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PubMed2005

Quantitative RT-PCR of Wilms tumor gene transcripts (WT1) for the molecular monitoring of patients with accelerated phase bcr/abl + CML.

The tyrosine kinase inhibitor imatinib inhibits the activity of the bcr/abl fusion protein present in patients with chronic myeloid leukemia. Although in chronic phase patients response to therapy can be monitored by quantitative RT-PCR for bcr/abl mRNA transcripts, in advanced disease (accelerated phase or blast crisis) only few patients respond on a molecular level. We investigated Wilms tumor gene (WT1) and bcr/abl mRNA transcripts in 16 accelerated phase CML patients by quantitative real time PCR. In contrast to the bcr/abl mRNA levels the WT1 mRNA levels were indicative for hematologic relapse (n = 6) versus response (n = 10).

Antineoplastic Agents↗

PubMed1998

Further characterization of cyclophosphamide resistance: expression of CD95 and of bcl-2 in a CML cell line.

Drug resistance is a common cause of treatment failure in oncology. In addition to the resistance caused by over-expression of p-glycoprotein and similar molecules other mechanisms are involved in the selection or induction of drug resistant tumor cells. In this study, we characterized a CML cell line made resistant to cyclophosphamide (KBM7-B5-1803) further for the expression of apoptosis promoting and inhibiting molecules. We found that KBM7-B5-1803 has a 3 4-fold over-expression of the receptor CD95 (Fas/Apo-1) compared with the parent line. The regulation of CD95 by cytokines was comparable to other types of cells. Despite the inducibility and over-expression of CD95, CD95 failed to trigger apoptosis in both the parent and the drug resistant line. The drug resistant line has a particular pattern of the expression of bcl-2 family members: bcl-2 protein and message were expressed to a similar extent, however, compared with the parent line, the message for bclx short was decreased. P-glycoprotein was not expressed in either cell line. Taken together we show here in a leukemia cell line that the phenotype of cyclophosphamide resistance is associated with a particular pattern of apoptosis-related molecules.

Apoptosis↗

PubMed1997

p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis.

A longitudinal investigation using fluorescence in situ hybridization (FISH) analysis, PCR-SSCP, and in situ detection of apoptosis by the terminal deoxynucleotidyl Transferase (TdT) method was carried out on 13 chronic myelogenous leukemia (CML) patients to study the p53 gene behavior and the apoptotic process during the course of the disease. At diagnosis, FISH showed no loss of the p53 gene on interphase nuclei, and no point mutation was detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. During the disease course, FISH analysis showed a significative loss of allele (LOA) rate for the p53 gene in eight patients that in seven cases was associated with a suppression of apoptotic process and the progressive expansion of the p53+/p53- clone. DNA sequencing showed in two of these eight patients a point mutation on the other allele, consisting in the formation of a stop codon in one case, and in a frameshift mutation in the other. Six patients had a myeloid blastic crisis (BC), five a lymphoid BC, and the other two an erythroid and an undifferentiated BC, respectively. All patients with myeloid BC and the one with undifferentiated BC disclosed a progressive expansion of the clone with p53 loss that was associated with a significant reduction in apoptosis. On the contrary in the 5 patients with lymphoid BC no significant p53 LOA rate was observed during the course of the disease. In these patients apoptotic process also persisted in the acute phase although in a lower rate as compared to CP.

Adolescent↗

PubMed1997

LDL-dependent regulation of Bcl-2 and cyclin 'D' gene expression in lymphocytes from normal and CML patients.

Effect of low-density lipoprotein (LDL) on the expression of Bcl-2 as well as cyclin 'D' genes was studied in Receptor 'Ck' (+ve) and Receptor 'Ck'(-ve) human lymphocytes. LDL had no effect upon the elevated levels of Bcl-2 and cyclin 'D' gene products in Receptor 'Ck' (-ve) lymphocytes (from untreated CML patients), whereas in Receptor 'Ck' (+ve) lymphocytes (from normal subjects), the exposure to LDL regulated the level of cyclin 'D' gene product without initiating the expression of bcl-2 gene product. However, blockage of Receptor 'Ck' in normal lymphocytes, through its specific antibody (Ab-RCk) in presence or absence of LDL, resulted in the induction of both cyclin 'D' (at 4 h interval) and bcl-2 (at 12 h interval) gene products. Based upon these results, we propose that Receptor 'Ck' deficiency in cells may inherit defective apoptosis and capacity proliferation leading to leukemic transformation.

Cyclin D↗

PubMed1997

TEL/AML1 fusion gene resulting from a cryptic t(12;21) is uncommon in adult patients with B-cell lineage ALL and CML lymphoblastic transformation.

TEL is a new member of the ETS-like family on chromosome 12 and forms fusion genes with several partners in leukemia. Among these fusion genes, the TEL/AML1 translocation resulting from t(12;21) is found in approximately one quarter of the childhood B-cell lineage acute lymphoblastic leukemia (ALL) cases and its prognosis is excellent. We examined 42 adult patients with B-cell lineage ALL and 13 adult patients with lymphoblastic transformation of chronic myeloid leukemia (CML) to detect TEL/AML1 fusion genes using the reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting, but no translocation was detected. These findings indicate that absence of the TEL/AML1 fusion transcript partly correlates with the poorer outcome of adult B-cell lineage ALL as compared with childhood ALL and the TEL/AML1 fusion transcript is specific for pediatric B-cell lineage ALL.

Adolescent↗

PubMed2002

Comprehensive comparison of FISH, RT-PCR, and RQ-PCR for monitoring the BCR-ABL gene after hematopoietic stem cell transplantation in CML.

The reverse transcriptase-polymerase chain reaction (RT-PCR) was compared with fluorescence in situ hybridization (FISH) and real-time quantitative RT-PCR (RQ-PCR) for minimal residual disease (MRD) monitoring in 266 post-transplant bone marrow samples from 78 patients with chronic myelogenous leukemia (CML). The sensitivities of FISH to BCR-ABL positive samples determined by first-round (1st) RT-PCR, second-round (2nd) RT-PCR, and RQ-PCR were 64.2%, 25.8%, and 20.7%, respectively. The BCR-ABL/ABL ratio by RQ-PCR had a mean of 0.000 13 in the 1st RT-PCR-negative samples and 1.42 in the 1st RT-PCR-positive samples (P<0.001), and means of 0.000 39 and 0.51 in the 2nd RT-PCR-negative and -positive samples (P< 0.001). The mean ratios of BCR-ABL/ABL by RQ-PCR were significantly different in N/N (1st/2nd RT-PCR) or N/P and P/P (P<0.001), but not in N/N and N/P, which showed that the discriminative power of RQ-PCR is confined to the 1st RT-PCR level. In this respect, monitoring of the 1st RT-PCR might be useful for estimating normalized BCR-ABL levels after transplantation. Nested RT-PCR was of limited use, as RQ-PCR quantified the BCR-ABL transcripts in 60 (91%) of 66 samples determined to be negative by 2nd RT-PCR. FISH was significantly correlated with RQ-PCR in FISH-positive samples (n=24, r=0.79, P=0.001). An increase of FISH preceded that of RQ-PCR in a few cases with molecular relapse. By analyzing a large number of samples post-transplant, we found that RQ-PCR might be the most useful assay for MRD monitoring; however, FISH and RT-PCR were found to be useful complementary tools.

Bone Marrow↗

PubMed1989

Diagnostic radiography as a risk factor for chronic myeloid and monocytic leukaemia (CML).

This interview study included 136 Los Angeles County residents aged 20-69 with CML diagnosed from 1979 to 1985 (cases) and 136 neighbourhood controls. During the 3-20 years before diagnosis of the case, more cases than controls had radiographic examinations of the back, gastrointestinal (GI) tract and kidneys, and cases more often had GI and back radiography on multiple occasions (odds ratio (OR) for back X-rays on five or more occasions = 12.0; P less than 0.01). Published estimates were used to assign a minimum dose to the active bone marrow for various radiographic procedures. ORs were estimated for cumulative marrow doses for each of four time periods (3-5 years, 6-10 years, 11-20 years and 3-20 years before the diagnosis of the case). The ORs for exposure to 0.99, 100-999, 1000-1999 and greater than or equal to 2000 mrad in the 3-20 years before diagnosis were 1.0, 1.4, 1.6 and 2.4 (P for highest exposure category and P for trend both less than 0.05). The association was strongest for the period 6-10 years before diagnosis, and the effects of radiation exposure during this period remained significant after consideration of other risk factors in a logistic regression analysis.

Adult↗

PubMed1997

CML blast crisis resulting in biliary obstruction following BMT.

Allogeneic BMT is the treatment of choice for various hematologic malignancies. Despite careful patient scrutiny, a large number of patients experience significant morbidity and mortality due to procedure-related toxicity. Hepatobiliary toxicity presenting as biliary cholestasis, due to the preparative regimen (ie venoocclusive disease), supportive pharmaceuticals, and/or GVHD have been implicated. We report a unique cause of cholestasis in a patient undergoing BMT for CML. The cholestasis was found to be secondary to relapsed leukemia, which resulted in a granulocytic sarcoma obstructing the biliary ductal system.

Blast Crisis↗

PubMed1998

Achievement of complete cytogenetic remission after two very low-dose donor leucocyte infusions in a patient with extensive cGVHD relapsing in accelerated phase post allogeneic BMT for CML.

We report the case of a 55-year-old female who despite having developed extensive chronic graft-versus-host disease (GVHD), relapsed 35 months after a T cell-replete sibling donor bone marrow transplant for Philadelphia-positive chronic myeloid leukaemia (Ph CML). She achieved complete cytogenetic remission after discontinuation of cyclosporin A and administration of two low-dose donor leucocyte infusions (DLI 1 x 10(6) and 5 x 10(6) CD3+ cells/kg). Eighteen months after the first infusion she remains well and in complete cytogenetic remission with a normocellular marrow and no exacerbation of GVHD.

Bone Marrow Transplantation↗

PubMed1998

Plasmodium vivax causing pancytopenia after allogeneic blood stem cell transplantation in CML.

A 20-year-old male patient with chronic myeloid leukemia (CML), in chronic phase, underwent allogeneic blood stem cell transplantation in August 1996. Engraftment was well documented in the marrow on day 19, but pancytopenia and mild splenomegaly continued. On day +70, the patient developed severe anemia and had one pyrexial episode. He was detected to have malaria (Plasmodiium vivax). After chloroquin therapy, the pancytopenia reversed completely. We suggest that malaria should be considered as a possible cause of pancytopenia in the post-transplant period in endemic areas.

Adult↗

PubMed1998

Autologous reconstitution with BCR-ABL-negative haematopoiesis after T cell-depleted allogeneic BMT for CML.

We report a patient with Ph chromosome-positive CML who underwent an HLA-identical T cell-depleted BMT from a sibling donor. DNA polymorphism analysis showed complete donor chimaerism after BMT, followed by mixed chimaerism of granulocytes, natural killer cells and B lymphocytes, with T lymphocytes host-derived at day +120 post BMT. From month +20 haematopoiesis was exclusively of host origin in all cell lineages. RT-PCR was used in order to detect residual disease, but at the time, analysis did not show BCR-ABL transcripts. This case is unusual in that non-malignant stem cells of recipient origin survived the transplant and reconstituted haematopoiesis after BMT. Two years post transplant, no molecular or haematological relapse was documented. The observation that subsequent recipient recovery without molecular relapse implies that, at least in this case, the GVL effect can occur in the absence of donor T cells.

Bone Marrow Purging↗

PubMed2000

Quantification of BCR-ABL transcripts in CML patients in cytogenetic remission after interferon-alpha-based therapy.

We measured using a competitive quantitative polymerase chain reaction-capillary electrophoresis (PCR-CE)-based assay, the levels of bcr-abl transcripts in 44 patients with chronic myeloid leukemia (CML) after interferon-alpha (IFN-alpha) therapy, who achieved a major (10 patients, MCR group) or complete (34 patients, CCR group) cytogenetic response. All 34 CCR patients had molecular evidence of residual disease detected in bone marrow samples at the time of best karyotypic response. The median number of bcr-abl transcripts of 34 evaluable patients in the CCR group at the time of complete cytogenetic remission was 4/microg RNA (range 3-4600), while the median number of bcr-abl transcripts of 10 patients in the MCR group at the time of best cytogenetic response was 4490/microg RNA (range 600-23 900) (P = 0.000024). In nine CCR and five MCR patients we were able to quantify the amount of bcr-abl transcript both at diagnosis and after interferon therapy: no statistical difference (P = 0.18) was found between the two groups at diagnosis (median bcr-abl transcripts/microg RNA was 30 000 vs. 39 650, respectively). During IFN-alpha therapy, the two groups were evaluable at the time of major karyotypic conversion: at this point, there was a statistical difference of expression of bcr-abl transcript between the CCR group (17 patients) (median 2700; range 76-40 000) and the MCR group (10 patients) (median 4490; range 600-23 900), respectively (P = 0.046). No differences of bcr-abl amount of transcript were found in patients with CCR obtained either by IFN-alpha therapy alone (20 patients) vs. IFN-alpha plus ABMT (13 patients) (P = 0.47). We firstly demonstrated that although the CCR and MCR groups were clinically, cytogenetically and molecularly indistinguishable at diagnosis, the two groups could be recognized successfully during interferon therapy based on the level of bcr-abl transcript.

Adolescent↗

PubMed2000

Mobilisation of haemopoietic progenitors in CML: a second course of intensive chemotherapy does not improve Ph-negativity in stem cell harvests.

We collected peripheral blood stem cells (PBSC) in 19 early chronic phase CML patients following each of two consecutive cycles of intensive chemotherapy (CT) to evaluate whether an additional cycle of CT would increase Philadelphia (Ph)-negativity of the PBSC harvest. Autologous SCT (autoSCT) was performed if a major cytogenetic response (MCR) of the PBSC harvest was obtained. CT consisted of cytarabine 200 mg/ m2/day (days 1-7)/idarubicin 12 mg/m2/day (days 1-2) (cycle one) and cytarabine 2000 mg/m2/day (days 1-6)/amsacrine 120 mg/m2/day (days 1-3) (cycle two). One patient died of fungal pneumonia after the first cycle. Stem cells were harvested in 18 patients after cycle one and in 16 patients after cycle two. After the first cycle, all patients showed a cytogenetic response of their graft (MCR in eight patients: three complete, five partial), after cycle two, seven patients obtained an MCR (one complete, six partial). Seven patients became eligible for autoSCT. All patients proceeded with IFNalpha maintenance. Currently, 16 patients are alive. At the latest cytogenetic examination of bone marrow, four patients showed an MCR and four a minor response. In conclusion, although a second cycle of CT may contribute to elimination of leukemia residing in the patient, it appeared to be ineffective in improving the Ph-negativity of the PBSC graft.

Adult↗

PubMed2000

Autologous transplantation with Philadelphia-negative progenitor cells for patients with chronic myeloid leukaemia (CML) failing to attain a cytogenetic response to alpha interferon.

Between October 1993 and March 1999, 29 patients with CML who were ineligible for allogeneic BMT underwent PBSC harvest using idarubicin, cytarabine and G-CSF. In 9/29 (31%) patients all collected stem cells were Ph-negative, and 15/29 patients' (52%) collections were substantially (>95%) Ph-negative. The proportion of patients from whom Ph-negative stem cells were obtained was similar between patients who had, or had not, received prior alphaIFN. Fifteen patients in chronic phase (median age 45) proceeded to PBSCT following busulphan 16 mg/m2 and cyclophosphamide 120 mg/m2. Nine of the 13 patients who had failed to respond to prior alphaIFN proceeded to stem cell transplantation as soon as was feasible and six of the newly diagnosed patients were transplanted after failing to achieve a cytogenetic response after a minimum of 12 months on alphaIFN following progenitor cell harvest. The median number of days to neutrophils >0.5 and platelet >50 was 18 (range 13-69) and 28 (range 13-234), respectively. There was no procedure-related mortality. At median follow-up of 2.3 years post autograft 10 of 15 patients remain alive and in chronic phase. Overall survival for all 27 patients at 5 years after initial diagnosis is 70% and median survival from diagnosis 7.3 years. Survival for alphaIFN non-responders who were transplanted is 74% at 5 years from diagnosis and 75% at 3 years from transplant. Cytogenetic analysis performed 3 months post transplant demonstrated one patient with a complete cytogenetic response, seven with a partial response and three with no response. Six patients remain partially Ph-negative, with one major CR. Survival for all patients in the protocol is favourable compared with conventional therapy and is particularly encouraging following PBSCT for alphaIFN non-responsive patients. Patients not responding to alphaIFN can be induced into Ph-negativity with PBSCT but this may not always be sustainable. There seems to be no obvious disadvantage in harvesting stem cells after prior exposure to alphaIFN, providing an adequate alphaIFN-free rest period is used.

Adult↗

PubMed2000

The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy.

Results in 164 patients who underwent allogeneic marrow transplantation following busulfan and cyclophosphamide over a 15 year period were analyzed. Age (median 37, range 14-66 years) did not significantly affect the incidence of graft-versus-host disease (GVHD), but patients who received methotrexate with cyclosporine had a significantly lower incidence (P = 0.002) of chronic GVHD compared to those who received methylprednisolone with cyclosporine. Hepatic veno-occlusive disease (VOD) occurred less frequently in chronic phase patients (P = 0.002) and in those transplanted shortly after diagnosis (P = 0.001). Five year leukemia-free survival (LFS) for the entire group was 49% (95% CI 41-57%). For 102 patients who underwent transplantation in chronic phase, results were significantly improved by transplantation at a short interval following diagnosis, particularly within 3 months (P = 0.01), by the use of methotrexate and not corticosteroids for GVHD prevention (P = 0.03), and by use of HLA-identical sibling donors (P = 0.01). Age was not a significant adverse prognostic factor and transplantation was successfully performed in individuals up to age 66. Allogeneic transplantation in CML, including older patients and those with unrelated donors, can be most safely and effectively performed shortly after diagnosis.

Adolescent↗

PubMed2001

Reconstitution of the CD45RO(+) and CD20(+) lymphoid marrow population following allogeneic bone marrow transplantation for Ph(+) CML.

Following bone marrow transplantation (BMT) investigations on the recovery of the B and T lymphocyte populations have focused on the peripheral blood and only marginally regard the bone marrow. An immunohistochemical and morphometric study was performed on 352 trephine biopsies derived from 123 patients with chronic myelogenous leukemia (CML) at standardized endpoints before and after allogeneic BMT and compared to a control group. The purpose of this investigation was to quantify the B-CD20(+) and T-CD45RO(+) lymphocyte subsets and to determine possible relationships with the occurrence of acute and chronic GVHD. Moreover, we studied the dynamics of lymphocyte repopulation in the post-transplant period, correlations with the total peripheral lymphocyte count and differences associated with sibling vs alternate HLA-compatible (unmanipulated) marrow grafts. Morphometric analysis revealed a very fast regeneration of CD45RO(+) and CD20(+) marrow lymphocytes in the first 2 weeks following BMT. In less than 2 months, in most patients, the post-transplant quantity of lymphocytes was comparable to that of the normal bone marrow. This finding was opposed to the profound depression of the absolute lymphocyte count in the peripheral blood. No relevant relationships could be calculated between engraftment status and the lymphocyte repopulation in the bone marrow. On the other hand, significant correlations were calculable between the development of (chronic and acute) GVHD including severity with the number of CD45RO(+) lymphocytes. In non-related graft constellations a more frequent evolution of acute grade III + IV GVHD was detectable. This complication was accompanied by an increased quantity of CD45RO(+) lymphocytes in the marrow.

Adolescent↗

PubMed2001

Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens.

Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.

Adolescent↗

PubMed2001

Autologous reconstitution combined with durable leukemic remission after allogeneic BMT for CML: absence of persistence of a donor-derived T cell effector population.

We report a case of autologous hematopoietic recovery with durable leukemic remission after BMT from a phenotypically HLA-identical donor in a 30-year-old male with CML. Graft loss was diagnosed from day 60 post-BMT by VNTR PCR. To assess for the presence of a minor donor-derived T cell population that could exert an anti-leukemic effect, we serially applied a sensitive process of chimerism analysis by fluorescent PCR on sorted T cells. No residual donor T cells could be detected. We also showed retrospectively that a very sensitive method of MRD analysis by real-time quantitative PCR could have permitted prediction of relapse in this case.

Adult↗