Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia with imatinib in combination with chemotherapy

The presence of the Philadelphia chromosome (Ph) is associated with a very poor prognosis in acute lymphoblastic leukemia (ALL). Although hematologic complete remission (CR) is achieved in 50% to 80% of adult patients by intensive chemotherapy in multicenter studies, long-term outcome is dismal, with overall survival of approximately 10%. Currently, allogeneic hematopoietic stem cell transplantation (allo-SCT) is thought to be the only curative therapeutic modality for this leukemia in adults, but the long-term survival rates are about 40% or less, far from satisfactory. Imatinib mesylate, a recently introduced specific tyrosine kinase inhibitor of BCR-ABL, in combination with chemotherapy, resulted in more than 90% hematologic CR in adult Ph-positive ALL, including molecular CR in more than 50% of patients. The higher CR rate and less frequent relapse gave more patients a chance to receive SCT. Patients who did not qualify for allo-SCT because of the lack of a suitable donor, advanced age, or underlying medical conditions apparently showed better survival than historical control patients treated with chemotherapy alone. Although longer follow-up is required to determine the effect on survival, imatinib in combination with chemotherapy clearly has a major potential to improve the treatment of Ph-positive ALL and may cure a substantial proportion of patients without SCT.     

Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15-67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600 mg/day during remission induction and 400 mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n = 20) and reversible > or = grade 3 hyperbilirubinemia (n = 4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.     

伊马替尼联合化疗治疗成年人费城染色体阳性急性淋巴细胞白血病效果分析

目的分析伊马替尼联合化疗治疗成年人费城染色体阳性(Ph^+)急性淋巴细胞白血病(ALL)的临床疗效。方法收集2012年6月至2016年1月就诊于中国医科大学附属第一医院的成年Ph^+ALL患者35例,其中联合化疗组21例,单纯化疗组14例。定期监测血常规、骨髓细胞形态学、免疫分析、染色体及融合基因等,评估疗效。联合化疗组4例患者第1次完全缓解(CR1)后行造血干细胞移植治疗。结果联合化疗组诱导治疗后完全缓解(CR)率为76%(16/21),单纯化疗组为36%(5/14),两组比较差异有统计学意义(χ^2=5.734,P=0.033)。联合化疗组(除移植患者)中位总生存(OS)时间为14个月(2~18个月),单纯化疗组5个月(0.33~10个月),两组比较差异有统计学意义(U=12.0,P=0.007)。联合化疗组中位无病生存(DFS)时间为8个月(0~15个月),单纯化疗组为2个月(0~6个月),两组比较差异有统计学意义(U=12.5,P=0.007)。4例移植患者中位OS时间26个月(22~39个月),中位DFS时间22个月(17~36个月)。结论Ph+ALL患者诱导治疗期采用伊马替尼联合化疗可提高CR率,延长DFS及OS时间,为移植赢得时间与机会。CR1后有条件者及时行造血干细胞移植治疗可延长生存时间。     

Treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

In the pre-imatinib era, treatment outcomes of adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) were dismal. Despite the use of intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), complete remission and overall survival rates were less than 70% and 20%, respectively. However, imatinib, in combination with conventional chemotherapy, has dramatically changed outcomes, producing approximately 95% complete remission and 50% overall survival with or without allogeneic HSCT. Current research is now focusing on how to prevent relapse. Improvement of postremission therapy is indispensable. Although allogeneic HSCT during first complete remission is still the first choice for feasible patients, post-HSCT imatinib therapy and imatinib plus chemotherapy combinations should also be studied. New BCR-ABL tyrosine kinase inhibitors are expected to improve outcomes in imatinib-resistant leukemia. Our hope is that, in the near future, Ph-positive ALL will become a leukemia in which allogeneic HSCT is offered only for relapsed or refractory cases.     

Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called "hyper-CVAD". The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers. Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P>0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P>0.5). Patients with hyperdiploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.     

伊马替尼联合化疗序贯异基因造血干细胞移植治疗费城染色体阳性急性淋巴细胞白血病疗效的Meta分析

目的 系统评价伊马替尼联合化疗序贯异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗费城染色体阳性的急性淋巴细胞白血病（Philadelphia chromosome+acute lymphoblastic leukemia,Ph+ALL）的疗效。方法 采用Cochrane图书馆、Embase、PubMed、CNKI、CBM、Google 学术搜索等数据库,按纳入标准和排除标准筛选相关文献并提取资料、评估质量,采用RevMan 5.2软件进行Meta 分析。结果 纳入12个研究共620例患者。Meta分析显示,与非移植组比较,移植组治疗提高了患者无瘤生存率（disease free survival,DFS）（HR＝0.48, 95% CI：0.31~0.74,P<0.001）及总生存率（overall survival,OS）（HR=0.49,95% CI：0.35~0.68,P<0.001）,减少了死亡事件（RR＝0.62,95% CI：0.39~0.97,P=0.04）。结论 在伊马替尼联合化疗治疗Ph+ALL患者的基础上,序贯allo-HSCT可能优于无allo-HSCT方案。     

bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to CML, do not exhibit chromosomal breakpoints in the major cluster region or mcr (Ph+ mcr- ALL). These cases may have a novel bcr-abl fusion gene instead. We tested this hypothesis in eight Ph+ mcr- ALL patients by amplifying the putative hybrid part of the bcr-abl cDNA, using the polymerase chain reaction method. All cases examined showed the same joining of the first exon of the bcr gene to the c-abl oncogene. Thus, the novel bcr-abl fusion in Ph+ mcr- ALL is the result of a molecularly distinct Ph chromosome. This allows the definition of Ph+ leukemias by their respective bcr-abl oncogene activation. Moreover, the cDNA amplification method we use is a clinically useful tool to screen for bcr-abl oncogene activations in leukemia patients.     

Poor treatment outcome of Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia despite intensive chemotherapy

Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. This study included 1322 children enrolled between 1988 and 1994 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22) and are referred to as Ph+; 1292 were Ph-. 23 of these 30 patients were treated on the CCG-1882 high risk ALL protocol. The event-free survival (EFS) outcome in CCG-1882 was significantly worse for Ph+ compared with Ph- patients, with 4-year estimates of 11.3% (SD = 9.8%) and 73.4% (SD = 2.3%), respectively (p < 0.0001).     

Molecular heterogeneity of adult Philadelphia chromosome-positive acute lymphoblastic leukemia

The (9;22) translocation which produces the Philadelphia (Ph1) chromosome activates the abl oncogene from chromosome 9 by recombination with the bcr gene from chromosome 22. This fusion gene is transcribed into a new 8.5-kilobase chimeric mRNA which is translated into a novel Mr 210,000 fusion protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the activity of the normal abl protein. Studies from this laboratory and others have shown that virtually all patients with chronic myelogenous leukemia have this new bcr/abl fusion gene. In contrast to these findings in chronic myelogenous leukemia, a small number of patients with Ph1(+) acute lymphoblastic leukemia (ALL) have been studied and were found to lack the bcr/abl fusion gene [bcr(-)], but to have a new activation of abl, by recombination with an as yet undetermined region on chromosome 22. In this study, nine adults with Ph1(+)-ALL have been examined for evidence of a bcr/abl fusion gene. Of the nine patients, five have a bcr/abl recombination, whereas the remaining four patients do not. In contrast, the children studied to date have all been bcr(-). These data suggest that adults with Ph1(+)-ALL are a more heterogeneous group on a molecular level than are children, and that further studies will be required to determine the spectrum of molecular defects in patients with Ph1(+)-ALL, and the relationship of these various molecular defects to the clinical disease state of the individuals.     

Imatinib combined chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia: major challenges in current practice

The prognosis of Philadelphia chromosome-positive (Ph+) and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL) is extremely poor, and for decades allogeneic hematopoietic stem cell transplantation (HSCT) has been considered the only option for a cure. However, the treatment for Ph+ ALL has been rapidly changing since imatinib, a selective inhibitor of the ABL tyrosine kinase, was introduced. Earlier clinical trials in which a moderate anti-leukemic effect of imatinib monotherapy was demonstrated have prompted investigators to explore the combination of imatinib and chemotherapy. The results of multiple studies indicate that chemotherapy combined with imatinib is well tolerated, induces complete hematological remission in almost every patient with newly diagnosed Ph+ ALL, and molecular remission in more than half of the cases. Future clinical studies need to focus on how imatinib can be incorporated into chemotherapy more effectively by determining the optimal dosage of imatinib, the optimal combinational schedule, and the role of allogeneic HSCT.     

氟马替尼联合多药化疗治疗费城染色体阳性急性淋巴细胞白血病的疗效和安全性分析

  目的  评价氟马替尼联合多药化疗在费城染色体阳性急性淋巴细胞白血病（Philadelphia chromosome-positive acute lymphoblastic leukemia,Ph+ALL）患者中的疗效和安全性。  方法  回顾性分析南昌大学第一附属医院2019年12月至2022年2月收治的25例行氟马替尼联合CALLG-2008化疗方案治疗的成人Ph+ALL患者的临床资料,分析其疗效和安全性。  结果  25例患者中,21例（84%）患者于初次诱导期联合氟马替尼,4例（16%）患者于第1个疗程诱导结束后联合氟马替尼。患者化疗28天、3个月和6个月的完全缓解（complete response,CR）率分别为88%、91.67%和90.48%;主要分子学反应（major molecular response,MMR）率分别为68%、79.17%和80.95%;完全分子学反应（complete molecular response,CMR）率分别为60%、75%和80.95%。中位随访时间180（75.6～458.1）天,随访时总生存（overall survival,OS）率为82.61%,无复发生存（recurrence-free survival,RFS）率为73.91%。氟马替尼用药过程中,有22例（88%）患者出现Ⅳ度骨髓抑制,非血液学不良反应主要有腹泻、转氨酶升高、疲乏、恶心等,经对症治疗后均可好转。  结论  氟马替尼联合多药化疗治疗Ph+ALL患者安全有效。      

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

PURPOSE: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. EXPERIMENTAL DESIGN: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. RESULTS: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.     

Oligoclonal immunoglobulin gene rearrangements in Philadelphia chromosome-positive common acute lymphoblastic leukemia

The occurrence of more than two rearranged bands of immunoglobulin heavy chain (IgH) genes in B precursor acute lymphoblastic leukemia (ALL) has recently been documented. To elucidate the nature of such leukemias, we studied 30 patients with common ALL, including 6 patients with Philadelphia chromosome (Ph1)-positive ALL, by immunophenotyping and genotyping. In 10 of the 30, Southern blotting showed oligoclonal patterns of IgH gene arrangements, which were frequently detected in Ph1-positive ALL. In one patient of the 10, three rearranged bands of Ig kappa chain genes were detected. Ph1 abnormality and co-expression of myeloid associated antigens were found in 5 and 5 of the 10, respectively. Detection of multiple fragments of IgH genes would be suggestive of multipotent progenitor origin of these ALL.     

CD34 antigen expression in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

One characteristic of Philadelphia chromosome (Ph')-positive acute leukemia is the occasional presence of both lymphoid and myeloid features in the same leukemia. This phenomenon supports the theory that this subtype of acute leukemia arises from lymphoid-myeloid stem cell, pluripotent progenitors. Very few reports, however, describe the immunophenotype, especially CD34 antigen, of Ph'-positive acute lymphoblastic leukemia (ALL). It has been shown that CD34, the human progenitor cell antigen, is found on 1% or less of normal human bone marrow cells, approximately 30% of acute leukemias, and multipotent progenitor cells; CD34 is not found on normal peripheral blood cells. A high frequency of CD34 expression was found in children with Ph'-positive ALL: CD34 was positive for all six patients tested, and one had an acute mixed-lineage leukemia. These findings suggest the involvement of a pluripotent stem cell in Ph'-positive ALL.     

双费城染色体阳性急性淋巴细胞白血病一例

患者 女性,53岁,2016年12月因出现发热、乏力,就诊当地医院,查血常规:白细胞计数(WBC)52.09×109/L,血红蛋白(Hb)137 g/L,血小板计数(Plt)22×109/L.2017年1月3日因发热、乏力半月余,就诊于兰州军区兰州总医院. 入院查体:全身皮肤未见皮疹及出血点,浅表淋巴结未触及肿大.咽部无充血,扁桃体不大. 胸骨压痛明显,双肺呼吸音清晰,心律齐,未闻及病理性杂音. 腹部平坦,无压痛及反跳痛,肝脾肋缘下未触及,四肢无水肿.查血常规:WBC 95.39×109/L,Hb 100 g/L,Plt 18×109/L.外周血细胞形态示:原始淋巴细胞44个,幼稚淋巴细胞50个,成熟淋巴细胞3个. 骨髓细胞学示:原始淋巴细胞+幼稚淋巴细胞占0.98,胞体大小不一,以大为主;白血病细胞免疫分型:主要表达HLA-DR、CD10、CD13、CD19、CD20、CD22、CD33、CD34、CD38、CD123、cCD79a和TdT.染色体核型分析示:47~50,XX,+5,+8,t(9;22)(q34;q11), der(22)t(9;22)(图1). 腹部彩色超声示:餐后胆囊、脾大(脾门处厚4.8 cm,肋缘下及边),肝、胰、肾声像图未见明显异常. 诊断为急性淋巴细胞白血病(ALL),B细胞型,双费城染色体(Ph染色体)阳性.予VDP(长春新碱+柔红霉素+泼尼松)方案化疗,同时予甲磺酸伊马替尼(400 mg/d)靶向治疗,并定期鞘内注射甲氨蝶呤和地塞米松预防中枢神经系统白血病.化疗第22天复查骨髓细胞学示完全缓解骨髓象.此后予CAM(环磷酰胺+阿糖胞苷+巯基嘌呤)方案化疗1个周期,复查骨髓细胞学示完全缓解骨髓象. 监测脑脊液常规、生化及细胞形态均正常,复查染色体核型:46,XX(图2).目前患者仍在后续治疗随访中.     

Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives

The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL). Before the advent of tyrosine kinase inhibitors (TKIs), Ph-positive ALL carried a dismal prognosis and was characterized by a poor response to most chemotherapy combinations, short remission durations, and poor survival rates. Outcomes for patients with Ph-positive ALL improved substantially with the introduction of TKIs, and the TKI imatinib induced complete remissions in >95% of patients with newly diagnosed Ph-positive ALL when it was combined with chemotherapy. However, imatinib resistance remains a problem in a substantial proportion of patients with Ph-positive ALL, and multiple molecular mechanisms that contribute to imatinib resistance have been identified. Second-generation TKIs (eg, dasatinib and nilotinib) have demonstrated promising efficacy in the treatment of imatinib-resistant, Ph-positive ALL. Future strategies for Ph-positive ALL include novel, molecularly targeted treatment modalities and further evaluations of TKIs in combination with established antileukemic agents. For this article, the authors reviewed past, current, and future treatment approaches for adult and elderly patients with Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens.     

Comparison of microtransplantation,chemotherapy and allogeneic transplantation in post-remission therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) have poor prognosis, and the efficacy of chemotherapy plus tyrosine kinase inhibitors (TKIs) followed by mismatched donor stem cell infusion (microtransplantation, MST) has not been determined. We retrospectively summarized 45 patients including 11 undergoing MST with TKIs, 17 receiving allogeneic transplant and 17 undergoing chemotherapy with TKIs. Improved 4-year overall survival rate was observed in the MST group (91%) compared with either transplant group (31%, P = .005) or chemotherapy group (36%, P = .013). The MST group also had higher 2-year and 4-year leukemia-free survival rates (91% and 72%, respectively) compared with either transplant group (33%, P = .005 and 33%, P = .021, respectively) or chemotherapy group (41%, P = .017 and 31%, P = .023, respectively). 2-year and 4-year cumulative incidences of hematologic relapse were lower in the MST group (9% and 28%, respectively) compared with those in the chemotherapy group (56%, P = .025 and 67%, P = .034, respectively). In patients undergoing MST, donor microchimerism was detected (1.07 × 10^-5 to 6.6 × 10^-4 copies from 9 to 1499 days) in 7 patients, and donor/patient-derived HLA*0201/2402⁺WT1⁺CD8⁺ T cells were found from 0.05% to 0.67% in 6 patients. MST may provide a favorable treatment for patients with Ph⁺ ALL.     

Philadelphia chromosome-positive acute lymphocytic leukemia

On a molecular and cellular level, Ph+ ALL seems to be a heterogeneous disease. Unfortunately, the unifying theme of Ph positivity is the poor outcome associated with its presence. Further characterization of molecular subtypes of Ph+ ALL may in the future distinguish those few patients with a potentially good outcome from the majority who face inevitable relapse. Also, novel targeted biologic therapy especially in combination with aggressive, early chemotherapy, may soon be able to temper the disease. Most patients who obtain a remission would be best served by transplantation during remission. For those without a donor, following the disease by PCR-based techniques may detect early relapse. For relapsed patients without the option of transplantation, investigative studies are appropriate.