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PubMed2006

The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib.

The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 - in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 - in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 - in four other patients the total level of transcripts remained high (n = 2) or fell (n = 2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.

Adult↗

PubMed2006

Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL.

Real-time quantitative polymerase chain reaction (PCR) for BCR-ABL mRNA in the peripheral blood (RQ-PCR) provides an accurate and reliable measure of response to therapy in chronic myeloid leukaemia (CML). We wanted to determine in what circumstances additional clinically relevant information was provided by simultaneous cytogenetic analysis in RQ-PCR monitored patients receiving imatinib treatment. We analysed 828 simultaneous RQ-PCR and bone marrow cytogenetic analyses from 183 patients with chronic phase CML with a median follow-up of 20 months. Cytogenetic progression was defined as Philadelphia (Ph)-positive clonal evolution, loss of complete cytogenetic response or an increase of > or = 20% Ph-positive cells. Cytogenetic progression occurred in 24/183 (13%) patients. At the time of cytogenetic progression, none of the 24 patients had a major molecular response (MMR; > or = 3-log reduction in BCR-ABL from standardised baseline). There were 320 RQ-PCR results from 95 patients indicating MMR. No abnormality was detected in any of the corresponding cytogenetic analyses. A policy of regular RQ-PCR monitoring with cytogenetic analysis targetted only to patients who have not achieved, or have lost MMR would represent a rational approach to monitoring and spare most patients the discomfort of multiple marrow aspirates. This approach depends upon availability of an accurate, reproducible RQ-PCR assay with ongoing quality assurance.

Adolescent↗

PubMed2006

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach.

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.

Adolescent↗

PubMed1997

PTHrP-mediated hypercalcaemia in a case of CML blast crisis.

We report a 52-year-old man with chronic myelogenous leukaemia (CML) who developed hypercalcaemia in blast crisis. There was a high serum level of parathyroid hormone-related protein (PTHrP). The leukaemia cells secreted PTHrP into culture medium when cultured in vitro and were shown to express PTHrP mRNA by reverse transcription-polymerase chain reaction. Transplantation of the leukaemia cells into nude mice resulted in the production of Ph1 chromosome-positive tumours which caused increased levels of calcium and PTHrP in the blood. These results indicated that the hypercalcaemic event in the patient was induced by PTHrP of CML cell origin.

Blast Crisis↗

PubMed1998

Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML.

Mobilization and transplantation of peripheral blood progenitor cells (PBPCs) was investigated in patients with stage IA or stage IIA chronic myelogenous leukaemia (CML) using combination chemotherapy with idarubicin, cytosine arabinoside and etoposide (ICE) followed by simultaneous administration of rhG-CSF and rhIL-2 or rhG-CSF alone. 17 patients (stage IA: 12; stage IIA: five) were mobilized. Chemotherapy, cytokine priming and collection of PBPCs were well tolerated. Using large-volume aphereses, a median number of 10.6 x 10(7)/kg b.w. of MNC were harvested, which yielded between 0.15 and 21.0 x 10(6) CD34+ cells/kg b.w. High numbers of CD34+ HLA-DR- cells could be obtained. Autologous transplantation of mostly Ph- apheresis products was performed in 16/17 patients after high-dose chemotherapy, 10 patients achieved a complete or major cytogenetic remission (stage IA: seven; stage IIA: three), but six patients did not respond cytogenetically. Median follow-up after transplantation was 18+ months. Our data show that this very efficient treatment modality for PBPC mobilization in CML was safe and able to induce major and sustained cytogenetic responses in the majority of patients.

Adult↗

PubMedDate not supplied

[Treatment of chronic myeloid leukemia in children and adolescents--concept of the multicenter pilot study CML-ped].

CML is a rare malignancy in childhood not yet being treated by an established protocol of the Society of Pediatric Oncology and Hematology (GPOH). Up to now only allogeneic bone marrow transplantation (BMT) offers a curative treatment option. After being enrolled into the study "CML-päd" patients with a matched sibling donor should undergo BMT within six months after diagnosis and within one year if an unrelated donor can be identified. Progress in palliative therapy results from the experience in adult patients: Hydroxyurea in combination with interferon alpha (IFN) is the treatment of choice. One aim of the study is to monitor quantitatively in bone marrow aspirates the activity of the disease in all patients on treatment every three months by performing cytogenetics and molecular analysis. As a pilot protocol intensification of treatment by idarubicine and cytarabine is scheduled one year after diagnosis for those patients not undergoing BMT and exhibiting after IFN treatment less than partial response. After progress to the accelerated phase of the disease a decision has to be made on an individual basis whether the patient should undergo new experimental treatment approaches.

Adolescent↗

PubMed2002

Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells.

The mitogen-activated protein (MAP) kinase family is activated in response to a wide variety of external stress signals such as UV irradiation, heat shock, and many chemotherapeutic drugs and leads to the induction of apoptosis. A novel series of pyrrolo-1,5-benzoxazepines have been shown to potently induce apoptosis in chronic myelogenous leukemia (CML) cells, which are resistant to many chemotherapeutic agents. In this study we have delineated part of the mechanism by which a representative compound known as PBOX-6 induces apoptosis. We have investigated whether PBOX-6 induces activation of MAP kinase signaling pathways in CML cells. Treatment of K562 cells with PBOX-6 resulted in the transient activation of two JNK isoforms, JNK1 and JNK2. In contrast, PBOX-6 did not activate the extracellular signal-regulated kinase (ERK) or p38. Apoptosis was found to occur independently of the small GTPases Ras, Rac, and Cdc42 but involved phosphorylation of the JNK substrates, c-Jun and ATF-2. Pretreatment of K562 cells with the JNK inhibitor, dicoumarol, abolished PBOX-6-induced phosphorylation of c-Jun and ATF-2 and inhibited the induced apoptosis, suggesting that JNK activation is an essential component of the apoptotic pathway induced by PBOX-6. Consistent with this finding, transfection of K562 cells with the JNK scaffold protein, JIP-1, inhibited JNK activity and apoptosis induced by PBOX-6. JIP-1 specifically scaffolds JNK, MKK7, and members of the mixed-lineage kinase (MLK) family, implicating these kinases upstream of JNK in the apoptotic pathway induced by PBOX-6 in K562 cells.

Activating Transcription Factor 2↗

PubMed2004

Subdural hematomas during CML therapy with imatinib mesylate.

Seven of one hundred twenty-one patients with chronic myeloid leukemia (CML) treated with imatinib mesylate developed subdural hematomas. All had advanced disease and were treated initially at a dose of 600 mg per day. Three patients had thrombocytopenia (platelet < 10 x 10(9)/l), one had leukocytosis (white blood cell count > 150 x 10(9)/l) and three had neither around the time of diagnosis of the subdural hematomas. Four patients required surgical evacuation. One patient, in blast crisis, died as a consequence of the subdural hematoma. Three patients survived but died of progressive CML. The remaining three patients having recommenced imatinib, are alive and well, and one has achieved a major cytogenetic response. Subdural hematomas must be considered even in mildly symptomatic patients receiving imatinib regardless of their peripheral blood counts. Patients who survive can be cautiously restarted on imatinib. Further studies are required to study the potential relationship between imatinib mesylate and subdural hematomas.

Aged↗

PubMed2005

E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to Imatinib.

Chronic myeloid leukemia (CML) is characterized in 90% of patients by the presence of the reciprocal translocation t(9;22)(q34;q11) leading to the fusion of the BCR and ABL genes. Most patients with Philadelphia chromosome positive CML express either the e13a2 (b2a2) or e14a2 (b3a2) MBCR-ABL mRNA. Some variant cases have been reported expressing the fusion e1a2 (mBCR-ABL) or e19a2 (microBCR-ABL). Very rare atypical transcripts such as e13a3, e14a3 or e6a2 have been described. We report here a sixth case of a Ph positive patient with an e6a2 BCR-ABL fusion transcript and describe for the first time a chimeric molecule alternatively spliced for exon 5 of the BCR gene.

Aged↗

PubMed2006

Intermittent dosage of imatinib mesylate in CML patients with a history of significant hematologic toxicity after standard dosing.

Hematologic toxicity is reported as one of the most important problems connected with imatinib mesylate (IM) treatment in patients with chronic myelogenous leukemia (CML). Withholding the drug or application of growth factors is recommended in this situation. This study introduced a novel approach using intermittent dosage of IM in order to avoid prolonged interruptions in therapy, to allow spontaneous recovery in blood count and, simultaneously, to achieve intermittently therapeutic plasma drug levels. A retrospective analysis of intermittent therapy (iT) in 12 patients with CML is presented. All patients had intermediate-to-high prognostic scores. Two patients had history of autologous stem cell transplantation. Initial standard therapy with IM was indicated for resistance to interferon (eight subjects) and for accelerated phase in four cases (one of them cytogenetic) and lasted for 1 - 6 months. iT with 300 - 600 mg of IM 1 - 5 times a week was started after significant hematologic toxicity occurred. In three patients treated 3 - 5 times a week, hematologic recovery allowed reintroduction of full dose after 3 - 7 (mean 4.6) months. In three patients, one-to-three doses per week were sufficient to maintain the cytogenetic response for a mean of 30.6 months (range 29 - 33). Six patients tolerated more frequent dosage of 4 - 5 times a week for a mean of 17.8 months (range 3 - 28). Five patients improved their cytogenetic response during iT, while hematologic progression occurred in one patient. Development of a cytogenetic abnormality in a Ph-negative clone was observed in one patient. Overall, two complete and five major cytogenetic responses were achieved. The sensitivity of Bcr/Abl kinase to inhibition by IM was proved in seven patients tested by Crkl phosphorylation assay. Measurement of plasma IM concentrations in three subjects showed concentrations fully compatible with the dosage applied suggesting normal intestinal absorption. iT with IM is a feasible and safe strategy for short-time 'bridging' management of patients with significant hematologic toxicity after standard daily dosing. Long-term iT with IM does not seem to compromise the cytogenetic response in patients with sensitivity of Bcr/Abl kinase to IM and should be considered as a plausible treatment option in patients with persistent signs of myelotoxicity.

Adenosine Triphosphate↗

PubMed2004

Interaction between normal and CML hematopoietic progenitors and stroma influences abnormal hematopoietic development.

Several studies have shown defective progenitor-stromal interactions in chronic myeloid leukemia (CML), and adhesive defects induced by BCR/ABL have been described. However, controversial results have been reported, and the role of the stroma in abnormal development of the hematopoietic system is not clear. In this study, CML hematopoietic and irradiated stromal cells were co-cultured in different combinations for 10 or 21 days. Maintenance of viable cells was dependent both on the sources of hematopoietic progenitors and stromal adherent layers, with normal cells performing better than their leukemic counterparts. The frequency of CD34(+) CD38(-) cells in the non-adherent fraction was more related to the source of hematopoietic cells than of stroma, and hematopoietic cells from normal subjects showed better performance. The simultaneous analysis of different combinations of normal and leukemic precursor cells and stromal layers, as done in the present work, suggests that the outcome of the interaction depends on characteristics of both compartments. This hematopoietic system development is influenced by intrinsic qualities of both hematopoietic stem cells and the supportive stroma.

ADP-ribosyl Cyclase 1↗

PubMed1993

Relative sensitivity of leukemic (CML) and normal progenitor cells to treatment with the photosensitizer benzoporphyrin derivative and light.

Normal bone marrow and peripheral blood committed progenitor cells were found to be significantly more resistant to treatment with the photosensitizer benzoporphyrin derivative (BPD) and white fluorescent light (11 J/cm2) than were clonogenic cells from two cell lines (K562 and EM2) derived from nonremission patients with myelogenous leukemias. Bone marrow and peripheral blood committed progenitor cells from normal donors were also found to be more resistant to this treatment than were equivalent cells from patients with chronic myelogenous leukemia (CML). Normal bone marrow mononuclear cells grown in long-term marrow culture (LTMC) following treatment with BPD and light showed that no differences in stem cell productivity existed between control and treated samples. When bone marrow from CML patients was treated in the same manner, the numbers of progenitors detected in the nonadherent population during culture were greatly reduced compared to control material. Two rounds of PCR using nested primers to detect BCR-ABL mRNA showed that while this treatment significantly decreased the numbers of stem cells bearing the Philadelphia chromosome, it did not eliminate them.

Blood Cells↗

PubMed2000

Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients.

Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr-Abl-CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr-Abl-positive patients. Activation-specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr-Abl-CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down-regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.

Adaptor Proteins, Signal Transducing↗

PubMed1991

Activation of class I HLA expression by TNF-alpha and gamma-interferon is mediated through protein kinase C-dependent pathway in CML cell lines.

The combination of tumour necrosis factor alpha (TNF alpha) and gamma-interferon induced transcription of class I HLA genes in chronic myelogenous leukaemia (CML) cell lines through the formation of a complex between nuclear proteins and the transcriptional enhancers associated with these genes. Although gamma-interferon or TNF-alpha stimulated expression of class I HLA antigens in the EM2 and K562 CML cell lines when used alone, the effect of the combination of TNF-alpha and gamma-interferon was greater than that observed with either agent alone. The induction of class I HLA expression by gamma-interferon and TNF-alpha was inhibited completely by the isoquinoline sulfonamide H7, an inhibitor of protein kinase C. We conclude that the enhancement of the gamma-interferon induced transcriptional activation of class I HLA gene expression by TNF-alpha involves a protein kinase C-dependent pathway.

Base Sequence↗

PubMed1991

Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non-cirrhotic portal hypertension. Results from MRC CML. II. Trial comparing busulphan with busulphan and thioguanine.

Portal hypertension with varices developed in 18/675 patients with chronic myeloid leukaemia (CML) in a randomized trial comparing busulphan with busulphan and thioguanine. All 18 had received the drug combination and none busulphan alone (P less than 0.0001). Ascites was also seen significantly more often in the combination arm (P less than 0.05). These results strongly suggest that the addition of thioguanine was responsible for the development of portal hypertension. The histological features were predominantly those of non-cirrhotic portal hypertension--either idiopathic portal hypertension with minimal morphological abnormalities, nodular regenerative hyperplasia or in two cases leukaemic infiltration only was noted. Cirrhosis was present in 3/16 cases studied. Both treatment groups developed abnormal liver function tests during the chronic phase, but particularly with progression of the disease. During chronic phase abnormalities were significantly more frequent in those receiving busulphan and thioguanine-alkaline phosphatase (P less than 0.02), transaminases (P less than 0.04), bilirubin (P less than 0.05), multiple abnormalities (P less than 0.01). The development of portal hypertension was often associated with abnormalities of these tests; however, lack of specificity precludes their use as a predictor of subsequent clinical problems. Thioguanine confers no survival advantage in this disease. In view of its hepatotoxicity it should not be used routinely for maintenance of control in chronic phase CML.

Alkaline Phosphatase↗

PubMed1994

Autografting for patients with CML in chronic phase: an update. Hammersmith BMT Team LRF Centre for Adult Leukaemia.

Between 1984 and 1992, 21 patients with chronic myeloid leukaemia (CML) in chronic phase (CP) were treated with high-dose chemotherapy (or chemoradiotherapy) followed by autografting with unmanipulated peripheral blood stem cells (PBSC). 12 of these patients survive at a median of 82 months from the time of autografting (range 9-105 months). Nine patients died, six of leukaemia in transformation and three from other causes. Survival of these 21 autograft patients was compared to that of 636 age-matched controls on the Medical Research Council's (MRC) data base, who had been treated with conventional chemotherapy over the same period. Autografted patients had a significantly longer survival at 5 years post autograft than chemotherapy patients (56% v 28%) even after appropriate allowance for time at risk before autograft (Mantel-Byar, 2P = 0.003). There was no difference in survival whether autografting was performed early in the disease or later or whether the PBSC had been harvested soon after diagnosis or later. If the benefits of autografting in chronic phase seen in this non-randomized series can be confirmed in a randomized study, autografting might be the treatment of choice for younger CML patients who do not have suitable donors for allogeneic transplant.

Adult↗

PubMed1995

Variable numbers of BCR-ABL transcripts persist in CML patients who achieve complete cytogenetic remission with interferon-alpha.

A substantial minority of patients with chronic myeloid leukaemia (CML) achieve a complete response to treatment with interferon-alpha (IFN-alpha), defined as the disappearance of Philadelphia chromosome positive metaphases or, for patients who are Philadelphia chromosome negative but BCR-ABL positive, the disappearance of the leukaemic clone as assayed by Southern blot. We have measured the levels of BCR-ABL transcripts in 20 such patients by quantitative PCR. Results were standardized for both quality and quantity of cDNA by quantification of ABL as an internal control. All 20 patients had evidence of residual disease; the median number of transcripts was 750/micrograms RNA (range 10-22,000) and the median BCR-ABL/ABL ratio was 0.17% (range 0.0008-3.6%). Our findings show that CML has not been eradicated in any patient and that the quantity of residual disease in complete responders may vary by as much as four orders of magnitude.

Adult↗

PubMed2005

CML clonal evolution with resistance to single agent imatinib therapy.

We describe a 58-year-old male diagnosed with chronic myeloid leukaemia (CML) who failed to have a cytogenetic response to interferon-alpha and hydroxyurea. On subsequent therapy with imatinib mesylate he failed to have any cytogenetic response but also developed a complex clonal evolution with an additional Philadelphia (Ph) chromosome and trisomy 8 respectively in two Ph-positive subclones. The addition of cytosine arabinoside to imatinib resulted in reversion to single Ph-chromosome positivity with the disappearance of the previous additional clonal abnormalities. The case demonstrates the efficacy of combined treatment with imatinib and cytarabine in the management of CML resistant to single agent imatinib.

Antineoplastic Combined Chemotherapy Protocols↗