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PubMed2004

Imatinib mesylate in conjunction with allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome positive leukemias: report of 4 cases.

We described here four patients diagnosed with Philadelphia chromosome positive (Ph+) leukemia, consisting of chronic myeloid leukemia (CML) (n=2) and Ph+ acute lymphoblastic leukemia (ALL) (n=2). All patients were treated with imatinib mesylate (300-400 mg/day) for the treatment of relapsed CML after allogeneic hematopoietic stem cell transplantation (SCT) (n=2), relapsed Ph+ ALL after SCT (n=1), and Ph+ ALL preceding SCT (n=1). Significant clinical and molecular responses were observed in all patients and three of them achieved sustained molecular remission. Imatinib was well tolerated and did not induce noticeable graft versus host disease although one patient presented severe skin rash (Grade III). Notably, serum cyclosporine A concentration increased after the initiation of imatinib treatment, probably through competitive inhibition of P450 3A4 isoenzyme. Our data suggest that imatinib in conjunction with SCT for the Ph+ leukemia may be a promising treatment strategy.

Adult↗
PubMed2004

[Bone marrow morphologic features in patients treated with imatinib for Philadelphia chromosome positive chronic myeloid leukemia].

OBJECTIVES: To assess bone marrow morphologic changes in Philadelphia-chromosome positive chronic myeloid leukemia (Ph(+)-CML) patients treated with Imatinib, and to evaluate the correlation of the morphologic changes with hematological or cytogenetic responses. METHODS: One hundred and seventeen patients with Ph(+) CML: 54 in chronic phase but failed to interferon-alpha treatment, 41 in accelerated phase, 22 in blastic phase received oral administration of Imatinib 400 or 600 mg once daily for more than 18 months. RESULTS: All of the patients responded to the treatment, including complete hematological response, bone marrow response and return to chronic phase, bone marrow cellularity and myeloblast count reduced significantly to non-CML picture. Myeloid/erythroid ratio and megkaryocyte count were decreased significantly in most patients in chronic and accelerated phases (P < 0.05). Bone marrow hypoplasia or aplasia was associated with lower cytogenetic response rates in patients in chronic phase (58.8% vs 86.5%, P = 0.035), lower complete hematological response in patients in accelerated phase (26.3% vs 75.0%, P = 0.004), and 6-month overall survival in patients in blastic phase (77.8% vs 16.7%, P = 0.009). Patients in advanced stage obtained non-CML marrow picture in 1 month of treatment had better prognosis. 18-month disease progression rates were lower (25% vs 75%, P = 0.028) and overall survival rates higher (75.0% vs 11.8%, P = 0.004) in patients obtained non-CML picture marrows than in those with CML marrows picture in accelerated phase. Hematological response rate and overall survival of more than 6 months were higher in patients with non-CML marrows picture than those with CML marrows picture (100.0% vs 40.0%, P = 0.017 and 83.3% vs 26.7%, P = 0.046 respectively) in blastic phase. CONCLUSIONS: Normal marrow appearance can be sustained under continuous treatment of Imatinib in CML patients who achieved hematological responses.

Adolescent↗
PubMed2005

Multiple constitutional chromosome translocations of familial nature in Philadelphia chromosome-positive chronic myeloid leukemia: a report on a unique case.

A case of Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) featuring 2 additional balanced translocations, t(2;5) and t(6;12), as well as a robertsonian translocation, t(13;14), was diagnosed by routine bone marrow karyotyping. The breakpoints did not involve previously described CML-related chromosomal regions in any of the 3 translocations. Despite the patient's partial response following imatinib therapy, all Ph(-) bone marrow metaphases persistently had the 3 additional chromosomal changes. Moreover, stimulated peripheral B-lymphocytes from the patient also showed the same chromosomal changes, suggesting that we had found a complex constitutional chromosome aberration unrelated to the leukemia. Peripheral blood karyotype analyses of 6 of the 7 closest relatives from 3 generations demonstrated at least 1 of these aberrations, although in different combinations. Standard bone marrow or peripheral blood karyotyping of hematologic disorders may uncover otherwise symptomless, unrelated constitutional changes together with disease-specific chromosome aberrations.A triple constitutional chromosome aberration combined with a hematologic disorder has not been described until now. In addition, multiple constitutional aberrations persisting through at least 3 generations seem to be extremely rare. At present, no direct evidence exists to support a causative relationship between the familial translocations and leukemogenesis.

Adult↗
PubMed1986

Establishment of two Ph1 chromosome-positive cell lines, KPB-M8 and KPB-M15.

Two new Philadelphia (Ph1) chromosome-positive cell lines, designated KPB-M8 and KPB-M15, were established from the peripheral blood of two patients with chronic myelogenous leukemia in blastic crisis. Both cell lines were characterized by blastic appearance, the presence of acid phosphatase activity, Fc gamma-receptor, and C3-receptor, and reactivity to monoclonal antibodies such as OKM1, MCS2, MY906, MY4 and MY7. These results indicate that KPB-M8 and KPB-M15 cells are of an undifferentiated blast nature. Both cells retained Ph1 chromosome, and showed numerical and structural changes upon chromosomal analysis. These cell lines should provide a useful source for studying differentiation of hemopoietic cells.

Adult↗
PubMed1999

Fluorescence in situ hybridization analysis of complex translocations in two newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia patients.

Two different complex translocations from newly diagnosed cases of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) were characterized by G-banding and fluorescence in situ hybridization (FISH) analysis. In one case, a unique balanced t(9;22;9;11) (q34;q11;p22;q23) was identified by G-banding, and confirmed by FISH using MBCR/ABL and painting probes. In the second case, an apparently balanced t(19;22) was identified by G-banding analysis. FISH using MBCR/ABL probe detected the fusion gene on the derivative chromosome 22, indicating the involvement of chromosome 9. Further FISH analysis with selected painting probes showed that the t(19;22) was a result of a complex translocation involving chromosomes 9, 19, 21, and 22.

Adult↗
PubMed2001

Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia relapsing as Ph-negative leukaemia after allogeneic bone marrow transplantation.

Two patients with Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukaemia (CML) relapsed 1.5 and 5 years after allogeneic bone marrow transplantation (BMT). Although the leukaemias were of recipient origin, t(9;22) could no longer be detected using conventional cytogenetics/fluorescence in situ hybridization or molecularly. Both patients responded to immunotherapy with donor lymphocytes/peripheral blood stem cells, although one patient ultimately relapsed again. These patients were similar to the occurrence of Ph(-) leukaemias previously described in Ph(+) CML after treatment with interferon or autologous BMT, and might be relevant in the pathogenesis and monitoring of treatment after BMT in CML.

Adult↗
PubMed2004

[Analysis of the factors associated with prognosis in patients with Ph chromosome positive adult acute lymphoblastic leukemia].

OBJECTIVE: To investigate factors associated with survival of patients with Ph chromosome positive adult acute lymphoblastic leukemia (aALL) in a period of 11 years. METHODS: All the clinical parameters of 31 Ph positive patients were statistically analyzed by SPSS software. RESULT: Ph(+) patients account for 15.3% (31/203) of all the aALL patients. Clinically, these patients manifested older in age, higher white blood cell counts with high blast fractions and lower platelet counts (PC). Phenotypically 82.6% of them were common ALL, 39.1% coexpressed myeloid antigens, and 56.5% expressed CD34 antigen. 65.4% of them (17/26) achieved complete remission (CR) and the median remission and survival durations were 4 months and 8 months, respectively. Patients with Ph(+) and additional chromosomal aberrations accounted for 42% of all the Ph(+) patients, including monosomy 7, +Ph, del(9)(p11-12) and add/t(16)(p13), and they had lower PC as compared with those with sole Ph(+) (P = 0.012) and variant Ph translocation (P = 0.01). CD34 positive patients had a shorter remission and survival duration than CD34 negative ones (0 vs 9 months for median remission time, P = 0.024; and 6 vs 12 months for median survival time, P = 0.034). There was no evidence to support the correlation between myeloid antigen expression and survival time in these patients. CONCLUSION: Ph(+) aALL is associated with adverse prognosis and CD34 expression is a poorer prognostic factor in Ph(+) aALL patients. There is no significant clinical difference between Ph(+) aALL with or without additional chromosomal aberrations.

Adult↗
PubMed2002

Requirement for NK cells in CD40 ligand-mediated rejection of Philadelphia chromosome-positive acute lymphoblastic leukemia cells.

We have previously developed a murine model of Philadelphia chromosome-positive acute lymphoblastic leukemia by i.v. injection of a pre-B ALL cell line (BM185) derived from Bcr-Abl-transformed BALB/c bone marrow. We are studying the potential to elicit autologous antileukemic immune responses by introducing genes encoding immunomodulators (CD40 ligand (CD40L), CD80, and GM-CSF) into leukemia cells. BM185 cells expressing CD40L or CD80 alone, when injected into BALB/c mice, were rejected in approximately 25% of mice, whereas cohorts receiving BM185 cells expressing two or more immunomodulator genes rejected challenge 50-76% of the time. The greatest protection was conferred in mice receiving BM185 cells expressing all three immunomodulators. Addition of murine rIL-12 treatments in conjunction with BM185/CD80/CD40L/GM-CSF vaccination allowed rejection of preestablished leukemia. BM185 cell lines expressing CD40L were rejected in BALB/c nu/nu (nude) mice, in contrast to cell lines expressing CD80 and/or GM-CSF. Nude mice depleted of NK cells were no longer protected when challenged with BM185/CD40L, demonstrating a requirement for NK cells. Similarly, NK cell depletion in immunocompetent BALB/c mice resulted in a loss of protection when challenged with BM185/CD40L, confirming the data seen in nude mice. The ability of CD40L to act in a T cell-independent manner may be important for clinical applications in patients with depressed cellular immunity following chemotherapy.

Animals↗
PubMed2006

Outcome of treatment in adults with Philadelphia chromosome-positive and/or BCR-ABL--positive acute lymphoblastic leukemia-retrospective analysis of Polish Adult Leukemia Group (PALG).

Patients with Philadelphia chromosome-positive (Ph+) and/or BCR-ABL+ acute lymphoblastic leukemia (ALL) have extremely poor prognoses. Most of these patients have additional, heterogenous karyotype abnormalities, the majority of which have uncertain clinical significance. In this study we analyzed the clinical characteristics, karyotype abnormalities, and outcome of 77 patients with Ph+ and/or BCR-ABL+ ALL registered in Poland in 1997-2004. In 31/55 patients with known karyotype, the sole t(9;22)(q34;q11) abnormality had been diagnosed; in one patient, variant translocation t(4;9;22)(q21q31.1;q34;q11), and additional abnormalities in 23 (42%) patients, had been diagnosed. The characteristics of the patients with Ph chromosome and additional abnormalities were not significantly different when compared with the entire analyzed group. Out of 77 patients, 54 (70%) achieved first complete remission (CR1) after one or more induction cycles. The overall survival (OS) probability of 2 years was 63, 43, and 17% for patients treated with allogeneic stem cell transplantation (alloSCT), autologous SCT, and chemotherapy, respectively (log rank p=0.002). Median OS from the time of alloSCT was significantly longer for patients transplanted in CR1 compared with alloSCT in CR >1 (p=0.032). There were no significant differences in CR rate, disease-free survival (DFS), and OS for patients with t(9;22) and additional abnormalities compared with the whole group. Only WBC >20 G/l at diagnosis adversely influenced OS probability (log rank p=0.0017). In conclusion, our data confirm poor outcome of Ph+ and/or BCR-ABL+ ALL. Only patients who received alloSCT in CR1 had longer DFS and OS. We have shown that additional karyotype abnormalities did not influence the clinical characteristics of the patients; however, their influence on treatment results needs to be further assessed.

Adolescent↗
PubMed1989

Rearrangements in the p53 gene in Philadelphia chromosome positive chronic myelogenous leukemia.

Molecular structural analysis of the p53 gene in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) indicates a significant incidence of gene rearrangements in patients at either accelerated phase or blastic crisis. Southern blot analysis of genomic DNA hybridizing with either genomic or cDNA p53 specific probes indicated that 30% of the CML patients at blastic crisis phase exhibited rearrangements, mostly mapping downstream to the first non-coding exon. This is compatible with the observation that the progression of CML from the chronic to the acute phase involves frequent aberrations in chromosome 17, to which the p53 oncogene has been mapped. Therefore, we suggest that one of the pathways of development of CML to the acute phase is associated with aberrations in the p53 nuclear oncogene.

Blast Crisis↗
PubMed1995

Deletion 20q in association with Philadelphia chromosome positive acute lymphoblastic leukemia. A report of two cases.

Cytogenetic deletions involving the long arm of chromosome 20 are thought to be characteristic of myeloid disorders. We report clinical and cytogenetic observations of two adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia: one with a smaller 20q deletion that was the sole cytogenetic abnormality in a persisting remission clone, the other with a larger 20q deletion that was a late addition to the leukemic clone at disease relapse following allogeneic bone marrow transplantation.

Adolescent↗
PubMed2000

[Effects of gene copy number and chromosomal position on the expression of a modified HBsAg gene SA-28 in yeast].

The effect of gene copy number and chromosomal position on heterologous gene expression in Saccharomyces cerevisae has been tentatively investigated using a modified hepatitis B virus surface antigen SA-28 gene. The plasmids containing different copies of SA-28 gene expression cassette were integrated into different chromosomal loci via FLP recombinase mediated targeted integration. The expression of SA-28 gene in the resultant transformants was then measured. The result indicated that the expression of SA-28 gene was positively related to the gene dosage at HIS3 locus and had chromosomal polarity at several chromosomal loci.

Chromosome Mapping↗
PubMed1994

Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients.

BACKGROUND: Philadelphia-Chromosome-positive (Ph-positive) acute lymphocytic leukemia (ALL) is associated with poor outcome in children as well as in adults. We report our experience in patients with Ph-positive ALL and review their clinico-laboratory characteristics, response to different therapies, and overall prognosis. PATIENTS AND METHODS: Since 1980, 41 newly diagnosed patients with Ph-positive ALL were referred to our service. In addition to confirmation of their diagnosis by morphologic studies of bone marrow aspiration and biopsy specimens, patients underwent cytogenetic, immunophenotypic, and molecular studies. Thirty-five patients received vincristine-Adriamycin-dexamethasone (VAD) or cyclophosphamide (CVAD) induction regimens, and 6 patients were treated with other combinations. Thirty-seven patients received salvage therapy that included VAD, high-dose cytosine arabinoside (ara-C)-containing regimens, methotrexate-asparaginase, and high-dose chemotherapy with autologous or allogeneic bone marrow transplantation (BMT). RESULTS: The 41 patients were among 334 patients with ALL (12%) seen during that same period. Patients with Ph-positive ALL were older and had a significantly lower incidence of anemia and a higher incidence of peripheral leukocytosis, FAB L2 (French-American-British) morphology, common acute lymphocytic leukemia antigens (CALLA), and CD34 marker positivity. With induction chemotherapy, 23 of 41 Ph-positive ALL patients (56%) achieved complete remission, and their median survival and remission duration were 11 months and 9 months, respectively. Thirteen of 31 Ph-positive ALL patients (42%) achieved complete response with high-dose ara-C regimens during salvage therapy. CONCLUSIONS: In our experience, patients with Ph-positive ALL are usually older, have FAB L2 morphology, and are CALLA-positive and CD34-positive. These patients have a poor prognosis when treated with conventional approaches with lower overall complete response rate, shorter remission duration, and shorter survival. There appears to be a selective sensitivity to high-dose ara-C in these patients that suggests a possible role of this agent as part of early consolidation or induction regimens.

Adult↗
PubMed1994

Adult Philadelphia-chromosome-positive acute lymphoblastic leukemia: experience of treatments during a ten-year period.

Adult Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph1-positive ALL) represents about 30% of all adult ALL, and is considered a poor prognosis disease, since complete remission (CR), which can be achieved in 50-70% of cases, is usually short in patients treated with conventional chemotherapy. Presently bone marrow transplantation, performed early in first CR is becoming the treatment of choice, as it has shown to be able to cure some cases. In a ten-year period, at our department, among 108 adult ALL patients, in which cytogenetics was successfully carried out at diagnosis, 24 (22%) resulted Ph1-positive. Molecular biology was performed in 13 out of these 24 patients: 10 patients showed a p210 rearrangement and three p190. All patients have been treated at induction with conventional drugs, with a CR rate of 96%. As post-remission therapy, the first 17 cases (group 1) followed a chemotherapeutic program, like the other adult ALL; while the remaining six patients (group 2) have been enrolled in a pilot study including early BM transplantation. In group 1, the median overall duration of first CR is 7 months; 50% of relapses were recorded within the first 6 months, although in this group five patients exhibited a first CR prolonged more than 30 months. In group 2, among the six patients, three were submitted to allogeneic bone marrow transplantation (BMT), and three to autologous bone marrow transplantation (ABMT). Overall median duration of first CR is 13 months. Three patients relapsed, three are in continuous CR for 11, 31 and 32 months.

Adult↗
PubMed2006

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.

BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).

Adolescent↗
PubMed2002

Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL).

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.

Adenocarcinoma↗
PubMed2001

[Multivariate analysis of prognostic factors in Philadelphia chromosome-positive chronic granulocytic leukemia].

OBJECTIVE: To investigate the prognostic factors of the patients with Philadelphia chromosome-positive chronic granulocytic leukemia (CGL). METHODS: Clinical and laboratory parameters of 209 CGL patients at diagnosis were analyzed in relation to survival. COX regression analysis were used to identify the statistically significant prognostic factors. RESULTS: The median survival time was 57 (3 - 179) months, and 5 year survival rate was 48%. From the COX regression model, the four main poor prognostic factors were as follows: percentage of bone marrow blasts (>or= 0.04), percentage of peripheral blood blasts and promyelocytes and presence of erythroid precursors in peripheral blood. According to the prognostic scores, three groups of CGL were identified. The low-risk group was with a median survival time of 76 months, the intermediate-risk group with 56 months, and the high-risk group with 31.5 months (P < 0.01). The 5 year survival rate was 70.42%, 46.30% and 18.18% (P < 0.01), respectively. CONCLUSIONS: A prognostic scoring system suitable for Chinese CGL patients was proposed.

Adolescent↗
PubMed1991

[Immunogenotypic and clonal culture studies in Philadelphia chromosome-positive acute leukemia].

Molecular analysis and blast colony assay were performed on patients with Philadelphia chromosome-positive acute leukemia (Ph+ AL). All patients were diagnosed as ALL- L2 and 3 were My+ ALL. Nine of the 12 cases had rearranged immunoglobulin heavy chain, and 4 had rearranged TCR beta. TCR gamma rearrangement was noted in 3 patients, and TCR delta involvement was also noted in 6 patients. Clonal culture analysis revealed that leukemia cells of M-BCR rearranged Ph+ AL cases had a potential to proliferate by myelopoietic CSFs and ILs, however, M-BCR nonrearranged Ph+ AL did not. These results indicate biological and immunogenotypic heterogeneity of Ph+ AL.

Acute Disease↗