Acute Myeloid Leukemia with t(11;17)(q23;q21)

    

    

    Figure 10:  Inmunophenotype on bone marrow: the blast population was
characterized by markers CD45 +, + CD13, CD33 +, CD117 + DR - CD56 +
CD11c +, CD32 +, CD64 +, CD38 +, MPO +, CD34-, CD11b-, CD16-, CD14-,
CD4 -.
    
    

The cytogenetics and molecular studies on BM were:

• Rearrangement PML-RARα (q21; q22) t(15;17) (RT-PCR): negative.
• FISH: nucish 15q22 (PMLx2), 17q21 (RARax3) [23/100] (Figure 11).



Figure 11: Technique of FISH on the bone marrow aspirate showing a signal on chromosome 11.

    

    

    Figure 11:  Technique of FISH on the bone marrow aspirate showing a signal
on chromosome 11.
    
    

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Karyotype: 46, XX, del(5)(q13q31), t(11;17)(q23;q21) [20/30] / 46, XX [10/30] (Figure 12).



Figure 12: Cytogenetics of BM which confirms the t(11;17))(q23;q21), in addition to one of the (5q) (q13q31) in 20/30 metaphases.

    

    

    Figure 12:  Cytogenetics of BM which confirms the t(11;17))(q23;q21), in
addition to one of the (5q) (q13q31) in 20/30 metaphases.
    
    

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Rearrangement PLZF-RARα positive (RT-PCR) (Figure 13).



Figure 13: Rearrangement PLZF-RARa: RT-PCR that demonstrates the presence of a band of 269bp; C-: negative control, P:patient, MPM: molecular weights marker.

    

    

    Figure 13:  Rearrangement PLZF-RARa: RT-PCR that demonstrates the
presence of a band of 269bp; C-: negative control, P:patient, MPM: molecular
weights marker.
    
    

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Rearrangement RARα-PLZF positive (RT-PCR).

Diagnostic: Acute Promyelocytic Leukemia with variant translocation RARα (WHO classification).

Follow up: on 6/28/2013 the patient began induction chemotherapy (Idarubicin, 12 mgr/m2/d on days 1, 3 and 5; ARA-C, 500 mg/m2twice daily on days, 1, 3, 5 and 7 and Etoposide, 100 mg/ m2/d on days 1 through 3) + ATRA, 45 mg/m2day divided into 2 doses till achieving complete remission).

BMA on day + 37 post-induction showed a 3% blast cells, residual disease (MRD) by flow cytometry of 0.4% and a karyotype: 46, XX, del(5)(q13q31), t(11;17)(q23;q21) [4/50] / 46, XX [46/50]; and PLZFRARα rearrangement was positive.

After that treatment of consolidation was started (2 cycles of ARA-C, 500 mg/m2 / 12 h, on day 1 to 6; Mitoxantrone 12 mg/m2/d on days4, 5 and 6 and ATRA, 45 mg/m2/d divided into two doses, on day 1 to 15, after which normalized the karyotype, the MRD: 0.072% and the PLZF-RARα and RARα-PLZF rearrangements were negative.

In February 2013 allogeneic hematopoietic stem cell transplantation (HSCT) obtained from peripheral blood of her sister with myeloablative conditioning was done, without significant adverse events.

Discussion

APL is included among leukemias with recurrent cytogenetic anomalies and characterized by translocation t(15;17)(q22;q12) PMLRARα. However, in 10%of cases, this alteration is not detected by cytogenetic techniques, either by technical problems, submicroscopic chromosomal insertions or more complex rearrangements. In spite of this, an accurate diagnosis can be done since the PML-RARa transcript would be positive.

In distinction to, approximately 2% of cases of APL carry a fusion gene alternative to the PML (PLZF with t(11;17)(q23q21), NPM1 with t(5;17), NuMA with t(11;17)(q13q21), FIPIL1 with the t(4;17), BCORSTAT5b , the t(X;17), PRKAR1A with rearrangements of 17q).

The most frequent of all of them is the PLZF (promielocytic zinc finger) [1]; this gene also known as Zbtb16 was described at first time in 1993 in a Chinese patient who suffered an atypical APL; It’s located on chromosome 11q23 among a cluster of family zinc finger genes, coding of proteins with high content of cysteine and histidine that require one or more unions of zinc to stabilize its structure [2]; It has a high capacity repressor of transcription and his expression is very high in stem cells and progenitor, but decreases as cells get madure.

The clinical relevance of these variants of APL is without a doubt the different response to treatment with ATRA and Arsenic Trioxide, due to all of them are sensitive with the exception of carriers of the rearrangements with PLZF and STAB5b genes.

In cases of APL with t(11;17)(q23q21) there is evidence of this resistance both in vivo as in vitro, particularly in those patients who have the reverse rearrangement RARα-PLZF, whose product would play an important role in mediating resistance to ATRA [1,3].

Since 1993 there have been reported 16 cases of patients with this variant translocation [4-7], with a very low incidence in women (14 men versus two women) and frequent coagulopathy (11 patients). t(11;17) was detected in all of them by conventional cytogenetics or by FISH, and molecular assays was positive to the PLZF-RARα and RARα-PLZF rearrangements. According to treatment, 14 received ATRA, 13 with concomitant chemotherapy following different schemes; 4 were undergone to Allo-HSCT and one to Auto-HSCT, getting responses of variable duration in all patients.

In our case disease onset was peculiar, with “sub-acute” presentation, absence of hemorrhagic diathesis and acute renal failure.

Relationship between treatment with stimulating factors and kidney damage lead us to think that the pro-inflammatory or thrombotic effects of the G-CSF could play some role. However, it was not demonstrated the existence of a renal thrombosis, or data that support a clear endothelial damage. In the other hand one reported case was treated with the association of ATRA plus G-CSF with good results [8] and our patient resolved her kidney disease with chemotherapy.

15 days before to diagnosis of APL the patient received multiple plasma transfusions and dialysis that could have masked hemostasis alterations in this type of leukemia; even so, we detected signs of fibrinolysis days prior to the treatment.

A history of rheumatoid arthritis treated with Methotrexate and presence of a del5q in the karyotype, allows us to speculate with the possible existence of a myelodysplasia prior to the development of leukemia or relate both diseases. In this regard, we do not have data that showing the first possibility.

Otherwise, majority of studies that have investigated the association of autoimmune diseases and their treatments with AML, have described an increase in the risk of developing it, although does not reach statistical significance, so considering these leukemia as related to therapy (t-AML) it does not seem appropriate [9].

In the PETHEMA (Spanish Protocol for the study of malignant hemopathies) registry, there are 1771 patients diagnosed with APL recorded with assessable cytogenetic or molecular studies from 1996 to 2015, of which only two patients presented the variant translocation t(11;17)(q23; q21)(the present case and other), representing the 0.1% of the total. Both of them were treated with chemotherapy plus ATRA achieving a molecular complete response with a follow-up in our case of 38 months.

Morphological diagnosis of the variant APL´ is always challenging; in the literature many cases were described as an hybrid between AML-M2 and M3 (FAB classification) [7] and the blasts, were defined as cells blocked at an intermediate stage promyelocytemyelocyte, with a nucleus of mature appearance and condensed chromatin, as well as presence of dysplastic traits associated (hypo granulation, nuclear pseudo pelger). Description of the blasts which makes the WHO classification of 2008 does not differ much from these initial descriptions [10].

However, immunophenotypic profile of APL is independent of underlying cytogenetic variations, a quick and essential tool for the diagnosis [11] which of course must be completed with the cytogenetic and molecular studies.

References

1. Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocyticleukemia. Frontiers in oncology. 2011; 35: 1-8.
2. Suliman BA, Xu D, Williams BR. The promyelocytic leukemia zinc finger protein: two decades of molecular oncology. Front Oncol. 2012; 2: 74.
3. Guidez F, Parks S, Wong H, Jovanovic JV, Mays A, Gilkes AF, et al. RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2007; 104: 18694-18699.
4. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M et al. On behalf of Group e Francais de Cytogénétique Hematologique, Groupe Francaisd’ Hematologie Cellulaire, UK Cancer Cytogenetics Group, and BIOMED 1 European Community-Concerted. Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies” Characterization of acute promyelocyticleukemia cases lacking the classic t(15;17): results of the European Working Party. Blood. 2000; 96: 1297-1308.
5. Rohr SS, Flores Pelloso LA, Borgo A, De Nadai LC, Yamamoto M, Rego EM et al. Acute promyelocyticleukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations. Med Oncol. 2011; 266-271.
6. Cassinat B, Guillemot I, Moluçon-Chabrot C, Zassadowski F, Fenaux P, Tournilhac O, et al. Favourable outcome in an APL patient with PLZF/RARalpha fusion gene: quantitative real-time RT-PCR confirms molecular response. Haematologica. 2006; 91: ECR58.
7. Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood. 1995; 85: 1083-1094.
8. Jansen JH, de Ridder MC, Geertsma WM, Erpelinck CA, van Lom K, Smit EM, et al. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood. 1999; 94: 39-45.
9. Ramadan SM, Fouad TM, Summa V, Hasan SKh, Lo-Coco F. Acute myeloid leukemia developing in patients with autoimmune diseases. Haematologica. 2012; 97: 805-817.
10. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008; Vol 2. Geneva (Switzerland) WHO Press.
11. Dong HY, Kung JX, Bhardwaj V, McGill J. Flow cytometry rapidly identifies all acute promyelocytic leukemias with high specificity independent of underlying cytogenetic abnormalities. Am J Clin Pathol. 2011; 135: 76-84.