OBJECTIVE: To explore the genetic basis for a rare case of acute B-lymphocytic leukemia (B-ALL) with double Philadelphia chromosomes (Ph) and double derivative chromosome 9s [der(9)]. METHODS: A patient with double Ph and double der(9) B-ALL who presented at Shanghai Zhaxin Intergrated Traditional Chinese and Western Medicine Hospital in June 2020 was selected as the subject. Bone marrow morphology, flow cytometry, G-banding karyotyping, fluorescence in situ hybridization (FISH), genetic testing and chromosomal microarray analysis (CMA) were used to analyze bone marrow samples from the patient at various stages. RESULTS: At initial diagnosis, the patient's bone marrow morphology and flow immunotyping have both supported the diagnosis of B-ALL. G-banded karyotyping of the patient indicated double Ph, in addition with hyperdiploid chromosomes involving translocations between chromosomes 9 and 22. BCR-ABL1 fusion gene was positive. Genetic testing at the time of recurrence revealed presence of a heterozyous c.944C>T variant in the kinase region of the ABL1 gene. FISH showed a signal for ABL1-BCR fusion on both chromosome 9s. CMA showed that the mosaicism homozygosity ratio of chromosome 9 was about 40%, and the mosaicism duplication ratio of chromosome 22 was about 43%. CONCLUSION Since both der(9) homologs were seen in 40% of cells, the possible mechanism for the double der(9) in this patient may be similar to that of double Ph, which might have resulted from non-disjunction during mitosis in the Ph chromosome-positive cell clone.
Humans ; Philadelphia Chromosome ; In Situ Hybridization, Fluorescence/methods* ; China ; Chromosome Aberrations ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Translocation, Genetic ; Fusion Proteins, bcr-abl/genetics* ; Chromosomes, Human, Pair 9/genetics*

Humans ; Philadelphia Chromosome ; Neoplasms ; Myelodysplastic Syndromes/genetics* ; Disease Progression

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ² test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×10⁹/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ²=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ²=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.
Male ; Female ; Humans ; Child ; Prognosis ; Philadelphia Chromosome ; Retrospective Studies ; Receptor, Platelet-Derived Growth Factor beta/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Neoplasm, Residual

UNLABELLED: AbstractObjective: To explore the effect of Philadelphia chromosome karyotype (Ph) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the treatment of acute lymphoblastic leukemia (ALL). METHODS: The data of 429 patients with all from January 2012 to December 2020 were retrospectively analyzed. According to the results of cytogenetic karyotype analysis, they were divided into Ph⁺ group (n=64), Ph^- monomeric karyotype (MK) group (n=53) and Ph^- NMK group (n=312). According to the treatment plan, they were divided into allo-HSCT group (n=236) and non-allo-HSCT group (n=193). The effects of karyotype and allo-HSCT on the short-term and long-term outcomes of all patients were analyzed. RESULTS: Among the 429 patients, 6 (1.40%) died during induction therapy, 60 (13.99%) had no response, 363 (84.62%) achieved complete remission (CR) and 287 (66.90%) achieved minimal residual disease negative (MRD-). There was no significant difference in short-term efficacy (CR%, CR1%, MRD-%) among Ph⁺ group, Ph^- MK group and Ph^- non-MK group (P>0.05). The median OS was 6.9 months (95% CI: 4.6-8.2 months) for 60 unresponsive patients and 39.8 months (95% CI: 28.6-45.9 months) for 363 CR patients. There was no significant difference in the long-term efficacy ［5-year cumulative recurrence rate (CIR%), disease-free survival rate (DFS%) and overall survival rate (OS%) among Ph^- group, Ph^- MK group and Ph^- non-MK group (P>0.05). Among 429 patients, 55.01% (236/429) underwent allo-HSCT. The short-term efficacy (CR%, MRD-%) and long-term efficacy (CIR%, DFS%, OS%)］ of patients with allo-HSCT after more than 2 consolidation cycles were better than those of patients with non-allo-HSCT (P<0.05). For the three subgroups of Ph⁺ group, Ph^- MK group and Ph^- non-MK group, the short-term and long-term efficacy of allo-HSCT patients was better than that of non-allo-HSCT patients. Multivariate logistic regression analysis showed that liver/spleen/lymph node enlargement was a risk factor for CIR, DFS and OS, with adjusted or of 1.23 (95% CI: 1.08-2.78, P=0.032), 1.21 (95% CI: 1.03-2.34, P=0.038) and 1.25 (95% CI: 1.08-2.97, P=0.028), respectively. No transplantation was a risk fator for CIR, DFS, OS. The adjusted or were 2.34 (95% CI: 1.18-5.39, P<0.001), 2.15 (95% CI: 1.10-4.34, P<0.001) and 2.28 (95% CI: 1.09-4.11, P<0.001), respectively. CONCLUSION Karyotype (Ph^+/- and MK/non-MK) seems to have no effect on the short-term and long-term efficacy of all patients; allo-HSCT can affect the short-term and long-term efficacy of all patients and improve their prognosis; liver/spleen/lymph node enlargement and non-implementation of allo-HSCT treatment strategy are the risk factors for poor prognosis of all patients.
Acute Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Karyotype ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Prognosis ; Retrospective Studies

OBJECTIVE: To analyze the outcomes of the children suffered from philadelphia chromosome positive acute lymphoblastic leukemia (Ph METHODS: 21 cases of firstly diagnosed Ph RESULTS: Among 21 patients, 17 were male and 4 were female with a median age of 8 years old (range, 4-12 years), the median follow-up time was 30 moths (range, 10-133 months). All the patients were treated with chemotherapy induced by the high-risk project of CCLG-ALL 2008. Among 14 patients treated with TKI plus chemotherapy, nine patients achieved complete remission. During 3 months after treatment, patients without complete molecular response or with the second complete remission and intensity desire of transplantation were treated with allo-HSCT, among 9 patients with allo-HSCT, six patients achieved long term survival. CONCLUSION At TKI era, TKI combined with strong chemotherapy can make Ph
Aged ; Child ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Male ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Protein Kinase Inhibitors ; Retrospective Studies

OBJECTIVE: To investigate the overview of thrombosis in myeloproliferative neoplasms(MPN) patients, and to explore the risk factors of thrombosis at diagnosis and during follow-up. METHODS: The clinical data of 388 MPN patients treated in our hospital were collected. The patients were followed up by outpatient and phone. The risk factors of thrombosis were analyzed by statistical methods. RESULTS: Among 388 MPN patients, 161 patients (41.49%) showed thromboses at diagnosis or during follow-up. Among them, 92.55% were arterial thromboses, 146 cases (96.27%) were complicated with thromboses at diagnosis, and 36 cases (11.46%) showed newly thromboses or progression of previous thromboses among the 314 received full follow-up patients. Age (P＜0.001, HR:1.033, 95%CI:1.016-1.051), JAK2V617F mutation (P=0.037, HR:1.72, 95%CI: 1.033-2.862), hypertension (P＜0.001, HR:2.639, 95%CI:1.659-4.197) and hyperlipidemia (P＜0.001, HR:2.659, 95%CI:1.626-4.347) were the independent risk factors affecting thrombosis at diagnosis of the patients. During the follow-up, age (P=0.016, HR:1.032, 95%CI: 1.006-1.059) and previous thrombosis history (P=0.019, HR:2.194, 95%CI: 1.135-4.242) were the independent risk factors affecting the progression of thrombosis at different sites or on the basis of the previous thrombosis in the patients. CONCLUSION Patients with advanced age, JAK2V617F mutation or complicated with hypertension and hyperlipidemia shows a higher risk of thrombosis at diagnosis, while the patients with advanced age or previous thrombosis history shows a higher risk of progression of thrombosis during the follow-up.
Humans ; Myeloproliferative Disorders/genetics* ; Neoplasms ; Philadelphia Chromosome ; Risk Factors ; Thrombosis

OBJECTIVE: To trace a rare case of chronic myeloid leukemia (CML) with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment. METHODS: Bone marrow morphology, chromosomal karyotyping, fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RQ-PCR) were used for the diagnosis and staging of the disease. Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing. RESULTS: The patient was initially diagnosed as CML in chronic phase (CML-CP) with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25), while FISH revealed presence of a variant Philadelphia chromosome translocation. Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor (TKI) treatment, when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25) and t(5;9;22;6;17)(q13;q34;q11;q25;q11). After 57 months of TKIs treatment, only the t(5;9;22;6;17) clone was detected. Three months later, hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17). Three mutations, including p.Tyr253Phe, p.Thr315Ile and p.Gly250Glu, were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease. The patient did not attain cytogenetic and molecular response to TKIs. CONCLUSION The four-way variant translocation may be genetically unstable. Clonal evolution and genetic mutations are likely to occur during TKIs treatment, resulting in poor response to drug therapy. This observation, however, needs to be confirmed by large-scale studies.
Enzyme Inhibitors/therapeutic use* ; Evolution, Molecular ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Mutation/genetics* ; Philadelphia Chromosome ; Translocation, Genetic

The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.
Child ; Dasatinib ; Humans ; Neoplasm, Residual ; Philadelphia Chromosome ; Precision Medicine ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*

Abstract　　The curative efficacy of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) has been improved substantially with the introduction of tyrosine kinase inhibitors (TKIs). However, there is no consensus so far on the following issues, which TKIs should be chosen in combination with chemotherapeutic regimens; which regimen of intensive chemotherapy incorporated into TKIs would be more beneficial to patients. The prognosis of the patients with Ph ALL has been so significantly improved by the combinatorial treatment of TKIs and chemotherapy, thus it is necessary to reevaluate the role of allogeneic hematopoietic stem cell transplantation in the management of Ph ALL. In addition, immunotherapy has achieved an initial success in the treatment of Ph ALL. In this review, the treatment paradigms for the disease are summrized briefly.
Chromosomes ; Hematopoietic Stem Cell Transplantation ; Humans ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Protein Kinase Inhibitors

BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a subset of ALL with poor prognosis. Here, we analyzed the outcomes and prognostic factors of children with Ph+ ALL who received imatinib and chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). METHODS: Thirty-one Ph+ ALL patients (female 10) diagnosed from January 2005 to December 2016 were included in the study. All patients were treated with imatinib and chemotherapy before HCT. Bone marrow (BM) evaluations included real-time quantitative polymerase chain reaction (RQ-PCR) study of the BCR-ABL1 fusion transcript. All patients received HCT with total body irradiation (TBI)-based conditioning at a median of 6.4 (range, 4.2–47.1) months from diagnosis. RESULTS: Compared to values at diagnosis, the median decrement of RQ-PCR value post-consolidation, and prior to HCT was −3.7 Log and −4.8 Log, respectively. The 5-year event-free survival (EFS) and overall survival of the patients were 64.5±9.4% (20/31) and 75.0±8.3% (23/31) respectively. Events included relapse (N=5) and death in CR post-HCT (N=6). The 5-year incidence of molecular relapse was 30.9±9.1% (9/31). An RQ-PCR decrement of at least −4 Log post-consolidation significantly predicted lower incidence of molecular relapse: 7.7±7.7% for ≥−4 Log decrement, 50.0±13.8% for <−4 Log decrement (P=0.027). CONCLUSION: Decrement in RQ-PCR for the BCR-ABL1 transcript that was determined after consolidation was the only significant prognostic factor for incidence of molecular relapse. In the post-induction TKI initiation setting, steadfast imatinib treatment during consolidation may allow for optimum post-HCT outcomes.
Bone Marrow ; Cell Transplantation ; Child ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Humans ; Imatinib Mesylate ; Incidence ; Philadelphia Chromosome ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Recurrence ; Transplants ; Whole-Body Irradiation