Skip to main content
Download PDF

Acute promyelocytic leukemia with the translocation t(15;17)(q22;q21) associated with t(1;2)(q42~43;q11.2~12): a case report

Journal of Medical Case Reports volume 10, Article number: 203 (2016) Cite this article

Abstract

Background

Acute promyelocytic leukemia is characterized by a typical reciprocal translocation t(15;17)(q22;q21). Additional chromosomal abnormalities are reported in only 23–43 % of cases of acute promyelocytic leukemia.

Case presentation

Here we report the case of a 46-year-old Syrian Alawis woman with acute promyelocytic leukemia with the typical t(15;17) translocation, but with a second clone presenting a t(1;2)(q42~43;q11.2~12) translocation as an additional abnormality. To the best of our knowledge, an association between these chromosomal abnormalities has not previously been described in the literature. Our patient started treatment with all-trans retinoic acid 10 days after diagnosis but died the same day of treatment initiation due to hemolysis, intracranial hemorrhage, thrombocytopenia, and disseminated intravascular coagulation.

Conclusion

The here reported combination of aberrations in a case of acute promyelocytic leukemia seems to indicate an adverse prognosis, and possibly shows that all-trans retinoic acid treatment may be contraindicated in such cases.

Peer Review reports

Background

Acute promyelocytic leukemia (APL) accounts for 5–10 % of acute myeloid leukemia (AML) and is a very distinct subtype (subtype M3) with regard to clinical, morphologic, and prognostic features. The median age of patients with APL is 30–40 years [1]. APL is characterized by the reciprocal translocation t(15;17)(q22;q21) in ~90 % of cases [1]. At the molecular level, as a result of the t(15;17) translocation, the gene for retinoic acid receptor alpha (RARA) on 17q21 fuses with a transcription factor gene (promyelocytic leukemia or PML) on 15q22, giving rise to a PML/RARA gene fusion product [2]. This PML/RARA fusion gene transcript is known to play a pivotal role in the pathogenesis of APL and the sensitivity to all-trans retinoic acid (ATRA) [3]. Approximately 70–80 % of patients with newly diagnosed APL carrying PML/RARA achieve long-term remission; however, some patients still have a poor outcome [3].

Balanced chromosomal rearrangements are detected in 25–30 % of adults with de novo AML [3, 4] and have attracted a great deal of attention because of specific translocations and inversions associated with the prognosis for these patients. Additional chromosomal aberrations (ACAs) associated with t(15;17) are reported in 23–43 % of APL cases [5–7]. The clinical impact of these ACAs has not yet been clearly elucidated.

Here we report the case of a patient exhibiting an immunophenotype consistent with APL, a t(15;17)(q22;q21) translocation, and a t(1;2)(q42~43;q11.2~12) translocation, with the clinical characteristics of hyperleukocytosis (HL), thrombocytopenia, and disseminated intravascular coagulation (DIC). Our patient did not benefit from ATRA treatment and died due to hemolysis, intracranial hemorrhage, thrombocytopenia, and DIC.

Case presentation

A 46-year-old Syrian Alawis woman without a significant personal or familial medical history presented with a 1-month history of multiple sclerosis, fatigue, loss of weight, fever, and an elevated white blood cell (WBC) count. An initial evaluation revealed that she had anemia (8.5 g/dL), leukocytosis (total leukocyte count 134 × 109/L), and thrombocytopenia (23 × 109/L). She was pale and did not have lymphadenopathy.

Our patient was transferred to the hospital because she was unconscious and making noise during breathing. Novel hematological parameters included anemia (8.2 g/dL), thrombocytopenia (29 × 109/L), leukocytosis (229 × 109/L), a plasma concentration of fibrinogen of 37 mg/dL (normal value, 200–400 mg/dL), and a prothrombin time of 18 s (normal value, 10.0–13.0 s). She received several blood transfusions. Our patient stayed in the hospital for 1 week. On the same day of treatment initiation with ATRA (45 mg/m2 daily dose), our patient died, 10 days after her diagnosis. An autopsy revealed death was due to hemolysis, intracranial hemorrhage, thrombocytopenia, and DIC. Cytogenetic and immunophenotyping analyses were also carried out. Our patient was diagnosed with APL according to the World Health Organization (WHO) classification and was considered high risk based on her WBC. Her brother gave consent for a scientific evaluation of her case and the study was approved by the ethical committee of the Atomic Energy Commission, Damascus, Syria.

A chromosome analysis using GTG-banding was performed according to standard procedures [8] before treatment with ATRA and revealed a karyotype of 46,XX,t(15;17)[8]/46,XX,t(1;2),t(15;17)[11]/46,XX [1] (Fig. 1). Further studies were performed based on molecular cytogenetics (Figs. 2 and 3). Dual-color fluorescence in situ hybridization (D-FISH) using a specific probe for PML and RARA (Abbott Molecular/Vysis, Des Plaines, IL, USA) revealed the presence of the PML/RARA fusion gene on der(15) (Fig. 2). Chromosomes 1, 2, 15, and 17 were studied with Whole Chromosome Paint (WCP) probes (MetaSystems, Altlussheim, Germany) [8], which did not provide any information on the cryptic translocations (data not shown). Array-proven high-resolution multicolor banding (aMCB) [9] was performed using probes corresponding to chromosomes 1 and 2, which were identified by GTG-banding as being involved (Fig. 3). The following final karyotype was determined prior to chemotherapy treatment using a fluorescence microscope (AxioImager.Z1 mot, Carl Zeiss Ltd., Welwyn Garden City, UK) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes plus the counterstain DAPI (4',6- diamino-2-phenylindole). Image capture and processing were performed using an ISIS imaging system (MetaSystems, Altlussheim, Germany):

Fig. 1
figure 1

GTG-banding revealed the following karyotype: 46,XX,t(1;2)(q42~43;q11.2~12),t(15;17)(q22;q21). All derivative chromosomes are marked and highlighted by arrow heads

Full size image
Fig. 2
figure 2

Fluorescence in situ hybridization using an LSI PML/RARA dual-color translocation probe for RARA (green) and PML (red) confirmed the presence of the PML/RARA fusion gene on der(15). # chromosome, der derivative chromosome

Full size image
Fig. 3
figure 3

Array-proven multicolor banding (aMCB) was used to determine which chromosomes were involved in the present case. Each lane shows the results of aMCB analysis using probe sets for chromosomes 1 and 2. The normal chromosomes are shown in the first column and the derivatives of the two chromosomes in the subsequent ones. The unstained regions on the derivative chromosomes are shown in gray. # chromosome, der derivative chromosome

Full size image

46,XX,t(15;17)(q22;q21)[8]/46,XX,t(1;2)(q42~43;q11.2~12),t(15;17)(q22;q21)[11]/46,XX[1].

Image capture and processing were performed using an ISIS imaging system (MetaSystems).

Immunophenotyping was performed using a general panel of fluorescent antibodies against the following antigens typical for different cell lineages and cell types: CD1a, CD2, CD3, CD4, CD5, CD8, CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD19, CD20, CD22, CD23, CD32, CD33, CD34, CD38, CD41a, CD45, CD56, CD57, CD64, CD103, CD117, CD123, CD138, CD209, CD235a, and CD243. In addition, antibodies to kappa and lambda light chains, IgD, sIgM, and HLADr were tested. All antibodies were purchased from BD Biosciences, San Jose, CA, USA. Samples were analyzed on a BD FACSCalibur™ flow cytometer. Autofluorescence, viability, and isotype controls were included. Flow cytometric data acquisition and analysis were conducted by BD Cellquest™ Pro software. Flow cytometric analysis of a peripheral blood specimen from our patient characterized this case as APL according to WHO classifications. The abnormal cell population (97 % of tested cells) was positive for MPO++, CD45+dim, CD34−, HLADr−, CD33+, CD13+, CD16−, CD64+, CD15+dim, and CD14−.

Discussion

According to the literature, APL is characterized by the t(15;17) translocation that generates the PML/RARA fusion gene and induces sensitivity to ATRA [3]. To date, 1402 APL cases with t(15;17) have been reported in the Mitelman Database [10]. Only three cases demonstrated involvement of a t(1;2) translocation in addition to t(15;17): the first case was a t(1;2)(p22;q31), the second a t(1;2)(q43;p21), and the third a t(1;2;3)(p36;q21;p21) [10]. To the best of our knowledge, this is the first report of a case of APL with t(15;17)(q22;q21) associated with t(1;2)(q42~43;q11.2~12).

In addition, chromosomal band 1q42 is reported in two cases, 1q43 in one, and 2q12 in one case in the Mitelman Database [10]. Chromosomal band 2q11.2 has not yet been reported in APL [10].

Additional chromosome aberrations to t(15;17) have been observed in 23–43 % of APL cases, but their prognostic significance remains controversial [5–7]. The majority of evidence supports the concept that patients with additional chromosomal abnormalities have the same favorable prognosis as patients with t(15;17) alone [5, 7]; however, a previous study has found that chromosomal abnormalities in addition to t(15;17) are associated with a poorer prognosis [6].

In contrast, another study showed that additional chromosomal abnormalities are associated with a slightly better prognosis (no effect on overall survival) [11]. Moreover, some reports found that ACAs had no effect on prognosis [7, 12]. However, some newly diagnosed patients and patients with relapsing disease with identical cytogenetic changes showed an adverse outcome [6, 13]. The most frequent secondary aberration to t(15;17) is trisomy 8 (+8). Other additional chromosome changes include del(9q); del(7q); abnormalities of chromosome 1, 3, and 6; trisomy 21; and isochromosome of the long arm of the derivative chromosome 17 originating from the translocation t(15;17) [ider(17)(q10)t(15;17) or ider(17q)] [5].

Zaccaria et al. [14] reported that a patient with APL associated with a PML/RARA fusion gene on chromosome 17 responded poorly to ATRA treatment. However, complete remission rates are usually 87–94 % using ATRA alone at a classical dosage of 45 mg/m2/day for 4–6 weeks [15].

Thus, it is not clear whether the novel cytogenetic findings in the present case relate to a slower than usual response to ATRA induction therapy. Furthermore, the presence of specific ACAs associated with translocation t(15;17) might be indicative of a poor outcome.

Clinically, APL has a high frequency of hemorrhage due to DIC, which contributes to the high mortality rates of this disease [16, 17]. However, DIC is a coagulopathy induced by the formation of small clots consuming coagulation proteins and platelets, resulting in disruption of normal coagulation and severe bleeding tendency [18]. Acute DIC is characterized by a decrease in platelet count and fibrinogen, an elevation of D-dimers, and prolongation of prothrombin time and activated partial thromboplastin time; it occurs in 30–40 % of HL-AML [19].

Five to twenty percent of patients with untreated AML present with HL, that is, WBC counts of >100,000 cells/mL [20]. HL may cause three main complications: (i) DIC, (ii) tumor lysis syndrome, and (iii) leukostasis. These may cause life-threatening complications in patients with AML [19]. Early mortality in this patient group is higher than in AML without HL and ranges from 6 % versus 1 % after 1 week and 13 % versus 7 % after 30 days [19]. The main causes of death are bleeding, thromboembolic events, and neurologic and pulmonary complications [21]. HL is a negative prognostic factor, as indicated by significantly shorter overall survival [22].

Approximately 44–50 % of patients with AML with a WBC count >100,000 cells/mL have a high probability of leukostasis. Organs most frequently affected are lung, brain, and kidneys [20]. As well as the tissue damage caused by stasis and leukocyte infiltration, hemorrhage and thromboembolic events are frequent and relevant complications of leukostasis [18].

Conclusions

Here, we have described a case of APL characterized by HL, thrombocytopenia, and DIC associated with translocation t(15;17) and translocation t(1;2)(q42~43;q11.2~12). Because translocation t(15;17) is normally successfully treatable with ATRA even when ACAs are present, the adverse outcome in the present patient was surprising. Thus, the translocation t(1;2)(q42~43;q11.2~12) may be a new predictor for a more severe course of APL.

Abbreviations

ACAs, additional chromosomal aberrations; aMCB, array-proven high-resolution multicolor banding; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; DAPI, (4′,6- diamino-2-phenylindole); D-FISH, dual-color fluorescence in situ hybridization; DIC, disseminated intravascular coagulation; HL, hyperleukocytosis; PML, promyelocytic leukemia gene; RARA, retinoic acid receptor alpha gene; WBC, white blood cell; WHO, World Health Organization

References

  1. Avvisati G, Lo Coco F, Mandelli F. Acute promyelocytic leukemia: clinical and morphological features and prognostic factors. Semin Hematol. 2001;38:4–12.

    Article  CAS  PubMed  Google Scholar 

  2. Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani F, Peschle C, Nicoletti I, Pelicci PG. The acute promyelocytic leukemia-specific PML-RAR α fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993;74:423–31.

  3. Manola KN, Karakosta M, Sambani C, Terzoudi G, Pagoni M, Gatsa E, Papaioannou M. Isochromosome der(17)(q10)t(15;17) in acute promyelocytic leukemia resulting in an additional copy of the RARA-PML fusion gene: report of 4 cases and review of the literature. Acta Haematol. 2010;123:162–70.

  4. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100:4325–36.

  5. De Lourdes CM, Borri D, Proto-Siqueira R, Moreira ES, Alberto FL. Acute promyelocytic leukemia with t(15;17): frequency of additional clonal chromosome abnormalities and FLT3 mutations. Leuk Lymphoma. 2008;49:2387–9.

    Article  Google Scholar 

  6. Hiorns LR, Swansbury GJ, Mehta J, Min T, Dainton MG, Treleaven J, Powles RL, Catovsky D. Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukemia. Br J Haematol. 1997;96:314–21.

  7. Schoch C, Haase D, Haferlach T, Freund M, Link H, Lengfelder E, Loffler H, Büchner T, Fonatsch C. Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15; 17)(q22;q21): a report on 50 patients. Br J Haematol. 1996;94:493–500.

  8. AL-achkar W, Wafa A, Nweder MS. A complex translocation t(5;9;22) in Philadelphia cells involving the short arm of chromosome 5 in a case of chronic myelogenous leukemia. J Exp Clin Cancer Res. 2007;26:411–5.

    CAS  PubMed  Google Scholar 

  9. Liehr T, Heller A, Starke H, Rubtsov N, Trifonov V, Mrasek K, Weise A, Kuechler A, Claussen U. Microdissection based high resolution multicolor banding for all 24 human chromosomes. Int J Mol Med. 2002;9:335–9.

  10. Mitelman Database of Chromosome Aberrations in Cancer. 2015. http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed 09 Aug 2015.

  11. Slack JL, Arthur DC, Lawrence D, Mrozek K, Mayer RJ, Davey FR, Tantravahi R, Pettenati MJ, Bigner S, Carroll AJ, Rao KW, Schiffer CA, Bloomfield CD. Secondary cytogenetic changes in acute promyelocytic leukemia: prognostic importance in patients treated with chemotherapy alone and association with the iron 3 breakpoint of the PML gene. J Clin Oncol. 1997;165:1786–95.

  12. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A. The importance of iagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood. 1998;1998(92):2322–33.

  13. Xu L, Zhao WL, Xiong SM, Su XY, Zhao M, Wang C, Gao YR, Niu C, Cao Q, Gu BW, Zhu YM, Gu J, Hu J, Yan H, Shen ZX, Chen Z, Chen SJ. Molecular cytogenetic characterization and clinical relevance of additional, complex and/or variant chromosome abnormalities in acute promyelocytic leukemia. Leukemia. 2001;15:1359–68.

  14. Zaccaria A, Valenti A, Toschi M, Salvucci M, Cipriani R, Ottaviani E, Martinelli G. Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukaemia. Cancer Genet Cytogenet. 2002;138:169–73.

  15. Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol 2011;29:495–503.

    Article  PubMed  Google Scholar 

  16. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–15.

    Article  CAS  PubMed  Google Scholar 

  17. Kwaan HC, Wang J, Boggio LN. Abnormalities in hemostasis in acute promyelocytic leukemia. Hematol Oncol. 2002;20:33–41.

    Article  PubMed  Google Scholar 

  18. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and leukapheresis: practice management. Blood Rev. 2012;26:117–22.

    Article  PubMed  Google Scholar 

  19. Rollig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015;125:3246–52.

    Article  PubMed  Google Scholar 

  20. Pastore F, Pastore A, Wittmann G, Hiddemann W, Spiekermann K. The role of therapeutic leukapheresis in hyperleukocytotic AML. PLoS One. 2014;9, e95062.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Atallah E, Cortes J, O’Brien S, et al. Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia. Blood 2007;110:3547–51.

    Article  CAS  PubMed  Google Scholar 

  22. Löwenberg B, Suciu S, Archimbaud E, et al. Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood. 1997;90:2952–61.

Download references

Acknowledgements

We thank Prof. I. Othman, the Director General of the Atomic Energy Commission of Syria (AECS) and Dr N. Mirali, Head of the Molecular Biology and Biotechnology Department, for their support. This work was supported by the AECS.

Funding

This work was supported by the Atomic Energy Commission of Syria (AECS).

Authors’ contributions

AW, FM, AA and WA performed banding cytogenetics and provided the clinical data; AW, FM, and TL performed the molecular cytogenetic analyses; AW and FM did the immunophenotyping. AW and TL drafted the paper and all authors worked on the final version of the paper. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Written informed consent was obtained from the patient’s brother for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Author information

Authors and Affiliations

  1. Human Genetics Division, Department of Molecular Biology and Biotechnology, PO Box 6091, Damascus, Syria

    Abdulsamad Wafa, Faten Moassass, Ayman Al-Ablog & Walid Al-Achkar

  2. Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, D-07743, Jena, Germany

    Thomas Liehr

Authors
  1. Abdulsamad Wafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faten Moassass
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Liehr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayman Al-Ablog
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walid Al-Achkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Walid Al-Achkar.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wafa, A., Moassass, F., Liehr, T. et al. Acute promyelocytic leukemia with the translocation t(15;17)(q22;q21) associated with t(1;2)(q42~43;q11.2~12): a case report. J Med Case Reports 10, 203 (2016). https://doi.org/10.1186/s13256-016-0982-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13256-016-0982-8

Keywords

Journal of Medical Case Reports

ISSN: 1752-1947