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

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

Antigens, CD↗

Philadelphia chromosome-positive acute lymphoblastic leukaemia following radiotherapy for carcinoma of the cervix.

We report the case of a 70-year-old woman in whom Philadelphia chromosome-positive acute leukaemia occurred 12 years after radiation therapy for a carcinoma of the cervix. Morphology of the blasts was undifferentiated and immunological studies were in favour of a CALLA-positive acute lymphoblastic leukaemia. A possible relationship between the onset of leukaemia and the former radiation therapy is suggested.

Aged↗

Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts.

To substantiate the reported sensitivity of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) to St Jude-type multiagent chemotherapy and to identify means of selecting patients most likely to benefit from such treatment, we analyzed the clinical and biologic characteristics of 12 patients with classic Ph+ ALL who were treated in either of two total therapy programs at St Jude Children's Research Hospital (1989-1994). Event-free survival estimates for this cohort were compared with historical data on 11 patients from an earlier total therapy study (Lancet 1994; 343: 331-332). The prognostic importance of age, white blood cell count and other presenting features was assessed by the logrank test in all 23 patients. Complete remissions were induced in 92% of the patients treated since 1989, compared with 82% of the historical control group (P > 0.05). There was essentially no difference in event-free survival between the study group and historical controls (4-year Kaplan-Meier estimates, 33 +/- 19% s.e. vs 36 +/- 13%). Further analysis of potentially informative risk factors identified a good-prognosis subgroup defined by an initial white blood cell count of < or =25 x 10(9)/l and a 4-year event-free survival of 73 +/- 19%. In conclusion, intensive multiagent chemotherapy offers an attractive therapeutic option for children and adolescents with Ph+ ALL and low presenting leukocyte count.

Adolescent↗

Philadelphia (Ph) chromosome-positive thrombocythemia without features of chronic myeloid leukemia in peripheral blood: natural history and diagnostic differentiation from Ph-negative essential thrombocythemia.

We have evaluated the clinical symptoms, hematological features, and natural history of 3 cases and 20 reported cases described as Philadelphia chromosome-positive (Ph+) essential thrombocythemia (ET). The presence of increased small mononuclear megakaryocytes in bone marrow smears and biopsy material in patients with pronounced thrombocytosis and no evidence of chronic myeloid leukemia (CML) in peripheral blood appeared to be a diagnostic clue to the diagnosis of Ph+ (essential) thrombocythemia. As compared to cases of reactive thrombocytosis, the megakaryocytes in Ph+ thrombocythemia are smaller than normal ones and typically have hypolobulated round nuclei. This contrasts with the finding of clustered mature and enlarged megakaryocytes in Ph-negative true ET. Patients diagnosed as Ph+ ET may progress to CML and show a high tendency to myelofibrosis and blastic transformation. These observations indicate that both Ph+ ET and Ph+ thrombocythemia associated with CML can be regarded as early manifestations of the chronic stable phase of CML.

Aged↗

Serous retinal detachment in an elderly patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia.

PURPOSE: To describe an elderly woman who presented with a serous retinal detachment (SRD) as the first sign of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). DESIGN: Observational case report. METHODS: A complete ophthalmic and systemic evaluation was performed on a 62-year-old woman because of decreased vision of 20/60 OD and 20/25 OS. RESULTS: Fundus examination revealed a SRD involving the fovea, OU. Fluorescein angiography disclosed multifocal spots of hyperfluorescence in the early phase, and diffuse subretinal accumulation of fluorescein in the late phase. She was diagnosed with Ph(+) ALL because of systemic findings. She underwent systemic chemotherapy and went into complete remission. Visual acuity improved to 20/20 in both eyes with resolution of the bilateral SRD. CONCLUSIONS: Our observations indicate that a sudden appearance of SRD, even in an elderly patient, warrants a thorough systemic screening for underlying leukemia. This is especially important, because prompt systemic chemotherapy can improve the visual acuity and the prognosis.

Antineoplastic Agents↗

[Allogeneic hematopoietic stem cell transplantation for treatment of Philadelphia chromosome positive acute lymphoblastic leukemia].

OBJECTIVE: To explore the optimal time of allogeneic hematopoietic stem cell transplantation (allo-HSCT) applied in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and the optimum order of donor selection. METHODS: From Mar 2000 to Jul 2004, 32 patients with Ph+ ALL were treated by Allo-HSCT, and the follow up ended at Dec 30.2004 with medium of 13 months. Of whom, 24 were male, and 8 were female. Twenty-three patients have been transplanted in CR1, 9 patients beyond CR1 (1 in CR2, 8 in refractory or relapse status). Twelve cases received HSCT from identical sibling donor, 4 unrelated Cord Blood Transplantation (CBT), 3 HSCT from matched unrelated donor (MUD), and 13 HSCT from mismatched related donor (MMRD), of which, 6 cases were M(BCR/ABL) subtype, and 20 m(BCR/ABL) subtype. The Kaplan-Meier method was used to estimate the probabilities of leukemia-free survival (LFS), overall survival (OS) and relapse incidence (RI), and the factors were compared by means of the Log-rank test. Simultaneous effect of multiple covariates were estimated with Cox model. RESULTS: Of all the 32 cases engrafted, 4-year OS was 57.19%, LFS 37.09%, and RI 56.36%. In univariate prognostic analysis model, the OS was higher in CR1 group pre-HSCT than that in non-CR1 group (74.50% vs 22.22%, P=0.0046), LFS was higher (49.06% vs 11.11%, P=0.0057), RI was lower (44.80% vs 84.76%, P=0.0157); the OS was higher in M(BCR/ABL) group than that in m(BCR/ABL) group (100% vs 40.91%, P=0.0318), LFS was higher (75% vs 17.72%, P=0.0057), RI was lower (25% vs 77.88, P=0.0116); OS was similar in HLA MM RD group to that in HLA identical group (52.65% vs 55.56%, P=0.6247), LFS was similar (45.12% vs 30.00%, P=0.8315), and RI was also similar (50.77% vs 60.62%, P=0.8217). In multiple covariate analysis model, the BCR/ABL type was the risk factor of LFS [P=0.005, Exp(B)=9.971] and RI (P=0.006, Exp(B)=9.488), the status of disease pre-HSCT and BCR/ABL subtype was the risk factor of OS [P was 0.010 and 0.038, Exp(B) was 4.532 and 37.537 respectively]. CONCLUSION: We had better do HSCT in CR1 to treat Ph+ ALL, if patient is refractory to chemotherapy, we can try STI571, and HSCT should be done as soon as possible if the patients get CR. Mismatched related donor is considered as regular donor for Ph+ ALL patients without identical donors. We should pay more attention to monitoring and prophylaxis of relapse in m(BCR/ABL) patients after HSCT.

Adolescent↗

Philadelphia chromosome-positive chronic myelocytic leukemia in children. Survival and prognostic factors.

The survival and the prognostic significance of the diagnostic characteristics of 39 children with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph1-positive CML), seen between 1963-1976 at the Hôpital Saint-Louis of Paris, have been analyzed. The disease predominated in children older than age 4 years (95%), with girls being more affected than boys (24 versus 15). The clinical and hematological picture at presentation was similar to that observed in adults with Ph1-positive CML. Most children of this series were treated with busulfan which, as in adults, led to reduction of leucocytosis and organomegaly but did not prevent the occurrence of blastic crisis. Well-documented blastic crisis was observed in 78% of cases. Of 39 children, 12 were still alive, all in the chronic phase. Twenty-seven have died, 21 of them after blastic crisis, 4-156 months after diagnosis (median survival, 53 months). The effect of each diagnostic characteristic on survival was evaluated using the log-rank test. Of the 14 characteristics studied, only the degree of blood and marrow blastosis was associated with a shorter survival. Age, sex, bleeding, lymphadenopathy, hepatomegaly, degree of splenomegaly, hemoglobin level, total leucocyte, immature granulocyte (promyelocytes + myelocytes + metamyelocytes), eosinophil, basophil, and platelet counts in the peripheral blood were of no prognostic significance. The failure to attain a level of statistical significance for some characteristics found to be of prognostic value for adults, could be due to the small sample size and/or to the disease homogeneity. The results of this study, however, stress the importance of the initial blastic infiltration in determining the duration of survival, which is ultimately determined by the occurrence of terminal acute leukemia. In conclusion, this study shows that the Ph1-positive CML of childhood exhibits the same course, incidence of blastic crisis, and survival as the disease of adults. It also indicates that treatment with moderate chemotherapy, such as busulfan, has no effect on the duration of survival. Therefore, new therapeutic approaches are urgently needed for the treatment of this disorder in children.

Adolescent↗

Immunophenotypes and outcome of Philadelphia chromosome-positive and -negative Thai adult acute lymphoblastic leukemia.

Little evidence exists in Asian countries regarding the incidence, immunologic characteristics, and clinical outcomes of adult patients with Philadelphia chromosome-positive (Ph+) and -negative (Ph-) acute lymphoblastic leukemia (ALL). In this study, we prospectively studied 324 Thai adult acute leukemia patients, 79 (24%) of whom were identified as having ALL. Immunophenotyping was performed by 5-parameter flow cytometry, and karyotyping was conducted by standard banding methods. The Ph chromosome was detected in 18.5% of cases. The mean age of Ph+ ALL patients was 29 years (50% male), and that of Ph- ALL patients was 33 years (62% female). The Ph+ ALL patients had significantly higher white blood cell (WBC) counts (mean, 93 x 10(9)/L), with 67% having WBC counts higher than 50 x 10(9)/L. In contrast, most Ph- ALL patients had WBC counts lower than 50 x 10(9)/L (mean, 36 x 10(9)/L; P < .05). CD10 and CD34 were more highly expressed in the Ph+ ALL patients (mean expression, 83% and 87%, respectively) than in the Ph- ALL patients (45% and 57%; P < .005). The aberrant expression of myeloid antigens, including CD33 and CD13, was also significantly observed in the Ph+ ALL patients. The median survival time of Ph+ ALL patients was 8 months, compared with 22 months for the Ph- ALL patients. In conclusion, immunophenotyping results showed that Ph+ ALL in Thai adults arises from B-cells at an earlier stage of development. Extreme leukocytosis, a younger age, male sex, high expression levels of CD10 and CD34, aberrant myeloid antigens, and poorer rates of survival appeared to be associated with the Ph chromosome in Thai adult ALL cases. The incidence of the Ph chromosome among Thai adult ALL patients was not different from that found in Western countries.

Adolescent↗

Derivative chromosome 9 deletions are a significant feature of childhood Philadelphia chromosome positive acute lymphoblastic leukaemia.

Deletions from the derivative chromosome 9, der(9), of the translocation, t(9;22)(q34;q11), at the site of the ABL/BCR fusion gene, have been demonstrated by fluorescence in situ hybridisation (FISH), in both Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). In CML they occur in 10-15% of cases and appear to indicate a worse prognosis, whereas in ALL, the situation is unclear. This study presents the findings of dual fusion FISH used to detect such deletions in a series of 27 BCR/ ABL-positive childhood ALL patients. Metaphase FISH was essential for the accurate interpretation of interphase FISH signal patterns. Three cases (11%) had a single fusion signal, resulting from deletions of the der(9). Three other patients with variant translocations and one with an insertion, also had a single fusion, but with no evidence of deletions. Gain of a fusion in approximately one-third of patients indicated a second Ph, which appears to be a diagnostic marker of Ph-positive ALL. This study shows that the incidence of deletions from the der(9) in childhood ALL is at least as high as that reported for CML.

Child↗

Detection of Philadelphia chromosome-positive acute lymphoblastic leukemia by polymerase chain reaction: possible eradication of minimal residual disease by marrow transplantation.

Minimal residual disease (MRD) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) who received allogeneic (n = 9) or autologous (n = 6) bone marrow transplantation (BMT) was evaluated by the polymerase chain reaction (PCR) for the bcr-abl transcript. Twelve patients received BMT at the time of hematologic and cytogenetic remission. However, MRD was detected in 8 of 10 patients evaluated. Seven patients, including three who had MRD before BMT, continue to have a disease-free survival 5 to 64 months after BMT. Twenty-one specimens obtained from these patients at various times after BMT did not show MRD. In three patients, MRD detected just before BMT seems to be eradicated by BMT protocol. The other eight patients developed cytogenetic or hematologic relapses 2 to 8 months after BMT. Seven of 14 samples from these patients demonstrated MRD, which preceded clinical relapse by 3 to 9 weeks. Thus, this technique for the detection of MRD appears to be useful for the more precise assessment of various antileukemia therapies and for early detection of leukemia recurrence.

Adolescent↗

Heterotransplantation and clonal growth of human Ph'-chromosome-positive leukemia-cell (NALM-1) and B-cell leukemia-cell (BALM-2) lines.

Human hematopoietic cell lines, NALM-1, derived from Ph'-chromosome-positive chronic myelocytic leukemia (CML) in blastic crisis, and BALM-2, derived from B-cell acute lymphoblastic leukemia (ALL), were tested for their heterotransplantability and clonability. Two previously established cell lines, a Burkitt's lymphoma cell line, B35M, and a B-lymphoblastoid cell line, B411-4, derived from a hematologically normal person, were used for comparison. Ten million cells were needed in order for the BALM-2 cell line to grow with 74% success in the immunosuppressed mice, but 1000 million cells were needed in order for the NALM-1 cell line to grow with 74% success in those mice. As in the case of the BALM-2 line, 10 million cells of the B35M cell line were needed for 100% success in heterotransplantation, whereas 30 million cells of the B411-4 cell line resulted in 20% success of heterotransplantation. In a semisolid agarose (0.15%) medium, the cloning efficiencies of BALM-2, B35M, and B411-4 were 1.52--2.08, 26.31--38.46, and 0.09--0.12, respectively. With as many as 25,000 cells per well plated, NALM-1 did not produce any colonies in the semisolid agarose medium. Unlike most previous findings, those of the present study suggest that the heterotransplantability and clonability of cultured cells may not be invariably reliable characteristics of all proven human leukemia-lymphoma cell lines. The behavior of these leukemia cell lines representing their respective original leukemia clones is interpreted as reflecting the heterogeneity inherent in the biologic characteristics seen in human leukemias.

Animals↗

Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease.

Disease-free survival in Philadelphia chromosome-positive ALL (Ph + ALL) is very poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently considered the only procedure with curative potential. To identify factors affecting transplant outcome, we analyzed the data from 197 Ph + ALL patients aged 16 years or older who had undergone allo-HSCT. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (P < 0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation, and HLA-identical sibling donor (P < 0.0001, P < 0.0001, P = 0.0301, P = 0.0412, respectively). Severe acute GVHD increased the risk of treatment-related mortality (TRM) without diminishing the risk of relapse, whereas chronic GVHD reduced the risk of relapse without increasing the risk of TRM. Thus, patients who developed extensive chronic GVHD had better survivals (P = 0.0217), and those who developed grade III-IV acute GVHD had worse survivals (P = 0.0023) than did the others.

Adolescent↗

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

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

Adolescent↗

Extramedullary relapse in the left proximal femur with Philadelphia chromosome positive acute lymphoblastic leukemia after allogeneic bone marrow transplantation.

We describe a rare presentation of extra-medullary relapse in an adolescent boy with Philadelphia chromosome-positive acute lymphoblastic leukemia who had undergone allogeneic bone marrow transplantation after first remission. In spite of enduring bone marrow remission, the patient experienced a local relapse in the left proximal femur within 3 years of the transplant. The findings from radiography, bone scintigraphy, and chimerism analysis with short tandem repeats as well as bone marrow aspirates taken via the iliac crests were indeterminate. Magnetic resonance imaging at the onset of hip pain was characterized by decreased signal intensity of the left proximal femur, a finding characteristic of bone marrow edema. Confirmation of extra-medullary relapse of the proximal femur was delayed until histologic proof of the computed tomography-guided biopsy samples was obtained. Overt bone marrow relapse was identified 14 months later. Reestablishment of normal donor hematopoiesis was achieved with reinduction chemotherapy.

Acute Disease↗

Philadelphia chromosome-positive blastic leukaemia: ultrastructural and ultracytochemical evidence of basophil and mast cell differentiation.

Ultrastructural, ultracytochemical, immunologic and biochemical studies were performed on leukaemic cells from 41 patients with Philadelphia chromosome-positive blastic leukaemia; 28 patients were in blast transformation of chronic myelogenous leukaemia and 13 patients presented with 'acute' leukaemia. The patients were divided into two morphologic groups, lymphoid (16 cases) and myeloid (25 cases), on the basis of light microscopy and cytochemistry. All lymphoid cases studied for the presence of CALLA (10 patients) and TdT (11 patients) were positive. Two of 13 myeloid cases studied were TdT positive. The blasts from 10 of 16 lymphoid cases contained immature basophil/mast cell granules on ultrastructural examination. Peroxidase-positive 'lymphoid' blasts were noted in three of seven patients studied by ultracytochemical techniques. The reactivity was primarily confined to granular structures. Of the 25 cases in the myeloid group, blasts from 14 cases showed basophil/mast cell differentiation, nine cases showed neutrophil/monocyte features, and two cases were megakaryoblastic. Distinct patterns of ultrastructural peroxidase positivity were seen in the seven myeloid cases studied. In basophil/mast cell precursors the reactivity was primarily confined to granules; neutrophil precursors showed reactivity in the nuclear envelope, rough endoplasmic reticulum (RER), golgi and granules; in megakaryoblasts, only the nuclear envelope and RER were positive while the granules were consistently negative.

Basophils↗

Secondary chromosomal changes in 34 Philadelphia-chromosome-positive chronic myelocytic leukemia patients from the Mexican West.

The clonal evolution in t(9;22)-positive chronic myelocytic leukemia (CML) is well established. Four major changes occur in more than 70% of patients: +8, i(17q), +19, and an extra Philadelphia chromosome. The frequencies of secondary chromosomal changes in 34 patients from the states of Jalisco, Nayarit, Michoacán, and Colima (the Mexican West) with Philadelphia-chromosome-positive CML were assessed. The most frequent abnormalities were tetraploidy (12 cases); +8, inv(3)(q21q26), and octoploidy (3 cases each); and +der(22)(2 cases). Some translocations not previously associated with CML were observed, such as t(2;7)(p12;q36), t(3;6)(q26;p25), t(3;17)(q26;p13), and t(6;17)(q21;q23 approximately q25). Significant differences were found for +8 with respect to population results from Japan and from southern, eastern, and western Europe; for i(17)(q10) from eastern Europe; for +19 from Japan and western Europe; and for +der(22) from Japan, southern Europe, and western Europe. Although polyploidy could result from endomitosis, there is no direct evidence that the BCR/ABL protein influences such a process; however, protein kinases such as MAPK, which are involved in endomitosis, are activated by the BCR/ABL protein, and so the BCR/ABL protein could promote endomitosis through the MAPK pathway.

Adolescent↗

The effect of novel chromosome position and variable dose on the genetic behavior of the Responder (Rsp) element of the Segregation distorter (SD) system of Drosophila melanogaster.

In the Segregation distorter (SD) system of meiotic drive, a minimum of two trans-acting elements [Sd and E(SD)] act in concert to cause a certain probability of dysfunction for sperm carrying a sensitive allele at the Responder (Rsp) target locus. By employing a number of insertional translocations of autosomal material into the long arm of the Y chromosome, Rsp can be mapped as the most proximal locus in the 2R heterochromatin as defined both by cytology and lethal complementation tests. Several of these insertional translocations result in the transposition of Rsp to the Y chromosome, where its sensitivity remains virtually unaltered. This argues that Rsp is separable from the second chromosome centromere, that its behavior does not depend on its gross chromosomal position, and that meiotic pairing of the chromosomes carrying the various SD elements is not a prerequisite for sperm dysfunction. Several other translocations apparently leave both resulting chromosomes at least partially sensitive to SD action, suggesting that Rsp is a large subdivisible genetic element. This view is compatible with observations published elsewhere that suggest that Rsp is a cytologically large region of highly repetitive AT-rich DNA. The availability of Y-linked copies of Rsp also allows the construction of SD males carrying two independently segregating Rsp alleles; this in turn allows the production of sperm with zero, one or two Rsp copies from the same male. Examination of the relative recovery proportions of progeny arising from these gametes suggests that sperm with two Rsp copies survive at much lower frequencies than would be predicted if each Rsp acted independently in causing sperm dysfunction. Possible explanations for such behavior are discussed.

Animals↗

ABL-BCR mRNAs transcribed from chromosome 9q+ in Philadelphia-chromosome-positive chronic myeloid leukaemia.

Polymerase chain reaction amplification of reverse transcription products has demonstrated the presence of abl-bcr hybrid mRNAs in RNA from peripheral blood leucocytes of Philadelphia-chromosome-positive chronic myeloid leukaemia patients; such hybrid mRNAs can contain either of the alternative first exons of c-abl. A survey of 12 CMLs has shown that abl-bcr mRNAs occur in the leucocytes of some, but not all, patients, and that they are present both in chronic-phase and acute-phase leucocytes.

Base Sequence↗