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PubMed1994

Lineage switch in Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: An 8-year-old boy, initially diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (French-American-British [FAB]-L1), relapsed with Ph+ acute myelogenous leukemia (AML) (FAB-M2) 21 months after successful ALL treatment with standard therapy. METHODS: The initial ALL presentation and subsequent AML relapse were analyzed by conventional morphologic, cytochemical, immunophenotypic, and cytogenetic studies. RESULTS: Molecular analysis based on the polymerase chain reaction identified the presence of a bcr-I-abl fusion transcript at initial ALL presentation, the completion of ALL therapy, and AML relapse. CONCLUSIONS: The cytogenetic and molecular results support a common clonal origin for this process. This is a case of lineage switch in a Ph+ acute leukemia. This case thus illustrates a manifestation of heterogeneous lineage differentiation among Ph+ acute leukemias.

Base Sequence↗
PubMed1987

Philadelphia chromosome-positive acute leukemia: morphologic and clinical correlations.

Twenty-eight adult patients with Philadelphia chromosome positive (Ph+) acute leukemia were studied to determine if additional chromosomal changes were related to specific morphologic and clinical features. Twenty patients had chronic myeloid leukemia in blast crisis (CML-BC), three had Ph+ de novo acute nonlymphocytic leukemia (ANLL), and five had de novo acute lymphoblastic leukemia (ALL). Chromosomal abnormalities in addition to a single Ph were noted in 90% of patients with CML-BC and included a second Ph (five patients), +8 or duplication of part of 8q (five patients), dicentric isochromosome 17 (two patients), and +19 (two patients). Octaploidy with 4 Ph was seen in one patient with megakaryoblastic transformation. One of two patients with a progranulocytic blast crisis had a t(15;17) abnormality. Hypodiploidy was noted in 4 of 20 patients with CML-BC. Each of the four patients had prominent extramedullary manifestations of blast crisis. All had received intensive chemotherapy prior to the detection of hypodiploidy, and the cytogenetic findings were similar to those often seen in patients with therapy-related leukemia. An inv(3)(q21q26) was noted in two patients (one CML-BC, one de novo Ph+ ANLL), one of whom had hypolobulated micromegakaryocytes. Additional cytogenetic abnormalities in de novo Ph+ ANLL (especially +19) were similar to those in CML-BC. In contrast, the additional karyotypic changes in de novo Ph+ ALL (eg, +4, -7, -20, markers) were those commonly seen in ALL without a Ph and were generally different from those seen in CML-BC.

Acute Disease↗
PubMed1989

DNA rearrangement and restriction fragment length polymorphism within the first BCR intron in Philadelphia-positive acute leukemia.

In some patients with Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemias, breakpoints on chromosome 22 are reported to occur within the first BCR intron. To analyze the breakpoints in chromosome 22 of Ph-positive acute leukemia patients without rearrangement of the 5.8 kb bcr, we cloned the 3' part of the first BCR intron using a synthetic DNA probe. During the course of study, we mapped the region of the deletion/insertion of 1 kb that causes a restriction fragment length polymorphism (RFLP) and found a racial difference in the frequencies of the alleles giving rise to this RFLP. Analyses of the patients' samples indicated that breakpoints were located within the 8.5 kb EcoRl fragment of the first BCR intron in two of five Ph-positive acute leukemia patients. The data, together with the previous reports, indicate that breakpoints within this approximately 50 kb intron are widely scattered, in contrast to those confined within the 5.8 kb bcr in chronic myelogenous leukemias.

Acute Disease↗
PubMed1989

Distribution of breakpoint within the breakpoint cluster region (bcr) in chronic myelogenous leukemia with a complex Philadelphia chromosome translocation.

We analyzed, by Southern blot hybridization, the site of breakpoint within the breakpoint cluster region (bcr) in six patients with a complex Philadelphia chromosome (Ph) translocation and in 23 unselected patients with a standard Ph. The breakpoint was found within the 5.8 kb bcr in all 29 patients. When the bcr was subdivided into four parts, fragments I-IV, based on the restriction enzyme sites, among the six patients with a complex Ph, two had a breakpoint at fragment I, three at fragment II, and one at fragment III. This distribution of breakpoints in patients with a complex Ph did not differ significantly from that in patients with a standard Ph. A deletion of an allele within the bcr was found in three patients (50%) with a complex Ph and in three (13%) with a standard Ph. The internal bcr deletion may be more common in patients with a complex Ph.

Alleles↗
PubMed1991

Occurrence of high-grade T-cell lymphoma in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia with breakpoint cluster region rearrangement: case report and review of the literature.

In this report, we describe a patient with Philadelphia chromosome-negative chronic myelogenous leukemia (CML) with breakpoint cluster region gene rearrangement who developed T-cell lymphoblastic lymphoma. The occurrence of T-cell lymphoblastic lymphoma coincided with the appearance in the bone marrow of the cytogenetic abnormality, trisomy 22q11.2----22qter. This is the first report of high-grade T-cell lymphoma in a patient with documented CML.

Adult↗
PubMed1993

Simultaneous demonstration of the Philadelphia chromosome in T, B, and myeloid cells.

A patient presented with lymphoblastic lymphoma in lymph-nodes and chronic myelogenous leukemia (CML) in narrow and peripheral blood. All marrow and unstimulated peripheral blood cells contained the Philadelphia chromosome[t(9:22)]. Lymphoma cells were analyzed by flow cytometry and were identified as T cells (CD2+CD5+CD7+CD34+). All fresh lymphoma cells contained the t(9:22) translocation. Cultures of purified peripheral blood T and B cells and specifically stimulated NK cells revealed that 59% of the B cells, 10% of the NK cells, and none of the normal T cells contained the translocation. The lack of translocation in normal peripheral T cells is attributed to their long lifespan. No rearrangement of immunoglobulin or T cell receptor beta or gamma genes was found in either the leukemia or lymphoma cells. Analysis of the DNA from cryopreserved lymphoma biopsy showed clonal rearrangement within the common breakpoint cluster region of the bcr gene identical to the bcr rearrangement in DNA from leukemia blood cells. The data support the concept that T and B cells originate in the patient's totipotent stem cell from which the CML is also derived.

Antigens, CD↗
PubMed1995

Late appearance of the Philadelphia chromosome with monosomy 7 in a patient with de novo AML with trilineage myelodysplasia.

We report here a patient with de novo acute myelocytic leukemia with trilineage myelodysplasia (AML/TMDS) in whom cytogenetic analysis was normal at diagnosis and in whom Philadelphia chromosome (Ph1) with monosomy 7 emerged at the terminal stage of the disease. Reverse transcription polymerse chain reaction (RT-PCTR) on the Ph1 positive specimen detected the mRNA encoding p190bcr/abl but did not detect mRNA encoding p210bcr/abl. However, mRNA encoding p190bcr/abl was not detected at diagnosis and or at relapse. These observations support the hypothesis that late-appearing Ph1 and monosomy 7 might be the result of clonal evolution during the course of leukemia, and p190bcr/abl might play a role in the terminal transformation or progression of leukemia.

Acute Disease↗
PubMed2002

In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells.

BACKGROUND: Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML. METHODS: The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software. RESULTS: STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures. CONCLUSIONS: In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.

Antimetabolites, Antineoplastic↗
PubMed2003

Analysis of the impact of imatinib mesylate therapy on the prognosis of patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha regimens for early chronic phase.

BACKGROUND: The effect on prognosis of adding imatinib mesylate to the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) has not been explored fully. The objective of the current study was to evaluate the benefit of adding imatinib to the treatment sequence of patients with early chronic phase Ph-positive CML who received interferon alpha (IFN)-based regimens as frontline therapy. METHODS: A total of 201 patients with early chronic phase Ph-positive CML who were treated on our 3 recent frontline IFN-based programs and were impacted early by the availability of sequential therapy with imatinib were analyzed. Their outcome was compared with that of a historical control group of 293 patients treated from 1982 until 1990 who were treated with IFN programs for early chronic phase CML and who did not have the opportunity of early access to imatinib (because it was not available during that period). Multivariate analysis was used to evaluate the independent effect of imatinib therapy on survival. RESULTS: Of 201 patients who were treated, 159 patients (79%) had their regimen changed sequentially to imatinib after a median duration of 14 months of IFN therapy. Of 139 patients who continued evaluation at our institution, 101 patients (73%; 64% of the total group) achieved a complete cytogenetic response, and 20 of 80 patients analyzed (25%; 10% of the total group) had no disease according to molecular studies (quantitative polymerase chain reaction studies). The estimated 5-year survival rate for the total study group of 201 patients was 86%. Survival of this group was significantly superior to the historic control group of IFN-treated patients who did not have the benefit of imatinib (P = 0.03). The trend also was observed within defined CML risk groups. Imatinib therapy was confirmed as an independent, significant, favorable prognostic factor for survival by multivariate analysis, after accounting for the independent prognostic effect of pretreatment prognostic factors (P = 0.005). CONCLUSIONS: The current analysis is the first to indicate the independent, favorable effect of imatinib on the survival of patients with Ph-positive CML.

Aged↗
PubMed2003

Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data.

BACKGROUND: The International Randomized study of Interferon-alpha plus cytarabine (IFN-alpha plus ara-C) versus STI571 (imatinib mesylate) [IRIS trial] in patients with newly diagnosed Philadelphia chromosome (Ph)-positive, chronic-phase chronic myelogenous leukemia (CML) has not shown (to date) a survival advantage for imatinib. This was most likely because approximately 90% of patients receiving IFN-alpha plus ara-C changed to imatinib therapy after a median of 8 months into therapy. METHODS: The authors analyzed the results with imatinib therapy in patients with newly diagnosed Ph-positive CML in chronic phase and compared their outcome with patients who received IFN-alpha regimens. A total of 187 patients with Ph-positive CML in early chronic phase treated with imatinib were compared with a historic group of 650 similar patients treated with IFN-alpha regimens from 1982 until 1997. RESULTS: Patients who received imatinib were significantly older and had significantly more bone marrow basophilia and less leukocytosis. The complete cytogenetic response (Ph 0%) rates were better with imatinib (81% vs. 32%; P < 0.001), as were the survival rates (30-month estimated survival rates 98% vs. 88%; P = 0.01). A multivariate analysis of the total study group of 837 patients identified imatinib therapy to be a significant independent favorable prognostic factor for survival (P = 0.01). CONCLUSIONS: The current study is the first to indicate the survival advantage of imatinib compared with IFN-alpha, the previous standard of care, in patients with early chronic-phase CML.

Administration, Oral↗
PubMed2003

Imatinib mesylate in Philadelphia chromosome-positive leukemia of childhood.

BACKGROUND: Initial treatment for adult patients with Philadelphia chromosome-positive (Ph[+]) chronic myelogenous leukemia (CML) now includes imatinib mesylate. However, to our knowledge, there are few data regarding imatinib safety, efficacy, and response monitoring in patients age < 18 years. METHODS: In the current series, the authors report 5 consecutive patients ages 20 months to 12 years with Ph+ leukemia who were treated with imatinib and evaluated for a response using cytogenetics, fluorescent in situ hybridization (FISH), and real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on serial bone marrow aspirations. Doses of imatinib were escalated as tolerated from a starting dose of 400 mg/m2 (patients with a body surface area [BSA] < 1 m2) or 400 mg/day (patients with a BSA > 1 m2). RESULTS: After the initiation of imatinib therapy, all 4 patients with CML were found to have no detectable Ph chromosome by cytogenetics (median of 198 days of imatinib therapy; range, 138-346 days), FISH (median of 285 days of imatinib therapy; range, 138-366 days), and real-time RT-PCR (median of 287 days of imatinib therapy; range, 224-366 days). One patient with Ph+ acute mixed lineage leukemia achieved a morphologic disease remission with standard chemotherapy, but within 10 months had increasing Ph positivity in consecutive bone marrow aspirations. Imatinib was added to the intensive leukemia therapy, and within 26 days there were no detectable Ph+ cells in the bone marrow. Mild thrombocytopenia was noted in two patients and transient mild hepatic toxicity was noted in one patient. CONCLUSIONS: Imatinib mesylate was found to be effective in inducing undetectable residual disease in a small cohort of pediatric patients with Ph+ leukemia. Further studies of the use of imatinib in childhood Ph+ malignancies are needed.

Antineoplastic Agents↗
PubMed2006

Gliomatosis cerebri: 20 years of experience at the Children's Hospital of Philadelphia.

BACKGROUND: Gliomatosis cerebri (GC) is a rare and typically fatal glial neoplasm of the central nervous system. In this report, the authors describe the largest cohort of children to date with GC and explore relations between potential prognostic factors, treatment, and survival. METHODS: Imaging, pathologic, and outcome data were reviewed from 13 patients who were diagnosed with GC and were treated at the Children's Hospital of Philadelphia (CHOP) between 1982 and 2005. All patients had GC confirmed by biopsy. Twelve patients received cranial irradiation, and 8 of those patients received adjuvant chemotherapy. A single patient age 1 year received chemotherapy alone. A review of the literature identified 51 pediatric patients with GC. RESULTS: The progression-free survival rate in this study was 13% (range, 1.5-43 months), and the overall survival (OS) rate was 64% (range, 6.5-67 months) at 2 years. OS was significantly shorter for patients who presented in the first decade of life (P = .04). The time to progression was prolonged significantly for patients who had no evidence of tumor enhancement on imaging studies (P = .03). When survival data from patients reported in the literature were combined with the CHOP cohort, treatment prolonged OS significantly (P = .003). CONCLUSIONS: The outcome of pediatric patients with GC was extremely poor; however, the current results indicated that treatment may prolong OS. Age < 10 years and contrast enhancement on magnetic resonance imaging studies at diagnosis may be risk factors for shorter survival in pediatric patients with GC.

Adolescent↗
PubMed1994

CGG-repeat polymorphism of the BCR gene rules out predisposing alleles leading to the Philadelphia chromosome.

The Philadelphia chromosome (Ph) is associated with leukemia, most frequently of the chronic myelogenous variety. The Ph chromosome is a translocation chromosome which gains oncogenic potential through the fusion of the ABL oncogene of chromosome 9 with the BCR gene of chromosome 22. The Ph is believed to arise from random chromosome rearrangement with a subsequent selective advantage of the malignant cell line. However, alleles may be present in the population which predispose toward this specific rearrangement. We used a highly polymorphic CGG-repeat polymorphism within the first exon of the BCR gene to determine BCR allele frequencies among 26 leukemia patients with the Ph chromosome and 63 control individuals. Eight BCR alleles of variable CGG-repeat length were present in both groups at statistically similar frequencies and in Hardy-Weinberg equilibrium. We therefore concluded that there are no alleles of the BCR gene that have a major predisposing influence on the development of the Ph chromosome and subsequent leukemia.

Alleles↗
PubMed1995

Correlation between the proportion of Philadelphia chromosome-positive metaphase cells and levels of BCR-ABL mRNA in chronic myeloid leukaemia.

We have sought to define the relationship between the proportion of marrow metaphases showing the Philadelphia chromosome (Ph) and levels of BCR-ABL mRNA assessed by quantitative polymerase chain reaction (PCR) in patients with chronic myeloid leukaemia (CML). From a total of 141 patients, 164 PCR assays were performed on peripheral blood samples taken within 2 weeks of a bone marrow specimen analysed by cytogenetics. BCR-ABL mRNA was quantified in all 106 PCR-positive samples by competitive PCR; results ranged from < 10 to 3.4 x 10(6) transcripts/micrograms RNA. Twenty-one chronic-phase patients had a median of 5.0 x 10(5) BCR-ABL transcripts/micrograms RNA; no difference in levels of the fusion mRNA was found between 15 Ph-positive and six Ph-negative, BCR-ABL-positive patients. Ph-positive metaphases were not detected in any individual who was PCR negative (n = 58) and in only a single patient who was PCR positive with < 10(3) BCR-ABL transcripts/micrograms RNA (n = 44). Conversely, of 41 samples from patients in haematological remission who had > 10(3) BCR-ABL transcripts/micrograms RNA, 30 had at least one Ph-positive metaphase. The highest level of BCR-ABL transcripts at which Ph-positive metaphases were not detected was 1.5 x 10(4). For the 46 patients who had at least one Ph-positive metaphase, a good correlation (Spearman coefficient = 0.83, P < 0.0001) was found between the percentage of Ph-positive metaphases and BCR-ABL transcript levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow↗
PubMed2006

Efficient allocation of resources to prevent HIV infection among injection drug users: the Prevention Point Philadelphia (PPP) needle exchange program.

The objective of this study is to determine the allocation of resources within a multi-site needle exchange program (NEP) that achieves the largest possible reduction in new HIV infections at minimum cost. We present a model that relates the number of injection drug user (IDU) clients and the number of syringes exchanged per client to both the costs of the NEP and the expected reduction in HIV infections per unit time. We show that cost-effective allocation within a multi-site NEP requires that sites be located where the density of IDUs is highest, and that the number of syringes exchanged per client be equal across sites. We apply these optimal allocation rules to a specific multi-site needle exchange program, Prevention Point Philadelphia (PPP). This NEP, we find, needs to add 2 or 3 new sites in neighborhoods with the highest density of IDU AIDS cases, and to increase its total IDU client base by about 28%, from approximately 6400 to 8200 IDU clients. The case-study NEP also needs to increase its hours of operation at two existing sites, where the number of needles distributed per client is currently sub-optimal, by 50%. At the optimal allocation, the estimated cost per case of HIV averted would be dollar 2800 (range dollar 2300-dollar 4200). Such a favorable cost-effectiveness ratio derives primarily from PPP's low marginal costs per distributed needle.

Efficiency, Organizational↗
PubMedDate not supplied

Philadelphia chromosome without breakpoint cluster region rearrangement in a case of Lennert's lymphoma of suppressor phenotype.

A 60-year-old woman presented with diffuse lymphadenopathy. Diagnostic and staging work-up showed that the patient had diffuse small cleaved cell lymphoma (diffuse poorly differentiated lymphocytic lymphoma) with associated histiocytes (lymphoepithelioid cell lymphoma) by the Kiel classification system. Immunohistologic staining showed a T suppressor cell tumour phenotype. Cytogenetic studies revealed the Philadelphia chromosome (Ph1). On DNA studies, the breakpoint cluster region (BCR) gene was not rearranged suggesting that the Ph1 involvement was not identical to that seen in chronic myelogenous leukemia (CML). This case is presented because of the rarity of Ph1 in lymphoid malignancies, particularly in those of T-cell origin, and because of its potentially adverse implications.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2002

In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

University-assisted community school program of West Philadelphia: democratic partnerships that make a difference.

The university-assisted community school model is showing results for children and youth in West Philadelphia. The University of Pennsylvania's (Penn's) Center for Community Partnerships has coordinated universitywide efforts, in partnership with the community, in order to create and develop community school programs. The Sayre program aims to become a university-assisted community school, with a comprehensive community problem-solving curriculum and communitywide program that is fully integrated across both the Sayre curriculum and the curriculum of a number of Penn's schools. The Penn-Sayre project demonstrates that higher education can be a permanent anchor for revitalizing schools and communities if the vast resources it possesses, particularly its faculty, students, and staff, are brought to bear in a coordinated fashion.

Adolescent↗