Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

Cervera, José; Montesinos, Pau; Hernández-Rivas, Jesús M.; Calasanz, Marı́a José; Aventı́n, Anna; Ferrò, Maria Teresa; Luño, Elisa; Sánchez, Javier; Vellenga, Edo; Rayón, Chelo; Milone, Gustavo; Serna, Javier de la; Rivas, Concha; González, José D.; Tormo, Mar; Amutio, Elena; González, Marcos; Brunet, Salut; Löwenberg, Bob; Sanz, Miguel Á.

doi:10.3324/haematol.2009.013243

Cited by 83 publications

(78 citation statements)

References 22 publications

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“…It remains speculative whether this aspect could contribute to explain the weaker prognostic impact of the FLT3-ITD in Impact of FLT3-ITD mutation load in acute promyelocytic leukemia haematologica | 2011; 96(12) The frequency of ACA in our cohort (38.8%) was similar to that in previous studies. [32][33] In general we did not find that ACA had a significant impact on prognosis, which is in accordance with our previous study in 50 patients with APL. 34 Cervera et al from the PETHEMA study group found that ACA were associated with higher rates of coagulopathy, lower platelet counts, and higher relapse risk scores in APL, but remission rates of patients with and without ACA were nearly the same, being 90% and 91%, respectively.…”

Section: Flt3-tkd (N=18)supporting

confidence: 82%

“…In their study, no specific ACA was an independent risk factor for relapse. 33 The European APL group also did not find that ACA had a significant impact on prognosis, 32 and Slack et al found no difference in overall survival between APL patients with an isolated t(15;17)/PML-RARA and patients with ACA. 26 Accordingly, we were not able to show a significant influence of ACA on outcome in patients with APL.…”

Section: Flt3-tkd (N=18)mentioning

confidence: 99%

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Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

Schnittger¹,

Bacher²,

Haferlach³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundCombined treatment with all-trans-retinoic acid and chemotherapy is extremely efficient in patients with acute promyelocytic leukemia with t(15;17)/PML-RARA, but up to 15% of patients relapse. Design and MethodsTo further clarify the prognostic impact of parameters such as FLT3 mutations, we comprehensively characterized the relation between genetic features and outcome in 147 patients (aged 19.7-86.3 years) with acute promyelocytic leukemia. ResultsInternal tandem duplications of the FLT3 gene (FLT3-ITD) were detected in 47/147 (32.0%) and tyrosine kinase domain mutations (FLT3-TKD) in 19/147 (12.9%) patients. FLT3-ITD or FLT3-TKD mutation status did not have a significant prognostic impact, whereas FLT3-ITD mutation load, as defined by a mutation/wild-type ratio of less than 0.5 was associated with trends to a better 2-year overall survival rate (86.7% versus 72.7%; P=0.075) and 2-year event-free survival rate (84.5% versus 62.1%, P=0.023) compared to the survival rates of patients with a ratio of 0.5 or more. Besides the t(15;17), an additional chromosomal abnormality was detected in 57 of 147 cases and did not show a significant impact on survival. White blood cell counts of 10¥10 9 /L or less versus more than 10¥10 9 /L were associated with a better 2-year overall survival rate (88.3% versus 69.4%, respectively; P=0.015), as was male sex (P=0.040). In multivariate analysis, only higher age had a significant adverse impact. ConclusionsProspective trials should further investigate the clinical impact of the FLT3-ITD/wild-type mutation load aiming to evaluate whether this parameter might be included in risk stratification in patients with acute promyelocytic leukemia.

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Section: Flt3-tkd (N=18)supporting

confidence: 82%

Section: Flt3-tkd (N=18)mentioning

confidence: 99%

Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

Schnittger¹,

Bacher²,

Haferlach³

et al. 2011

Haematologica

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“…Other abnormalities involve number 7, 9, and 16 chromosomes; 14,15 however, the association of t(9;11)(q13;p13), which was observed in the present patient, has not been reported, and thus appears to be novel. Furthermore, t(9;11) itself with the breakpoints of (q13;p13) has not been reported in hematologic malignancies.…”

Section: Discussioncontrasting

confidence: 39%

“…It has been reported that APL patients showing additional chromosomal abnormality are associated with more marked coagulopathy and a poor prognosis. 15 However, several clinical trials reported that there were no significant differences in the complete remission and overall survival rates between APL patients with solely t(15;17) and additional abnormalities. 17,18 The mechanisms of the persistent hypoplasia in APL are unclear.…”

Section: Discussionmentioning

confidence: 99%

Persistent Hypoplastic Acute Promyelocytic Leukemia with a Novel Chromosomal Abnormality of 46, XY, t(15;17), t(9;11)(q13;p13)

Yamamoto

Kodaka

Maruoka

et al. 2015

J Clin Exp Hematopathol

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A diagnosis of acute promyelocytic leukemia (APL) is usually made when normal hematopoietic cells are substituted by APL cells. We encountered a unique APL patient who presented with persistent hypoplastic features of APL. An 84-year-old man presented with leukopenia (2.2 × 10 9 /L) and anemia (Hb 12.5 g/dL). Five months later, the bone marrow (BM) was hypoplastic with a normal proportion of blasts and promyelocytes (5.2%), although the latter cells were hypergranular. The karyotype of BM cells was 46, XY, t(15;17)(q22;q12), t(9;11)(q13;p13). Two months later, the BM remained hypoplastic with 8.5% hypergranular promyelocytes, some of which contained faggot of Auer rods. RT-PCR examination yielded the PMLRARa transcript, and its sequencing revealed the breakpoint of PML to be bcr2. The patient was treated with all-trans retinoic acid under a diagnosis of APL with improvement of the bicytopenia. FISH analysis of BM cells yielded a negative result regarding t(15;17), although RT-PCR was positive for PML-RARa mRNA. Six months later, APL recurred with the same karyotypic abnormalities and therapeutic resistance, and the patient died of pneumonia. A persistent hypoplastic state of APL may be a rare event, and the association of t(15;17) and t(9;11) is novel. 〔J Clin Exp Hematop 55(2) : 71-76, 2015〕

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“…It has been reported that trisomy 8 and 21 and abn (17) are the three most frequently observed aberrations, in addition to t(15;17), in APL (22)(23)(24)(25). To date, there has only been one case report describing 3q29 involved in translocation changes, rather than additional changes (26).…”

Section: Discussionmentioning

confidence: 96%

Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

Guan

Liu

Guo

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), -7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. IntroductionAcute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with distinct clinical, morphological, immunophenotypic and cytogenetic characteristics (1). APL has two morphological subtypes: Hypergranular (typical) APL and microgranular APL. Both subtypes are associated with disseminated intravascular coagulation. Unlike typical APL, the leukocyte count in microgranular APL is very high. The genetic hallmark of APL is t(15;17)(q22;q21), which can be detected in >90% of APL cases (2-5). The reciprocal translocation results in a fusion gene product between the retinoic acid receptor α (RARα) gene on 17q21 and the promyelocytic leukemia (PML) gene on 15q22. This translocation is associated with particular sensitivity to treatment with all-trans retinoic acid (ATRA) (2) and a favorable prognosis; however, a subset of cases with APL morphology and variant translocations, such as t(11;17) and t(5;17), have been reported not to respond to ATRA (6) and have been associated with an unfavorable prognosis (7).The present study describes a case of microgranular APL with ins(17;15)(q12;q14q22) in a pediatric patient, along with its clinical and biological characteristics. The case demonstrates the importance of taking into consideration all clinical, morphological and cytogenetic/molecular findings in the diagnosis of APL when typical morphological characteristics and/or cytogenetic findings are absent. Case reportA 2-year-old boy, who had been suffering from recurring fever and cough for 5 days and epistaxis for 1 day, was admitted to the Affiliated Hospital of Qingdao University (Qingdao, China). He had an upper respiratory infection 5 days prior to admission. On admission, the patient was conscious but, according to physical examination, had pallor. No petechiae, xanthochromia or hemoptysis were observed and no hepatosplenomegaly or ly...

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Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

Cited by 83 publications

References 22 publications

Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

Persistent Hypoplastic Acute Promyelocytic Leukemia with a Novel Chromosomal Abnormality of 46, XY, t(15;17), t(9;11)(q13;p13)

Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

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