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Therapy-related acute promyelocytic leukemia in plasma cell myeloma treated with melphalan: a case report and literature review

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Therapy-related acute myeloid leukemia (t-AML) is a specific subtype of AML that accounts for 5% of secondary malignancies, among which therapy-related acute promyelocytic leukemia (t-APL) has been reported to be particularly rare, with a reported incidence rate of about 4.8% of all cases of acute promyelocytic leukemia (APL) according to a large Italian study... However, an increase in the proportion of t-APL has been reported over time, with an incidence rate of up to 22% by the 2000s, owing to the increased use of chemocytotoxic agents or radiation therapy (RT)... Cases of t-APL arising from plasma cell myeloma (PCM) are known to be rare, although they have been reported in a few instances associated with melphalan treatment... However, the effect of melphalan treatment alone on t-APL is obscure owing to the frequent use of combination therapy including topoisomerase II agents, other types of anti-cancer drugs, and/or RT... Herein, we report a very rare case of t-APL arising from PCM treated with melphalan only as a cytotoxic agent with a review of the literature... The mechanism underlying the occurrence of t-APL associated with topoisomerase II inhibitor is the existence of “hot spots” in the PML and RARA genes with translocation breakpoints that are vulnerable to topoisomerase II inhibitor, and the concentrated position of such hot spots at a specific location... However, t-APL cases associated with the use of alkylating agents including melphalan had been rarely reported, and the mechanism underlying this association had not yet been elucidated... Cases of t-AML following treatment of PCM with alkylating agents including melphalan and/or RT were reported from time to time... In the remaining 2 cases, melphalan and other cytotoxic agents without RT had been utilized in 1 case, and the name of the chemotoxic agent was not mentioned in the article for the other case, but RT was used... Based on the patient characteristics summarized in Table 1, the disease course shows more aggressive pattern without a pre-leukemic phase or myelodysplastic syndrome, compared to other diseases related to alkylating agents... To the best of our knowledge, this is the first report of t-APL occurring during melphalan treatment without RT or any other chemotherapeutic agents, and implies the relationship between melphalan and t-APL in PCM... Further comparative studies between primary APL and t-APL arising from PCM could contribute to the improved understanding of the pathogenesis of t-APL.

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(A) Conventional bone marrow chromosome analysis showing 46,XX,t(15;17)(q22;q12). (B) Fluorescence in situ hybridizations for PML-RARA rearrangement showing two fusion signals [nuc ish (PML,RARA) ×3(RARA con PML ×2)].
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Figure 2: (A) Conventional bone marrow chromosome analysis showing 46,XX,t(15;17)(q22;q12). (B) Fluorescence in situ hybridizations for PML-RARA rearrangement showing two fusion signals [nuc ish (PML,RARA) ×3(RARA con PML ×2)].

Mentions: Pancytopenia was observed before the 14th cycle of MP therapy, and the patient was admitted for further evaluation. The CBC consistently revealed pancytopenia (hemoglobin level 9.7 g/dL, WBC 0.84×109/L, platelet count 38×109/L). As a peripheral blood smear showed 16% abnormal promyelocytes and immature cells (Fig. 1A), BM examination was conducted, followed by cytogenetic and molecular analyses using BM specimens. The BM aspirate showed 74% abnormal promyelocytes with bilobed nuclei, densely packed large granules, and Auer rods. The proportion of plasma cells was counted up to 2.6% (Fig. 1B). Some plasma cells were positive for kappa on immunohistochemical staining. Monoclonal peak was continuously observed on serum IFE, showing IgG and kappa type monoclonal gammopathy, 0.8 g/L of M-protein in serum. Chromosome analysis using a BM sample revealed a karyotype of 46, XX, t(15;17)(q22;q12) in 18 out of 23 metaphase cells examined (Fig. 2A). Fluorescence in situ hybridization (FISH) analysis using a dual color dual fusion PML/RARA probe showed 2 fusion signals in 176 out of 200 interphase cells; nuc ish (PML,RARA)×3 (RARA con PML×2)[176/200] (Fig. 2B). Multiplex reverse transcription (RT)-PCR analyses using HemaVision assay (DNA Technology, Aarhus, Denmark) confirmed the presence of PML/RARA gene rearrangement. The patient was diagnosed with t-APL and treated with all-trans retinoic acid (ATRA) immediately. Despite therapeutic efforts, the patient died 2 weeks later owing to cerebral infarction and subsequent sepsis.


Therapy-related acute promyelocytic leukemia in plasma cell myeloma treated with melphalan: a case report and literature review
(A) Conventional bone marrow chromosome analysis showing 46,XX,t(15;17)(q22;q12). (B) Fluorescence in situ hybridizations for PML-RARA rearrangement showing two fusion signals [nuc ish (PML,RARA) ×3(RARA con PML ×2)].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383590&req=5

Figure 2: (A) Conventional bone marrow chromosome analysis showing 46,XX,t(15;17)(q22;q12). (B) Fluorescence in situ hybridizations for PML-RARA rearrangement showing two fusion signals [nuc ish (PML,RARA) ×3(RARA con PML ×2)].
Mentions: Pancytopenia was observed before the 14th cycle of MP therapy, and the patient was admitted for further evaluation. The CBC consistently revealed pancytopenia (hemoglobin level 9.7 g/dL, WBC 0.84×109/L, platelet count 38×109/L). As a peripheral blood smear showed 16% abnormal promyelocytes and immature cells (Fig. 1A), BM examination was conducted, followed by cytogenetic and molecular analyses using BM specimens. The BM aspirate showed 74% abnormal promyelocytes with bilobed nuclei, densely packed large granules, and Auer rods. The proportion of plasma cells was counted up to 2.6% (Fig. 1B). Some plasma cells were positive for kappa on immunohistochemical staining. Monoclonal peak was continuously observed on serum IFE, showing IgG and kappa type monoclonal gammopathy, 0.8 g/L of M-protein in serum. Chromosome analysis using a BM sample revealed a karyotype of 46, XX, t(15;17)(q22;q12) in 18 out of 23 metaphase cells examined (Fig. 2A). Fluorescence in situ hybridization (FISH) analysis using a dual color dual fusion PML/RARA probe showed 2 fusion signals in 176 out of 200 interphase cells; nuc ish (PML,RARA)×3 (RARA con PML×2)[176/200] (Fig. 2B). Multiplex reverse transcription (RT)-PCR analyses using HemaVision assay (DNA Technology, Aarhus, Denmark) confirmed the presence of PML/RARA gene rearrangement. The patient was diagnosed with t-APL and treated with all-trans retinoic acid (ATRA) immediately. Despite therapeutic efforts, the patient died 2 weeks later owing to cerebral infarction and subsequent sepsis.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Therapy-related acute myeloid leukemia (t-AML) is a specific subtype of AML that accounts for 5% of secondary malignancies, among which therapy-related acute promyelocytic leukemia (t-APL) has been reported to be particularly rare, with a reported incidence rate of about 4.8% of all cases of acute promyelocytic leukemia (APL) according to a large Italian study... However, an increase in the proportion of t-APL has been reported over time, with an incidence rate of up to 22% by the 2000s, owing to the increased use of chemocytotoxic agents or radiation therapy (RT)... Cases of t-APL arising from plasma cell myeloma (PCM) are known to be rare, although they have been reported in a few instances associated with melphalan treatment... However, the effect of melphalan treatment alone on t-APL is obscure owing to the frequent use of combination therapy including topoisomerase II agents, other types of anti-cancer drugs, and/or RT... Herein, we report a very rare case of t-APL arising from PCM treated with melphalan only as a cytotoxic agent with a review of the literature... The mechanism underlying the occurrence of t-APL associated with topoisomerase II inhibitor is the existence of “hot spots” in the PML and RARA genes with translocation breakpoints that are vulnerable to topoisomerase II inhibitor, and the concentrated position of such hot spots at a specific location... However, t-APL cases associated with the use of alkylating agents including melphalan had been rarely reported, and the mechanism underlying this association had not yet been elucidated... Cases of t-AML following treatment of PCM with alkylating agents including melphalan and/or RT were reported from time to time... In the remaining 2 cases, melphalan and other cytotoxic agents without RT had been utilized in 1 case, and the name of the chemotoxic agent was not mentioned in the article for the other case, but RT was used... Based on the patient characteristics summarized in Table 1, the disease course shows more aggressive pattern without a pre-leukemic phase or myelodysplastic syndrome, compared to other diseases related to alkylating agents... To the best of our knowledge, this is the first report of t-APL occurring during melphalan treatment without RT or any other chemotherapeutic agents, and implies the relationship between melphalan and t-APL in PCM... Further comparative studies between primary APL and t-APL arising from PCM could contribute to the improved understanding of the pathogenesis of t-APL.

No MeSH data available.