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197 LENALIDOMIDE TREATMENT IN 5Q(-) SYNDROME: A SINGLE CENTER EXPERIENCE
S98
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
196 A COMPLEX KARYOTYPE INCLUDING A TRANSLOCATION T(1;12)(Q21;P13) IN A CASE OF HIGH-RISK MYELODYSPLASTIC SYNDROME W. Sun1, R. Jia1, C. Liu1, H. Li2, H. Zhao1, S. Wan1, L. Su1 1 Department of Hematology, Xuanwu Hospital Capital Medical University, Beijing, China; 2Department of Hematology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Reciprocal translocation t(1;12)(q21;p13) is a rare karyotypic abnormality, which have been reported only in patients with hematological diseases, including one case of myelodysplastic syndrome (MDS) with such a sole abnormailty. We report a MDS case of refractory anemia with excess blast-2 with ring sideroblasts (MDS-RAEB2-RS) with a complex karyotype including a translocation t(1; 12)(q21; p13). A 53-year old man was admitted to hospital because of fatigue, poor appetide and weight loss for 6 months. No fever or bleeding were noted. Physical examination showed pallor, without hepato-splenomegaly or lymph node enlargement. The complete blood count was: leukocytes 3.28×109/L (including 5% myeloblasts), hemoglobin 45g/L and platelets 57×109/L. Bone marrow aspiration showed hypercellularity, dysplasia in neutrophil precursors and megakaryocytes, and 19% of
Fig. 1. Karyotype of the patient.
Fig. 2. FISH result with 1q21(green)/1p36(red) probe.
Fig. 3. FISH result with ETV6 break apart probe.
erythroid precursors were ring sideroblasts. The blast percentage in the bone marrow was 6%. Immunophenotypic markers of blast cells were positive for CD13, CD34, CD38, CD117 and HLA-DR. No RUNX1-RUNX1T1, CBFB-MYH11 or PML-RARA fusion genes were detected, and no mutation of FLT3-ITD, CEBPA or NPM1 were detected. By G-banding technique, the karyotype of bone marrow was 47,XY,+1,-der(1)t(1;12)(q21;p13),+8,t(1;12)(q21;p13) (Fig.1). A diagnosis of MDS-RAEB2-RS was established. To confirm such a rare karyotype, fluorescence in situ hybridization (FISH) was used. FISH with a panel of locus specific probes showed: (1) three signals were present with the CEP 8 probe, indicated the trisomy 8; (2) three signals were present on 1q and two on 1p with the 1q21/1p36 probe (Fig. 2), indicated the trisomy 1 and the loss of der(1)t(1;12); (3) one fusion signal was present with the ETV6 break apart probe (Fig. 3), indicated that the breakpoint was centromeric to ETV6 on the der(12)t(1;12). Combined use of banding and FISH teniques confirmed this rare complex karyotype happened in MDS.
197 LENALIDOMIDE TREATMENT IN 5Q(-) SYNDROME: A SINGLE CENTER EXPERIENCE H. Teke Uskudar1, N. Andıç1, E. Gündüz1, S. Özpolat2, B. Durak Aras2, O. Akay1 1 Hematology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey; 2Genetics, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey The most common chromosomal abnormality in myelodysplastic syndrome (MDS) is the interstitial deletion in the long arm of chromosome 5 (del[5q]) which is seen in 10-15% of the cases (1). WHO diagnostic criteria for the “5q- syndrome” (del[5q]) includes sole chromosomal abnormality, blast count less than 5% in bone marrow and less than 1% in peripheral blood and no Auer rods (2). Until recently, the only treatment option for patients with 5qsyndrome was the best supportive care. Lenolidomide; an analog of thalidomide offers an efficient treatment for these patients (3). Herein, we present five patients with 5q- syndrome who received lenalidomide treatment and followed by Osmangazi University School of Medicine Hematology Department. Our cases’ mean age was 72.4 years and most of them were women as reported in the literature (4). Three of five patients had macrocytic anemia and this finding was consistent with the literature. Only one patient
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Table 1. Clinical parameters of 5q- syndrome patients and treatment results with lenalidomide Case1
Case2
Case3
Case4
Case5
Gender/Age at time of diagnosis
F/73
F/70
F/66
F/80
M/73
Comorbidties
HT
HT, AF, COPD
HT, COPD, HT, CAD, CAD, SVE Hypothyroidism, Breast Cancer
Leukocytes/mm3
5400
6700
6400
1800
5900
Hgb (first/last) gr/dl
6,9/13,4
10,3/12
10,4/10,8
4,6/6,7
8,6/14,2
HT
MCV/fL
126,5
95,1
110,4
94
113
Platelets/x109/L
651
229
356
52
433
BM blast (%)
3
0
4,5
3
3
del[5q]FISH (%)
27,08
50
58,13
68,52
15,96
Conventional cytogenetics
-
-
46,XX, del(5),
46,XX, del(5) -
Low
Low
IPSS risk
Low
Lenalidomide side effect
Cytopenia Skin rash
Cytopenia Cytopenia None
Transfusion independency after lenalidomide
(+)
(+)
(+)
(-)
Time of Hematologic 2 response (months)
2
2
No response 2
Total time of lenalidomide treatment (months)
2
7
1
16
54
Low
(q22)[20]/ (q22)[10] 46,XX[2] Intermediate
(+)
OS (months)
63
69
10
70
24
Current status
Alive
Alive
Alive
Exitus
Alive
had thrombocytosis at diagnosis in contrast to previous reports (4). Hypolobulation of megakaryocytes was found in all five of bone marrow samples. Total time of lenalidomide usage was mean 16 months. One patient (No: 4) received lenalidomide only for one cycle and died because of sepsis. One patient (No: 2) developed serious skin rash after two cycles in whom the treatment was stopped while she had became transfusion-independent like other three cases. The most common side effect seen in our patients was myelosuppression as reported in the literature (5). However, this side effect was manageable without drug interruption. 198 OUTCOME OF AZACITIDINE TREATMENT AND INCIDENCE OF FEBRILE EVENTS IN “REAL WORLD” PATIENTS WITH MDS OR LOW-BLAST COUNT AML M.T. Voso1, P. Niscola2, A. Piciocchi3, L. Fianchi4, L. Maurillo1, P. Musto5, L. Pagano4, G. Mansueto5, M. Criscuolo4, M.A. Aloe-Spiriti6, F. Buccisano1, A. Venditti1, A. Tendas2, A.L. Piccioni7, G. Zini4, R. Latagliata8, N. Filardi9, R. Fragasso10, S. Fenu11, M. Breccia8 1 Hematology/ Biomedicine and Prevention, Universita’ Tor Vergata, Rome, Italy; 2Hematology, S. Eugenio Hospital, Rome, Italy; 3Statistical Sciences, Universita’ La Sapienza, Rome, Italy; 4Hematology, Universita’ Cattolica S. Cuore, Rome, Italy; 5 Hematology, IRCCS-CROB MDS Registry of Basilicata, Rionero in Vulture (Pz), Italy; 6Hematology, S. Andrea Hospital, Rome, Italy; 7Hematology, S. Pertini Hospital, Rome, Italy; 8Hematology, Universita’ La Sapienza, Rome, Italy; 9Hematology, S. Carlo HospitalMDS Registry of Basilicata, Potenza, Italy; 10Hematology, Madonna delle Grazie Hospital- MDS Registry of Basilicata, Matera, Italy; 11 Hematology, S. Giovanni Hospital, Rome, Italy We reviewed the results of azacitidine (Vidaza, CelgeneTM) treatment in 196 ‘real world” MDS/low-blast count AML patients
S99
(n=184 and 12, respectively), retrospectively collected by two Italian cooperative groups. Significant factors for febrile events and response were evaluated. In MDS, R-IPSS stratification (n=166 pts) was: very-low 0.5%, low: 4%, intermediate: 23%, high: 46%, very-high: 26.5%. MDS-specific comorbidity index (MDS-CI, n=155 patients) was low (0) in 52 patients, intermediate (1-2) in 84, and high in 19 patients (>2). Azacitidine was started at a median of 3.4 months from initial diagnosis, at the standard dose (SD) of 75 mg/ sqm (7 days continuously: 22%, 5-2-2 days: 64%, 6-1-1: 4%) in 163 patients, while 33 patients received AZA at 100 mg/day, 5-7 days. Response was achieved after a median of 4.5 azacitidine cycles (range 1-15 Cy), with 22% of patients requiring 7-15 cycles to obtain maximal response. According to IWG 2006 criteria (n=182 patients), 34 patients obtained complete remission (CR, 19%), 31 partial remission (PR, 17%), 39 (21%), hematological improvement (HI), the disease was reported stable (SD) in 52 patients (29%), whereas 26 patients presented disease progression (14%). Probability of response was significantly associated to a shorter time from diagnosis to therapy initiation (p=0.04) and to the 75 mg/sqm through 7 days vs 50 mg/sqm through 5-7 days schedule (60 vs 30% CR/PR/HI, p=0.007). No differences were observed comparing the 7 days continuously versus 5-2-2 or 6-11 schedules. At a median follow-up of 14.8 months (range 0-100 months), 57 patients are alive, resulting into a median overall survival of 17.2 months. IPSS and MDS-CI did not predict survival, while grouping according to IPSS-R was associated to significantly different survival probabilities. Across delivery of a total of 1524 AZA cycles, 149 (9.7%) febrile events (FE) were recorded. Fever of unknown origin was diagnosed in 18 patients (12%). Of 131 clinically documented events, a positive microbiologic test was available in 35 cases (23%, bacteria were isolated in 29 patients). Most frequent infections were: pneumonia (n=60 events), cutaneous abscesses (n=16), and genito-urinary or upper respiratory infections (n=14 and 13, respectively). FE occurred at a median of 3.3 months from therapy initiation and infections were the attributable cause of death in 19 patients (2 in CR, 10 with progressive disease and 7 SD). The risk of infectious complications was lower in IPSS low-risk (p=0.05) or IPSS-R low/int MDS (p=0.01), and in patients with MDS-CI 0-2 (p=0.0001).
199 EFFICACY OF AZACITIDINE IN MDS, CMML AND AML WITH PROLIFERATIVE FEATURES A.M. Almeida1, F. Pierdomenico1 1 Haematology, Instituto Português de Oncologia Francisco Gentil Lisboa, Lisbon, Portugal Azacitidine is a hypomethylating agent with demonstrated efficacy in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The trials that have led to its approval for these indications excluded patients with leucocytosis and most observational studies suggest that it is less efficacious in patients with proliferative disease. We present a single-centre retrospective analysis of the efficacy of azacitidine in 18 with MDS, CMML and AML with proliferative features and compare these with a similar cohort of patients with non-proliferative disease. The cohort with proliferative disease, defined by a leukocytosis >13x109/L, had a median age at diagnosis of 67 years; 55% were men. WHO 2008 diagnosis was MDS in 2 patients, AML in 8 patients and CMML in 8 patients. At diagnosis, the median hemoglobin was 8.9 g/dL (range 6.5-13.0), median WBC was 34.7x109/L (range 12.795.0) and median platelet count 89x109/L (range 12-695). Bone
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
196 A COMPLEX KARYOTYPE INCLUDING A TRANSLOCATION T(1;12)(Q21;P13) IN A CASE OF HIGH-RISK MYELODYSPLASTIC SYNDROME W. Sun1, R. Jia1, C. Liu1, H. Li2, H. Zhao1, S. Wan1, L. Su1 1 Department of Hematology, Xuanwu Hospital Capital Medical University, Beijing, China; 2Department of Hematology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Reciprocal translocation t(1;12)(q21;p13) is a rare karyotypic abnormality, which have been reported only in patients with hematological diseases, including one case of myelodysplastic syndrome (MDS) with such a sole abnormailty. We report a MDS case of refractory anemia with excess blast-2 with ring sideroblasts (MDS-RAEB2-RS) with a complex karyotype including a translocation t(1; 12)(q21; p13). A 53-year old man was admitted to hospital because of fatigue, poor appetide and weight loss for 6 months. No fever or bleeding were noted. Physical examination showed pallor, without hepato-splenomegaly or lymph node enlargement. The complete blood count was: leukocytes 3.28×109/L (including 5% myeloblasts), hemoglobin 45g/L and platelets 57×109/L. Bone marrow aspiration showed hypercellularity, dysplasia in neutrophil precursors and megakaryocytes, and 19% of
Fig. 1. Karyotype of the patient.
Fig. 2. FISH result with 1q21(green)/1p36(red) probe.
Fig. 3. FISH result with ETV6 break apart probe.
erythroid precursors were ring sideroblasts. The blast percentage in the bone marrow was 6%. Immunophenotypic markers of blast cells were positive for CD13, CD34, CD38, CD117 and HLA-DR. No RUNX1-RUNX1T1, CBFB-MYH11 or PML-RARA fusion genes were detected, and no mutation of FLT3-ITD, CEBPA or NPM1 were detected. By G-banding technique, the karyotype of bone marrow was 47,XY,+1,-der(1)t(1;12)(q21;p13),+8,t(1;12)(q21;p13) (Fig.1). A diagnosis of MDS-RAEB2-RS was established. To confirm such a rare karyotype, fluorescence in situ hybridization (FISH) was used. FISH with a panel of locus specific probes showed: (1) three signals were present with the CEP 8 probe, indicated the trisomy 8; (2) three signals were present on 1q and two on 1p with the 1q21/1p36 probe (Fig. 2), indicated the trisomy 1 and the loss of der(1)t(1;12); (3) one fusion signal was present with the ETV6 break apart probe (Fig. 3), indicated that the breakpoint was centromeric to ETV6 on the der(12)t(1;12). Combined use of banding and FISH teniques confirmed this rare complex karyotype happened in MDS.
197 LENALIDOMIDE TREATMENT IN 5Q(-) SYNDROME: A SINGLE CENTER EXPERIENCE H. Teke Uskudar1, N. Andıç1, E. Gündüz1, S. Özpolat2, B. Durak Aras2, O. Akay1 1 Hematology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey; 2Genetics, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey The most common chromosomal abnormality in myelodysplastic syndrome (MDS) is the interstitial deletion in the long arm of chromosome 5 (del[5q]) which is seen in 10-15% of the cases (1). WHO diagnostic criteria for the “5q- syndrome” (del[5q]) includes sole chromosomal abnormality, blast count less than 5% in bone marrow and less than 1% in peripheral blood and no Auer rods (2). Until recently, the only treatment option for patients with 5qsyndrome was the best supportive care. Lenolidomide; an analog of thalidomide offers an efficient treatment for these patients (3). Herein, we present five patients with 5q- syndrome who received lenalidomide treatment and followed by Osmangazi University School of Medicine Hematology Department. Our cases’ mean age was 72.4 years and most of them were women as reported in the literature (4). Three of five patients had macrocytic anemia and this finding was consistent with the literature. Only one patient
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Table 1. Clinical parameters of 5q- syndrome patients and treatment results with lenalidomide Case1
Case2
Case3
Case4
Case5
Gender/Age at time of diagnosis
F/73
F/70
F/66
F/80
M/73
Comorbidties
HT
HT, AF, COPD
HT, COPD, HT, CAD, CAD, SVE Hypothyroidism, Breast Cancer
Leukocytes/mm3
5400
6700
6400
1800
5900
Hgb (first/last) gr/dl
6,9/13,4
10,3/12
10,4/10,8
4,6/6,7
8,6/14,2
HT
MCV/fL
126,5
95,1
110,4
94
113
Platelets/x109/L
651
229
356
52
433
BM blast (%)
3
0
4,5
3
3
del[5q]FISH (%)
27,08
50
58,13
68,52
15,96
Conventional cytogenetics
-
-
46,XX, del(5),
46,XX, del(5) -
Low
Low
IPSS risk
Low
Lenalidomide side effect
Cytopenia Skin rash
Cytopenia Cytopenia None
Transfusion independency after lenalidomide
(+)
(+)
(+)
(-)
Time of Hematologic 2 response (months)
2
2
No response 2
Total time of lenalidomide treatment (months)
2
7
1
16
54
Low
(q22)[20]/ (q22)[10] 46,XX[2] Intermediate
(+)
OS (months)
63
69
10
70
24
Current status
Alive
Alive
Alive
Exitus
Alive
had thrombocytosis at diagnosis in contrast to previous reports (4). Hypolobulation of megakaryocytes was found in all five of bone marrow samples. Total time of lenalidomide usage was mean 16 months. One patient (No: 4) received lenalidomide only for one cycle and died because of sepsis. One patient (No: 2) developed serious skin rash after two cycles in whom the treatment was stopped while she had became transfusion-independent like other three cases. The most common side effect seen in our patients was myelosuppression as reported in the literature (5). However, this side effect was manageable without drug interruption. 198 OUTCOME OF AZACITIDINE TREATMENT AND INCIDENCE OF FEBRILE EVENTS IN “REAL WORLD” PATIENTS WITH MDS OR LOW-BLAST COUNT AML M.T. Voso1, P. Niscola2, A. Piciocchi3, L. Fianchi4, L. Maurillo1, P. Musto5, L. Pagano4, G. Mansueto5, M. Criscuolo4, M.A. Aloe-Spiriti6, F. Buccisano1, A. Venditti1, A. Tendas2, A.L. Piccioni7, G. Zini4, R. Latagliata8, N. Filardi9, R. Fragasso10, S. Fenu11, M. Breccia8 1 Hematology/ Biomedicine and Prevention, Universita’ Tor Vergata, Rome, Italy; 2Hematology, S. Eugenio Hospital, Rome, Italy; 3Statistical Sciences, Universita’ La Sapienza, Rome, Italy; 4Hematology, Universita’ Cattolica S. Cuore, Rome, Italy; 5 Hematology, IRCCS-CROB MDS Registry of Basilicata, Rionero in Vulture (Pz), Italy; 6Hematology, S. Andrea Hospital, Rome, Italy; 7Hematology, S. Pertini Hospital, Rome, Italy; 8Hematology, Universita’ La Sapienza, Rome, Italy; 9Hematology, S. Carlo HospitalMDS Registry of Basilicata, Potenza, Italy; 10Hematology, Madonna delle Grazie Hospital- MDS Registry of Basilicata, Matera, Italy; 11 Hematology, S. Giovanni Hospital, Rome, Italy We reviewed the results of azacitidine (Vidaza, CelgeneTM) treatment in 196 ‘real world” MDS/low-blast count AML patients
S99
(n=184 and 12, respectively), retrospectively collected by two Italian cooperative groups. Significant factors for febrile events and response were evaluated. In MDS, R-IPSS stratification (n=166 pts) was: very-low 0.5%, low: 4%, intermediate: 23%, high: 46%, very-high: 26.5%. MDS-specific comorbidity index (MDS-CI, n=155 patients) was low (0) in 52 patients, intermediate (1-2) in 84, and high in 19 patients (>2). Azacitidine was started at a median of 3.4 months from initial diagnosis, at the standard dose (SD) of 75 mg/ sqm (7 days continuously: 22%, 5-2-2 days: 64%, 6-1-1: 4%) in 163 patients, while 33 patients received AZA at 100 mg/day, 5-7 days. Response was achieved after a median of 4.5 azacitidine cycles (range 1-15 Cy), with 22% of patients requiring 7-15 cycles to obtain maximal response. According to IWG 2006 criteria (n=182 patients), 34 patients obtained complete remission (CR, 19%), 31 partial remission (PR, 17%), 39 (21%), hematological improvement (HI), the disease was reported stable (SD) in 52 patients (29%), whereas 26 patients presented disease progression (14%). Probability of response was significantly associated to a shorter time from diagnosis to therapy initiation (p=0.04) and to the 75 mg/sqm through 7 days vs 50 mg/sqm through 5-7 days schedule (60 vs 30% CR/PR/HI, p=0.007). No differences were observed comparing the 7 days continuously versus 5-2-2 or 6-11 schedules. At a median follow-up of 14.8 months (range 0-100 months), 57 patients are alive, resulting into a median overall survival of 17.2 months. IPSS and MDS-CI did not predict survival, while grouping according to IPSS-R was associated to significantly different survival probabilities. Across delivery of a total of 1524 AZA cycles, 149 (9.7%) febrile events (FE) were recorded. Fever of unknown origin was diagnosed in 18 patients (12%). Of 131 clinically documented events, a positive microbiologic test was available in 35 cases (23%, bacteria were isolated in 29 patients). Most frequent infections were: pneumonia (n=60 events), cutaneous abscesses (n=16), and genito-urinary or upper respiratory infections (n=14 and 13, respectively). FE occurred at a median of 3.3 months from therapy initiation and infections were the attributable cause of death in 19 patients (2 in CR, 10 with progressive disease and 7 SD). The risk of infectious complications was lower in IPSS low-risk (p=0.05) or IPSS-R low/int MDS (p=0.01), and in patients with MDS-CI 0-2 (p=0.0001).
199 EFFICACY OF AZACITIDINE IN MDS, CMML AND AML WITH PROLIFERATIVE FEATURES A.M. Almeida1, F. Pierdomenico1 1 Haematology, Instituto Português de Oncologia Francisco Gentil Lisboa, Lisbon, Portugal Azacitidine is a hypomethylating agent with demonstrated efficacy in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The trials that have led to its approval for these indications excluded patients with leucocytosis and most observational studies suggest that it is less efficacious in patients with proliferative disease. We present a single-centre retrospective analysis of the efficacy of azacitidine in 18 with MDS, CMML and AML with proliferative features and compare these with a similar cohort of patients with non-proliferative disease. The cohort with proliferative disease, defined by a leukocytosis >13x109/L, had a median age at diagnosis of 67 years; 55% were men. WHO 2008 diagnosis was MDS in 2 patients, AML in 8 patients and CMML in 8 patients. At diagnosis, the median hemoglobin was 8.9 g/dL (range 6.5-13.0), median WBC was 34.7x109/L (range 12.795.0) and median platelet count 89x109/L (range 12-695). Bone