OBJECTIVETo observe the pregnancy outcome among patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).

METHODSData associated with pregnancy, delivery and neonate from the patients or patient's spouse who conceived while receiving TKIs were collected retrospectively.

RESULTSTwo young female patients (who had been on imatinib therapy for 90 and 91 months, respectively) and spouses of 10 male patients (involving 7 patients who had received imatinib for a median of 60 months and 3 who had received dasatinib for 2.5 months to 7 months, respectively) with median age of 33.5 years (range 26 - 46 years) conceived and gave birth to 12 babies. One woman took imatinib throughout her pregnancy except one month. The other one took imatinib throughout her pregnancy and had breast-fed while on imatinib therapy for nearly half a year postpartum. Among the 12 babies, one was born prematurely with low birth weight and hypospadias (surgical repair after birth), the others were all healthy with no congenital defects. The median age of the children at the date of this report is 17.5 months (range 3 to 101 months), and they all have a normal pattern of growth and development.

CONCLUSIONSConception among patients with CML while receiving TKIs may result in normal pregnancies. The possible effects of TKIs on birth abnormalities cannot be ruled out. It is recommended that childbearing female patients should be advised to practice adequate methods of contraception and should not breast-feed while on TKIs therapy. In cases of accidental pregnancy, risk/benefit evaluations must be carried out carefully on an individual basis. No special precautions apply for male patients being treated with imatinib.

Adult ; Antineoplastic Agents ; therapeutic use ; Benzamides ; Dasatinib ; Female ; Humans ; Imatinib Mesylate ; Infant ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Male ; Middle Aged ; Piperazines ; therapeutic use ; Pregnancy ; Pregnancy Outcome ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; therapeutic use ; Retrospective Studies ; Thiazoles ; therapeutic use ; Treatment Outcome

Objectives: To explore the incidence and factors of severe leukopenia and/or thrombocytopenia in newly diagnosed patients with chronic myeloid leukemia (CML) to probe their impacts on cytogenetic and molecular responses, progression free survival (PFS) and overall survival (OS) . Methods: Data of newly diagnosed patients with CML in the chronic phase (CP) and/or accelerated phase (AP) were retrospectively collected and analyzed. Results: 855 CML patients [including 744 (87%) in the CP and 111 (13.0%) in the AP] were included in this study. 523 (61.2%) patients were male with a median age of 39 years (range, 14-87 years) . 749 (87.6%) patients received imatinib, 93 (10.9%) nilotinib, and 13 (1.5%) dasatinib, respectively as front-line therapy. At a median treatment of 1 month (range, 0.1-7.0 months) , 137 (16.0%) developed ≥grade 3 leukopenia and/or thrombocytopenia and recovered 0.6 month (range, 0.3-6.5 months) . Multivariate analysis showed that female gender (OR=1.5, 95%CI 1.0-2.2, P=0.033) , WBC ≥100×10⁹/L (OR=1.9, 95%CI 1.3-2.8, P=0.001) , CP in Sokal high-risk (OR=2.2, 95%CI 1.2-3.9, P=0.005) , AP with ≥15% blast cells in blood or bone marrow (OR=5.1, 95%CI 1.9-13.3, P=0.001) were factors associated with higher incidence of ≥grade 3 leukopenia and/or thrombocytopenia. Severe leukopenia and/or thrombocytopenia with time of drug discontinuance >2 weeks was associated with lower probabilities of achieving complete cytogenetic (OR=0.4, 95%CI 0.3-0.6, P<0.001) , severe leukopenia and/or thrombocytopenia, no matter the time of drug discontinuance >2 weeks or ≤2 weeks, were associated with lower probabilities of achieving major molecular responses (OR=0.3, 95%CI 0.2-0.5, P<0.001; OR=0.7, 95%CI 0.5-1.0, P=0.036) and MR4.5 (OR=0.2, 95%CI 0.1-0.5, P=0.002; OR=0.7, 95%CI 0.4-1.1, P=0.110) ; however, those had no impacts on PFS and OS. Conclusions: Severe leukopenia and/or thrombocytopenia were common adverse events during TKI therapy. Female patients, WBC ≥100×10⁹/L at diagnosed, CP in Sokal high-risk, CML-AP with ≥15% blast cells in blood or bone marrow were at high risk for higher incidence of severe leukopenia and/or thrombocytopenia. Those severe adverse events had impacts on lower cytogenetic and molecular response.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Dasatinib ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Male ; Middle Aged ; Protein Kinase Inhibitors ; Protein-Tyrosine Kinases ; Retrospective Studies ; Treatment Outcome ; Young Adult

OBJECTIVETo compare the immunophenotypic and clinical characteristics between NPM1 mutated acute myeloid leukemia (AML) (NPM1m(+)AML) and unmutated AML(NPM1m(-)AML) not otherwise characterized (NOS) under similar FAB subtypes constituent ratio.

METHODSImmunophenotyping and NPM1 gene mutation type-A, B and D and other leukemic related fusion genes were detected by multiparameter flow cytometry and real time RT-PCR or PCR, respectively. 104 AML patients with NPM1m(+)AML and performed immunophenotyping assay were included, 97 with NPM1m(-)AML.

RESULTSThere were significant difference between the two groups at presentation in terms of sex, white blood count(WBC), platelet counts (PLT), blast ratio, normal karyotype ratio, WT1 expression level, FLT3-ITD mutation positive rate and remission rate of first course of induction therapy (P < 0.05). On the immunophenotype, the expression of early differentiation antigens (CD34, HLA-DR, CD117, CD38), lymphocytic antigens (CD7, CD4, CD19, CD2), myeloid and monocytic differentiation-associated antigens (CD13, CD14, CD15) were lower, and that of CD33 as well as CD123 were higher in NPM1m(+)AML patients. Among them, only CD34, HLA-DR, CD7, and CD4 positive cases were significantly lower in NPM1m(+)AML group than in NPM1m(-)AML group (P < 0.05), the rest of them had significant difference in the number of positive cells (P < 0.05). Above features were further analyzed between the M1/M2 and M4/M5 subgroups. M1/M2 cases retained the women prominent and had a higher WT1 expression level (P < 0.05). The expression of monocytic differentiation-associated antigens including HLA-DR and lymphocytic antigens were higher and that of CD117 were lower in M4/M5 subtype (P < 0.05). Among them, the positive rates of HLA-DR, CD64, CD11b, CD10, CD15, and CD4 were significantly higher in M4/M5 than in M1/M2 in NPM1m(+)AML group (P < 0.05).

CONCLUSIONThe most clinical characteristics in NPM1m(+)AML patients are consistent with reports, but some immunophenotype are different to the previous reports under similar FAB subtypes constituent ratio. The major immunophenotypic features of NPM1m(+)AML patients are lower expression of progenitor, myeloid and lymphoid lineage antigens. Monocytic differentiation-associated antigens are only higher expression in M4/M5 cases when comparison with M1/M2 cases within NPM1m(+)AML group.

Adolescent ; Adult ; Aged ; Antigens, CD ; metabolism ; Child ; Child, Preschool ; Female ; HLA-DR Antigens ; immunology ; Humans ; Immunophenotyping ; Leukemia, Myeloid, Acute ; diagnosis ; genetics ; immunology ; Male ; Middle Aged ; Mutation ; Nuclear Proteins ; genetics ; Young Adult

This article aimed to report two cases of Burkitt lymphoma/leukemia with concurrent t(8;14) and t(14;18). Morphology, immunophenotype, cytogenetics and molecular biology (MICM) methods were applied to diagnosis. The results showed that the two cases were both acute lymphocytic leukemia L3 type according to FAB criteria. Conventional cytogenetic technique or interphase fluorescence in situ hybridization (FISH) demonstrated that t(8;14) and t(14;18) were detected concurrently in both patients. CD20, CD10, FMC7, CD38 and CD19 were expressed in both patients by immunophenotyping. According to MICM, they were both diagnosed as Burkitt lymphoma/leukemia. The first patient died in one month after chemotherapy, and the second patient survived 19 months after rituximab- combined high-dose chemotherapy and subsequently allogeneic hematopoietic stem cell transplantation (HSCT). In conclusion, t(8;14) and t(14;18) may present simultaneously in Burkitt lymphoma/leukemia and indicate poor prognosis. Rituximab-combined chemotherapy and subsequently HSCT could improve the outcomes of such cases.
Burkitt Lymphoma ; genetics ; Chromosomes, Human, Pair 14 ; genetics ; Chromosomes, Human, Pair 18 ; genetics ; Chromosomes, Human, Pair 8 ; genetics ; Female ; Humans ; Lymphoma ; genetics ; Male ; Middle Aged ; Translocation, Genetic

Interleukin (IL)-20, a proinflammatory cytokine of the IL-10 family, is involved in acute and chronic renal failure. The aim of this study was to elucidate the role of IL-20 during diabetic nephropathy development. We found that IL-20 and its receptor IL-20R1 were upregulated in the kidneys of mice and rats with STZ-induced diabetes. In vitro, IL-20 induced MMP-9, MCP-1, TGF-β1 and VEGF expression in podocytes. IL-20 was upregulated by hydrogen peroxide, high-dose glucose and TGF-β1. In addition, IL-20 induced apoptosis in podocytes by activating caspase-8. In STZ-induced early diabetic nephropathy, IL-20R1-deficient mice had lower blood glucose and serum BUN levels and a smaller glomerular area than did wild-type controls. Anti-IL-20 monoclonal antibody (7E) treatment reduced blood glucose and the glomerular area and improved renal functions in mice in the early stage of STZ-induced diabetic nephropathy. ELISA showed that the serum IL-20 level was higher in patients with diabetes mellitus than in healthy controls. The findings of this study suggest that IL-20 induces cell apoptosis of podocytes and plays a role in the pathogenesis of early diabetic nephropathy.
Animals ; Apoptosis ; Blood Glucose ; Caspase 8 ; Diabetes Mellitus ; Diabetic Nephropathies* ; Enzyme-Linked Immunosorbent Assay ; Glucose ; Humans ; Hydrogen Peroxide ; In Vitro Techniques ; Interleukin-10 ; Interleukins ; Kidney ; Kidney Failure, Chronic ; Mice ; Podocytes* ; Rats ; Vascular Endothelial Growth Factor A

The study aimed to examine a rare case of Philadelphia (Ph)-negative chronic myeloid leukemia (CML) with t(9;13). Chromosome samples were prepared after culture of bone marrow cells for 24 hours, the karyotypes were analyzed by G banding technique. Chromosome painting analysis was performed by using whole chromosome paints for chromosomes 9 and 22. Fluorescence in situ hybridization (FISH) was done with dual color dual fusion LSI bcr/abl probe. Bcr/abl transcripts were detected by real time fluorescence quantitative polymerase chain reaction (RQ-PCR). As a result, G banding analysis showed a karyotype of 45, XX, der(9)t(9;13)(q34;q10), -13[20]. FISH assay using LSI bcr/abl DNA probe showed a red abl signal inserted into der(22) and a fusion signal of bcr/abl rearrangement was discovered. RQ-PCR detected high copies of bcr/abl transcripts. In conclusion, insertion of bcr/abl rearrangement was a rare variant t(9;22) and could be well detected by molecular techniques, however, regular cytogenetic banding technique and whole chromosome paintings may probably lead a misdiagnosis to such cases.
Chromosome Painting ; Chromosomes, Human, Pair 13 ; Chromosomes, Human, Pair 22 ; Chromosomes, Human, Pair 9 ; Female ; Humans ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ; genetics ; Middle Aged

OBJECTIVETo evaluated the impact of baseline ABL kinase domain point mutations on responses to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia (CML).

METHODS34 CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The median follow-up duration of nilotinib therapy was 14 (1.5-50) months. ABL kinase domain point mutations were detected from bone marrow of CML patients at baseline and once every 6 months before and after nilotinib therapy. Hematologic, cytogenetic, molecular response and progression were evaluated respectively at the same time.

RESULTSAmong 34 patients, 13 were in chronic phase (CP), 11 were in accelerated phase (AP), 10 were in blastic crisis (BC). Major cytogenetic response (MCyR) was achieved in 70% of patients with CP, 30% of patients with AP and BC (P = 0.027). Complete cytogenetic response (CCyR) was achieved in 70% of patients with CP and 20% of patients with AP and BP, respectively (P = 0.005). The 4-year progressive free survival of patients with CP and AP was (81.8 +/- 11.6)% and (20.5 +/- 12.9)%, respectively (P < 0.01). The cases of ABL kinase domain point mutations at baseline was 17 (50%). CHR was achieved in 56%, MCyR in 43%, CCyR in 37%, MMR in 31% of patients with baseline mutations versus 59% (P > 0.05), 53% (P > 0.05), 41% (P > 0.05), 18% (P > 0.05), respectively, of patients without baseline mutations. The CHR, MCyR, CCyR and MMR in patients who harbored mutations with high sensitivity to nilotinib in vitro (IC50 < or = 150 nmol/L) or mutations with unknown nilotinib sensitivity in vitro were equivalent to those responses in patients without mutations. Patients with mutations less sensitive to nilotinib in vitro (IC50 > 150 nmol/L, Y253H, F359V/C, T315I) achieved 17% of CHR and MCyR, none of them (6 cases) achieved CCyR, and 6 cases had disease progression within 24 mouth after treatment.

CONCLUSIONSNilotinib is a more effective option for imatinib-resistant or-intolerant CML patients. Response for patients with CP was better than patients with AP and BC. Mutational status at baseline may influence response. Less sensitive mutations may be associated with less favorable responses to nilotinib.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Benzamides ; Female ; Fusion Proteins, bcr-abl ; genetics ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; Male ; Middle Aged ; Piperazines ; pharmacology ; therapeutic use ; Point Mutation ; Protein-Tyrosine Kinases ; genetics ; Pyrimidines ; pharmacology ; therapeutic use ; Treatment Outcome ; Young Adult

Objective: To analyze the characteristics of myeloid neoplasms with t (3;21) (q26;q22) . Methods: Clinical data of patients with t (3; 21) (q26; q22) , diagnosed as hematologic malignancies in Peking University people's hospital from January 2011 to March 2018, were collected retrospectively. 19 patients in our hospital and forty-eight patients bearing t (3;21) (q26;q22) with detailed survival data reported in literature were summarized. Kaplan- Meier method was used for survival analysis. Results: Among 19 patients, including 15 males and 4 females with a median age of 36 years (22-68 years) , 4 cases was diagnosed as de novo acute myeloid leukemia (AML) , 4 as myelodysplastic syndromes (MDS) , 3 as MDS-AML and 8 as chronic myelogenous leukemia (CML) in myeloid blast transformation. All of the 19 patients were detected to have t (3;21) (q26;q22) by G-banding technique and 13 carried additional cytogenetic aberrations. 9 of the 19 patients were detected for positive AML1-MDS1 fusion genes. In the 9 patients with detailed follow-up data, 6 patients received chemotherapy and only 2 achieved complete remission (CR) while 4 with no response. During the follow-up period, 8 patients died and the median overall survival (OS) was 6 months (4.5 to 22 months) . Survival analysis of the present 9 patients together with the literature data showed that the prognosis was poor and the median OS was 7 months. In particular, AML/t-AML had the worst prognosis. Hematopoietic stem cell transplantation (HSCT) could significantly improve survival, the median OS in HSCT group and non-HSCT group were 20.9 and 4.7 months respectively (P<0.001) . Conclusions: t (3; 21) (q26; q22) is a rare recurrent chromosomal abnormality which is detected mainly in myeloid neoplasm and confer to poor clinical prognosis. HSCT should be recommended to improve the outcomes.
Adult ; Aged ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 3 ; Female ; Humans ; Leukemia, Myeloid, Acute ; Male ; Middle Aged ; Myeloproliferative Disorders ; Retrospective Studies ; Translocation, Genetic ; Young Adult

Objectives: To compare the efficacy and safety of Chinese generic imatinib with branded imatinib as frontline therapy in adults with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) (Frontline group) , and to explore the efficacy and safety of Chinese generic imatinib in CML-CP patients switching from branded imatinib (Switching group) . Methods: Frontline group: Data of adults with newly diagnosed CML-CP receiving Chinese generic imatinib (Xinwei(®)) or branded imatinib (Glivec(®)) between October 2013 and August 2018 were retrospectively collected and analyzed. Switching group: Data of adults diagnosed with CML-CP who received branded imatinib and then switched to Chinese generic imatinib after achieving at least complete cytogenetic response (CCyR) were retrospectively collected and analyzed. Results: Frontline group: In total, 409 adult patients receiving Chinese generic imatinib (n=201) or Glivec (n=208) were included in this study. Median age was 42 years (range, 18-83 years) . Comparison of baseline showed significant difference on demographic characteristics among two cohorts: lower education level (P<0.001) , and divorced or widowed status (P=0.004) and rural household registration (P<0.001) were more common in the generic imatinib cohort than those in the Glivec cohort. There was no significant difference on age, gender, Sokal risk score, WBC and HGB between the 2 cohorts. With a median follow-up of 25 months (range, 3-62 months) , there was no significant difference on the 3-year cumulative incidence of achieving CCyR (97.5% vs 94.5%, P=0.592) , major molecular response (MMR) (84.3% vs 93.1%, P=0.208) , molecular response(4.0) (MR(4.0)) (42.7% vs 41.7%, P=0.277) , molecular response(4.5) (MR(4.5)) (25.4% vs 33.0%, P=0.306) as well as the 3-year probabilities of failure free survival (FFS) (76.7% vs 81.0%, P=0.448) , progression free survival (PFS) (91.8% vs 96.3%, P=0.325) and overall survival (OS) (95.8% vs 98.5%, P=0.167) between the generic and branded imatinib cohorts. Multivariate analysis showed the type of imatinib was not associated with treatment responses and outcomes. The incidences of adverse effects were comparable in the 2 cohorts. Switching group: In total, 39 patients switching from branded imatinib to Chinese generic imatinib after achieving at least CCyR were included in this study. Median age was 42 years (range, 23-80 years) . With a median follow-up of 39 months (range, 6-63 months) , molecular responses were maintained in 23 (58.9%) patients and improved in 12 (39.8%) patients. Adverse effects were tolerable. Conclusion: Demographic characteristics might influence the choice of the type of TKI used in CML-CP patients. There was a comparable efficacy and safety between the Chinese generic imatinib and the branded imatinib in adults with newly diagnosed CML-CP under standard management and closely monitoring. Patients could safely switch from the branded imatinib to the Chinese generic imatinib.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; Demography ; Humans ; Imatinib Mesylate/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Middle Aged ; Protein Kinase Inhibitors ; Retrospective Studies ; Treatment Outcome ; Young Adult

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.
Dasatinib/therapeutic use* ; Female ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Pyrimidines/therapeutic use* ; Retrospective Studies ; Treatment Outcome