Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome.

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Clinical characteristics and outcomes of Epstein-Barr virus viral load after allogeneic hematopoietic stem cell transplantation.

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II-IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival ("not reached" vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.

Pulmonary tumor thrombotic microangiopathy during good response to immuno-chemotherapy for advanced non-small cell lung cancer: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a rapidly progressive and fatal disease in which tumor cells embolize to the pulmonary microvasculature. This condition is characterized by severe dyspnea and right heart failure. Although pulmonary tumor thrombotic microangiopathy typically occurs in patients with untreated and/or advanced cancer, its occurrence in patients who are responding well to medical therapy is poorly documented. CASE PRESENTATION: A 68-year-old Japanese woman who had received four cycles of immuno-chemotherapy (pembrolizumab, carboplatin, and pemetrexed) followed by three cycles of maintenance therapy (pembrolizumab and pemetrexed) for advanced non-small cell lung cancer and had achieved a partial response with a stable clinical course was admitted to the emergency ward because of worsening breathlessness and general fatigue for 1 week. Chest computed tomography showed no evidence of tumor progression or any new lung lesion. Two-dimensional transthoracic echocardiography demonstrated right atrial and ventricular dilatation, tricuspid regurgitation, and a high trans-tricuspid pressure gradient of 65 mmHg. Despite her percutaneous oxygen saturation being 96% on room air at the time of admission, it worsened rapidly; the patient requiring 8 L/min of oxygen within 4 h. Repeat computed tomography with contrast medium revealed no evidence of pulmonary embolism. The patient developed progressive respiratory failure that was unresponsive to optimal cardio-pulmonary supportive therapy. An autopsy revealed tumorous clusters in pre-capillary lung vessels, whereas the primary lesion had shrunk to the point of almost complete resolution. CONCLUSION: Pulmonary tumor thrombotic microangiopathy occurs not only in patients with advanced and/or uncontrolled cancer but also in those whose primary lesion seems to have been well controlled by medical treatment.

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01.

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

Clinical and genetic diagnosis of Cowden syndrome: A case report of a rare PTEN germline variant and diverse clinical presentation.

INTRODUCTION: Cowden syndrome is a rare autosomal dominant disease characterized by the development of hamartomas and increased risks of other tumors, including breast, thyroid, and uterine cancers. Most patients with Cowden syndrome show mutations of the phosphatase and tensin homolog (PTEN) gene on chromosome 10; however, some patients with mutations do not show clinical symptoms, while patients with clinical symptoms may not have detectable PTEN mutations. CASE PRESENTATION: A 39-year-old woman with macrocephaly had previously been diagnosed with Cowden syndrome at another hospital, when she presented with the onset of breast cancer. A wide variety of complications were detected, including cerebellar tumors treated by resection, hydrocephalus, and multiple polyps in the stomach and large intestine. She was further diagnosed with adult-onset Lhermitte-Duclos disease as a complication of Cowden syndrome. She subsequently developed a dural arteriovenous fistula treated by transvenous embolization. After transfer to our hospital, she developed adenomatous goiter treated by resection, recurrent breast cancer treated with hormonal therapy, and multifocal oral mucosal papillomatosis. Her older sister had previously been diagnosed with Cowden syndrome and her father was undiagnosed but had macrocephaly, hydrocephalus, and multifocal oral mucosal papillomatosis, suggestive of Cowden syndrome. After consultation with a genetic specialist, analysis of the PTEN gene showed a rare but likely pathogenic germline c.801 + 2T>A variant located at the splice donor site of intron 7. The patient's clinical diagnosis of Cowden syndrome was accordingly confirmed by the genetic findings. Appropriate surveillance procedures were put in place to detect any further tumors. CONCLUSIONS: The clinical symptoms of Cowden syndrome do not always correlate with the genetic results. However, recent improvements in genetic testing suggest the importance of diagnosing this disease using both clinical and genetic approaches, in collaboration with genetic experts, to ensure an accurate diagnosis and appropriate surveillance for malignant tumors.

Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia.

Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML.

Catheter-related bloodstream Mycobacterium wolinskyi infection in an umbilical cord blood transplant recipient: a case report.

BACKGROUND: Catheter-related bloodstream infection (CRBSI), caused by rapidly growing mycobacteria (RGM), is a rare infectious complication in hematopoietic stem cell transplant (HSCT) recipients and can often be misdiagnosed as Gram-positive rod (GPR) bacteremia. CASE PRESENTATION: We present a case of CRBSI caused by Mycobacterium wolinskyi, a rare RGM, in a 44-year-old female patient who received an umbilical cord blood transplant. CONCLUSIONS: Rapidly growing mycobacteria can stain as GPRs and may grow in routine blood culture media after 3-4 days of incubation. These features are not widely known to clinicians, and acid-fast staining is therefore recommended when unidentifiable GPRs are detected in blood cultures, especially in immunocompromised patients, such as those with hematologic malignancies or intravascular devices.

Paraneoplastic Opsoclonus-myoclonus Syndrome with Anti-Hu and Anti-SOX-1 Antibodies after Immune-checkpoint Inhibitor Treatment Combined with Chemotherapy in a Patient with Small-cell Lung Cancer.

A 69-year-old man with advanced small-cell lung cancer achieved partial remission after 3 courses of immunochemotherapy that included atezolizumab. Ten days after the last treatment, he developed paraneoplastic opsoclonus-myoclonus syndrome and required mechanical ventilation. Serology testing detected anti-Hu and anti-SOX-1 antibodies. Despite steroid pulse therapy, various anticonvulsants, continuous intravenous sedation, and a fourth course of chemotherapy without atezolizumab, his condition failed to improve. Paraneoplastic opsoclonus-myoclonus syndrome with autoantibodies after immune-checkpoint inhibitor treatment has not been reported previously. Although a causal relationship between immune-checkpoint inhibitors and paraneoplastic syndromes has been suggested, the mechanism remains unknown.

[Simultaneous Double Cancer of Unknown Primary and Advanced Lung Cancer-A Case Report].

A 60-year-old woman was diagnosed with simultaneous double cancer of the inguinal lymph node(squamous cell carcinoma) and the right lung(combined small cell carcinoma; cT3N0M0, Stage ⅡB)after observing and reporting a right inguinal swelling. Both were local lesions, and standard definitive treatments were administered. Right inguinal malignant tumor resection and right femoral arteriovenous resection with artificial blood vessel replacement and pedicled transverse rectus abdominis musculocutaneous flap were performed for the unknown primary cancer. Right upper lobectomy, lymph node dissection, and chest wall resection were performed for the right lung cancer. The postoperative stage of the right lung cancer was pT3N0M0, Stage ⅡB, and cisplatin(CDDP)/vinorelbine(VNR)was administered as postoperative adjuvant chemotherapy. The 2 surgeries and adjuvant chemotherapy were well-tolerated, and there has been no recurrence for 1 year and 5 months.

Changes in Central Venous Catheter Use in the Hematology Unit with the Introduction of Ultrasound Guidance and a Peripherally Inserted Central Venous Catheter.

Objective A central venous catheter (CVC) is often needed to treat hematologic diseases, but it is accompanied by many complications. Ultrasound guidance (USG) or a peripherally inserted central venous catheter (PICC) can reduce such complications. Meterials We collected data of patients with attempted CVC placement in our hematology unit in 2012 (before introduction of USG and PICC) and 2018 (after introduction) and compared both periods. Results In total, 187 CVC insertions were attempted in 2018 and 198 in 2012. USG was used 154 times (82%) in 2018 and 4 times (2%) in 2012 (p<0.001). The success rates of insertion were 95% in 2018 and 89% in 2012 (p=0.063). The incidence of acute complications was 4.3% in 2018 and 9.1% in 2012 (p=0.069). The incidence of CVC removal owing to delayed complications was 26% in 2018 and 21% in 2012 (p=0.327). The sites of approach in 2018 and 2012 were the internal jugular in 42 (22%) and 54 (27%), subclavian in 52 (28%) and 128 (65%), brachial (PICC) in 89 (48%) and 14 (7%), and femoral in 4 (2%) and 2 (1%), respectively (p<0.001). Conclusion USG has become commonplace since its introduction. The landmark-based subclavian approach was largely replaced by PICC with USG in 2018. USG and PICC can help improve success rates and safety profiles.

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin.

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 107/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 109/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

Randomized phase II study of a bendamustine monotherapy schedule for relapsed or refractory low-grade B-cell non-Hodgkin lymphoma or mantle cell lymphoma (RABBIT-14).

The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m2 on days 1 and 15, repeated every 4 weeks for a total of 6 cycles) with those of the standard treatment in relapsed indolent lymphoma and/or mantle cell lymphoma. Forty-six patients were randomly assigned to the treatments from September 2012 to February 2016. Treatment accomplishment rate and median relative dose intensity were similar in both arms: 38 and 63.4% in the Benda-14 arm and 41 and 66.3% in the standard treatment arm, respectively. The overall response rate and median progression-free survival, respectively, were 83% and 21.0 months for Benda-14, and 77% and 15.5 months for the standard treatment. Benda-14 induced favorable responses with less frequent hematological toxicities.

A prospective multicenter phase II study of intrabone marrow transplantation of unwashed cord blood using reduced-intensity conditioning.

Cord blood transplantation (CBT) is associated with delayed hematopoietic recovery and graft failure. To overcome these problems, we conducted a prospective, multicenter phase II study of intrabone marrow transplantation in which patients received reduced-intensity conditioning without anti-thymocyte globulin (ATG). The primary endpoint was the probability of full donor engraftment. Forty patients with hematologic malignancies were enrolled. Cord blood (CB) cells were injected without washing into 4 iliac bone sites (2 at each hemipelvis), at which approximately 6 mL of CB was administered at one site with local anesthesia. Full donor engraftment rate was 86.8%. The cumulative incidence of neutrophil and platelet engraftment was 86.4% and 85.5%, respectively. The median time to neutrophil (>0.5 × 109 /L) and platelet (2.0 × 109 /L) recovery was 17.5 and 44 days, respectively. The probability of severe acute graft-vs-host disease (GVHD) was 47.5%. The cumulative incidence of extensive chronic GVHD was 3.0%. The probability of relapse and non-relapse mortality was 30.4% and 28.0%, respectively. The survival rate at 3 years was 45.6%, although most patients were at an advanced stage. These results suggest that our intrabone marrow-CBT procedure without using ATG improves hematopoietic recovery and decreases the incidence of chronic GVHD, but does not decrease the incidence of acute GVHD.

Influence of dose reduction of vincristine in R-CHOP on outcomes of diffuse large B cell lymphoma.

Dose intensity (DI) of chemotherapy affects prognosis of diffuse large B cell lymphoma (DLBCL). Myelotoxicity is the major dose-limiting toxicity (DLT) of most cytotoxic agents for hematological malignancies, whereas DLT of vincristine (VCR) is mainly neurological toxicity. Although VCR is a key drug and its combination with other cytotoxic agents needs consideration, studies focused on relative DI (RDI) of VCR have not been done before. We retrospectively analyzed 86 cases of DLBCL that received six or more cycles of cyclophosphamide (CPM), doxorubicin (DXR), VCR, prednisolone, and rituximab [R-CHOP] and calculated RDI of each cytotoxic agent to analyze its influence on treatment outcome. The median RDI of CPM, doxorubicin, and VCR was 80.0, 81.7, and 78.4 %, respectively (p = 0.002). The average RDI (ARDI) of these three agents was 80.0 %. The overall survival was significantly worse in the low ARDI (<85 %) than in the high ARDI (>85 %) group (2-year survival rate 67.2 vs 93.4 %, p = 0.011). The survival rate with low RDI VCR (<85 %) was lower than that with high RDI VCR (>85 %), even when the remaining two agents had high ARDI (2-year survival rate 74.3 vs 95.8 %, p = 0.047). In conclusion, VCR dose tended to be reduced compared with CPM and DXR in R-CHOP. Lower ARDI of cytotoxic agents and lower RDI of VCR could lead to poor prognosis in the treatment of DLBCL with R-CHOP. We thought these observations should be confirmed in a prospective study.

[Atypical onset of therapy-related acute promyelocytic leukemia after combined modality therapy including (89)Sr for metastatic breast cancer].

A 51-year-old woman diagnosed as having left breast cancer with axillary lymph node and liver metastases seven years earlier was seen in our office because of severe pancytopenia. She had received chemotherapy including several cycles of doxorubicin plus cyclophosphamide and docetaxel followed by hormone therapy containing leuprorelin and tamoxifen over four years. For management of bone pain due to metastasis, she had also undergone stereotaxic radiation therapy of the neck one and a half years earlier and unsealed internal radiation therapy with (89)Sr injection five months prior to the current presentation, Subsequently, myelosuppression progressively worsened and she finally required a blood transfusion. Although bone marrow examination showed severe hypoplasia, but neither blastic nor dysplastic, a test for PML-RARA fluorescence in situ hybridization was positive. After administration of all-trans retinoic acid, hematogenesis improved within three weeks. Neither disseminated intravascular coagulation nor retinoic acid syndrome was observed during the course of her illness. This is the first report describing acute promyelocytic leukemia after administration of (89)Sr, to our knowledge, and with an atypical onset and progression. As the number of cancer survivors increases due to improvements in medical intervention, clinicians must take more notice of special characteristics of therapy-related leukemia modified by previous treatments.