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189 ALL MDS-SPECIFIC STRUCTURAL CHROMOSOMAL REARRANGEMENTS IN A SINGLE CASE
S94
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
In our patient, despite a less than CCyR, lenalidomide interruption appeared to be safe leading to one of the longest erythroid response described in literature.
188 MYELODYSPLASTIC SYNDROME TYPE REFRACTORY ANEMIA WITH EXCESS OF BLASTS-1 WITH CLONAL EVOLUTION THAT ACCOMPLISHED COMPLETE CYTOGENETIC REMISSION K. Galvez1, S.C. Penagos1 1 Hematology, Hospital Pablo Tobón Uribe, Medellín, Colombia 65 year-old patient evaluated three years ago because of severe anemia requiring transfusional support. Studies of iron metabolism, folic acid, vitamin B12, thyroid function and hemolysis were negative. A bone marrow biopsy and aspiration was performed and reported a myelodysplastic syndrome type refractory anemia with excess of blasts-1 (5% of blasts) with a karyotype that revealed a 47XX +8 (6), 46XX (14) mosaicism (Figure 1). The calculated prognostic indexes were IPSS 1.5 points (intermediate-2 risk) and WPSS 2 points (intermediate risk). The patient did not have an HLA-identical sibling donor. Treatment with decitabine was started. At the end of the fourth cycle the patient persisted with anemia and transfusion dependency. Another bone marrow biopsy and aspiration was performed and reported an increse in the blast count (7%), because of this treatment with azacytidine was started. After the third cycle the patient accomplished transfusion independency and the bone marrow studies showed a progressive descent in blast count until normalization. The cytogenetic analysis after the 17th cycle of azacytidine revealed a clonal evolution from trisomy 8 to del(5q) (Figure 2). Based on this finding the hypomethylating agent was stopped and lenalidomide 10 mg per day for 21 days was initiated. After the third cycle a FISH for del(5q) was performed, it did not detect this alteration in 100% of the studied nuclei (Figure 3). The last hemogram is completely normal, with no cytopenias. This case is reported because the patient accomplished complete remision of two genetic lesions with the administered treatment. First trisomy 8 desapeared with azacytidine therapy and then del(5q) with lenalidomide. This case is important because it shows how the new medications used in the treatment of myelodysplastic syndrome, both
Fig. 1.
Fig. 2. Karyotype with 8 trisomy.
Fig. 3. Karyotype with del(5q).
hypomethylating agents and immunomodulators, accomplish complete cytogenetic remission which was no observed with conventional chemotherapy.
189 ALL MDS-SPECIFIC STRUCTURAL CHROMOSOMAL REARRANGEMENTS IN A SINGLE CASE B.B. Ganguly1, S. Mandal2, T.K. Dolai3, R. De3, P. Prasad3, P. Chakraborti3 1 MGM Center for Genetic Research & Diagnosis, MGM New Bombay Hospital, Mumbai, India; 2Genetics, Genetics Center, Mumbai, India; 3 Hematology, NRS Medical College, Kolkata, India MDS represents heterogeneous pre-malignant clonal changes that are typically associated with peripheral cytopenia, ineffective hematopoiesis, hypercellular bone marrow with defined dysplasia of one or more lineages. Chromosomal anomalies in MDS are important indicators of risk assessment and treatment response and powered in IPSS/WHO-classification. Karyotypic analysis has frequently reported del(5q/7q/11q/12p/20q), -(5/7/Y), +(8/19), i(17q), and occasionally translocations such as t(1;3), t(2;11), t(3;21), t(6;9), t(11;16), etc. Chromosomal alterations in MDS are not static; however, accumulation of aberrations contributes to disease progression. We present cytogenetic result of a 71Y/M suspected MDS with bicytopenia. He had weakness/ fatigability/exertional breathlessness/fever/progressive pallor/jaundice and wet purpura without lymphadenopathy/hepatosplenomegaly/comorbidity. Hemogram showed Hb 4.9/TLC 9600/Platele 60000, in addition to hypochromasia/anisocytosis/polychromasia, Cabot rings, atypical mononuclear cells, blast <5%, adequate megakaryocytes with high nucleo-cytoplasmic ratio. Conventional G-banding analysis of 34 metaphases revealed variable abnormalities in different cells, including monosomy
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Fig. 1. Complex karyotypic anomalies with 45,X,-Y,del(5q/7q/20q), dic(12;19),+15,(18/19),+mar detected in one single MDS.
Table1. Combinatorial distribution of chromosomal alterationsAberration/ Chromosome No. (cells) Abn./Chrom.No. (cell no. )
44 (3)
45 (26)
46 (3)
47 (2)
All
All
All
All
-7 [9]
1
6
1
1
Del7q [25]
2
20
2
1
Del5q/20q/-19/-/dic(12;19) [34]
i(17q) [2]
-
2
-
-
-18 [29]
3
24
1
1
+15 [23]
2
17
2
2
+mar [33]
2
26
3
2
+min(?+21) [13]
1
9
1
2
+ring [14]
1
9
2
2
(5/7/12/18/19/Y), del(5q/7q/20q), der(12)dic(12;19), +(15/ markers/rings/minutes) in different numerical combination of 44, 45, 46 and 47 chromosomes with a modal number of 45 (Table 1, Fig.1). Del(5q/20q), dic(12;19), -12, -19, –Y and at least one marker were consistently present. Apart from conventional chromosomal alterations, sequencing of whole genome/exome have reported mutations in NRAS, FLT3ITD,CBL, JAK2, KIT (signaling), RUNX1, TP53, ETV6 (transcription), TP53, WT1(tumor suppressors), TET2, ASXL1, IDH1, IDH2, EZH2, DNMT3A (DNA methylation), SF3B1, U2AF, SRSF2, ZRSR2 (RNAsplicing) genes and components of the cohesion complex (STAG2, RAD21, SMC3, SMC1A) (reviewed elsewhere), which have contribution in disease-evolution and treatment-outcome. In the present case, i(17q), der(12), del(7q36) and del(20q11) indicates alteration in TP53, ETV6, EZH2, SRSF2, ASXL1 genes. Complex chromosomal rearrangements demonstrated the severity of the disease status. This is most likely the first case, which possessed all MDS-specific chromosome abnormalities. Additional abnormalities in this case are valuable for clinical and therapeutic monitoring. Array-CGH would have been useful for genome-wide detection of copy number variation in such complex scenario. 190 AZACITIDINE CAUSING PLEUROPERICARDIAL EFFUSIONS. SHOULD THE TREATMENT BE CONTINUED OR NOT? V. Ganipisetti1, M. Akhtari2 1 Hematology/ Oncology, University of Illinois at Chicago, Chicago, USA; 2Hematology/ Oncology, University of Nebraska Medical Center, Omaha, USA Case: A 54-year-old man diagnosed with MDS, was started on his first 7-day cycle of chemotherapy treatment with Azacitidine
S95
SQ (75 mg/m2). Ten days after he completed the first cycle, he presented with abdominal wall cellulitis near the injection site. On his third day of admission, he exhibited acute dyspnea, tachypnea and tachycardia, along with increased oxygen requirements. JVD was elevated, and his heart sounds were distant and muffled. A chest X- ray compared to prior, demonstrated an enlarged cardiac silhouette and newly found unequal pleural effusions. An emergent echocardiogram was performed showing a large pericardial effusion and collapsed right ventricle, concerning for cardiac tamponade. Pericardiocentesis and drain placement were performed emergently and 550ml serosanguinous fluid was drained. The patient improved symptomatically and was later discharged on tapering corticosteroids and maintenance colchicine. Taking into consideration of the temporal association and ruling out other causes, we concluded that Azacitidine was the most likely cause of effusions. He resumed subsequent cycles of Azacitidine according to the original dosing schedule, a 7-day course of 75 mg/m2 SQ daily at 28-day intervals. He tolerated the remaining three cycles well without any further complications and the effusions did not recur. Discussion: Azacitidine in general, is a very well tolerated drug. Pericardial effusions (PE) with Azacitidine were occasionally reported before in AML, CMML and MDS patients, but information regarding continued Azacitidine chemotherapy in patients in clinical settings who developed PE is limited. In a retrospective analysis on the characteristics of pericardial effusions in patients treated with chemotherapeutic agents, which included patients with MDS on hypomethylating agents, it was revealed that most of the effusions occurred were minimal in size on initial echocardiograms and regressed in size with continued treatment, (1). The presence of PEs did not affect survival in this cohort, underscoring their benign course. Therefore, the development of a PE should not trigger automatic withdrawal of chemotherapy. This case illustrates that Azacitidine could cause pleuropericardial effusions. Treatment should be continued as long as the patient tolerates it, and any adverse events should be managed promptly to prevent unnecessary delay or discontinuation of treatment. Clinicians using this drug in their practice should be aware of its possible cardiac toxicity profile and look to detect early signs of cardiac compromise in their patients. Reference 1. Sampat K, et al. Characteristics of pericardial effusions in patients with leukemia, Cancer, vol. 116, no. 10, pp. 2366-71, 2010.
191 THE EXPERIENCE OF A SINGLE CENTER OF HEMATOLOGY IN THE TREATMENT WITH HYPOMETHYLATING AGENTS D. Georgescu1, M. Popescu1, M. Tevet1, O. Patrinoiu1, M. Murat1, A. Ciuhu2 1 Hematology, Colentina Hospital, Bucharest, Romania; 2Oncology, Saint Luke Hospital, Bucharest, Romania Introduction: The clinical studies demonstrated that treatment with hypomethylating agents, 5-azacytidine and decitabine, in intermediate/high risk MDS resulted in complete cytogenetic responses even in cases with a complex karyotype. On the other hand, patients with AML who do not qualify for aggressive chemotherapy and allogeneic medullary transplantation, treatment with hypomethylating agents leads to transfusional independence and increase in quality of life in half of treated patients. Materials and methods: We present the evolution under treatment with hypomethylating agents in 12 patients, diagnosed with intermediate/high risk MDS and AML in our Department
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
In our patient, despite a less than CCyR, lenalidomide interruption appeared to be safe leading to one of the longest erythroid response described in literature.
188 MYELODYSPLASTIC SYNDROME TYPE REFRACTORY ANEMIA WITH EXCESS OF BLASTS-1 WITH CLONAL EVOLUTION THAT ACCOMPLISHED COMPLETE CYTOGENETIC REMISSION K. Galvez1, S.C. Penagos1 1 Hematology, Hospital Pablo Tobón Uribe, Medellín, Colombia 65 year-old patient evaluated three years ago because of severe anemia requiring transfusional support. Studies of iron metabolism, folic acid, vitamin B12, thyroid function and hemolysis were negative. A bone marrow biopsy and aspiration was performed and reported a myelodysplastic syndrome type refractory anemia with excess of blasts-1 (5% of blasts) with a karyotype that revealed a 47XX +8 (6), 46XX (14) mosaicism (Figure 1). The calculated prognostic indexes were IPSS 1.5 points (intermediate-2 risk) and WPSS 2 points (intermediate risk). The patient did not have an HLA-identical sibling donor. Treatment with decitabine was started. At the end of the fourth cycle the patient persisted with anemia and transfusion dependency. Another bone marrow biopsy and aspiration was performed and reported an increse in the blast count (7%), because of this treatment with azacytidine was started. After the third cycle the patient accomplished transfusion independency and the bone marrow studies showed a progressive descent in blast count until normalization. The cytogenetic analysis after the 17th cycle of azacytidine revealed a clonal evolution from trisomy 8 to del(5q) (Figure 2). Based on this finding the hypomethylating agent was stopped and lenalidomide 10 mg per day for 21 days was initiated. After the third cycle a FISH for del(5q) was performed, it did not detect this alteration in 100% of the studied nuclei (Figure 3). The last hemogram is completely normal, with no cytopenias. This case is reported because the patient accomplished complete remision of two genetic lesions with the administered treatment. First trisomy 8 desapeared with azacytidine therapy and then del(5q) with lenalidomide. This case is important because it shows how the new medications used in the treatment of myelodysplastic syndrome, both
Fig. 1.
Fig. 2. Karyotype with 8 trisomy.
Fig. 3. Karyotype with del(5q).
hypomethylating agents and immunomodulators, accomplish complete cytogenetic remission which was no observed with conventional chemotherapy.
189 ALL MDS-SPECIFIC STRUCTURAL CHROMOSOMAL REARRANGEMENTS IN A SINGLE CASE B.B. Ganguly1, S. Mandal2, T.K. Dolai3, R. De3, P. Prasad3, P. Chakraborti3 1 MGM Center for Genetic Research & Diagnosis, MGM New Bombay Hospital, Mumbai, India; 2Genetics, Genetics Center, Mumbai, India; 3 Hematology, NRS Medical College, Kolkata, India MDS represents heterogeneous pre-malignant clonal changes that are typically associated with peripheral cytopenia, ineffective hematopoiesis, hypercellular bone marrow with defined dysplasia of one or more lineages. Chromosomal anomalies in MDS are important indicators of risk assessment and treatment response and powered in IPSS/WHO-classification. Karyotypic analysis has frequently reported del(5q/7q/11q/12p/20q), -(5/7/Y), +(8/19), i(17q), and occasionally translocations such as t(1;3), t(2;11), t(3;21), t(6;9), t(11;16), etc. Chromosomal alterations in MDS are not static; however, accumulation of aberrations contributes to disease progression. We present cytogenetic result of a 71Y/M suspected MDS with bicytopenia. He had weakness/ fatigability/exertional breathlessness/fever/progressive pallor/jaundice and wet purpura without lymphadenopathy/hepatosplenomegaly/comorbidity. Hemogram showed Hb 4.9/TLC 9600/Platele 60000, in addition to hypochromasia/anisocytosis/polychromasia, Cabot rings, atypical mononuclear cells, blast <5%, adequate megakaryocytes with high nucleo-cytoplasmic ratio. Conventional G-banding analysis of 34 metaphases revealed variable abnormalities in different cells, including monosomy
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Fig. 1. Complex karyotypic anomalies with 45,X,-Y,del(5q/7q/20q), dic(12;19),+15,(18/19),+mar detected in one single MDS.
Table1. Combinatorial distribution of chromosomal alterationsAberration/ Chromosome No. (cells) Abn./Chrom.No. (cell no. )
44 (3)
45 (26)
46 (3)
47 (2)
All
All
All
All
-7 [9]
1
6
1
1
Del7q [25]
2
20
2
1
Del5q/20q/-19/-/dic(12;19) [34]
i(17q) [2]
-
2
-
-
-18 [29]
3
24
1
1
+15 [23]
2
17
2
2
+mar [33]
2
26
3
2
+min(?+21) [13]
1
9
1
2
+ring [14]
1
9
2
2
(5/7/12/18/19/Y), del(5q/7q/20q), der(12)dic(12;19), +(15/ markers/rings/minutes) in different numerical combination of 44, 45, 46 and 47 chromosomes with a modal number of 45 (Table 1, Fig.1). Del(5q/20q), dic(12;19), -12, -19, –Y and at least one marker were consistently present. Apart from conventional chromosomal alterations, sequencing of whole genome/exome have reported mutations in NRAS, FLT3ITD,CBL, JAK2, KIT (signaling), RUNX1, TP53, ETV6 (transcription), TP53, WT1(tumor suppressors), TET2, ASXL1, IDH1, IDH2, EZH2, DNMT3A (DNA methylation), SF3B1, U2AF, SRSF2, ZRSR2 (RNAsplicing) genes and components of the cohesion complex (STAG2, RAD21, SMC3, SMC1A) (reviewed elsewhere), which have contribution in disease-evolution and treatment-outcome. In the present case, i(17q), der(12), del(7q36) and del(20q11) indicates alteration in TP53, ETV6, EZH2, SRSF2, ASXL1 genes. Complex chromosomal rearrangements demonstrated the severity of the disease status. This is most likely the first case, which possessed all MDS-specific chromosome abnormalities. Additional abnormalities in this case are valuable for clinical and therapeutic monitoring. Array-CGH would have been useful for genome-wide detection of copy number variation in such complex scenario. 190 AZACITIDINE CAUSING PLEUROPERICARDIAL EFFUSIONS. SHOULD THE TREATMENT BE CONTINUED OR NOT? V. Ganipisetti1, M. Akhtari2 1 Hematology/ Oncology, University of Illinois at Chicago, Chicago, USA; 2Hematology/ Oncology, University of Nebraska Medical Center, Omaha, USA Case: A 54-year-old man diagnosed with MDS, was started on his first 7-day cycle of chemotherapy treatment with Azacitidine
S95
SQ (75 mg/m2). Ten days after he completed the first cycle, he presented with abdominal wall cellulitis near the injection site. On his third day of admission, he exhibited acute dyspnea, tachypnea and tachycardia, along with increased oxygen requirements. JVD was elevated, and his heart sounds were distant and muffled. A chest X- ray compared to prior, demonstrated an enlarged cardiac silhouette and newly found unequal pleural effusions. An emergent echocardiogram was performed showing a large pericardial effusion and collapsed right ventricle, concerning for cardiac tamponade. Pericardiocentesis and drain placement were performed emergently and 550ml serosanguinous fluid was drained. The patient improved symptomatically and was later discharged on tapering corticosteroids and maintenance colchicine. Taking into consideration of the temporal association and ruling out other causes, we concluded that Azacitidine was the most likely cause of effusions. He resumed subsequent cycles of Azacitidine according to the original dosing schedule, a 7-day course of 75 mg/m2 SQ daily at 28-day intervals. He tolerated the remaining three cycles well without any further complications and the effusions did not recur. Discussion: Azacitidine in general, is a very well tolerated drug. Pericardial effusions (PE) with Azacitidine were occasionally reported before in AML, CMML and MDS patients, but information regarding continued Azacitidine chemotherapy in patients in clinical settings who developed PE is limited. In a retrospective analysis on the characteristics of pericardial effusions in patients treated with chemotherapeutic agents, which included patients with MDS on hypomethylating agents, it was revealed that most of the effusions occurred were minimal in size on initial echocardiograms and regressed in size with continued treatment, (1). The presence of PEs did not affect survival in this cohort, underscoring their benign course. Therefore, the development of a PE should not trigger automatic withdrawal of chemotherapy. This case illustrates that Azacitidine could cause pleuropericardial effusions. Treatment should be continued as long as the patient tolerates it, and any adverse events should be managed promptly to prevent unnecessary delay or discontinuation of treatment. Clinicians using this drug in their practice should be aware of its possible cardiac toxicity profile and look to detect early signs of cardiac compromise in their patients. Reference 1. Sampat K, et al. Characteristics of pericardial effusions in patients with leukemia, Cancer, vol. 116, no. 10, pp. 2366-71, 2010.
191 THE EXPERIENCE OF A SINGLE CENTER OF HEMATOLOGY IN THE TREATMENT WITH HYPOMETHYLATING AGENTS D. Georgescu1, M. Popescu1, M. Tevet1, O. Patrinoiu1, M. Murat1, A. Ciuhu2 1 Hematology, Colentina Hospital, Bucharest, Romania; 2Oncology, Saint Luke Hospital, Bucharest, Romania Introduction: The clinical studies demonstrated that treatment with hypomethylating agents, 5-azacytidine and decitabine, in intermediate/high risk MDS resulted in complete cytogenetic responses even in cases with a complex karyotype. On the other hand, patients with AML who do not qualify for aggressive chemotherapy and allogeneic medullary transplantation, treatment with hypomethylating agents leads to transfusional independence and increase in quality of life in half of treated patients. Materials and methods: We present the evolution under treatment with hypomethylating agents in 12 patients, diagnosed with intermediate/high risk MDS and AML in our Department