Hong Jun Kim,Sun Kyung Baek,Chi Hoon Maeng,Si-Young Kim,Tae Sung Park,Jae Joon Han

Hong Jun Kim,Sun Kyung Baek,Chi Hoon Maeng,Si-Young Kim,Jae Joon Han,Department of Hematology and Medical Oncology,Kyung Hee University,Seoul 02447,South Korea

Tae Sung Park,Department of Laboratory Medicine,Kyung Hee University,Seoul 02447,South Korea

Abstract

Key words: Acute myeloid leukemia;Gastrointestinal stromal tumor;Imatinib;KMT2A;Myelodysplastic syndrome;Case report

INTRODUCTION

Gastrointestinal stromal tumors (GISTs),the most common mesenchymal tumors of the digestive tract,generally occur in the stomach (60%) and small intestine (35%)[1].The interstitial cells of Cajal were identified as the precursor cells,and the mutational activations in receptor tyrosine kinases,c-KIT,or platelet-derived growth factor receptor-α (PDGFRA) were involved in the main pathogenesis[1,2].This understanding of the pathogenesis led to the application of imatinib mesylate (IM),a c-KIT/PDGFRA tyrosine kinase inhibitor,for the treatment of advanced or metastatic GISTs[3].

Acute myeloid leukemia (AML) with 11q23 translocations involving theKMT2A(previously calledMLL) gene has been categorized as AML with recurring genetic abnormalities according to the 2016 World Health Organization classification[4].However,AML with 11q23 translocations should be classified as therapy-related AML (t-AML) in patients who have undergone prior treatment with cytotoxic agents,including topoisomerase inhibitors such as etoposide.

There have been only a few reports of AML that subsequently developed during IM treatment for GISTs.Herein,we describe a patient who developed AML with an 11q23 translocation while receiving IM for GISTs.

CASE PRESENTATION

A 63-year-old woman was diagnosed with a gastric GIST in March 2007 and underwent subtotal gastrectomy.The GIST recurred in the liver in April 2012,and she was administered IM 400 mg/d (Figure 1A).She was transferred to our department in May 2012,and a partial response was observed while IM treatment was continued for 42 mo (Figure 1B).In November 2015,she developed dyspnea with pancytopenia.Her hematological data were as follows:Hemoglobin level,4.0 g/dL;platelet count,27 ×109/L;and white blood cell count,1.05 × 109/L.Bone marrow examination showed hypercellularity with 70% blasts containing abundant cytoplasm,which were moderately-to-intensely basophilic,and some of them exhibited pseudopod formations and scattered fine azurophilic granules.

Leukemic blasts stained positively upon myeloperoxidase staining.However,the results of periodic acid-Schiff (PAS) and non-specific esterase (NSE) stains were negative.A chromosome study using a bone marrow sample showed a 46,XX karyotype with t(11;19)(q23;p13.1) in 22 out of 26 analyzed metaphase cells (Figure 2A).Fluorescencein situhybridization using the locus-specific indicator (11q23) gene break-apart probe showed positive rearrangement in 82% of interphase cells (Figure 2B).Reverse-transcription polymerase chain reactions subsequently confirmed theKMT2A/ELL transcript.

在當(dāng)前公路工程建設(shè)施工的監(jiān)管工作中，監(jiān)管人員的專業(yè)知識(shí)水平亟待提高。公路工程建設(shè)具有較強(qiáng)的復(fù)雜性，在不同地段的建設(shè)施工中，需要關(guān)注不同的注意事項(xiàng)。比如有的地段需要注重做好超前地質(zhì)預(yù)測(cè)預(yù)報(bào)工作，從而及時(shí)采取超前防護(hù)措施；有的地段需要強(qiáng)化地下水的檢測(cè)工作，以避免地下水因素影響公路建設(shè)質(zhì)量與安全。因此，監(jiān)管工作涉及到許多領(lǐng)域的內(nèi)容，要求監(jiān)管人員要提高自身的專業(yè)知識(shí)水平，才能滿足復(fù)雜條件下的公路工程建設(shè)施工監(jiān)管需要。此外，有些監(jiān)管人員的安全隱患敏感度較低，不能及時(shí)發(fā)現(xiàn)問題并予以糾正，影響著公路工程建設(shè)的安全系數(shù)[2]。

Figure1 Four-phase computed tomography images.

FINAL DIAGNOSIS

The final diagnosis of the presented case is AML with KMT2A/ELL rearrangement.

TREATMENT

The patient was not considered for intensive treatment because of poor performance status.Therefore,decitabine (20 mg/m2) was administered for 5 d.

OUTCOME AND FOLLOW-UP

She achieved a complete response with incomplete neutrophil recovery after two treatment cycles.Cytogenetic analysis showed a response with residual disease with the 46,XX,t(11;19)(q23;p13.1) karyotype remaining in 18% of metaphase cells.After the third decitabine treatment cycle,the disease relapsed with 66% blasts in the bone marrow,and cytogenic analysis showed an additional cytogenetic abnormality of del(13)(q12a14).The patient died of severe intracerebral hemorrhage 5 mo after diagnosis.

DISCUSSION

To the best of our knowledge,this is the first report of AML withKMT2Agene rearrangements in a patient with a GIST receiving IM treatment.Although there is no known mechanism by which IM causes acute leukemia,there have been reports supporting the speculation that IM may have a direct mutagenic effect on normal hematopoietic precursors.

Previously,there have been sporadic reports suggesting the association between hematologic malignancy and GISTs[5,6],and in the late 2000s,a non-random association between GISTs and myeloid leukemia was suggested in a retrospective study that enrolled 1892 patients with GISTs diagnosed between 1970 and 1996[7].Six(0.3%) of the study patients developed AML 1.7-21 years after the diagnosis of GISTs.Although IM was not available at the time of diagnosis,some of the patients could have received IM during the course of their treatments.In another report,12 of the 314 patients developed hematologic malignancies after the diagnosis of GISTs[8].These studies revealed no information onKMT2Agene rearrangements.

Although the long-term experience of IM in patients with chronic myeloid leukemia (CML) was reported as only one case (0.2%) of secondary AML on an IM treatment arm after more than 10 years of follow-up[9],there have been some reports of hematologic malignancies associated with IM treatment.Despite its low prevalence(0.5%),the emergence of 11q23 translocations has been reported in patients with CML during IM treatment.In two cases,the translocation companion for 11q23 was t(11;19)[10].Subsequent AML or MDS after treatment with second generation Bcr-Abl tyrosine kinase inhibitors including dasatinib,nilotinib,and ponatinib for CML was also reported[11-13].Spadaroet al[14]studied the bone marrow of 49 patients with unresectable or metastatic GISTs before and during IM treatment.They found that 8(16%) of 49 patients acquired chromosomal abnormalities,7 of whom had trisomy 8.Three patients with trisomy 8 developed myelodysplastic syndrome (MDS),and one patient who had monosomy 7 developed MDS with excess blasts,which rapidly transformed into AML.Ganjooet al[15]reported three cases of AML in patients with GISTs during IM treatment.Bone marrow cytogenetic analyses revealed trisomy 8 in one patient andMLLduplication in another patient.Summary of data of the patients with GISTs who subsequently developed AML is shown in Table 1.These findings suggest that IM may play a role in the acquisition of specific cytogenetic abnormalities associated with t-AML or MDS.

Figure2 A chromosome study and fluorescence in situ hybridization study.

The important issue in previous findings and the current case is whether IM has mutagenic effects on normal hematopoietic cells.Direct induction of an oncogene leading to the outgrowth of the transformed cell is one of the suggested pathogenic models for t-AML development in association with topoisomerase inhibitors[16].Topoisomerase inhibitors stabilize double-strand breaks and delay the ligation of free DNA ends during replication.Free DNA ends can easily recombine with DNA from another chromosome,which could produce specific gene fusions such asKMT2A/MLL-MLL3.IM induces apoptosis in human CML cell lines by inhibiting topoisomerase I and II[17],supporting the idea that similar pathophysiologies may be responsible for the development of t-AML with 11q23 translocations after IM treatment in patients with GISTs.Since the pathogenesis is not yet elucidated,it is impossible to clearly demonstrate that AML occurred due to IM administration even in the present case.The risk of leukemia may be increased with IM treatment alone,but may not be increased without a combination of IM and some predisposing genetic abnormalities,such as an isocitrate dehydrogenase mutation.

CONCLUSION

In conclusion,physicians should consider the potential risks of developing hematologic malignancies,including t-AML,in patients with GISTs receiving IM treatment.Systematic collection of data on the occurrence of t-AML or MDS during long-term IM treatment in patients with GISTs should be considered along with cytogenetic analysis to better understand the mechanism of t-AML or MDS during IM treatment.Finally,further studies are warranted to identify the off-target effects of tyrosine kinase inhibitors in association with the mechanisms of therapy-related myeloid neoplasms.

Table1 Summary of clinicopathologic data of the 11 patients with gastrointestinal stromal tumors who subsequently developed acute myeloid leukemia