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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Managing Philadelphia chromosome-positive acute lymphoblastic leukemia: role of tyrosine kinase inhibitors

Before the introduction of tyrosine kinase inhibitors, the prognosis for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was poor. The treatment of choice, stem cell transplantation, is a potentially curative option, but it is available only for a minority of patients and is associated with significant risk of morbidity and mortality. Although imatinib is largely effective, a substantial proportion of patients become resistant or intolerant to it. The activity of imatinib may be enhanced by coadministration with chemotherapy; such treatment is effective in many patients. Dasatinib is established as a second-line treatment in patients with resistance to or intolerance of imatinib. Recent data suggest that dasatinib, either alone or in combination with chemotherapy, has utility as first-line therapy. Dasatinib is more potent than imatinib, is less susceptible to drug-resistance mechanisms, and has been shown to penetrate the blood-brain barrier, making it potentially effective for treating central nervous system disease. Patients who relapse during treatment with dasatinib frequently carry the T315I mutation of BCR-ABL. Future regimens combining dasatinib with an agent able to inhibit this mutation may further improve outcome.     

费城染色体阳性成年急性淋巴细胞白血病患者治疗效果及预后因素分析

目的 分析费城染色体阳性(Ph+)的成年急性淋巴细胞白血病(ALL)患者治疗效果及预后影响因素.方法 回顾性分析49例Ph+ALL患者的临床资料,探讨治疗效果及不同因素对预后的影响.结果49例患者中,男性24例,女性25例;中位年龄38岁(15~77岁),酪氨酸激酶抑制剂(TKI)治疗组血液学完全缓解(CR)率、主要分子生物学反应(MMR)率及完全分子生物学缓解(CMR)率均高于单纯化疗组(96.8 %比72.2 %,64.5 %比16.7 %,25.8 %比11.1 %),差异均有统计学意义(χ2=4.308,P=0.038;χ2=10.468,P=0.001;χ2=4.250,P=0.039).生存分析提示中位总生存(OS)时间为24个月(3~70个月),3年OS率及无复发生存(RFS)率分别为32.7 %、21.4 %;TKI治疗组3年OS率及1年RFS率高于单纯化疗组(40.3 %比11.1 %,67.8 %比11.1 %),差异有统计学意义(χ2=12.725, P<0.001;χ2=17.401,P<0.001);异基因造血干细胞移植(allo-HSCT)组3年OS率及RFS率高于非移植组(62.5 %比25.7 %、41.7 %比15.0 %),差异有统计学意义(χ2=6.196,P=0.013;χ2=8.032,P=0.005);经2个疗程治疗后达MMR组3年OS率及RFS率分别为45.1 %和28.9 %,高于未达MMR组(17.6 %和11.7 %),差异有统计学意义(χ2=5.446,P=0.020;χ2=6.484,P=0.011);Cox多因素分析结果显示,联合TKI治疗(HR=0.227,95 % CI 0.094~0.550,P=0.001)是OS的独立预后因素;联合TKI治疗(HR=0.225,95 % CI 0.082~0.618,P=0.004)及移植(HR=0.275,95 % CI 0.077~0.983,P=0.047)是RFS的独立预后因素.结论 联合TKI治疗能提高患者CR、MMR及CMR率,提高长期生存,为患者接受移植提供更多机会;在TKI时代,移植仍是治疗Ph+ALL的重要方法,尤其那些经化疗联合TKI治疗但早期未达MMR者预后差,应尽早行造血干细胞移植.     

Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, with the greatest prevalence in children, but it also affects adults, and has an increasing incidence with age. Chromosomal abnormalities in ALL have been frequently described, the most common is the Philadelphia chromosome (Ph). The resulting fusion gene, BCR-ABL1, encodes for a chimerical oncoprotein (BCR-ABL) with constitutive tyrosine kinase activity, which leads to uncontrolled cell proliferation, reduced apoptosis, and impaired cell adhesion. Treating Philadelphia chromosome-positive (Ph+) ALL patients with conventional chemotherapy has not substantially improved their long-term outcomes. Recently, however, BCR-ABL-targeted strategies have been successfully adopted. Imatinib is an oral competitive inhibitor of ABL with demonstrated phase 2 efficacy in patients with treatment-naive and pretreated ALL. Despite its efficacy, imatinib may induce specific resistance in a large proportion of patients, mainly because of the occurrence of ABL1 mutations. Therefore, novel inhibitors have been developed. Dasatinib is a multitargeted kinase inhibitor of BCR-ABL, SRC, C-KIT, PDGFRs, and ephrin A receptor kinases. Unlike imatinib, it binds both the active and inactive BCR-ABL as well as the majority of ABL mutants. Dasatinib is approved for treatment of imatinib-pretreated Ph+ ALL, and chronic myeloid leukemia (CML) on the basis of phase 2 trials that demonstrated impressive efficacy and favorable tolerability profiles. Nilotinib is another BCR-ABL targeted agent that is similar in structure to imatinib but has significantly greater binding affinity. It also has demonstrated promising efficacy in Ph+ ALL but is still being evaluated in phase 2 trials. In this article, the authors reviewed current knowledge on novel tyrosine-kinase inhibitors in adult Ph+ ALL patients.     

Philadelphia chromosome-positive acute lymphoblastic leukemia cell lines without classical breakpoint cluster region rearrangement

The Philadelphia (Ph) chromosome translocation which is classically observed in chronic myeloid leukemia (CML) is sporadically found in acute lymphoblastic leukemia (ALL). In CML the translocation breakpoint on chromosome 22 is within the breakpoint cluster region, while in childhood ALL, no detectable change in breakpoint cluster region is routinely observed. In order to investigate the nature of this difference, we have established and characterized two cell lines from a child with Ph positive ALL. The cell lines have retained the cytochemical staining pattern, enzyme activity, monoclonal antibody profile, and immunoglobulin gene rearrangements of the child's malignant cells. The cell lines had the same Ph translocation t(9;22) (q34;q11) as the child's malignant cells along with additional chromosome changes. Southern blot analysis showed that the Ph translocation did not involve the 5.8-kilobase breakpoint cluster region segment characteristically seen in CML. The cell lines reported here will be a valuable resource in ascertaining the biological significance of the Ph translocation seen in ALL.     

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).     

Activated protein kinase C directly phosphorylates the CD34 antigen in acute lymphoblastic leukemia cells.

The precursors of all blood cell lineages are contained within the 1-3% of bone marrow cells which express the CD34 antigen, and this population can reconstitute the hematopoietic system of lethally irradiated animals and humans. A potential regulatory role for the CD34 antigen in progenitor cell function and differentiation was indicated by our recent findings that the CD34 antigen can be phosphorylated in vivo to high stoichiometry in primitive CD34+ cell-lines by activated protein kinase C. To exclude the possibility that these effects were restricted to cell-lines, we have performed similar experiments on fresh cells from a patient with drug-resistant acute lymphoblastic leukemia. Similar to our previous findings, we found the CD34 antigen to be hyperphosphorylated in lymphoblasts labeled in the presence of active phorbols. The same peptides which were hyperphosphorylated in phorbol-stimulated cell-lines were also phosphorylated in phorbol-stimulated lymphoblasts. These data indicate that CD34 is a substrate molecule for PKC in fresh CD34+ lymphoblasts and underline the role of modulators of PKC activity in the biology of primitive leucocytes.     

A novel variant of the bcr-abl fusion product in Philadelphia chromosome-positive acute lymphoblastic leukemia

Two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia showed novel variants of the chimeric bcr-abl mRNA. The bcr-abl breakpoint region on cDNA derived from the chimeric mRNA was amplified using the polymerase chain reaction (PCR). Sequence analysis of the breakpoint-containing fragment showed that in both patients exon a2 of the abl gene was deleted, giving rise to an in-frame joining at the mRNA level of 5' bcr sequences to the abl exon a3. These findings were confirmed by Southern blot analysis and cloning of chromosomal DNA. Protein studies showed a bcr-abl protein with heightened tyrosine kinase activity in blast cells of both patients: one of the P190 type, the other of the P210 type. The significance of these findings and the role of this new type of translocation in the disregulation of the abl gene are discussed.