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PubMed2004

Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations.

Mutations within the BCR-ABL kinase domain in imatinib-treated chronic myeloid leukemia (CML) are the main mechanism of acquired resistance. The early detection of mutations should provide clinical benefit by allowing early intervention. Quantitative polymerase chain reaction (RQ-PCR) results of BCR-ABL mRNA were correlated with mutation analysis in 214 patients treated with imatinib. We determined whether there was a difference in the incidence of mutations between the patients with a more than 2-fold rise in BCR-ABL and patients with stable or decreasing levels. Of the 56 patients with a more than 2-fold rise, 34 (61%) had detectable mutations (median rise, 3.0-fold; 25th-75th percentiles, 2.3-5.2). In 31 (91%) of these 34 patients, the mutation was present at the time of the rise and became detectable within 3 months in the remaining patients. Only 1 (0.6%) of 158 patients with stable or decreasing BCR-ABL levels had a detectable mutation, P less than .0001. Thus, a more than 2-fold rise identified 34 (97%) of 35 patients with a mutation. We conclude that a rise in BCR-ABL of more than 2-fold can be used as a primary indicator to test patients for BCR-ABL kinase domain mutations.

Benzamides↗
PubMed2006

BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML.

Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a complete cytogenetic response (CCR), some patients will relapse. To determine the potential of real-time quantitative BCR-ABL reverse transcriptase-polymerase chain reaction (RT-PCR) to predict the duration of continued CCR, we monitored 85 patients treated with imatinib mesylate who achieved a CCR. With a median follow-up of 13 months after CCR (29 months after imatinib mesylate; median 6 RQ-PCR assays), 23 patients (27%) had disease progression (predominantly loss of CCR). Compared with the median baseline level of BCR-ABL mRNA, 42% of patients achieved at least a 2-log molecular response at the time of first reaching CCR. Failure to achieve a 2-log response at the time of CCR was an independent predictive marker of subsequent progression-free survival (hazard ratio = 5.8; 95% CI, 1.7-20; P = .005). After CCR, BCR-ABL mRNA levels progressively declined for at least the next 15 months, and 42 patients (49%) ultimately achieved at least a 3-log reduction in BCR-ABL mRNA. Patients failing to achieve this 3-log response, at any time during therapy, had significantly shorter progression-free survival (hazard ratio = 8.1; 95% CI, 3.1-22; P < .001). The achievement of either a 2-log molecular response at the time of CCR or a 3-log response anytime thereafter is a significant and independent prognostic marker of subsequent progression-free survival.

Adult↗
PubMed2006

Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy.

One of the challenges of cancer therapeutics is to discover targets unique to the tumor cell population. Constitutively activated tyrosine kinases play a role in the malignant phenotype in a number of different cancers. While the kinases may be present in the normal cell, the cancer cell is often dependent upon the activation of the kinase for the maintenance of malignant growth. Inhibition of kinase activation may therefore selectively inhibit malignant proliferation. In the case of chronic myelogenous leukemia (CML), the activated tyrosine kinase (BCR-ABL) is due to a chromosomal translocation that defines this disease, and is necessary for malignant transformation. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor, developed through the chemical modification to be selected for a small number of tyrosine kinases present in human cells. This agent is also orally bioavailable and has been found to be effective in clinical trials. We have learned much through the clinical use of this agent. 1) Specific targeting of activated signal transduction pathways may be effective in inhibiting cancer cells. 2) Cancer cells may not only be inherently resistant to small molecule inhibitors, but may also develop resistance after exposure to the inhibitor. 3) Increased knowledge regarding critical signal transduction pathways, the structure of the molecules that are being targeted and the inhibitors themselves, will allow us to understand resistance as it develops and create new molecules to bypass resistance. We will discuss imatinib as an important example of the success and pitfalls of targeted therapeutics for cancer.

Benzamides↗
PubMed1993

A multicentric randomised study of alpha 2b interferon (IFN) and hydroxyurea (HU) with or without cytosine-arabinoside (Ara-c) in previously untreated patients with Ph+ chronic myelocytic leukemia (CML): preliminary cytogenetic results.

The CML 88 study was designed to evaluate the efficacy of maintenance therapy in a multicentric randomised protocol using IFN combined with low-dose Ara-C versus IFN alone, following an induction with IFN + HU. Between April 1988 and February 1991, 237 patients from 36 French Hematology Centres were entered in the study. Preliminary cytogenetic results show a slightly higher, although not statistically significant, proportion of major chromosomal responses, including complete cytogenetic remissions, in the IFN + Ara C arm.

Adolescent↗
PubMed1993

Peripheral blood stem cell autografts in CML.

The treatment of patients with CML in chronic phase by high dose chemotherapy followed by transfusion of autologous haemopoietic stem cells collected and cryopreserved previously may theoretically prolong survival. This benefit could result from reducing the number of leukaemia stem cells at risk for transformation or by partial re-establishment of Ph-negative haematopoiesis. In practice some patients achieve partial Ph-negative haematopoiesis after autografting but most patients have entirely Ph-positive haematopoiesis by one year after autografting. Results may be improved if methods to favour reconstitution with Ph-negative haematopoiesis can be perfected.

Antigens, CD↗
PubMed1994

A Ph+ acute myeloid leukaemia expressing both CML-type and ALL-type BCR/ABL mRNA transcripts.

This report describes a patient presenting with acute myeloid leukaemia (AML-FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for monocyte/macrophage, megakaryocyte, and T-cell lineages. The occasional blast was positive for CALLA. All blasts carried the Philadelphia chromosome (Ph+), with 20% also harbouring a monosomy 7 (a cytogenetic marker for AML). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed the presence of two BCR/Abl mRNA transcripts; b2a2, the CML-type and E1a2, the ALL-type. Immunoglobulin (Ig) gene analysis demonstrated the presence of a small population of cells containing rearranged Ig genes. After a short remission, the patient relapsed. At relapse the leukaemia had undergone a major phenotypic switch from AML to ALL, with blasts bearing B-cell markers. Ig gene analysis confirmed a monoclonal population of B-cells. The Ph+ persisted, but the monosomy 7 had disappeared. The same two BCR/Abl mRNA transcripts were found at relapse as at presentation. To our knowledge, this is the first report of an AML simultaneously expressing BCR/Abl transcripts from both the minor and major BCR. The possible mechanisms of this dual expression are discussed.

Base Sequence↗
PubMed1999

Stage, percentage of basophils at diagnosis, hematologic response within six months, cytogenetic response in the first year: the main prognostic variables affecting outcome in patients with chronic myeloid leukemia in chronic phase treated with interferon-alpha. Results of the CML89 trial of the Spanish Collaborative Group on interferon-alpha2a and CML.

BACKGROUND AND OBJECTIVE: Interferon-a (IFN) is increasingly being used as the drug of choice in chronic myeloid leukemia patients. The main objectives of the study were to study the influence of the classic prognostic variables and response to IFN, and to assess the influence of this response on the course of the disease and survival. DESIGN AND METHODS: Single arm, prospective, multicenter study, without a control group. Only Ph1-positive CML patients were included. The treatment scheme was biphasic: the patients first received standard chemotherapy and thereafter IFN-a2a was used as monotherapy, with a target dose of 9 MU/d/s.c. RESULTS: Twenty-one centers in Spain enrolled 132 patients (72 men, 60 women). The median dose of IFN given was 5.8 MU/d, and the median treatment duration was 431 days (range: 18-2,597). Seventy-two percent of patients obtained a hematologic response in the first six months of IFN treatment. Genetic response was obtained in 47% of the patients, and the response was major or complete in 27% and 19%, respectively. The median time to obtain this response was 7, 9, and 18 months for minimal, partial and complete genetic response, respectively. Multivariant analysis showed that only a higher percentage of basophils at diagnosis was associated with a worse hematologic response at six months (p=0.001) (OR: 1.23) and with a worse cytogenetic response in the first year of IFN therapy (p=0.018) (OR: 1.4). Over an observation period of 8 years, 35.6% of the patients died, and 85 (64.4%) remained alive. With a median follow-up of 42 months (3.7-98), the 6-year projected probabilities of survival and transformation-free survival were 0.61+/-0.07 vs. 0.54+/-0.07, respectively. Patients with Kantarjian's stage 3 disease or in a high-risk Sokal group had lower probabilities of survival, but these systems did not adequately discriminate in our series. Obtaining a complete hematologic response in the first six months of IFN therapy was favorable in terms of overall survival (p=0.05; HR=0.33). Cox's analysis demonstrated that obtaining a cytogenetic response in the first year was independently associated with better overall survival (p=0.04; HR=0.19) and better transformation-free survival (p=0.0035; HR=0.11). INTERPRETATION AND CONCLUSIONS: Nearly half of the patients obtained some degree of Philadelphia suppression, which was major in 27%, and complete in 19%. A higher percentage of basophils at diagnosis was the only variable associated with a lower probability of cytogenetic response. Obtaining a cytogenetic response during the first year of IFN treatment was a favorable and independent variable in terms of survival and transformation-free survival. Obtaining a major cytogenetic response during this period decreased the risk of transformation twenty times. Our results suggest that the effect of IFN on survival is independent of the classic prognostic variables.

Adolescent↗
PubMed1976

Regulation of bone marrow cell growth in diffusion chambers: the effect of adding normal and leukemic (CML) polymorphonuclear granulocytes.

Inhibition of granulopoiesis was studied using the diffusion chamber (DC) technique. When mature granulocytes from human blood or syngeneic mouse peritoneal fluid were added to mouse bone marrow cells cultured in DC, a significant depression of granulopoiesis took place, and a stimulation of macrophage formation was observed in 7-day cultures. Human granulocytes had a stronger inhinitory capacity than mouse granulocytes. The inhibition appeared to be tissue-specific and caused by a diffusible factor. A time study showed that the added granulocytes had no observable effect on the growth of proliferative granulocytes and CFU-C during the first days of culture. A rapid decrease of proliferative granulocytes after day 5 was preceded by a similar reduction of CFU-C 1 day earlier. The effect of CFU-S was more variable. In one strain of mice, there was a consistent increase in the granulocyte co-culture group, whereas in another strain a significant increase was observed only on day 2. Hislotologic examination showed that mature granulocytes changed the colony distribution, so that a significant relative decrease of granuloid colonies occurred. The nature of this delayed suppression of granulopoiesis is not evident from these data. A possible explanation is that factors released by mature granulocytes prevent recruitment of CFU-C and granulocyte precursors from the CFU-S compartment by blocking the granulopoietic pathway. Leukemic (CML) granulocytes isolated from blood were less able to inhibit granulopoiesis than normal granulocytes with mouse bone marrow as well as human bone marrow as target cells.

Animals↗
PubMed2001

Detection of trisomy 8 in philadelphia chromosome-positive CML patients using conventional cytogenetic and interphase fluorescence in situ hybridization techniques and its relation to c-myc involvement.

Trisomy 8 (+8) is a common clonal evolution marker for progression in chronic myelogenous leukemia. The relationship of +8 to various stages of t(9;22) leukemias is not firmly established. To explore this association we examined bone marrow (BM) cells from 10 Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients in different stages of the disease, using conventional cytogenetic technique(CCT) and interphase fluorescence in situ hybridization (FISH). FISH detection of chromosome 8 was accomplished using the D8Z2 (Oncor) probe specific for the centrometric region of chromosome 8. Five hundred interphase nuclei were counted for each patient. Three of the 10 patients were selected for detection of c-myc gene locus located in the 8q24.2-24.3 region using the L

Adult↗
PubMed2002

A complex translocation event between the two homologues of chromosomes 5 leading to a del(5)(q21q33) as a sole aberration in a case clinically diagnosed as CML: characterization of the aberration by multicolor banding.

We report on a patient with a clinically diagnosed Philadelphia negative chronic myelogenous leukemia (CML) with a so far unrecorded complex translocation event between the two homologue chromosomes 5. At the GTG-band level the karyotype was normal, apart from an enlarged chromosome 5 and an extremely shortened second chromosome 5. Both derivative chromosomes 5 consisted exclusively of #5 derived material as proven by 24-color FISH. To characterize the complex aberration in more detail the multicolor banding (MCB) technique using a chromosome 5 specific probe set was applied. Using this DNA-based high resolution banding procedure, the karyotype could be described as 46,XX,del(5)(pterright curved arrow q12::q33right curved arrow qter),ins(5)(pterright curved arrow q15::q12right curved arrow q21::q21right curved arrow qter). In consequence, the aberration leads to a partial deletion of the long arm of chromosome 5: del(5)(q21q33), which would not have been identified using conventional banding techniques or 24-color FISH.

Aged↗
PubMed2002

[External quality assessment of the genetic testings for hematopoietic tumor, CML].

Genetic testings are commonly employed in various fields of clinical medicine and the test items performed at clinical laboratories are increasing rapidly in number. They are utilized to make early and/or definite diagnoses of infectious diseases, leukemia, cancers and molecular inherited diseases and also to monitor the progress of the diseases. However, these genetic testings except for infectious diseases have been developed independently at each clinical laboratory and the test results obtained at each laboratory are not always compatible each other. Under these situations it is widely expected to construct advanced genetic testing systems that can supply standardized data at any of domestic and international clinical laboratories. For the period from April, 1999 to March, 2002 three major clinical laboratories, SRL, Inc., BML, Inc. and MBC, Inc., were consigned by JBA (Japan Bioindustry Association) to collaborate in standardizing the evaluation methods for genetic testing systems among the clinical laboratories. The aim of the study is to develop the standardized genetic testing systems and to propose them as international standard operational procedures to the ISO/TC212 working group. Although one of the most important issues for standardization is the external quality assessment, they have not been carried out in reality. In this study we evaluated the difference of the genetic testing results obtained during the year of 2000 and 2001 among the clinical laboratories. The genetic testings for hematopoietic tumor, CML were selected to be evaluated since they are widely accepted as clinically useful tests.

Blotting, Southern↗
PubMed1992

Fractionated TBI and methotrexate-cyclosporin do not seem to increase relapses in BMT for first chronic phase CML patients: results of a single centre study.

Fractionated total body irradiation (FTBI) and methotrexate-cyclosporin A(MTX-CSA) have been found useful in reducing interstitial pneumonia (IP) and acute graft-versus-host-disease (GVHD) in bone marrow transplantation patients, but an increase in relapse rate has been observed by some authors when these strategies are used. To evaluate this relapse risk, we performed a retrospective analysis in 24 consecutive first chronic phase chronic myeloid leukemia patients who received an HLA-identical non-T cell-depleted graft in a single institution. All were conditioned with cyclophosphamide plus FTBI (12 Gy in six fractions delivered twice daily for 3 days) (CY-FTBI) and received MTX-CSA as GVHD prophylaxis. Serial hematologic and cytogenetic bone marrow analysis were performed at least three times (days +30, +100, +360) and at variable intervals thereafter in long-term survivors. Actuarial probabilities of developing IP and acute GVHD greater than or equal to II were respectively 5.9% and 44.2%, with a GVHD-associated mortality of 33%. Four-year actuarial relapse and disease-free survival rates were 7.7% and 48.2% respectively. No exclusively cytogenetic relapses were observed. Our results suggest that CY-FTBI and MTX-CSA are not associated with an increase in relapse rate in 1CP-CML patients.

Adolescent↗
PubMed2001

Molecular follow up of donor lymphocyte infusion in CML children after allogeneic bone marrow transplantation.

In this study we present the applicability of fluorescence in situ hybridisation (FISH) and RT-PCR to detect the minimal residual disease (MRD) in relapsed Ph+ children after donor lymphocyte infusion (DLI) post bone marrow transplantation (BMT). In both patients BCR/ABL fusion was detected and its transcript at the moment of relapse. After the DLI treatment in short time intervals a decreasing number of cells with BCR/ABL fusion were noticed and the expression of the hybrid gene disappeared. These results demonstrate that all the methods presented in this study provide a feasible, rapid and accurate way for the detecting of the minimal residual disease after DLI in Ph positive CML patients.

Journal Article↗
PubMed2004

[Second hematologic response and disappearance of the ABL gene mutant clone by cessation of imatinib in a CML patient with resistance to imatinib].

A seventy-six year old female patient with chronic myelogenous leukemia (CML), (chronic phase), was treated with imatinib and obtained a major cytogenetic response after 6 months of treatment. However, resistance to imatinib appeared 9 months later due to an ABL gene point mutation, and the patient's platelet count and BCR/ABL positive rate had remarkably increased. We discontinued imatinib and used IFNalpha or hydroxyurea, resulting in the disappearance of the ABL gene mutation clone. After that, we obtained a secondary hematologic response with the administration of imatinib.

Aged↗
PubMed1992

[CML with autoimmune thrombocytopenia observed in the course of IgG (kappa) type monoclonal gammopathy].

An 80-year-old male with IgG (kappa) type benign monoclonal gammopathy was admitted to our hospital because of marked leukocytosis. At the time of admission, thrombocytopenia was also noted. A bone marrow aspirate showed marked granulocytosis with a normal megakaryocyte count. PAIgG was elevated and the NAP score was low. Ph1 chromosome and rearrangement of the breakpoint cluster region were detected. On the basis of these findings, he was diagnosed as having CML with autoimmune thrombocytopenia. This case was of interest with respect to blood cell differentiation and immunological findings.

Aged↗
PubMed1991

A complicated translocation involving five chromosomes (Nos. 9, 11, 12, 21 and 22) in a patient with chronic myelocytic leukemia (CML).

A new complicated Ph1 translocation involving five chromosomes, t(9;22;21;11;inv ins(12)-(q15p12p13))(q34;q11;q22;q13;q15), was found in a 64-year-old Korean woman with chronic myelocytic leukemia (CML). At presentation, the patient was found to be in the accelerated phase, she entered the chronic phase after six cycles of chemotherapy including a vincristine (VCR) and prednisolone (PSL) regimen (VP). The chronic phase continued for 2 years, and 33 months after her first admission she died due to severe pneumonia and congestive heart failure in the re-accelerated phase. In the literature, the frequency of the involvement of chromosome No. 11 in three-way Ph1 translocations (4.9%) is lower than that in four- and five-way Ph1 translocations (33.3%). It may be worth noting that chromosome No. 11 is easily involved in highly complicated Ph1 translocations.

Chromosomes, Human, Pair 11↗
PubMed1990

Interferon therapy for Ph1 positive CML patients relapsing after T cell-depleted allogeneic bone marrow transplantation.

Eighteen chronic myeloid leukemia patients with hematological (four patients) or only cytogenetic (14 patients) relapse occurring after T cell-depleted allogeneic bone marrow transplantation (BMT) have been treated with alpha 2b interferon (IFN) at a starting dose of 5 x 10(6) i.u./m2 subcutaneously three times a week. All four patients with hematological relapse achieved long-lasting hematological remission without reduction of bone marrow Ph1 positive cells. When IFN was started the median percentage of bone marrow Ph1-positive metaphases was 50% (range 9-100) for the 14 patients with cytogenetic relapse. Twelve (85.7%) of these patients are alive with a median follow-up of 25 months (range 20-37 months) from cytogenetic relapse and 33 months (range 27-49 months) from BMT. Six (43%) of the 14 patients progressed to hematological relapse and eight patients (57%) are still in hematological remission with two patients achieving complete cytogenetic remission confirmed at molecular level by disappearance of the M-BCR rearranged band. IFN therapy may be a good alternative to conventional chemotherapy for transplanted CML patients with hematological relapse and the treatment of choice for patients with a persistent cytogenetic relapse occurring after T cell-depleted BMT.

Adolescent↗