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Non-Commercial Use Only Hematology Reports 2019; volume 11:7971 A variant of acute promyelo- cytic leukemia with Case Report Correspondence: Aya Nakaya, First Department of Internal Medicine, Kansai t(4;17)(q12;q21) showed two A 63-year-old man was admitted to our Medical University 2-5-1, Shin-machi, different clinical symptoms hospital because he had fever and thrombo- Hirakata, Osaka 573-1010, Japan. cytopenia. The initial laboratory evaluation Tel.: +81.72.804.2503. of peripheral blood revealed that his white E-mail: [email protected] 1 1 Takahisa Nakanishi, Aya Nakaya, blood cell count was 31500 cells/µL with 2 1 Yusuke Nishio, Shinya Fujita, 58.5% blast cells, hemoglobin was 10.1 Key words: acute promyelocytic leukemia, 1 1 Atsushi Satake, Yoshiko Azuma, g/dL, and platelet count was 1,100 cells/μL. t(4;17)(q12;q21), PML-RARA, all-trans Yukie Tsubokura,1 Ryo Saito,1 Coagulopathy was absent. Bone marrow retinoic acid. Akiko Konishi,1 Masaaki Hotta,1 examination showed a total nucleated cell Acknowledgments: the authors would like to Hideaki Yoshimura,1 count of 168,000 cells/µL with 31.6% 2 1 thank Ms. Nomura A for helpful discussions Yoshihiko Kadosaka, Kazuyoshi Ishii, myeloblasts and 28.0% promyeloblasts. and technical assistance. Tomoki Ito,1 Koji Tsuta,2 Most myeloblasts had regular nuclei, and a Shosaku Nomura1 few promyeloblasts contained azurophilic Contributions: Conception and design of the granules and Auer rods; however atypical 1First Department of Internal Medicine, study, or acquisition of data, or analysis and APL cells were <1% of the total cells interpretation of data: TN, AN, SF, AS, TN, and 2Department of Pathology and (Figure 1). Myeloperoxidase staining YT, YA, AK, MH, HY, KI, TI. Drafting the Laboratory Medicine, Kansai Medical revealed that both myeloblasts and article or revising it critically for important University, Osaka, Japan promyeloblasts were positive; however, the intellectual content: TN, AN, SN. Final staining was not as strong as the typical approval of the version to be submitted: AN, SN. APL pattern (Figure 2b). These morpholog- ical findings revealed features of both M2 Conflict of interest: the authors declare no Abstract and APL according to the French- potential conflict of interest. American-British (FAB) Classification, and only A 63-year-old man was diagnosed with a did not correlate with typical APL findings. Funding: none. rare variant of acute promyelocytic leukemia Blasts were positive for CD13/34/HLA- (APL) with t(4;17)(q12; q21) that showed DR, and negative for CD33 by flow cytom- Received for publication: 14 December 2018. atypical morphological features and two dif- etry. Wilms’ tumor gene 1 (WT1)use mRNA Accepted for publication: 5 July 2019. ferent clinical symptoms. He was started on levels in peripheral blood were 39×104 standard induction chemotherapy for acute This work is licensed under a Creative copies/μg RNA. Reverse transcription poly- myeloid leukemia, which decreased Commons Attribution-NonCommercial 4.0 merase chain reaction (RT-PCR) analysis myeloblast numbers; however, APL-like International License (CC BY-NC 4.0). was negative for PML-RARA, AML1- blasts remained. He then received a salvage MTG8, DEK-CAN, NUP98-HOXA9, CBFβ- ©Copyright: the Author(s), 2019 therapy that added all-trans retinoic acid MYH11, MLL-AF9, MLL-AF6, MLL-ENL, Licensee PAGEPress, Italy (ATRA). After ATRA commenced, APL-like minor-BCR, BCR-ABL, MLL-AF4, ETV6- Hematology Reports 2019; 11:7971 blasts disappeared and cytogenetic analysis AML1, E2A-PBX1, SIL-TAL1, FLT-3, and doi:10.4081/hr.2019.7971 became normal. However, myeloblasts sub- C-KIT (multi-kinase screening exam). Thus, sequently increased, and he became resistant. he was initially diagnosed with acute In summary, this patient exhibited two differ- myeloid leukemia with maturation accord- RNA; thus, he was diagnosed with induc- ent clinical courses of acute myeloid ing to the World Health Organization classi- tion failure. From the morphological fea- leukemia and APL. fication from 2008 (M2 in FAB). tures and FISH results, we diagnosed him as An induction chemotherapy regimen an APL variant with t(4;17)(q12;q21). We consisting of idarubicin (12 mg/m2/d; days assumed there were two kind of blast stem Non-commercial1-3) and cytarabine (100 mg/kg/d; days 1-7) cells of different origin, and that following Introduction was administered (Figure 1). During induc- initial treatment, blasts from the M2 origin decreased, while blasts of APL origin Acute promyelocytic leukemia (APL) is tion therapy, the karyotype analysis from characterized by the PML-RARA fusion diagnosis arrived and revealed an abnor- remained. gene that results from t(15;17)(q24.1;q21.2) mality: 46, XY, t(4;17)(q12;q21) in 6/20 We then started a salvage treatment reg- cells (Figure 2c). After induction therapy, imen to be effective for both M2 and APL: rearrangements. PML-RARA is a specific 2 fusion transcript that is present in >95% of blasts in peripheral blood disappeared; mitoxantrone (7 mg/m /d; days 1–3) and 2 APL cases.1 Additionally, variant rearrange- however, 3.7% of myeloblasts and 24.0% of cytarabine (200 mg/m /d; days 1–5) were 2 ments involving RARA have previously promyeloblasts remained in bone marrow. added to ATRA (25 mg/m ). With the sal- been identified, and partners including Karyotype analysis revealed: 46, XY, vage therapy, he achieved hematological PLZF, NPM1, NUMA, SAT5b, PRKAR1A t(4;17)(q12;q21) in 12/20 cells. remission in peripheral examination, FISH and FIP1L1 have been found.2 The RARA Fluorescence in situ hybridization (FISH) for PML2:RARA3 was 0%, and karyotype fusion partner plays important roles in the of PML2:RARA3 was 34% positive (2 analysis was normal in bone marrow. morphology, clinical features, and response intact PML signals and 3 split RARA sig- However, blasts in bone marrow remained to all-trans retinoic acid (ATRA). In this nals; Figure 2d). at 19.5%, the morphological features of case report, we document a rare Vysis LSI PML/RARA dual-color, dual- which were normal myeloblasts without t(4;17)(q12;q21) APL variant that showed fusion translocation probe was used for azurophilic granules or Auer rods. WT1 atypical morphologic features and two dif- FISH analysis (Vysis). WT1 mRNA levels mRNA levels in peripheral blood were ferent clinical courses. in peripheral blood were 5.4×104 copies/μg 2.4×104 copies/μg RNA. Blasts were posi- [Hematology Reports 2019; 11:7971] [page 49] Case Report tive for CD13/34/HLA-DR by flow cytom- for APL clones with t(4;17)(q12;q21). ever, it showed contradiction after salvage etry. Adding to them, CD71 and gly- However, it is uncertain whether the differ- therapy. It decreased and remained low lev- cophorin-A were positive, those were not ent clinical features happened accidentally els, although bone marrow myeloblasts positive at the diagnosis. The second sal- or were related to cytogenetic abnormali- increased (Figure 1). vage treatment (high dose cytarabine: 4000 ties. We tried to use WT1 mRNA levels in In conclusion, we report a variant APL mg/m2/d; days 1–5) was started with contin- peripheral blood as a biomarker. We expect- with t(4;17)(q12;q21) that demonstrated uous ATRA. After this treatment, 45% of ed it would reflect M2 clones, however, it two different clinical symptoms. However, blasts, whose morphology was typical did not. Our results showed that it respond- the relationship between genetic abnormali- myeloblast, remained in bone marrow, and ed in proportion to the number of bone mar- ties and clinical symptoms for this patient is WT1 mRNA levels in peripheral blood were row myeloblasts in induction therapy, how- unclear. Further studies are required to elu- 3.3×104 copies/μg RNA. Thus, he was diag- nosed as resistant to second salvage treat- ment. At this time, he became so weak that he could not continue aggressive chemotherapy; thus, we changed to pallia- tive therapy. The patient died of pneumonia eight months after diagnosis. Discussion and Conclusions Variant fusion genes containing RARA are frequently associated with APL. The FIP1L1-RARA fusion gene was reported to result from t(4;17)(q12;q21).3,4 There are only two APL cases with FIP1L1-RARA. Kondo et al.3 reported a case of a 90-year-old woman where they found split RARA sig- nals without a PML-RARA fusion signal by use FISH. They examined the effect of FIP1L1- RARA on ATRA response and found that FIP1L1-RARA was ATRA responsive, simi- lar to patients with PML-RARA. Consistent with this result, the patient achieved a com- plete remission by oral ATRA alone (50 4 mg/d). Menezes et al. reported a case of a Figure 1. Clinical course. 77-year-old woman who was started on ATRA. The case revealed morphologically typical APL. Thus, they diagnosed her as PML-RARA-negative APL and started an APL protocol. Although we did not confirm the presence of a FIP1L1-RARA fusion gene in our case, the patient had the same karyotype abnormality as the two previous cases. Although the precise role of FIP1L1- RARA is unknown, the previousNon-commercial cases reported that patients with FIP1L1-RARA showed APL-like clinical symptoms. However, our case revealed atypical APL morphology at diagnosis and different clin- ical features. The most interesting point of our case is that it showed two different clin- ical characteristics. The induction therapy was standard regimen for acute myeloid leukemia and was effective for the M2 clone, as the number of blasts in bone mar- row decreased. However, the APL clone remained, as the number of karyotype Figure 2. Morphological and cytogenetic analysis.
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