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CASE REPORT
Year : 2022 | Volume
: 59
| Issue : 3 | Page : 419-421
Derivative 6 as an additional chromosomal abnormality along with t(15;17): A case report
Rupa C Dalvi1, Swarna Mandava1, Anurita P Pais1, Prajakta P Kokate1, Nilanjan Sinha2, Uttam K Nath2
1 Department of Cytogenetics, SRL Ltd., Mumbai, Maharahshtra, India
2 Institute of Haematology and Transfusion Medicine, Medical College, Kolkata, West Bengal, India
Correspondence Address:
Rupa C Dalvi
Department of Cytogenetics, SRL Ltd., Mumbai, Maharahshtra
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijc.IJC_1066_20
Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) characterized by the presence of t(15;17)(q22;q21) translocation leading to fusion between PML and RARa gene. Treatment combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved the prognosis of APL. We report a rare finding of primary clone of t(15;17) followed by a sequential clonal evolution of additional derivative chromosome 6 formation by a two hit mechanism. Our case showed a good clinical response with a four years and nine months event free survival after ATRA and ATO combination therapy in spite of existence of three chromosomal abnormalities stating that targeted therapy overcomes the adverse effects of additional genetic markers. However, close monitoring with assessment for long term prognostic behavior is required.
Keywords: Acute promyelocytic leukemia, derivative 6, MLL, t(15;17)
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with overgrowth of immature promyelocytes in the blood and bone marrow due to the PML-RARA fusion generated as a result of t(15;17)(q22;q21) chromosomal translocation.[1],[2]
APL can be fatal with a high risk of disseminated intravascular coagulation (DIC), and this warrants APL to be treated as a medical emergency with prompt diagnosis followed by a combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and hence due to targeted treatment, APL has now become the most curable hematological malignancy.[3],[4]
Additional chromosomal aberrations (ACAs) associated with t(15;17) are reported in 23%-43% of newly diagnosed APL cases; however, prognostic significance is still controversial. The most frequent secondary aberration to t(15;17) like trisomy 8 (+8), deletion 9q, and isochromosome 17 predominantly have been reported to show a strong association with poor prognosis.[5],[6],[7],[8]
Here we report a rare finding of the coexistence of three genetic abnormalities with t(15;17) as a basic stem line (idem) clone followed by a subclonal evolution of an additional abnormality of derivative 6 formed as a result of translocation with 11q23 and interstitial deletion at 6q13q21. We present the patient characteristic and treatment outcome after 4 years and 9 months follow-up.
Case HistoryA 46-year-old man presented with complaints of acute onset of spontaneous gum bleeding, epistaxis, easy bruising, and fatigue for about 5 days with no complaints of fever, bone pain, or bleeding from any other site. His symptoms were not preceded by any recent febrile illness or intake of any drug. His past medical history and family history were unremarkable. Physical examination revealed mild pallor, multiple cutaneous ecchymoses and purpura, gingival bleeding at multiple sites, and oral mucosal wet purpura. Ophthalmoscopy showed multiple superficial retinal hemorrhages in both eyes. There was no icterus, lymphadenopathy, hepatosplenomegaly, gingival hypertrophy, cranial nerve palsy, or any other abnormal finding. His vital signs were stable. A complete hemogram on admission showed pancytopenia (hemoglobin 7.8 g/dL, total leukocyte count 1.9 × 109/L, and platelet count 5 × 109/L). Differential leukocyte count on peripheral blood smear revealed 4% neutrophils, 55% lymphocytes, 3% monocytes, and 38% hypergranular promyelocytes. Coagulation parameters were deranged – prothrombin time (PT) of 22 seconds, activated partial thromboplastin time (APTT) of 42 seconds, fibrinogen level of 120 mg/dL, and an elevated D-dimer level of 11.5 mg/L, and suggestive of DIC. With the high suspicion of acute APL, treatment was immediately started with ATRA 45 mg/m2/day orally in two divided doses, and ATO 0.15 mg/kg once daily administered by intravenous (IV) infusion. Intensive blood product transfusion support was initiated with platelet concentrates, cryoprecipitate, fresh frozen plasma, and red blood cells. Bone marrow aspiration cytology revealed hypercellular marrow with suppressed trilineage hematopoiesis, and hypergranular promyelocytes comprising 70% of marrow nucleated cells. Immunophenotyping of bone marrow sample was suggestive of APL (atypical promyelocytes with high SSC/dim CD45; expression of CD13, CD33, and CD64; and negative for other markers, including HLA- DR).
Real-time polymerase chain reaction (RT-PCR) of bone marrow was positive for PML-RARA fusion transcript (long isoform), confirming diagnosis of APL. Conventional cytogenetic study on bone marrow cells showed clonal karyotype at diagnosis represented by 46,XY,t(15;17)(q22;q21)[8]/46, idem,der(6)t(6;11)(p21;q23),del(6)(q13q21)(10)/46,XY[2] [Figure 1].
Figure 1: Karyotype showing translocation t(15;17)(q22;q21) and derivative chromosome 6Karyotype analysis revealed the presence of a primary event of t(15;17) as a stem line clone and a subclone of an additional derivative chromosome 6. Derivative chromosome 6 was formed as a result of a translocation between chromosome 6 and 11 at regions p21 and q23, respectively, and a simultaneous occurrence of interstitial deletion on the long arm of chromosome 6 at bands q13q21.
Interphase fluorescence in situ hybridization (FISH) and metaphase chromosome analysis using LSI Dual Color Dual Fusion probes for PML-RARA and Break Apart Rearrangement probes for MLL (Abbott Molecular/Vysis, Des Plaines, IL, USA) confirmed the presence of PML-RARA fusion and the absence of adverse genetic event of MLL gene rearrangement [Figure 2].
Figure 2: (a) Interphase cell showing dual fusion signals of PML-RARA gene (arrows). (b). Interphase cell showing two normal intact copies of MLL geneAfter confirmation of the diagnosis of APL (Sanz intermediate risk disease), ATRA, and ATO, induction therapy was started. The induction therapy got complicated by the development of APL differentiation syndrome; however, the patient responded to IV dexamethasone.
Complete morphological remission (CR) was documented by peripheral blood and bone marrow examination on Day 31 of ATRA and ATO induction therapy. Subsequently, the patient received ATRA and ATO consolidation therapy comprising IV arsenic trioxide 0.15 mg/kg/day IV 5 days/week for 4 weeks every 8 weeks for a total of 4 cycles, plus ATRA 45 mg/m2/day for 2 weeks every 4 weeks for a total of 7 cycles. Bone marrow PCR was done after the completion of third cycle ATO consolidation was negative for PML-RARA by RT-PCR studies, thereby confirming molecular remission. The patient continues to remain in morphological and molecular remission after approximately 4 years and 9 months follow-up.
DiscussionWe report a rare occurrence of two distinct prognostic markers t(15;17) and the presence of derivative chromosome 6 as a result of clonal evolution in the same patient.
Derivative 6 observed in our case is formed as a result of two hit mechanisms, that is, one hit where p arm of chromosome 6 was involved in translocation with 11q23 region with negative status for MLL gene rearrangement and another hit with chromosome 6 interstitial deletion on the q arm at breakpoints between q13 and q21.
Gene fusions and deletions on derivative 6 would possibly be an adverse effect; however, the present case was promptly treated with combinatorial APL therapy with an intensive support management approach and showed a good molecular response.
As the karyotype analysis showed t(6;11) with 11q23 involvement, FISH studies confirmed the negative status for MLL gene rearrangement indicating interphase and metaphase FISH are important to characterize the region/gene involved at the molecular level that is unresolved by karyotyping.
Our case showed that the application of a targeted therapy led to a molecular remission with a long follow-up, and this proved an effective treatment irrespective of the co-occurrence of two additional hits.
In addition to PML-RARA fusion, the significance of secondary cooperating chromosomal or mutational events in pathogenesis and progression is yet not clearly understood; hence mutational profiling along with expression studies would be a comprehensive means in better understanding, characterization, subclassification, prognosis, and outcome prediction of the disease.[9]
Our study reinforces the role of the extensive diagnostic workup for better characterization of the disease along with a long-term disease assessment that is necessary to strongly document the clinical significance of ACAs.
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Conflicts of interest
There are no conflicts of interest.
References
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