Lin D

Optimal treatment of adult Ph negative acute lymphoblastic leukemia

OBJECTIVE To analyze the difference of safety and efficacy between the traditional and the pediatric inspired acute lymphoblastic leukemia (ALL) chemotherapy regimen, and to further observe whether patients in different age group will benefit from the two regimens. METHODS Adult de novo Ph negative ALL patients in our hospital from Jan 4, 2009 to Sep 4, 2013 were involved in this study and divided into 2 groups according to treatment regimens, the traditional regimen (regimen 1) and modified pediatric regimen (regimen 2) groups, respectively. The safety and the efficacy of all patients and different regimen groups were evaluated statistically. RESULTS All 144 patients received the induction therapy. The total complete remission (CR) rate was 95.8%, one course CR rate was 92.4%, and 5 year overall survival (OS) and progression free survival (RFS) were 59.0% and 48.6% respectively. The CR rate, 3 year OS and 3 year RFS between the two different regimens were 95.6% vs 96.1% (P = 0.783), 65.3% vs 63.4% (P = 0.885) and 56.0% vs 50.0% (P = 0.931), respectively. Further analysis stratified with age was also performed. For the patients treated with regimen 1, the 3 year OS and RFS between the two different age groups (14-30 years and 31-60 years) was 69.6% vs 54.7% (P = 0.042) and 56.5% vs 57.0% (P = 0.472). For the patients treated with regimen 2, the 3 year OS and RFS between the two different age groups (14-30 years and 31-60 years) was 65.7% vs 60.3% (P = 0.423) and 51.5% vs 46.6% (P = 0.655). No differences were found on the respiratory failure, cardiac dysfunction, fungal infection and intestinal obstruction between the two treatment regimen groups. The incidence of renal dysfunction for regimen 1 was lower than that of regimen 2 (P = 0.011). The incidence of bacteremia for regimen 1 was higher than that of regimen 2 (P = 0.000). CONCLUSION The two treatment regimens for adult Ph negative ALL patients were well tolerated and showed relative favorable CR rate and long term survival rate. The older patients (31-60 years) tended to benefit from the regiment 2 which was less intensive and consisted of more agents with low suppression to bone marrow.

[Acute myeloid leukemia with t(11;12)(p15;q13) translocation: two cases report and literature review].

OBJECTIVE To investigate the clinical and laboratory features of acute myeloid leukemia (AML) with t(11;12)(p15;q13) translocation. METHODS Two cases of AML with t(11;12)(p15;q13) translocation were reported and the related literatures were reviewed. RESULTS The diagnosis of AML-M3 was supported by morphological, cytochemical staining and electron microscope tests. A rare t(11;12)(p15;q13) translocation, but not classical t(15;17)(q22;q12) translocation and PML- RARα fusion gene, was detected in both cases. Both of the patients were refractory to differentiation induction therapy such as retinoic acid and arsenic trioxide. CONCLUSION AML is a group of heterogeneous disease derived from hematopoietic stem cell. Cytogenetic characteristic is important for diagnosis, prognosis stratification and therapy selection. Because of the heterogeneity of clinical and molecular features, it is unsuitable to classify AML with t(11;12)(p15;q13) as AML with recurrent cytogenetic aberration. This group of disease may benefit from allogeneic hematopoietic stem cell transplantation.

[Detection of heterogeneity and evolution of subclones in t(8;21) AML by QM-FISH].

OBJECTIVE To explore the heterogeneous subclones in acute myeloid leukemia (AML) with t(8;21) by quantitative multicolor- fluorescence in situ hybridization (QM-FISH), and to figure out whether there is putative ancestral relationship among different subclones. METHODS Bacterial artificial chromosomes (BAC) clones that contain the targeted genes including AML1, ETO, WT1, p27 and c-kit were searched in the data base UCSC Genome Bioinformatics. Multicolor FISH probes were prepared by linking fluorescein labeled dUTP or dCTP to targeted genes by nick translation. Bone marrow mononuclear cells from t (8;21) AML patients are dropped on to the wet surface of glass slides after hypotonic treatment and fixation. After hybridization, the fluorescence signals were captured by Zeiss fluorescence microscope. The copy number of AML1, ETO, WT1, p27, c- kit and the AML1-ETO fusion gene in AML1-ETO positive cells was counted. The cells with same signals were defined as a subclone. Various subclones were recorded and their proportions were calculated, and their evolutionary relationship was deduced. The subclones in matched primary and relapsed samples were compared, the evolution of dominant clones were figured out and the genomic abnormality that is associated with relapse and drug resistance were speculated. RESULTS In this study, 36 primary AML with t(8;21) cases and 1 relapsed case paired with the primary case were detected. In these 36 primary cases, 4 cases (11.1%) acquired additional AML1-ETO fusion signal, 3(8.3%) had additional AML1 signal, 4(11.1%) had additional ETO signal, 20(55.6%) had additional WT1 signal, 15(41.7%) had additional p27 signal and 14(38.9%) had additional c-kit signal. In addition, 10(27.8%) displayed AML1 signal deletion, and such an aberration represents statistic significance in male patients. It seems that male patients usually accompany AML1 signal deletion. Of 36 cases, 28(77.8 %) harbored at least 2 subclones (ranged from 2 to 10). According to the genetic signature of subclones, we can assemble a putative ancestral tree, and the genetic architecture is linear or branching. In particular, the clonal architecture of the relapsed sample exhibited significant clonal evolution compared to its paired sample at diagnosis, including proportion changes in dominant clone, subclone disappearance and appearance of new dominant clones. CONCLUSION Genomic abnormality is very diverse in t(8;21) AML. Subclones have linear or complex branching evolutionary histories, and clonal architecture is dynamic.

[A clinical study of acute lymphoblastic leukemia in adolescents: a single center experience].

OBJECTIVE To explore the clinical and laboratory characteristics, treatment, prognostic factors of acute lymphoblastic leukemia (ALL) in adolescents. METHODS Adolescents de novo ALL patients in Blood Disease Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences from September 1999 to September 2013 were enrolled in this study. Clinical data, therapeutic effect and prognostic factors were retrospectively analyzed. RESULTS Of all 94 patients, 91 patients were treated in our center. The overall complete remission (CR) rate was 96.7% (88/91), CR rate after one cycle was 91.2%(83/91). The median follow-up time was 18 months. In all patients, the 6-year anticipated overall survival (OS) rate and disease free survival (DFS) rate were (47.6 ± 6.7)% and (45.4 ± 6.0)% respectively. In standard risk ALL patients , 6-year anticipated OS rate and DFS rate were (65.7 ± 8.1)% and (65.3 ± 7.4)%. Hyperleukocytosis (white blood cell count ≥30 × 10(9)/L in B-ALL; ≥100 × 10(9)/L in T-ALL), Ph(+) , MLL(+) , hypodiploid were risk factors associated with poor clinical outcome. CONCLUSIONS The therapeutic effect and clinical outcome in adolescents with ALL are relatively favorable, especially in standard risk group. In high risk ALL patients, allogeneic hematopoietic stem cell transplantation may improve therapeutic efficacy.

Characteristics of karyotypes and gene mutations for elder acute myeloid leukemia

OBJECTIVE To investigate the incidence of karyotypes and gene mutations for elder acute myeloid leukemia and to explore the relationship between each other. METHODS Clinical data and bone marrow samples of elder AML patients were collected. Karyotype and gene mutation (FLT3, NPM1, C-Kit, CEBPα, DNMT3A) test were performed, characteristics of karyotypes and gene mutations were analysed. RESULTS The incidence of better risk karyotype was 16.6%, in which the incidences of t(15;17), t(8;21) and inv (16)/t(16;16) were 3.90%, 10.73%, and 1.95% respectively; the incidence of intermediate risk karyotype was 72.2%, in which the incidence of normal karyotype was 57.86%; the incidence of poor risk karyotype was 11.20%, in which the incidence of of MLL/11q23, complex karyotype and monosomal karyotype were 1.95%, 6.34%, 5.85% respectively; the incidences of FLT3, NPM1, C-Kit, CEBPα, DNMT3A mutation were 12.57%, 22.06%, 2.16%, 14.71%, 15.71% respectively. Compared with patients older than 60 years, patients with age of 55-60 years were with less complex karyotype (1.09% vs 10.62%)(P=0.003) and monosomal karyotype (2.17% vs 8.85%)(P=0.032), and more t(8;21)(17.39% vs 5.31%)(P=0.008) and inv (16)/t(16;16)(4.35% vs 0.00%)(P=0.045). CONCLUSION For older AML patients, great difference in the distribution of karyotyes was found between the patients older than 60 years and patients with age of 55-60 years, while no such characteristics was found for gene mutations. Good elucidation of karyotypes and gene mutations are key for the treatment of older acute myeloid leukemia patients.

[Characteristics and treatment outcomes in 822 adult patients with acute myeloid leukemia:a single center experience].

OBJECTIVE To investigate the characteristics and the short- or long-term treatment outcomes of the adult patients with acute myeloid leukemia (AML) in China. METHODS From 1999 to 2010, 822 adult cases with AML were enrolled, diagnosed and classified by the FAB and WHO criteria, respectively. The treatment outcomes and prognostic factors were analyzed retrospectively. RESULTS In all patients with a median age of 38.5(15-83) years, acute monoblastic and monocytic leukemia (M5), AML with t(15;17)/PML-RARα (APL) and AML with t(8;21)/AML1-ETO(M2b) were the most common subtypes, accounting for 29.7%, 20.9% and 14.6% respectively. In APL patients, CR was achieved in 95.2%, with an early death (ED) rate of 4.8%. And the estimated overall survival (OS) and disease-free survival (DFS) at 5 year was 87.5% and 88.8%, respectively. Patients with other AML subtype (Non-APL) revealed a CR rate of 82.0%, ED of 4.3%, and estimated 5-year OS and DFS both of 48.8%. The OS rate of Non-APL patients at 3-year varied significantly (P<0.01) among three prognostic groups by cytogenetic risk stratification:favorable, 69.5%; intermediate, 52.8%; unfavorable, 29.8%. The prognostic factors for OS among Non-APL included age, cytogenetic abnormalities, courses of the median/high-dose cytarabine and allogeneic hematopoietic stem cell transplantation. CONCLUSION When compared with the previous reports, the AML patients in our study were younger and showed a different subtype distribution. Treatment outcomes of APL and Non-APL were just the same as those in international leukemia centers. Chemotherapy by risk stratification, after diagnosis and classification according to the WHO criteria, is a key point to improve the outcomes in AML.