Contributions
Abstract: PB2103
Type: Publication Only
Background
Lenalidomide (LEN) is the approved first line treatment for lower risk myelodysplastic syndromes (MDS) with del (5q) and transfusion-dependent anemia. However, the acquisition of a TP53 mutation in these patients is considered a high-risk factor, predictive of a poor clinical outcome, due to a high risk of evolution in acute myeloid leukemia (AML).
Aims
To present the clinical, biological and molecular data, sequentially assessed, of a patient with low-risk MDS with del(5q, who acquired a TP53 mutation during the course of the disease, but, nevertheless showed a particularly favourable clinical course.
Methods
The patient at the time of the first diagnosis, on November 1996, underwent a complete diagnostic work-up, with complete blood counts, bone marrow aspiration and cytogenetic study. Subsequently, starting from July 2009, when she started LEN, she also underwent biological and molecular studies, performed sequentially throughout the subsequent course, until now. Mutation analysis of TP53 exons 5-9 was performed on mononuclear cells by PCR and direct bidirectional Sanger sequencing. Each chromatogram was compared with wild-type sequence (GenBank; NM_001126114). Gene expression analyses were performed on mononuclear cells at diagnosis and during treatment by a TaqMan-based Real-Time approach ( Follo, PNAS 2009).
Results
At diagnosis ( November 1996) the patient, a 55-year-old female, showed transfusion-dependent anemia. Refractory anemia (according to FAB) with the presence of del (5q)(q13;q33) in 8/9 metaphases was diagnosed. IPSS risk was low, and IPSS-R risk was intermediate. The patient, refractory to erythropoietin, continuously received red cell transfusions, and also iron chelation, (subcutaneous deferoxamine from March 1998, and subsequently oral deferasirox , starting on July 2003), until July 2009, when LEN was started. At that time no mutation of TP53 was detected. The patient discontinued transfusions after 2 months of LEN, after 3 months the Hb level reached 12.2 g /dL, and after 6 months no del(5q) metaphases were detectable, while 3 metaphases with + 8 were observed. Complete cytogenetic remission was achieved after 12 months, and persisted after 24 months, on July 2011, when LEN was discontinued. Cytogenetic remission was maintained for another 6 months, and hematologic remission, in the absence of treatment, lasted for 55 months, until February 2016, when the patient showed hematologic relapse, with transfusion need, but without excess of marrow blasts or high-risk cytogenetic alterations. LEN was restarted on April 2016, and a quick second hematologic response was observed after 2 cycles (Hb 11.1 g/dL), with a partial cytogenetic response (14/30 normal metaphases) on November 2017, after 11 cycles. The patient is still continuing LEN, still maintaining complete hematologic remission. Starting from February 2015, a TP53 mutation was detected for the first time, and was confirmed on November 2015 and November 2017: a missense variant in exon 5 C135Y (c.404G>A), intron variant in intron 6-7 (rs1825895). As to biological studies, the patient showed an increased expression of Beta-Globin mRNA during response to LEN, that was associated with an induction of PI-PLCgamma1, therefore hinting at an activation of erythroid differentiation.
Conclusion
This case shows that the detection of a TP53 mutation is not necessarily associated with a poor clinical outcome in all cases, and that probably not all types of TP53 mutations might have a negative prognostic impact.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Chromosomal abnormality, Immunomodulatory thalidomide analog, Myelodysplasia, P53
Abstract: PB2103
Type: Publication Only
Background
Lenalidomide (LEN) is the approved first line treatment for lower risk myelodysplastic syndromes (MDS) with del (5q) and transfusion-dependent anemia. However, the acquisition of a TP53 mutation in these patients is considered a high-risk factor, predictive of a poor clinical outcome, due to a high risk of evolution in acute myeloid leukemia (AML).
Aims
To present the clinical, biological and molecular data, sequentially assessed, of a patient with low-risk MDS with del(5q, who acquired a TP53 mutation during the course of the disease, but, nevertheless showed a particularly favourable clinical course.
Methods
The patient at the time of the first diagnosis, on November 1996, underwent a complete diagnostic work-up, with complete blood counts, bone marrow aspiration and cytogenetic study. Subsequently, starting from July 2009, when she started LEN, she also underwent biological and molecular studies, performed sequentially throughout the subsequent course, until now. Mutation analysis of TP53 exons 5-9 was performed on mononuclear cells by PCR and direct bidirectional Sanger sequencing. Each chromatogram was compared with wild-type sequence (GenBank; NM_001126114). Gene expression analyses were performed on mononuclear cells at diagnosis and during treatment by a TaqMan-based Real-Time approach ( Follo, PNAS 2009).
Results
At diagnosis ( November 1996) the patient, a 55-year-old female, showed transfusion-dependent anemia. Refractory anemia (according to FAB) with the presence of del (5q)(q13;q33) in 8/9 metaphases was diagnosed. IPSS risk was low, and IPSS-R risk was intermediate. The patient, refractory to erythropoietin, continuously received red cell transfusions, and also iron chelation, (subcutaneous deferoxamine from March 1998, and subsequently oral deferasirox , starting on July 2003), until July 2009, when LEN was started. At that time no mutation of TP53 was detected. The patient discontinued transfusions after 2 months of LEN, after 3 months the Hb level reached 12.2 g /dL, and after 6 months no del(5q) metaphases were detectable, while 3 metaphases with + 8 were observed. Complete cytogenetic remission was achieved after 12 months, and persisted after 24 months, on July 2011, when LEN was discontinued. Cytogenetic remission was maintained for another 6 months, and hematologic remission, in the absence of treatment, lasted for 55 months, until February 2016, when the patient showed hematologic relapse, with transfusion need, but without excess of marrow blasts or high-risk cytogenetic alterations. LEN was restarted on April 2016, and a quick second hematologic response was observed after 2 cycles (Hb 11.1 g/dL), with a partial cytogenetic response (14/30 normal metaphases) on November 2017, after 11 cycles. The patient is still continuing LEN, still maintaining complete hematologic remission. Starting from February 2015, a TP53 mutation was detected for the first time, and was confirmed on November 2015 and November 2017: a missense variant in exon 5 C135Y (c.404G>A), intron variant in intron 6-7 (rs1825895). As to biological studies, the patient showed an increased expression of Beta-Globin mRNA during response to LEN, that was associated with an induction of PI-PLCgamma1, therefore hinting at an activation of erythroid differentiation.
Conclusion
This case shows that the detection of a TP53 mutation is not necessarily associated with a poor clinical outcome in all cases, and that probably not all types of TP53 mutations might have a negative prognostic impact.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Chromosomal abnormality, Immunomodulatory thalidomide analog, Myelodysplasia, P53