<p>Percentage changes from baseline in sums of target lesion diameters over time per RECIST v1.1 by investigator assessment. Tumor types of patients with at least a 30% reduction at any timepoint are listed. <sup>a</sup>Plus nivolumab 360 mg every 3 weeks; <sup>b</sup>plus nivolumab 240 mg every 2 weeks. Q#W, every # weeks; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1.</p>
<p>Maximum percentage change from baseline in sums of tumor diameters and best overall response per RECIST v1.1. E7389-LF, eribulin liposomal formulation; PD, progressive disease; PR, partial response; Q#W, every # weeks; RECIST v1.1, Response Evaluation Criteria In Solid Tumors, version 1.1; SD, stable disease.</p>
Acute megakaryoblastic leukaemia (AMKL) is a rare subtype of acute myeloid leukaemia (AML) that accounts for 1% of adult AML cases. AMKL is a more common subtype of childhood or infant AML, that occurs especially in children with Down syndrome. The cytogenetic abnormality t(1;22)(p13·3;q13·1) results in the fusion of two genes, namely the RNA-binding motif protein-15 (RBM15) and megakaryoblastic leukaemia-1 (MKL1). AMKL with t(1;22)(p13·3;q13·1)/RBM15-MKL1 has been reported only in infants or young children (age < 3 years), with most cases occurring in the first 6 months of life (median patient age 4 months).1-3 Here, we report the first documented adult patient with AMKL carrying t(1,22)(p13·3;q13·1)/RBM15-MKL1 following treatment for a non-mediastinal germ cell tumour (GCT). A 31-year-old man was diagnosed with a non-mediastinal GCT with a bulky retroperitoneal mass lesion. After receiving four cycles of bleomycin, etoposide and cisplatin (BEP) therapy followed by surgical resection of the residual mass lesion, the patient achieved complete remission. Five months after the completion of BEP therapy, a follow-up blood test demonstrated thrombocytopenia with a platelet count of 62 × 109/l. The white blood cell count was 5·1 × 109/l without the appearance of blastic cells, while the haemoglobin level was 10·4 g/dl. The patient was subsequently referred to our department for thrombocytopenia. A bone marrow (BM) examination indicated a slightly hypocellular marrow with proliferation of blastic cells Fig 1. Flow cytometry analysis revealed that the blastic cells were positive for CD34, CD117, CD13, CD41a and CD61. The BM biopsy revealed an increase in tumour cells positive for CD41 (Fig 1), however, they were negative for GCT markers, including AE1/3, OCT3/4 and SALL4. Based on these findings, the patient was diagnosed with AMKL. Cytogenetic analysis revealed t(1;22)(p13·3;q13·1) present in four of 20 metaphase cells, while the cells tested negative for isochromosome 12p [i(12p)], a clonal marker common in GCTs. The RBM15-MKL1 fusion gene was detected in a BM sample by reverse transcription polymerase chain reaction (RT-PCR). Thus, the patient was diagnosed with AMKL with t(1;22)(p13·3;q13·1)/RBM15-MKL1. He had no sign of Down syndrome nor family history of hematologic malignancies. We also evaluated an initial biopsy sample of the GCT; however, RBM15-MKL1 was not detected by RT-PCR (Fig 2).4 After receiving a conventional 7 + 3 induction regimen with cytarabine and idarubicin, the patient achieved complete cytogenetic remission (CCyR). Subsequently, the patient received three cycles of high-dose cytarabine consolidation. As AMKL is generally considered to be of high risk of relapse in adult patients,5, 6 the patient underwent allogeneic haematopoietic stem cell transplantation (allo-HSCT) at the first remission. As he did not have a human leukocyte antigen (HLA)-identical sibling nor non-sibling donor, he underwent transplantation of a single unit of cord blood (number of mononuclear cells, 2·34 × 107/kg) following a conditioning regimen comprising 30 mg/m2 fludarabine for 6 days, 3·2 mg/kg intravenous busulfan for 4 days, and 40 mg/m2 melphalan for 2 days.7 Neutrophil engraftment was achieved on day 13, and BM aspiration on day 30 showed CCyR. Although the patient experienced severe acute graft-versus-host disease of the gut, he remains in remission more than 200 days after the transplantation. To the best of our knowledge, this is the first case of an adult patient with AMKL with t(1;22)(p13·3;q13·1)/RBM15-MKL1, which usually occurs in infants or young children aged < 3 years. It is difficult to determine whether the AMKL in this case was a GCT-related AML or a so-called therapy-related myeloid neoplasm (t-MN). In this case, the AMKL was a second primary malignancy, following non-mediastinal GCT. According to previous reports, primary mediastinal GCT is closely associated with subsequent AML. Furthermore, Taylor et al.8 recently demonstrated myeloid neoplasms developing in patients with primary mediastinal GCT, representative of secondary somatic differentiation of a haematologic progenitor from totipotent aberrant cells that were present in the original GCT. According to the study by Taylor et al., GCT-associated leukaemias have characteristic genomic alterations hallmarked by frequent i(12p) combined with mutations that activate the RAS-PI3K-AKT signalling pathway and inactivate TP53. However, in this case, the AMKL did not include i(12p) or any other mutations that are frequently observed in GCT-associated leukaemia. The results do not necessarily deny the molecular relationship between GCT and AMKL as previous data regarding mutations of GCT-associated leukaemia focused on ‘primary mediastinal’ GCTs. Further evaluation in patients with ‘non-mediastinal’ GCTs is warranted. Although, in this case, the AMKL might be a t-MN associated with conventional cytotoxic chemotherapy, considering the relatively short interval between the chemotherapy for GCT and onset of AMKL, along with the relatively lower cumulative dose of cytotoxic agents (1800 mg/m2 of etoposide and 360 mg/m2 of cisplatin before the onset of AMKL), it appears to be an atypical clinical course compared to that of previously documented t-MNs. Next-generation target sequencing or whole exome sequencing might be useful for further genetic evaluation. Unfortunately, we cannot perform an additional evaluation in the present case owing to an insufficient amount of sample. Because of its rarity, the optimal treatment for adult patients with AMKL with t(1;22)(p13·3;q13·1)/RBM15-MKL1 is unclear. Infants or young children with the disease are usually treated with intensive myeloid-directed therapies, such as anthracycline and cytarabine regimens.9, 10 The benefit of consolidative allo-HSCT at the first complete remission is controversial.11-14 Therefore, we selected consolidative allo-HSCT for three reasons. First, AML that has developed as a second primary malignancy usually has poor prognosis. Second, patients with GCT-associated leukaemia have poor outcomes even when treated with aggressive contemporary chemotherapy. Third, chemotherapeutic regimens for adult patients are relatively less intensive than those for children with AMKL. In conclusion, we report the first documented case of an adult patient with AMKL with t(1;22)(p13·3;q13·1)/RBM15-MKL1 following a non-mediastinal GCT. The patient was successfully treated with conventional treatment for adult AML followed by consolidative allo-HSCT at the first remission. The pathogenesis of AMKL in this patient remains unclear. Further accumulation of data regarding the relationship between AMKL with t(1;22)(p13·3;q13·1) and non-mediastinal GCT is essential. We thank Y Aruga1, S Yoshimura and C Ikeda1 for performing flow cytometric analysis and T Takayama2 for performing RT-PCR analysis (1Departments of Clinical Laboratories and 2Clinical Support, National Cancer Center Hospital, Tokyo, Japan). The authors received no funding for this case report. YS and SM wrote the initial draft of the manuscript. SM is the attending physician of the patient. HM and AMM contributed to cytologic or pathologic interpretations. The other authors assisted in the preparation of the manuscript. The final version of the manuscript was approved by all authors. Dr. T Suzuki reports personal fees from Chugai Pharmaceutical, outside the submitted work. YS, SM, SC, MK, TF, HI, RH, TT, SF, .M, DM, AM, HM and KI have no competing interests.
Introduction: The understanding of neuroanatomy in emetic pathway has been re-evaluated recently, and the pharmacological care of patients, who suffer from cancer-related nausea and vomiting, has dramatically changed.Areas covered: This review will focus on innovative antiemetics in both aspects of basic pharmacology and evidence-based medicine by latest literatures in the palliative care field.Expert commentary: Although a number of studies have evaluated the clinical effectiveness of traditional antiemetics, such as metoclopramide, recommendations of these antiemetics are very weak due to a lack of well-designed randomized-control trials. Newer antiemetics have shown potential efficacy for the treatment of refractory nausea, which is non-responsive to traditional antiemetics. Olanzapine, asenapine, and mirtazapine are novel antipsychotics that target multiple neurotransmitter receptors, leading to a superior therapeutic outcome and fewer side effects. Cannabinoids can be said to be ‘innovative’ when used in this manner. Although this class of drugs has a possibility to effectively treat cancer-related emesis, major adverse effects were observed in recent systematic reviews and may limit its clinical application. Kampo medicines are widely used in Japan for the relief of gastrointestinal symptoms related to advanced cancer, and their mechanism of action is gradually becoming better understood. Innovative antiemetics are highly anticipated medications, and further investigations are warranted.
