Acute Myeloid Leukemia with t(11;17)(q23;q21) (2024)

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

  Figure 13:  Rearrangement PLZF-RARa: RT-PCR that demonstrates thepresence of a band of 269bp; C-: negative control, P:patient, MPM: molecularweights marker. 
 See Also
A variant acute promyelocytic leukemia with t(11;17) (q23;q12); ZBTB16-RARA showing typical morphology of classical acute promyelocytic leukemia

Rearrangement RARα-PLZF positive (RT-PCR).

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

Follow up: on 6/28/2013 the patient began inductionchemotherapy (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 dosestill achieving complete remission).

BMA on day + 37 post-induction showed a 3% blast cells, residualdisease (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 PLZFRARαrearrangement was positive.

After that treatment of consolidation was started (2 cycles ofARA-C, 500 mg/m2 / 12 h, on day 1 to 6; Mitoxantrone 12 mg/m2/don days4, 5 and 6 and ATRA, 45 mg/m2/d divided into two doses, onday 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 celltransplantation (HSCT) obtained from peripheral blood of hersister with myeloablative conditioning was done, without significantadverse events.

Discussion

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

In distinction to, approximately 2% of cases of APL carry a fusiongene alternative to the PML (PLZF with t(11;17)(q23q21), NPM1with 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 zincfinger) [1]; this gene also known as Zbtb16 was described at first timein 1993 in a Chinese patient who suffered an atypical APL; It’s locatedon chromosome 11q23 among a cluster of family zinc finger genes,coding of proteins with high content of cysteine and histidine thatrequire one or more unions of zinc to stabilize its structure [2]; It hasa high capacity repressor of transcription and his expression is veryhigh in stem cells and progenitor, but decreases as cells get madure.

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

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

Since 1993 there have been reported 16 cases of patients with thisvariant translocation [4-7], with a very low incidence in women (14men versus two women) and frequent coagulopathy (11 patients).t(11;17) was detected in all of them by conventional cytogenetics orby FISH, and molecular assays was positive to the PLZF-RARα and RARα-PLZF rearrangements. According to treatment, 14 receivedATRA, 13 with concomitant chemotherapy following differentschemes; 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 renalfailure.

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

15 days before to diagnosis of APL the patient received multipleplasma transfusions and dialysis that could have masked hemostasisalterations in this type of leukemia; even so, we detected signs offibrinolysis days prior to the treatment.

A history of rheumatoid arthritis treated with Methotrexate andpresence of a del5q in the karyotype, allows us to speculate with thepossible existence of a myelodysplasia prior to the development ofleukemia or relate both diseases. In this regard, we do not have datathat showing the first possibility.

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

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

Morphological diagnosis of the variant APL´ is alwayschallenging; in the literature many cases were described as an hybridbetween 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 condensedchromatin, as well as presence of dysplastic traits associated (hypogranulation, nuclear pseudo pelger). Description of the blasts which makes the WHO classification of 2008 does not differ much fromthese initial descriptions [10].

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

Acute Myeloid Leukemia with t(11;17)(q23;q21) (2024)

Discussion

References