Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lym...Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).展开更多
Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has bee...Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has been demonstrated in acute lymphoblastic leukemia(ALL),of which ALL with Philadelphia chromosome-positive(Ph+).The use of imatinib,a tyrosine kinase inhibitor(TKI),as part of front-line treatment and in combination with cytotoxic agents,has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL.New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations.An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs,such as nilotinib and dasatinib.However,in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells.None of the TKIs in clinical use target the LSC.Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs.Allogeneic stem cell transplantation(SCT) remains the only curative treatment available for these patients.Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations.Hence,TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy.Better understanding the biology of Ph+ ALL will open new avenues for effective management.In this review,we highlight recent findings relating to the question of LSCs in Ph+ ALL.展开更多
Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) pos...Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) positive ALL, a high-risk cytogenetic subset, accounts for 25% - 30% of adult ALL cases but occurs in less than 5% of children. We aimed with this study to detect BCR-ABL genes fusion, amplification and deletion in ALL patients, using extrasignal-fluorescence in situ hybridization (ES-FISH), and to assess their relation with other standard prognostic factors and therapeutic response. Patients and Methods: This study was carried out on 39 newly diagnosed ALL patients. All patients were subjected to: history, clinical examination and laboratory investigations, which included complete blood count (CBC), peripheral blood (PB), bone marrow (BM) examination, immunophenotyping and fluorescence in situ hybridization using extra-signal probe to detect BCR-ABL genes fusion. Results: This study showed statistical analysis of patients’ t(9;22) with other factors revealed, significant association (p 35 years, hepatosplenomegaly, absence of lymphadenopathy, TLC ≥ 50 × 109/L, absolute PB blasts ≥ 4.4 × 109/L, immunophenotyping and other aberrations. Conclusion: BCR/ABL fusion gene analysis by ES-FISH may serve as a prognostic marker in adulthood ALL. The age, TLC and t(9;22) represent the significant standard prognostic factors in relation to patients’ outcome.展开更多
Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the...Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated a dose of 260 mg·m^2·d^-1. Sixty-eight percent of the patients experienced various adverse events during imatinib therapy, hematological toxicity being the most common adverse event. The median duration of imatinib treatment was 3 months （range 7 days-18 months）. During the median follow-up of 24 months （range 16.0-54.5 months）, 3 out of 27 patients that could be evaluated for efficacy died from relapse. The 3-year probability of relapse for the evaluated patients was （11.34-0.61）%. The relapse rates among the subgroup of positive and negative bcr-abl patients before allo-HCT were 13.6% and 0, respectively （P 〉0.05）. The relapse rates among the subgroups of bcr-abl positive and negative patients after alIo-HCT were 20.0% and 5.9%, respectively （P 〉0.05）. The relapse rates among the patients in first complete remission （CR1） and second complete remission/non-remission （CR2/NR） before transplantation were 0 and 31.4%, respectively （P 〈0.05）. The 3-year probability of overall survival （OS） and disease-free survival （DFS） for the all enrolled patients were （75.3±8.1）%. The 3-year probabilities for OS and DFS among the subgroup of patients in CR1 and CR2/NR before transplantation were （87.7±8.2）% and （54.6±15.0）%, respectively （P 〈0.05）. Conclusions Administration of irnatinib at a dose of 300-400 mg/d in the first 90 days after allo-HCT is feasible in Ph^＋ ALL patients. With this treatment, bcr-abl positive patients before or after transplantation do not have a higher relapse rate after allo-HCT compared with the bcr-abl negative patients. Because of lower relapse rate and better OS and DFS, we recommend that Ph^＋ ALL patients receive allo-HCT in CRI.展开更多
A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Phil...A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome （Ph）-positive ALL enrolled into imatinib （400 mg/d） plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years （range, 18-68 years）, with 81 （52.3%） males. The overall hematologic complete remission （CR） rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival （OS） and event-free survival （EFS） rates were 49.5% （95% confidence interval （CI）： 38.5%-59.5%） and 49.2% （95% CI： 38.3%-59.2%）, respectively. Fifty-eight （36 with haploidentical donor） patients underwent allogeneic hematopoietic stem call transplantation （allo-HSCT） in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without alIo-HSCT group （73.2%, 95% CI： 58.3%-83.5% vs. 22.2%, 95% CI： 8.7%-39.6% and 66.5%, 95% CI： 50.7%-78.2% vs. 16.1%, 95% CI： 5.1%-32.7%, respectively）. Multivariate analysis showed that alIo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the alIo-HSCT cohort, the donor type （haploidentical versus matched donors） had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.展开更多
1文献来源
Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph＋ALL） [J]....1文献来源
Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph＋ALL） [J]. Cancer, 2007,109（10）：2068-2076.展开更多
文摘Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).
文摘Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has been demonstrated in acute lymphoblastic leukemia(ALL),of which ALL with Philadelphia chromosome-positive(Ph+).The use of imatinib,a tyrosine kinase inhibitor(TKI),as part of front-line treatment and in combination with cytotoxic agents,has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL.New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations.An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs,such as nilotinib and dasatinib.However,in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells.None of the TKIs in clinical use target the LSC.Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs.Allogeneic stem cell transplantation(SCT) remains the only curative treatment available for these patients.Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations.Hence,TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy.Better understanding the biology of Ph+ ALL will open new avenues for effective management.In this review,we highlight recent findings relating to the question of LSCs in Ph+ ALL.
文摘Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) positive ALL, a high-risk cytogenetic subset, accounts for 25% - 30% of adult ALL cases but occurs in less than 5% of children. We aimed with this study to detect BCR-ABL genes fusion, amplification and deletion in ALL patients, using extrasignal-fluorescence in situ hybridization (ES-FISH), and to assess their relation with other standard prognostic factors and therapeutic response. Patients and Methods: This study was carried out on 39 newly diagnosed ALL patients. All patients were subjected to: history, clinical examination and laboratory investigations, which included complete blood count (CBC), peripheral blood (PB), bone marrow (BM) examination, immunophenotyping and fluorescence in situ hybridization using extra-signal probe to detect BCR-ABL genes fusion. Results: This study showed statistical analysis of patients’ t(9;22) with other factors revealed, significant association (p 35 years, hepatosplenomegaly, absence of lymphadenopathy, TLC ≥ 50 × 109/L, absolute PB blasts ≥ 4.4 × 109/L, immunophenotyping and other aberrations. Conclusion: BCR/ABL fusion gene analysis by ES-FISH may serve as a prognostic marker in adulthood ALL. The age, TLC and t(9;22) represent the significant standard prognostic factors in relation to patients’ outcome.
文摘Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated a dose of 260 mg·m^2·d^-1. Sixty-eight percent of the patients experienced various adverse events during imatinib therapy, hematological toxicity being the most common adverse event. The median duration of imatinib treatment was 3 months （range 7 days-18 months）. During the median follow-up of 24 months （range 16.0-54.5 months）, 3 out of 27 patients that could be evaluated for efficacy died from relapse. The 3-year probability of relapse for the evaluated patients was （11.34-0.61）%. The relapse rates among the subgroup of positive and negative bcr-abl patients before allo-HCT were 13.6% and 0, respectively （P 〉0.05）. The relapse rates among the subgroups of bcr-abl positive and negative patients after alIo-HCT were 20.0% and 5.9%, respectively （P 〉0.05）. The relapse rates among the patients in first complete remission （CR1） and second complete remission/non-remission （CR2/NR） before transplantation were 0 and 31.4%, respectively （P 〈0.05）. The 3-year probability of overall survival （OS） and disease-free survival （DFS） for the all enrolled patients were （75.3±8.1）%. The 3-year probabilities for OS and DFS among the subgroup of patients in CR1 and CR2/NR before transplantation were （87.7±8.2）% and （54.6±15.0）%, respectively （P 〈0.05）. Conclusions Administration of irnatinib at a dose of 300-400 mg/d in the first 90 days after allo-HCT is feasible in Ph^＋ ALL patients. With this treatment, bcr-abl positive patients before or after transplantation do not have a higher relapse rate after allo-HCT compared with the bcr-abl negative patients. Because of lower relapse rate and better OS and DFS, we recommend that Ph^＋ ALL patients receive allo-HCT in CRI.
文摘A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome （Ph）-positive ALL enrolled into imatinib （400 mg/d） plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years （range, 18-68 years）, with 81 （52.3%） males. The overall hematologic complete remission （CR） rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival （OS） and event-free survival （EFS） rates were 49.5% （95% confidence interval （CI）： 38.5%-59.5%） and 49.2% （95% CI： 38.3%-59.2%）, respectively. Fifty-eight （36 with haploidentical donor） patients underwent allogeneic hematopoietic stem call transplantation （allo-HSCT） in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without alIo-HSCT group （73.2%, 95% CI： 58.3%-83.5% vs. 22.2%, 95% CI： 8.7%-39.6% and 66.5%, 95% CI： 50.7%-78.2% vs. 16.1%, 95% CI： 5.1%-32.7%, respectively）. Multivariate analysis showed that alIo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the alIo-HSCT cohort, the donor type （haploidentical versus matched donors） had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.
文摘1文献来源
Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph＋ALL） [J]. Cancer, 2007,109（10）：2068-2076.
