EXTINCT MEDICAL SCHOOLS OF NINETEENTH CENTURY PHILADELPHIA. VI. THE ECLECTIC MEDICAL COLLEGE OF PHILADELPHIA AND PHILADELPHIA UNIVERSITY OF MEDICINE AND SURGERY.
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Philadelphia-chromosome-negative peripheral blood stem cells can be mobilized in the early phase of recovery after a myelosuppressive chemotherapy in Philadelphia-chromosome-positive acute lymphoblastic leukaemia.
Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.
Adolescent↗
Acute myeloblastic leukaemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukaemia with Philadelphia chromosome.
We report a patient who developed Philadelphia chromosome negative acute myeloblastic leukaemia with trisomy 8 and trisomy 11 after receiving treatment with alkylating agents and interferon for chronic myelocytic leukaemia positive for Philadelphia chromosome. Leukaemic cells were positive for myeloperoxidase and expressed CD13, CD33 and DR; some expressed CD2, CD4 and CD34. The fluorescence in situ hybridization method revealed that bcr-abl fusion genes were absent from > 90% of the bone marrow cells. The major bcr rearrangement was not detected by Southern blot analysis. We conclude that the leukaemic cells negative for Philadelphia chromosome may have developed as a result of treatment with alkylating agents and interferon in the present case.
Aged↗
Molecular interactions between Hb alpha-G Philadelphia, HbC, and HbS: phenotypic implications for SC alpha-G Philadelphia disease.
We show here that alpha2(G-Phila.) beta2(C) has an increased rate of crystal nucleation compared to alpha2 beta2(C) (HbC). We conclude from this finding that position alpha68, the mutation site of alpha2(G-Phila.) beta2 (HbG(Philadelphia)), is a contact site in the crystal of HbC. In addition, that HbS enhances HbC crystallization (additive to the effect of alpha(G-Phila.) as shown here) and that alpha(G-Phila.) inhibits polymerization of HbS are pathogenically relevant previously known facts. All of these findings help explain the phenotype of an individual simultaneously heterozygous for the betaS, betaC, and the alpha(G-Phila.) genes (SC alpha-G Philadelphia disease). This disease is characterized by a mild clinical course, abundant circulating intraerythrocytic crystals, and increased folded red cells. This phenotype seems to be the result of increased crystallization and decreased polymerization brought about by the opposite effects of the gene product of the alpha(G-Phila.) gene on the betaC and betaS gene products. Some of the intraerythrocytic crystals in this syndrome are unusually long and thin, resembling sugar canes, unlike those seen in SC disease. The mild clinical course associated with increased crystallization implies that, in SC disease, polymerization of HbS is pathogenically more important than the crystallization induced by betaC chains. The SC alpha-G Philadelphia disease is an example of multiple hemoglobin chain interactions (epistatic effect among globin genes) creating a unique phenotype.
Adult↗
[Clonal evolution of abnormal Philadelphia chromosome-negative cells after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia].
OBJECTIVE: To investigate clonal evolution of abnormal Philadelphia chromosome-negative cells (Ph- CE) after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). METHODS: Bone marrow cells G-banding karyotype was evaluated every 3 months in 100 patients with Ph+ CML after achieving hematologic responses on the course of imatinib therapy. There were 54 patients in chronic phase (CP), 37 in accelerated phase (AP) and 9 in blast phase (BP). RESULTS: After a median follow-up of 32 months (ranged 25-34 months), 11 patients, including 5 cases in CP, 5 in AP and 1 in BP, developed transient, interrupted or continuous Ph- CE after 3 - 29 months on imatinib therapy. Ph- CE emerged at the beginning of Ph+ cells decreasing or after Ph+ cells disappearing. The proportion of Ph- CE, was negatively correlated with the proportion of Ph+ cells (P < 0.05). Ph- CE commonly included +8 (45.5%) and +Y (27.3%). Five patients had additional cytogenetic abnormalities besides Ph+ in Ph- CE. Seven of the patients with Ph- CE achieved a major cytogenetic response while 9 of them achieved a complete hematologic response. One patient with Ph- CE in AP progressed to BP 20 months after the initiation of the therapy while the rests remained in hematologic or cytogenetic responses. CONCLUSION: Ph- CE occurred in about 11% of the patients with Ph+ CML who achieved major or minor cytogenetic responses on imatinib therapy. After a median follow-up of more than 2 years, most of the patients with Ph- CE were in a stable status with no disease progression.
Adult↗
Development and progression of a Philadelphia-chromosome-negative acute myelocytic leukemia clone in a patient with Philadelphia-chromosome-positive chronic myelocytic leukemia.
We report a patient with typical Philadelphia-chromosome-positive chronic myelocytic leukemia who developed Philadelphia-chromosome-negative acute myelocytic leukemia following autologous stem cell transplantation. The implications of this observation for disease monitoring and treatment are discussed.
Antineoplastic Agents↗
Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome.
The blast crisis in chronic myelogenous leukemia (CML) is related to the evolution of a Philadelphia chromosome (Ph)-positive clone. Secondary chromosomal abnormalities accompanied by t(9;22) are found in 70-80% of blast crises. Here we describe a patient with Ph-positive CML, who developed Ph-negative acute lymphoblastic leukemia (ALL). A 52-year-old man was diagnosed with CML with the Ph chromosome in the chronic phase. He achieved a partial cytogenetic response after 4 months of imatinib mesylate therapy. After 8 months, common ALL occurred. At that time his karyotype was normal and the Ph chromosome was not noted.
Benzamides↗
Chromosome 22 breakpoints in variant Philadelphia translocations and Philadelphia-negative chronic myeloid leukemia.
The standard t(9;22)(q34;q11) found in Philadelphia (Ph) chromosome positive chronic myeloid leukemia (CML) involves a highly restricted (5.8 kb) chromosome 22 breakpoint cluster region (bcr), which results in the formation of a chimeric gene comprising exons from the 5' end of bcr and protooncogene c-abl coding sequences from chromosome 9. In a survey of 21 patients with hematologic and clinical features of CML we detected rearrangement of the chromosome 22 bcr by gene probe analysis in all cases, including 16 with a standard t(9;22), two with variant Ph translocations [t(10;22)(q26;q11);t(11;22)(p15;q11)], one with a complex Ph translocation [t(9;11;22)(q34;q13;q11)], one with a complex translocation and a masked Ph[t(9;14;22) (q34;q24;q11)], and one Ph-negative case with a t(1;9)(p32;q34). These observations further substantiate the suggestion that, despite karyotypic heterogeneity, a common underlying molecular lesion, the bcr-abl gene chimera, is involved in the disease pathogenesis of CML.
Adult↗
Philadelphia-positive acute lymphoblastic leukemia with multiple subclones including duplication of the Philadelphia chromosome and Abelson oncogene.
A case of Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) with multiple subclones including duplication of the BCR-ABL1 fusion gene and of the Abelson oncogene (ABL1) is reported. Cytogenetically, two different rearrangements of chromosome 9 not involved in the t(9;22) were found in two subclones. In one subclone the normal 9 was lost and replaced by an acrocentric marker, which contained an additional copy of the BCR-ABL1 fusion gene. Reverse transcriptase polymerase chain reaction detected the fusion transcripts p210 (e13a2 junction) and p190 (e1a2 junction), whereas fluorescence in situ hybridization showed the major BCR-ABL1 junction in both Ph chromosomes, strongly suggesting that the presence of the p210 and p190 proteins in this case was due to mechanisms of alternative or mis-splicing at the transcriptional level. The second subclone showed the classic t(9;22) plus an add(9)(p24) containing two copies of the ABL1 gene. Other molecular events involving chromosome 9 were a monoallelic loss of JAK2 in both subclones and an additional loss of P15/P16 in the subclone with the acrocentric marker bearing the extra Ph chromosome.
Acute Disease↗
Silent Philadelphia chromosome: a distinct developmental stage in a philadelphia chromosome-positive chronic myeloproliferation?
In this paper, a patient is described who presented with peripheral blood and bone marrow features uncharacteristic of chronic granulocytic leukemia, which proved to be Philadelphia (Ph) chromosome-positive by metaphase and interphase cytogenetic analyses but lacked the p210 type of BCR/ABL fusion gene mRNA product by two different sensitive RT-PCR assays. In the course of the 32-month follow-up with a termination into a myeloblastic crisis, molecular investigations were performed four times. They indicated a constantly high rate of Ph positive cells and lack of BCR/ABL mRNA expression, except in the second investigation, when the patient showed reverse transcription polymerase chain reaction positivity with b3/a2 type of chimera, fusion gene mRNA expression, and a striking change in the bone marrow histology. Our findings might indicate that the dormant Ph chromosome state may exist not only at the primitive progenitor, but also at the entire peripheral blood cell compartment level.
Base Sequence↗
Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.
BACKGROUND: Anecdotal cases of chromosomal abnormalities in Philadelphia chromosome (Ph)-negative metaphases have been reported in patients with chronic myelogenous leukemia (CML) in the chronic phase during treatment with interferon and, more recently, with imatinib. This phenomenon is different from true clonal evolution in that the additional cytogenetic abnormality occurs in Ph-negative cells. METHODS: The authors analyzed their experience with 342 patients with CML in chronic phase treated with imatinib to investigate the frequency and significance of this event. RESULTS: After a median follow-up of 30 months (range, 16-35 months), 21 patients (6%; 95% confidence interval, 0.04, 0.09) developed 25 chromosomal abnormalities in Ph-negative cells. Thirteen (54%) of these abnormalities were seen in 2 or more metaphases. The median time from the start of treatment with imatinib to the appearance of the abnormalities was 6 months (range, 3-22 months). The most common cytogenetic abnormality detected was trisomy 8 (33%). Twenty of 21 patients (95%) achieved a major (Ph < 35%) cytogenetic response (complete cytogenetic response in 13-62%). After a median follow-up of 22 months (range, 4-33 months), all 21 patients were alive, 20 of them in chronic phase and in complete hematologic response. None of the patients showed features of myelodysplasia. CONCLUSIONS: Cytogenetic abnormalities occur in Ph-negative cells in a fraction of patients with CML in chronic phase treated with imatinib. With a short follow-up, no clear clinical consequences can be identified.
Adult↗
Philadelphia chromosome negative acute lymphoblastic leukemia preceding Philadelphia positive chronic myelogenous leukemia.
A patient with Philadelphia chromosome (Ph) negative acute lymphoblastic leukemia (ALL, FAB type L1) developed Ph-positive chronic myelogenous leukemia (CML) after more than 2 years in complete remission. Subsequently, Ph-positive lymphoblastic transformation occurred, which was again successfully treated. Thereafter, the CML state was interrupted twice more by blast crisis. The additional chromosomal abnormalities were atypical for Ph-positive CML. The course is interpreted as a possible example of the multistep development of CML. Blastic transformation occurring prior to the Ph chromosome has been reported in only two cases previously.
Adult↗
Essential thrombocythemia with the Philadelphia chromosome and BCR-ABL gene rearrangement. An entity distinct from chronic myeloid leukemia and Philadelphia chromosome-negative essential thrombocythemia.
A 64-year-old woman presented with a platelet count of 3,225 x 10(9)/L. Bone marrow morphology showed massive megakaryocytic hyperplasia; cytogenetic studies showed the presence of the Philadelphia chromosome (Ph). The presence of a rearrangement involving the major breakpoint cluster region (mbcr) on chromosome 22 was confirmed by Southern blotting techniques. A diagnosis of Ph positive essential thrombocythemia (ET) was made. Such cases constitute less than 5% of patients with ET and it has been proposed that they be considered examples of chronic myelogenous leukemia (CML) because of a shared propensity to progress to blast crisis. An argument is presented for retaining Ph positive ET as an entity separate from Ph negative ET and Ph positive CML.
Blotting, Southern↗
Trisomy X in Philadelphia chromosome-negative cells during the course of Philadelphia chromosome-positive chronic myelocytic leukemia.
A Philadelphia chromosome-negative (Ph(-)) clone with trisomy X appeared in the bone marrow cells from a patient with Ph(+) chronic myelocytic leukemia in the chronic phase after hydroxyurea and interferon-alpha treatment.
Adult↗
Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia.
Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.
Adult↗
Specific point mutations that activate v-abl are not found in Philadelphia-negative chronic myeloid leukaemia, Philadelphia-negative acute lymphoblastic leukaemia or blast transformation of chronic myeloid leukaemia.
The involvement of the BCRlABL fusion gene in patients with Philadelphia (Ph) chromosome positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) is well characterised, but the molecular events underlying the cases of Ph-negative CML and ALL that lack BCR gene involvement and those that cause transformation of Ph-positive CML are unknown. The murine ABL gene can be activated by genetic events that do not involve the BCR gene, including the introduction of two specific point mutations in exons VII and XI respectively, as found in the homologous sequence of the v-abl oncogene. We therefore sought evidence for analogous point mutations in the ABL gene in patients with Ph-negative, BCR-negative CML (n = 25), Ph-negative ALL (n = 18) and in Ph-positive CML in transformation (n = 28). We used restriction fragment length polymorphism and single strand conformational polymorphism techniques to analyse DNA amplified fragments of selected ABL coding regions from leukaemia cells. We identified only normal wild-type DNA sequences. The absence of these transforming point mutations does not exclude the possibility that the ABL gene in such patients could be activated by other means.
Adult↗
Emergence of Philadelphia positive chronic myeloid leukaemia during treatment with hydroxyurea for Philadelphia negative essential thrombocythaemia.
A 58-yr-old male patient with essential thrombocythaemia (ET) developed chronic myeloid leukaemia (CML) after continuous uneventful treatment with hydroxyurea for 18 yr. G-banding analyses of bone marrow cells had repeatedly demonstrated normal male karyotype before this event, but t(9;22)(q34;q11) was demonstrated after the event. An unrelated allogeneic stem cell transplantation was performed. Blood and bone marrow morphology, and the karyotype were normalised and the patient is in good health 1 yr post-transplant. There are no previous reports in the literature about the emergence of CML during treatment with hydroxyurea.
Antineoplastic Agents↗
Rehabilitation of the tuberculous in Philadelphia; a study of the effectiveness of the program of rehabilitation in Philadelphia for a ten-year period, July 1, 1949.
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Humans↗