Research advances of small molecule inhibitors in the treatment of mixed lineage leukemia / 药学学报

Acute leukemia (AL) is a kind of malignant clonal disease of hematopoietic stem cells. Rearrangement of mixed lineage leukemia (MLL) gene can be observed in about 5%-10% of AL patients. Currently, AL patients with MLL-rearrangements (MLL-r) lack effective treatment and are usually associated with poor prognoses. Recent studies have shown that many epigenetic regulators are directly or indirectly involved in the occurrence and development of AL carrying MLL-r (MLL), which provides a biological basis for the use of epigenetic regulation strategies to treat MLL. In this review, we start from the epigenetic regulation mechanism of MLL, and select representative drug targets to briefly analyze the relationship between each target and MLL and summarize the development progress of their inhibitors, hoping to provide reference for the subsequent research and development of drugs for the treatment of MLL.

Outcome of allogeneic hematopoietic stem-cell transplantation in 50 patients with acutemyeloid leukemia and MLL rearrangement / 中华器官移植杂志

Objective:To investigate the efficacy of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia associated with 11q23/MLL.Methods:Retrospection and analysis 50 cases of acute myeloid leukemia with 11q23/MLL and who were treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT)in our hospital from September 2012 to December 2019. The efficacy was evaluated by analyzing the transplantation success rate, graft-versus-host disease rate, infection rate, transplant-related mortality(TRM), accumulative recurrence rate, disease-free survival rate(DFS), and overall survival rate(OS).Results:Except for 1 patient had an unsuccessful stem cell transplantationas the result of multiple organ failure, the remaining 49 patients were successfully transplanted. The median time of leukocyte transplantation was 15(9~18)days, and the median time of platelet transplantation was 13(8~33)days. Bone marrow was assessed 28 days after transplantation, and 49 patients were in CR status. The median follow-up time was 38(3~79)months. Between remission group and non-remission group after transplantation, the 3-year OS rates were(83.3±10.8)%, (30.9+ 8.2)%( P=0.002)and the 3-year DFS rates were(83.3+ 10.8)%, (28.4±8.0)%( P=0.003), respectively. Conclusions:Allogeneic hematopoietic stem cell transplantation is an effective method for the treatment of 11q23/MLL rearranged AML. Patients in remission before transplantation have a higher survival rate, and recurrence after transplantation is the primary problem currently faced.

Prognostic analysis of allogeneic hematopoietic stem-cell transplantation in 47 patients with acute myeloid leukemia and MLL rearrangement / 中华血液学杂志

Objective@#To investigate the prognosis of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for patients with acute myeloid leukemia and MLL rearrangement.@*Methods@#From September 2009 to May 2016, the clinical data of 47 patients with MLL-rearranged AML undergoing allo-HSCT in the First Affiliated Hospital of Soochow University were retrospectively analyzed.@*Results@#Among 47 MLL-rearranged AML patients, 24 were male and 23 female. The median age was 30 (15-58) years old. There are 36 (76%) patients were FAB-types M4/M5. Two-year overall survival (OS), disease-free survival (DFS), relapse incidence and transplant-related mortality (TRM) were (64.4±8.4)%, (47.3±9.3)%, 41.0% and 17.9%, respectively. Of them, 45 patients were detected with 11q23 translocations, and 2 patients with normal karyotype were MLL partial tandem duplication. According to different chromosome karyotype, 47 patients were divided into three groups: 16 cases of t (6; 11), 15 cases of t (9; 11) and 16 cases of other types. Overall survival was compared between the three groups, there was no significant difference (χ2=1.509, P=0.472). On multivariate analysis, independent risk factor on OS was transplant age >45 years [HR=4.454(95%CI 1.314-15.099), P=0.016]. The multivariate analysis also confirmed the higher TRM in patients at non-CR state when transplanted [HR=10.370(95%CI 1.043-103.110), P=0.046]. Positive minimal residual disease (MRD) before transplantation was a negative prognostic factor on DFS [HR=4.236(95%CI 1.238-14.495), P=0.021] and relapse incidence (RI) [HR=5.491(95%CI 1.371-21.995), P=0.016].@*Conclusion@#Transplant age (>45 years), allo-HSCT in non-CR state adn positive MRD before transplantation were negative prognostic factors in allo-HSCT for MLL-rearranged AML patients.

CALLA negative precursor B lymphoblastic leukemia with MLL gene translocation and an unusual FISH signal pattern.

Rearrangements of the mixed lineage leukemia (MLL) gene at 11q23 commonly occur in infants with CALLA negative B lymphoblastic leukemia (B-ALL). Most often, these are detected by conventional karyotyping; however, fluorescent in-situ hybridization (FISH) with the help of a dual-color break-apart probe is used to identify cryptic translocations. When there is an MLL gene translocations the usual FISH signal pattern is 1 red-1 yellow fusion signal pattern We present a case of an infant with CALLA negative precursor B-ALL with a characteristic translocations t(4;11) (q21;q23),however,with an unusual MLL FISH signal pattern.

Acute Monocytic Leukemia with t(11;17)(q23;q21) Involving a Rearrangement of Mixed Lineage Leukemia Gene / 대한진단검사의학회지

A case of acute monocytic leukemia (AMoL) by French-American-British (FAB) classification in a 63-year-old male showed the abnormal karyotype 46,XY,t(11;17)(q23;q21), previously reported as a variant translocation in acute promyelocytic leukemia (APL). Fluorescence in situ hybridization (FISH) analysis identified a mixed lineage leukemia (MLL) gene rearrangement, but not visible disruptions of promyelocytic leukemia (PML) or retinoic acid receptor alpha (RARA) genes. We suggest that a certain gene proximal to RARA was rearranged in this case onto a gene close to MLL on chromosome 11q. Now, a few cases of AMoL with a similar translocation have been reported in the literature, and these cases emphasize the importance of cytogenetic and FISH studies in addition to morphology, cytochemistry, and immunophenotype in classifying acute myeloid leukemia (AML).

Clinical Features of Acute Leukemia with Positive Mixed Lineage Leukemia Fusion Gene in Children / 实用儿科临床杂志

Objective To analyze the clinical features of acute leukemia(AL) with positive mixed lineage leukemia(MLL)fusion gene in children,and explore their treatment protocols,prognosis factors,and so on.Methods Clinical features,treatment protocols,and prognosis factors were studied retrospectively among 51 AL patients with MLL fusion gene.MLL fusion gene was detected by morphology immunology,cytogenetics,molecul arbiology and reverse transcrption polymerase chain reaction(RT-PCR).Results Fifty-one AL patients with MLL fusion gene positive,included 37 cases of acute lymphoblastic leukemia(ALL) and 14 cases of acute myelocytic leukemia(AML).Forty-two patients exhibited abnormal clonal chromosome 11.MLL fusion gene rearrangements and MLL fusion gene partial tandem duplication were found among 36 cases and 15 cases,respectively.Thirty-two cases who received regular chemotherapy were followed up.Twenty-four cases including 19 cases of ALL and 5 cases of AML had achieved complete remission(CR).Six cases including 5 cases of ALL and 1 cases of AML had achieved more than 2 years CR.Sixteen cases were alive update including 12 cases of ALL and 4 cases of AML.Ten cases of positive MLL fusion gene were turning negative.Up to now,6 cases relapsed and 6 cases were dead.Conclusions The incidence of AL children with positive MLL fusion gene is low.It has some features,such as,high replapse rate and poor prognosis.A few patients sensitive to chemotherapies can achieve CR.They live with constant negative MLL fusion gene.

Expression Patterns of Immunologic Surface Markers in Acute Leukemia / 대한혈액학회지

BACKGROUND: Immunophenotyping is an important technique for the diagnosis and classification of acute leukemia, as well as French-American-British (FAB) classification on the basis of morphologic characteristics and cytochemistry. We evaluated the expression patterns of immunologic surface markers in acute leukemia. METHODS: Peripheral or bone marrow leukemic cells from 75 leukemic patients (acute lymphoblastic leukemia, ALL 40 cases; children (26 cases), adults (14 cases) and acute myeloid leukemia, AML 35 cases; children (9 cases), adults (26 cases)) were studied. Monoclonal antibodies which were designed for two color direct immunofluorescence (IF) analysis with combination of fluoresceinisothiocynate (FITC) and phycoerythrin (PE) conjugated, CD10/CD19, CD20/CD5, CD3/CD22, CD7/CD33, HLA-DR/CD13 (Acute Leukemia Phenotyping Kit, Becton Dickinson; BD, USA) were analyzed by flow cytometry. RESULTS: Blasts from these patients could be classified as CALLA (+)B-ALL (26 cases, 65.0%), CALLA (-)B-ALL (6 cases, 15.0%), T-ALL (6 cases, 15.0%), biphenotypic ALL (2 cases, 5.0%). The positive expression rates were CD19 (100%), CD10 (78.1%), CD22 (75.0%) and CD20 (50.0%) in B-ALL, CD7 (100%), CD3 (50.0%) and CD5 (50.0%) in T-ALL and CD33 (85.7%), CD13 (74.3%) in AML, respectively. The incidence of acute mixed lineage leukemia (AMLL) was 26.7% and leukocytosis, anemia and thrombocytopenia were frequently seen in AMLL. CONCLUSION: By the study of immunophenotyping we could more exactly diagnosed ALL and AML, as well as AMLL which was not exactly diagnosed by characteristics of morphology and cytochemistry only. Therefore the best method for the diagnosis of acute leukemia will be achieved by using of immunophenotyping and FAB classification on the basis of morphology and cytochemistry.