteristics of AML stem cells. Initiating mutations convert normal hematopoietic stem cells (HSCs) to pre-leukemic HSCs. The repopulation advantage of pre-leukemic HSCs over normal HSCs leads to clonal evolution. Acquisition of additional mutations in pre-leukemic HSCs results in the development of AML composed of genetically distinct subclones. Each subclone contains LSCs with unique characteristics, and these LSCs contribute to therapeutic resistance and relapse. Interestingly, some LSCs can escape from antitumor immune responses, thereby survive the treatment. This article summarizes recent advances in the field of LSC biology from genomic and immunological perspectives.

Through intensive efforts of genome sequencing of myeloid malignancies, a comprehensive registry of driver mutations has been revealed, virtually providing us with a complete spectrum of driver mutations in these diseases. Importantly, there have been significant correlations between driver mutations, which suggests that some combinations of genetic events confer strong selective advantage on mutated stem cells. Next-generation sequencing technology have also revealed that clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. Furthermore, novel germline mutations were identified, indicating that mutated stem cells appear long before myelodysplastic syndrome (MDS) presentation. Such founding mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to acute myeloid leukemia (AML) in many patients.