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PubMed1996

Quantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR).

The quantification of Bcr-Abl transcript numbers in chronic myelogenous leukemia (CML) patients described here uses simultaneous competitive PCR amplification of the target gene (Bcr-Abl) and a reference gene (porphobilinogen deaminase; Pbgd) together with a single composite competitor molecule for both targets based on heterologous sequences. Using this technique, Bcr-Abl transcript numbers could be reproducibly determined even in clinical samples known to harbour poor quality RNA.

DNA Primers↗

PubMed1976

Blast crisis of chronic myeloid leukaemia (CML). I. Presentation simulating acute lymphoid leukaemia (ALL).

Seven patients presenting as an acute leukaemia caused difficulty in diagnosis. The lymphoid appearance of the balst cells either initially or during treatment suggested acute lymphoid leukaemia (ALL). In each case the Philadelphia chromosome was shown to be present thus suggesting that these cases were examples of chronic myeloid leukaemia (CML) presenting in blast crisis without a detectable chronic phase. The implications of these findings are discussed and the difficulty in achieving a precise diagnosis in the acute leukaemias is emphasised. Cytogenetic analysis should be carried out whenever the type of acute leukaemia present is of critical importance.

Adolescent↗

PubMed1980

Heteromorphisms of the Philadelphia (Ph1) chromosome in patients with chronic melogenous leukaemia (CML). I. Classification and clinical significance.

In patients with chronic myelogenous leukaemia (CML), we have found the break points on the long arm of chromosome 22 (22q) are variable (heteromorphic or polymorphic). Consequently, the Philadelphia (Ph1) chromosome is heteromorphic in size for the long arm. Based upon the break points and the relative size of chromosome 22, four types of Ph1 chromosomes are proposed. They are: Types I (very large), II (large), III (average) and IV (small) with the break points at bands 22q13.3, 22q13.1, 22q12 and 22q11.3, respectively. The break points are arbitrary and should not be considered absolute since they are based on length differences. In two cases the Ph1 chromosome involved a translocation between chromosome 9 and 22, and the other two cases chromosome 1 or 12. Because Types I and II are hard to recognize by conventional techniques, the RFA technique (R. band by fluorescence with acridine orange) must be performed on all cases. An earlier contention that only chromosome 22 band 12 is concerned with abnormal myeloid cell proliferation in human leukaemia is rejected. Furthermore, break points are not restricted at the junction of 22ql and q2 and 22q2 and q3 and can happen anywhere on the long arm of chromosome 22.

Acridine Orange↗

PubMed1984

Cytogenetic studies of early myeloid progenitor compartments in Ph1-positive chronic myeloid leukaemia (CML). I. Persistence of Ph1-negative committed progenitors that are suppressed from differentiating in vivo.

We have cytogenetically analysed individual haemopoietic colonies to investigate the level and extent of normal stem cell suppression that occurs in patients with Philadelphia chromosome (Ph1)-positive CML. Seventeen patients were studied at diagnosis prior to the initiation of chemotherapy and five of these were studied again 1-16 months later. Another nine patients were studied for the first time 2-96 months after diagnosis and initiation of chemotherapy. No chromosomally normal metaphases were found in either direct marrow preparations or in haemopoietic colonies obtained from simultaneous assays of marrow and/or blood samples from 20 of the 26 patients studied. In the other six, chromosomally normal haemopoietic progenitors (BFU-E, CFU-C and CFU-G/E) were readily demonstrable even though in five of these patients all dividing cells in the bone marrow appeared to belong to the Ph1-positive clone at the time of study. These results indicate that the suppressive effects of clonal expansion on normal haemopoiesis are more pronounced, and apparent sooner, in the more differentiated compartments. In addition, they support the view that the original population of normal stem cells does not disappear rapidly, although their numbers may be diluted to undetectable levels depending upon the extent of clonal expansion at the stem cell level by the time of diagnosis.

Adolescent↗

PubMed1994

Aplasia after donor lymphocyte infusion (DLI) for CML in relapse after sex-mismatched BMT: recovery of donor-type haemopoiesis predicted by non-isotopic in situ hybridization (ISH).

We report a patient with CML in relapse after a sex-mismatch bone marrow transplant who was treated with donor lymphocyte infusions and developed severe marrow aplasia 3 months later. As cytogenetic analysis at this point was not possible because of the very low number of marrow cells available, we used in situ hybridization (ISH) for sex chromosomes and the BCR/ABL gene together with quantitative PCR to monitor the patient's response. The results suggest that recovering haemopoiesis was derived from donor cells and contributed to the decision not to transfuse donor marrow cells on a second occasion.

Adult↗

PubMed2004

Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants.

The European Group for Blood and Marrow Transplantation (EBMT) devised a scoring system to predict survival after allogeneic haematopoietic stem cell transplantation (HSCT) for chronic myeloid leukaemia (CML). The present International Bone Marrow Transplant Registry study of 3211 patients tested the EBMT Risk Score in a independent population, investigated the value of adding other variables, evaluated a new risk score specifically for chronic phase and compared the allograft risk scores with risk scores established by Sokal in 1984 and Hasford in 1998 for survival with non-transplant treatments. The primary outcome was 5-year survival after HSCT; survival curves, regression models and measurements of explained variation were used to compare scores. Using the EBMT scoring system, survival in the independent dataset was almost identical to those in the original EBMT publication, thus validating the EBMT Risk Score. Adding one extra variable, performance status, or designing a score specifically for early chronic phase by using the original five variables with different breakpoints gave results only slightly better than the original EBMT Score. Sokal and Hasford Scores did not predict survival after HSCT. We concluded that the EBMT Risk Score does not currently require modification.

Adolescent↗

PubMed1991

Platelet apheresis for extreme thrombocytosis in an 11-year-old girl with CML.

This report describes the dramatic reduction in the platelet count and ablation of symptoms by consecutive platelet apheresis in a young girl with CML who presented with an extremely high platelet count of 10,320 x 10(9)/l. Extreme thrombocytosis, although quite rare, can be symptomatic and life-threatening in paediatric patients and should be considered an emergency. The mechanical removal of platelets by apheresis is effective therapy and should begin as soon as possible.

Child↗

PubMed1977

Experience on the treatment of chronic myelocytic leukaemia (CML) in blastic crisis.

A group of 50 patients with chronic myelocytic leukaemia in blastic crisis were treated with different chemotherapeutic regimens. A total of 19 remissions (6 CR + 13 PR) were achieved with an overall and complete response rate of 38% and 12% respectively. Of the 4 patients presenting with a lymphoblast-like appearance of the blasts, the 3 treated with the combination of vincristine and prednisone all achieved remission (2 CR + 1 PR). Duration of survival was significantly longer in responding patients (median 11.5 versus 4.5 months). Either more effective therapeutic regimens or prevention by aggressively approaching the chronic phase are to be sought in order to improve the prognosis of blastic crisis of CML.

Adolescent↗

PubMed1981

Phenotypic changes in a case of blast crisis of CML: characterization by TdT, cytochemistry, and cytogenetics.

Phenotypic changes in blast crisis of a case of Philadelphia chromosome (Ph1)-positive chronic myelogenous leukaemia were characterized by serial terminal transferase (TdT) determinations simultaneously related to cytochemical and cytogenetic data. At the onset of the blast crisis, 90% of the blast cells were acid phosphatase-positive (focal pattern), Ph1-positive, lymphoid cells. The TdT activity amounted to 29 units/10(8) mononuclear cells in the peripheral blood and to 57 units/10(8) mononuclear cells in the bone marrow. Therapy with vincristine and prednisone caused the elimination of the TdT-positive cell population. 4 months later, there was an increase in TdT-negative, myeloid blasts which was brought under control with busulfan. Cytogenetic analysis of the myeloid blasts still revealed Ph1 positivity in 100% of the metaphases examined and the lack of additional chromosomal abnormalities. A second relapse was again dominated by TdT-containing cells with the 46,XX,Ph1 karyotype. This time, the patient failed to achieve remission with vincristine and prednisone. Even though the TdT activity was markedly decreased, the lymphoid blast count remained elevated and the cells showed resistance to further therapy. This failure of morphology, cytochemistry as well as cytogenetics to distinguish between the individual phenotypes emerging during the course of blast crisis of CML characterized the TdT as a cell marker of important diagnostic and therapeutically prognostic value.

Adult↗

PubMed1991

Non-lymphoid blast crisis of CML with rearrangement of immunoglobulin and T-cell receptor delta genes.

We report a patient with chronic myeloid leukaemia (Philadelphia-positive with M-BCR rearrangement) in transformation whose blast cells had myelomonocytic morphology, absent terminal deoxynucleotidyl transferase expression and non-lymphoid cell surface markers (CD10-, CD19-, CD33+, CD14+, CD11+). Leukaemia cell DNA showed rearrangement of both immunoglobulin heavy chain and T-cell receptor delta genes. Such rearrangements may be a feature of a small proportion of patients with non-lymphoid transformation of CML as they are in a minority of cases of de novo acute non-lymphoblastic leukaemia.

Acute Disease↗

PubMed1994

Repeated PCR in CML during IFN-alpha therapy.

Repeated PCR analysis was performed on bone marrow and/or peripheral blood samples from 4 CML patients in complete cytogenetic remission during treatment with IFN-alpha. Two patients became PCR-negative. One was negative for the analyses carried out from the 9th to the 30th months, but reverted to PCR positivity 10 months after IFN was reduced from 1.5 x 10(6) IU/day to 1 x 10(6) IU and given on alternate days. Although the dose was again raised to 3 x 10(6) IU/day, 8 months later her peripheral blood cells were still PCR-positive, but remained persistently Ph'-negative. Another patient became PCR-negative at the 42nd month and remained so at the last analysis performed 3 months later. Two patients were persistently PCR-positive. Cytogenetic relapse was documented in both, in one while still on full therapy. Ph'-positive metaphases reappeared in the other patient 7 months after discontinuing IFN-alpha therapy.

Adult↗

PubMed1998

Impact of clinical and morphological variables in classification and regression tree-based survival (CART) analysis of CML with special emphasis on dynamic features.

To determine parameters of predictive value in CML, a retrospective clinico-pathological study was performed. This included laboratory data and (pretreatment) bone marrow biopsies of 120 patients with a monotherapy by busulfan (BU) and 50 patients with interferon-alpha 2b (IFN) treatment. Median survival in the BU group was 39 months and in the IFN-treated patients 65 months. Morphological features (CD61-positive megakaryocytes, argyrophilic fibres, pseudo-Gaucher cells) were evaluated by morphometry. Additionally, we measured the incidence of apoptosis (in situ end-labelling technique) and the expression of the proliferating cell nuclear antigen (PCNA). The ratio between the proliferative and apoptotic cell fraction was coined leukaemia turnover index (LTI). In order to estimate the impact of clinical and various morphological as well as dynamic features of prognostic significance, a multivariate analysis was carried out using the classification and regression tree approach (CART). Discrimination of single disease parameters revealed that fibrosis remained the most significant variable for survival in both therapeutic groups. Indicators of myeloid metaplasia such as occurrence of erythro-normoblasts and/or splenomegaly were important clinical parameters for prognosis. Inclusion of morphological as well as dynamic disease features in risk classification resulted in a substantial improvement of prognostic efficiency compared to other predictive scores which could be demonstrated by means of ROC-analysis.

Adult↗

PubMed1984

[Phase II study of the treatment of CML blast crisis with vindesine and prednisone].

16 patients with CML-BC were treated with vindesine/prednisone. Complete remissions were achieved in 3 cases which lasted 1 month (myeloid), 3 months (mixed) and 5 months (lymphoid). Minor responses, including less than 50% reduction of absolute blast counts and marked regression of organomegaly with a median duration of 3 weeks, occurred in 11 patients. Two patients did not respond to VDS. Leukopenia and thrombocytopenia were severe and prolonged, independent of their phenotype.

Adolescent↗

PubMed1987

[Prospective controlled study of therapy of chronic myeloid leukemia (CML)].

The current status of the prospective German multicenter study on the therapy of chronic myelogenous leukemia (CML) is reported. After three years 188 of the projected 300 patients have been randomized. The duration of the study will be 8 years. The clinical characteristics of the randomized patients correspond well to those reported in the literature. Risk factors are distributed equally in both arms. One problem is the relatively high drop-out rate of about 12% thus far. Survival curves for the two treatment arms will be presented, although at present the number of patients having reached the end of the chronic phase is too small to allow definitive evaluation.

Adult↗

PubMed2006

ABL kinase inhibitor therapy for CML: baseline assessments and response monitoring.

For chronic phase chronic myeloid leukemia (CML) patients treated with imatinib, the essential pre-therapy assessments include bone marrow morphology and cytogenetics as well as a baseline real-time quantitative PCR (RQ-PCR) for BCR-ABL. Baseline assessments of clinical relevance include Sokal and Hasford prognostic scores. Several other baseline assays are likely to be predictive of response, including IC50(imatinib), organic cation transporter-1 (OCT-1) mRNA level, and gene expression profiles, but further confirmation is required. RQ-PCR assays of blood at least every 3 months once patients have commenced imatinib is recommended. This will facilitate early identification of suboptimal responders who may benefit from higher doses of imatinib or alternative therapy, and identify at an early stage patients with acquired resistance. Management of the latter group can be further guided by the findings from cytogenetics and BCR-ABL kinase domain mutation screening. Bone marrow cytogenetics is indicated at least every 6 months until the patient achieves major molecular response. RQ-PCR is only clinically useful if it is conducted under a rigorous quality control regimen so that fluctuations in the BCR-ABL level can be confidently attributed to a biological cause rather than assay variation. To further improve the clinical value of RQ-PCR monitoring, expression of results on an international scale is needed. This will facilitate a more uniform and rational approach to management of suboptimal response and loss of response.

Disease Management↗

PubMed2002

High levels of BAX, low levels of MRP-1, and high platelets are independent predictors of response to imatinib in myeloid blast crisis of CML.

Imatinib induces remissions in approximately 30% of patients with chronic myeloid leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually relapse, allogeneic stem cell transplantation (SCT) in remission offers the best chance for cure. Remission induction with imatinib alone would seem ideal because it is less toxic than conventional chemotherapy. Conversely, patients unlikely to respond may benefit from combination therapy up front. To identify prognostic factors, we studied the mRNA expression of genes related to drug resistance and apoptosis in leukemic cells from patients with M-BC and their in vitro sensitivity to imatinib, and analyzed the results with other baseline factors for their impact on response. We show that high levels of BAX, low levels of MRP-1, and a high platelet count are independently predictive of response to imatinib. Combined into a score, these parameters may be clinically useful for risk-adapted patient stratification.

Adult↗

PubMed2003

Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.

Imatinib-treated chronic myeloid leukemia (CML) patients with acquired resistance commonly have detectable BCR-ABL kinase domain mutations. It is unclear whether patients who remain sensitive to imatinib also have a significant incidence of mutations. We evaluated 144 patients treated with imatinib for BCR-ABL kinase domain mutations by direct sequencing of 40 accelerated phase (AP), 64 late chronic phase (> or = 12 months from diagnosis, late-CP), and 40 early-CP patients. Mutations were detected in 27 patients at 17 different residues, 13 (33%) of 40 in AP, 14 (22%) of 64 in late-CP, and 0 of 40 in early-CP. Acquired resistance was evident in 24 (89%) of 27 patients with mutations. Twelve (92%) of 13 patients with mutations in the adenosine triphosphate (ATP) binding loop (P-loop) died (median survival of 4.5 months after the mutation was detected). In contrast, only 3 (21%) of 14 patients with mutations outside the P-loop died (median follow-up of 11 months). As the detection of mutations was strongly associated with imatinib resistance, we analyzed features that predicted for their detection. Patients who commenced imatinib more than 4 years from diagnosis had a significantly higher incidence of mutations (18 [41%] of 44) compared with those treated within 4 years (9 [9%] of 100), P <.0001. Lack of a major cytogenetic response (MCR) was also associated with a higher likelihood of detecting a mutation; 19 (38%) of 50 patients without a MCR had mutations compared with 8 (8.5%) of 94 with an MCR, P <.0001. In conclusion, the detection of kinase domain mutations using a direct sequencing technique was almost always associated with imatinib resistance, and patients with mutations in the P-loop had a particularly poor prognosis.

Adenosine Triphosphate↗

PubMed2003

Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate.

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P =.02), increased bands in the peripheral blood (P =.01), and clonal evolution (P <.0001). In a multivariate analysis, an elevated platelet count (P =.03) and clonal evolution (P <.0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P =.03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%).

Adult↗