Jeonghwan Youk

A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data

Background Mast cell leukemia (MCL) is the most aggressive form of systemic mastocytosis disorders. Owing to its rarity, neither pathogenesis nor standard treatment is established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing results of the patients own DNA and RNA. Methods First, tumor DNA and RNA were extracted from bone marrow at the time of diagnosis. Germline DNA was extracted from the patients saliva 45 days after induction chemotherapy and used as a control. Then, we performed whole-exome sequencing (WES) using the DNA and whole transcriptome sequencing (WTS) using the RNA. Single nucleotide variants (SNVs) were called using MuTect and GATK. Samtools, FusionMap, and Gene Set Enrichment Analysis were utilized to analyze WTS results. Results WES and WTS results revealed mutation in KIT S476I. Fusion analysis was performed using WTS data, which suggested a possible RARα-B2M fusion. When RNA expression analysis was performed using WTS data, upregulation of PIK3/AKT pathway, downstream of KIT and mTOR, was observed. Based on our WES and WTS results, we first administered all-trans retinoic acid, then dasatinib, and finally, an mTOR inhibitor. Conclusion We present a case of orphan disease where we used a targeted approach using WES and WTS data of the patient. Even though our treatment was not successful, use of our approach warrants further validation.

Successful desensitization of pemetrexed-induced anaphylaxis in a patient with malignant mesothelioma

Department of Internal Medicine, Seoul National University Hospital, Seoul; Departments of Radiology, Cardiothoracic Surgery, and Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea Successful desensitization of pemetrexed-induced anaphylaxis in a patient with malignant mesothelioma Jeonghwan Youk, Hyunkyung Park, Kwang Nam Jin, Hyun Jong Moon, Min-Suk Yang, Ki Hwan Kim, and Jin-Soo Kim

Depletion of nerve growth factor in chemotherapy-induced peripheral neuropathy associated with hematologic malignancies

Objective To investigate whether the depletion of nerve growth factor (NGF) is associated with the development of chemotherapy-induced peripheral neuropathy (CIPN) in patients with hematologic malignancy. Methods We prospectively enrolled hematologic cancer patients who had a plan to receive bortezomib, thalidomide, or vincristine. Baseline NGF levels were measured within one week before the start date of chemotherapy. Follow-up NGF levels were measured after four months from the start date of chemotherapy or the date when CIPN was initially diagnosed. Results Baseline and follow-up NGF pairs were measured in 45 patients (male/female = 27/18, median age = 63 years old). CIPN has developed in 28 patients. In the CIPN group, the level of NGF was significantly decreased after chemotherapy compared to the baseline (△NGF = −3.52 ±5.72; p-value = 0.003), while the NGF level of the no-CIPN group was not changed after chemotherapy. The differences in △NGF levels between the CIPN and no-CIPN group were more profound when analyzed in the subgroup of newly diagnosed multiple myeloma patients (△NGF = −4.14 ± 4.87 pg/ml for the CIPN group and +2.52 ± 8.39 pg/ml for the no-CIPN group; p-value = 0.043). Conclusions This study shows that the depletion of NGF occurs during the development of CIPN, suggesting pathogenesis based on the role of NGF and therapeutic implications.

Serum free light chain difference and beta-2 microglobulin levels are risk factors for thromboembolic events in patients with AL amyloidosis

&NA; AL amyloidosis might increase the risk of thromboembolism and other plasma cell dyscrasias. Therefore, we evaluated the features of thromboembolism in AL amyloidosis. The incidence of thromboembolism was substantial (12.3%); most events developed within the first year after the diagnosis, and arterial thromboembolism occurred frequently. In particular, patients with risk factors might require close monitoring for thromboembolism. Background: AL amyloidosis might increase the risk of thromboembolism and other plasma cell dyscrasias; however, only a few reports have described the clinical features of thromboembolism. The present study aimed to elucidate the clinical features of thromboembolic events and to identify the risk factors for these events. Materials and Methods: The medical records were retrospectively reviewed to define the clinically significant thromboembolic events. Results: A total of 106 patients with biopsy‐proven AL amyloidosis were included. During a median follow‐up of 18.1 months (range, 0.4‐166.9 months), 13 thromboembolism events were identified in 13 patients. Of the 13 patients, 9 (8.5%) experienced acute cerebral infarction, 2 (1.9%) experienced pulmonary embolism, and 2 (1.9%) experienced deep vein thrombosis. Patients with a higher serum free light chain (FLC) difference (≥ 172.4 mg/L) or &bgr;2‐microglobulin (&bgr;2MG) levels (≥ 2.78 mg/L) experienced significantly more thromboembolic events compared with those with a lower value according to multivariable analysis (for FLC difference: hazard ratio, 4.309; 95% confidence interval, 1.158‐16.032; P = .029; for &bgr;2MG: hazard ratio, 9.739; 95% confidence interval, 1.127‐84.174; P = .039). Most thromboembolic events (11 of 13; 84.6%) occurred within the first year after the AL amyloidosis diagnosis. Conclusion: The incidence of thromboembolism was substantial in those with AL amyloidosis. A greater FLC difference and for &bgr;2MG levels were risk factors for thromboembolic events.

Clinicopathological characteristics of extremely young Korean multiple myeloma patients: Therapeutic implications

Background/Aims Although multiple myeloma (MM) is typically a disease of the elderly, a certain subset of extremely young patients exists. It is necessary to establish clinicopathological characteristics for this population. Methods We reviewed the medical records of MM patients whose age was 40 years or younger at diagnosis. Results A total of 32 patients were analyzed (male to female ratio 19:13, median age 37 years). According to International Staging System, 29%, 48%, and 16% were in stage I, II, and III, respectively. Light chain myeloma accounted for 30%. Clinically significant anemia, hypercalcemia, azotemia, and hypoalbuminemia were present in 29%, 28%, 13%, and 28%, respectively. Three or more lytic bone lesions were detected in 45% of the patients, whereas 13% had no lytic bone lesions. Regarding treatment, 79% of patients received autologous hematopoietic stem cell transplantation. After a median follow-up duration of 64 months, the 1-, 3-, and 5-year overall survival (OS) rates were 84%, 62%, and 54%, respectively. The median OS was 61 months for the entire cohort. Conclusions In our study, MM patients aged 40 years or younger at diagnosis showed no superior survival compared to those of the moderately elderly patients based on historical data.

Abstract 5225: CDK11B, PTPRN2 and WDPCP were frequently duplicated genes in refractory/relapsed normal karyotype AML patients: Identifying structural variations using whole genome sequencing

Background According to the NCCN guideline, the prognosis of acute myeloid leukemia with normal karyotype (NK-AML) is classified based on the mutational status of NPM1, FLT3-ITD or CEBPA. However, patients with NK-AML without the above mutations, who are in intermediate risk, still show various clinical outcomes. Unfortunately, refractory/relapsed patients with intermediate risk NK-AML cannot be predicted before cytotoxic chemotherapy, yet. With the advent of next generation sequencing technology, we tried to reveal prognostic molecular marker in intermediate risk NK-AML, especially focusing on large structural variations (SVs). Methods A total of nine patients with intermediate risk NK-AML patients were included. Whole genome sequencing (WGS) was performed using a pair of tumor and germline DNA of the patients. Leukemic blasts were obtained from bone marrow aspiration specimens of each patient at the time of diagnosis. As a germline control, epithelial cells were collected from saliva of each patient at the time of complete remission. Then, genomic DNA was massively sequenced using HiSeq X10 system (Illumina Inc., San Diego, CA, USA). Possible SVs including inversion, duplication and translocation were identified with BreakDancer (Washington University School of Medicine, St. Louis, MO, USA), Pindel (The Wellcome Trust Sanger Institute, Cambridge, UK) and Delly (European Molecular Biology Laboratory, Heidelberg, Germany). Possible SVs were considered when they were recurrently identified from the three pipelines. Results This cohort consisted of 7 males and 2 females (median age = 55.6 years old). None of them had secondary AML. Eight patients were relapsed after complete remission and the other patient was refractory to 1st line induction chemotherapy. Through WGS, 25 inversions, 67 duplications and 10 translocations were identified in nine patients. Among them, 4 inversions, 13 duplications and 2 translocations were recurrently mutated. Especially, CDK11B, PTPRN2 and WDPCP were frequently duplicated more than 40% of the patients. Conclusions In this study, we performed WGS to investigate SVs of refractory/relapsed NK-AML patients with intermediate risk. Among various mutations, duplications of CDK11B, PTPRN2 and WDPCP were highly prevalent, so they could be a possible prognostic biomarker in NK-AML with intermediate risk. Further functional validation is required in order to clarify their roles. Citation Format: Jeonghwan Youk, Sunghoon Cho, Daeyoon Kim, Youngil Koh, Inho Kim, Murim Choi, Sung-Soo Yoon. CDK11B, PTPRN2 and WDPCP were frequently duplicated genes in refractory/relapsed normal karyotype AML patients: Identifying structural variations using whole genome sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5225.

Abstract 4309: Description of a scientific treatment approach of mast cell leukemia, an aggressive orphan hematologic disorder: strategy based on next-generation sequencing data

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background Mast cell leukemia (MCL) is the most aggressive form of disorder among systemic mastocytosis. Due to its rarity, neither pathogenesis nor standard treatment is not established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing result of the patients own DNA and RNA. Brief Case History and Results In October 2013, an 18-year-old Korean female were diagnosed as MCL after visiting our hospital due to left knee, ankle pain and inguinal lymphadenopathy. C-KIT overexpression was observed by immunohistochemistry. Whole exome sequencing result failed to demonstrate either noticeable single nucleotide variant (SNV) or copy number change. Interestingly, whole transcriptome sequencing (WTS) revealed mutation of KIT S476I, functionality of which is not known. Fusion analysis was performed using WTS data, possibility of RARα-B2M fusion has been arised. However, it was not validated by PCR sequencing. When RNA expression analysis was performed using WTS data, upregulation of PIK3/AKT pathway, which is a downstream of KIT (BAD phosphorylation) and mTOR has been observed. For the treatment perspective, she failed to achieve complete remission after cytarabine and idarubicin chemotherapy. Based on our WES and WTS result, we first tried all-trans retinoic acid targeting RARα, which failed to demonstrate efficacy. Then, she received dasatinib targeting KIT, which showed transient response for 2 weeks. Now she is under everolimus targeting mTOR pathway and, further treatment with PI3K inhibitor is planned in case of disease progression. Conclusions We are demonstrating a case of orphan disease, where we used targeted approach using WES and WTS data of the patient. Final results of our treatment outcome will be uncovered shortly, and utility of this kind of approach is to be validated. Citation Format: Jeonghwan Youk, Youngil Koh, Ji-Won Kim, Dae-Yoon Kim, Woo June Jung, Kwang-Sung Ahn, Sung-Soo Yoon, Hye Lim Jung. Description of a scientific treatment approach of mast cell leukemia, an aggressive orphan hematologic disorder: strategy based on next-generation sequencing data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2015-4309