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PubMed2003

Durable molecular response to imatinib mesylate following nonmyeloablative allogeneic stem-cell transplantation for persisting myeloid blast crisis in chronic myeloid leukemia.

We report a chronic myeloid leukemia (CML) patient in chronic phase (CP) who developed blast crisis (BC) under imatinib mesylate administered in a dose reduced and non-continuous fashion because of hematologic intolerance. The patient underwent nonmyeloablative stem-cell transplant from a matched unrelated donor, but failed to achieve full donor chimerism and antileukemic response resulting in persistence of advanced disease. Complete hematologic, cytogenetic and molecular responses were attained 5 weeks after readministration of regularly dosed imatinib and two-step nested RT-PCR confirmed molecular remission throughout a 6 month follow-up period. This is the first case demonstrating that imatinib mesylate is a highly effective and safe treatment option to induce durable molecular remission in patients with CML who remain in myeloid blast crisis after nonmyeloablative allogeneic stem-cell transplantation.

Antineoplastic Agents↗
PubMed2004

[Hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia].

BACKGROUND & OBJECTIVE: Chronic myelogenous leukemia (CML) is a malignant hematological disease.CML patients are commonly treated with hematopoietic stem cells transplantation (HSCT). This study was designed to evaluate the effect of HSCT on the patients with CML. METHODS: Forty-four patients with CML were treated by HSCT, including 8 cases treated with purging autologous transplantation, 30 cases with related donor allogeneic HSCT (allo-HSCT), and 6 cases with unrelated donor allo-HSCT. The conditioning regimen was TBI (total-body irradiation)+CY (CTX) protocol in 31 patients and modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 12 patients, and MACC (Melphalan, Ara-C, CTX and CCNU) protocol in one patient. CsA (cyclosporine) and MTX were used in the patients with related donor allo-HSCT, and CsA and MTX added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) were used in the patients with unrelated donor all-HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used in the patients with accelerated phase(AP) and blast crisis(BC) for GVHD prophylaxis. Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation. RESULTS: Eight patients with autologous transplantation, except one case died of transplantation-related-complication, obtained part or complete cytogenetic remission within 3 months after transplantation. One patient, who was BC and obtained complete remission (CR) in hematology before transplantation,obtained complete molecular remission for 81 months after autologous transplantation. All patients obtained CR, except one patient died of hepatic veno-occlusive disease (VOD) and one case did not obtained CR, in 36 patients with allo-HSCT after transplantation. The incidence of infection and VOD during transplantation were 38.6% and 9.1%, respectively. The incidences of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) pneumonia after transplantation were 15.9% and 11.4%, respectively. VOD, HC, and CMV pneumonia did not occur in the patients with autologous transplantation. The incidence of acute GVHD in the patients with related and unrelated donor transplantation were 40.0% and 33.3%, respectively. The incidence of chronic GVHD was 43.4% in the patients with related donor transplantation. The rates of transplant-related mortality (TRM) in the patients with autologous and allogeneic transplantation were 12.5% and 16.7%, respectively. The rates of relapse in patients with autologous and related donor transplantation were 37.5% and 13.3%, respectively. The DFSs at 5 years in patients with autologous and related donor transplantation after transplantation were 18.7% and 53.7%, respectively. The DFS at 5 years in patients with CP (chronic phase) or AP and BC before transplantation were 66.4% and 26.7%, respectively. CONCLUSION: all-HSCT shows higher clinical cure rate to CML patients with CP. CsA+MTX+MMF+ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and severity of acute GVHD in patients with unrelated donor transplantation. Autologous transplantation with bone marrow purged can prolong the survival time and a few patients may be cured with autologous transplantation in CML.

Adolescent↗
PubMed2000

Down's syndrome with myelodysplastic syndrome showing t(7;11)(p13;p14).

We report a boy with Down's syndrome (DS) who developed myelodysplastic syndrome (MDS) after spontaneous remission of transient myeloproliferative disorder (TMD) at birth. Chromosomal analysis of the blasts in the MDS phase demonstrated t(7;11)(p13;p14) which had not been detected in the TMD phase. NUP98-HOXA9 chimera mRNA, which is known to be involved in t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), was not detected by reverse transcriptase-polymerase chain reaction, and NUP98 rearrangement was not detected by Southern blot analysis of the blasts in the MDS phase. Reciprocal translocation is very rare in AML/MDS in DS, and the t(7;11)(p13;p14) found in our patient was different from the recurrent translocation t(7;11)(p15;p15) previously reported.

Blotting, Southern↗
PubMed1995

Cell cycle regulation of immunoglobulin class switch recombination and germ-line transcription: potential role of Ets family members.

Previous studies have indicated that transcription of germ-line (GL) CH genes is necessary to obtain immunoglobulin (Ig) class switching. We report here a correlation between proliferation, switching and GL transcripts. Smu-S gamma 1 switch recombination in lipopolysaccharide (LPS) + interleukin-4 (IL-4)-activated mouse B cells was assayed by a digestion-circularization polymerase chain reaction. Switching to gamma 1 is reduced upon inhibition of DNA synthesis with hydroxy-urea (HU) or aphidicholin (AC). Incubation of activated B cells with HU severely reduces steady-state levels of GL gamma 1 and epsilon RNA. By utilizing elutriation to synchronize B cell blasts in different phases of the cell cycle, it was found that GL gamma 1 transcripts are mainly expressed in G1 and S phases, but not in G0. Using the electrophoretic mobility shift assay, we characterized two major LPS-induced complexes, which bind to the GL gamma 1 promoter and are expressed at levels which correlate with the amount of LPS-induced DNA synthesis. Furthermore, the intensity of the complexes is reduced when cells are arrested with the DNA synthesis inhibitors HU or AC. Elutriation experiments revealed that the complexes are expressed in G1 and S, but not in G0. They bind to an Ets consensus element near the major initiation sites used in proliferating cells. The possible implications of these findings for Ig isotype switching are discussed.

Animals↗
PubMed1978

Tumors as clonal proliferation.

Cytogenetic studies indicate that most tumors are clonal (i.e. unicellular in origin) and have karyotypic alterations. These are not consistent, but non-random abnormalities are being increasingly identified by banding techniques, pointing to the sites on human chromosomes where genes important in neoplastic development are located. It is postulated that tumor progression occurs as a result of genetic lability within the neoplastic clone, leading to emergence of increasingly mutant subpopulations (often recognizable cytogenetically) with more malignant properties. In the context of this hypothesis, acute leukemia, chronic leukemia, and preleukemia can be viewed as differing only in the rate at which an abnormal hemic clone is expanding, with progression to a more aggressive phase (e.g. the "blast crisis" of chronic granulocytic leukemia) reflecting emergence of a new predominant subpopulation as the result of an additional genetic change. These concepts, and the cytogenetic data from which they have been derived, may help our understanding of basic tumor biology, and have some practical applications in the diagnosis of human neoplasms.

Cell Division↗
PubMed2005

Isolated lytic bone lesion as extramedullary disease in chronic myelogenous leukemia: a report of three new cases.

This short report describes three patients with chronic myeloid leukemia and isolated extramedullary bone disease with isolated lytic bone lesions. All these patients were in chronic phase when skeletal blast crisis took place. All the patients developed a full-blown blastic crisis within 3 months, with a rapidly fatal outcome, despite several intensive therapies.

Journal Article↗
PubMed2003

Resistance to imatinib (Glivec): update on clinical mechanisms.

Imatinib mesylate, an orally administered 2-phenylaminopyrimidine derivative that inhibits BCR/ABL tyrosine kinase activity, has shown great promise in the treatment of chronic myelogenous leukemia (CML). This small molecule, tyrosine kinase inhibitor, has also been shown to be effective against metastatic gastrointestinal stromal tumors (GISTs) expressing the stem cell factor (SCF) receptor kit. However, the threat of resistance in patients has prompted investigators to uncover the mechanisms whereby malignant cells develop resistance to imatinib, and has also led to the establishment of strategies designed to over-ride imatinib resistance. Here, we provide a comprehensive overview of the effectiveness of imatinib in the treatment of chronic, accelerated and blast crisis-phase CML, Philadelphia chromosome-positive (Ph+) acute lymphoid leukemia (ALL) and metastatic GIST. Established mechanisms of resistance to imatinib are discussed, as are novel therapeutic approaches to improving drug responsiveness by reversing development of imatinib resistance in patients.

Administration, Oral↗
PubMed2003

Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice.

SPA-1 (signal-induced proliferation-associated gene-1) is a principal Rap1 GTPase-activating protein in hematopoietic progenitors. SPA-1-deficient mice developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia (CML) in chronic phase, CML in blast crisis, and myelodysplastic syndrome as well as anemia. Preleukemic SPA-1-deficient mice revealed selective expansion of marrow pluripotential hematopoietic progenitors, which showed abnormal Rap1GTP accumulation. Overexpression of an active form of Rap1 promoted the proliferation of normal hematopoietic progenitors, while SPA-1 overexpression markedly suppressed it. Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo. These results unveiled a role of Rap1 in myeloproliferative stem cell disorders and a tumor suppressor function of SPA-1.

Animals↗
PubMed1981

The ENT problems following the Birmingham bombings.

The ENT problems following the Birmingham bombings of 1974 are presented. It is during the positive phase of bomb blast that the tympanic membrane ruptures. Spalling is a likely explanation for the mechanism of rupture of the tympanic membrane specially in large perforations. Tympanic membrane defects involving 80 per cent of the surface area of the drumhead or more persisted, whereas those involving less than 80 per cent healed with conservative treatment. The majority of perforations (81.4 per cent) healed spontaneously, with a three-layered membrane. A month should be allowed for the healing of every 10 per cent loss of the surface area of the drumhead. During surgical repair of persistent perforations, the malleus handle was found to be on a deeper plain than the long process of the incus. Tympanic membrane perforations did not protect the inner ear, the sensorineural deafness producing either a high tone or a flat loss. One in four of the victims seen in the hospital complained of deafness. A patient who suffered blast injuries to the lung also developed cord palsy.

Blast Injuries↗
PubMedDate not supplied

Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukemia patients treated with STI571 measured by quantitative real-time polymerase chain reaction.

The activated tyrosine kinase, which arises as a result of the balanced t(9,22) translocation in chronic myeloid leukemia (CML), is thought to be essential for the development of the leukemic phenotype. Recently, designer drugs have been introduced which specifically inhibit such specific kinases. Among these, STI571 (Glivec) has entered clinical trials and shown promising activities in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) as evidenced by significant hematological and cytogenetic responses in CML patients. To evaluate the effect of STI571 at the molecular level we have employed quantitative real-time PCR (RQ-PCR) to measure the amount of BCR-ABL fusion transcript in a series of 19 patients treated with STI571, either in CP(11) or in (AP)(8) of the disease for 3--9 months (median 6 months). Employing this method, which is able to detect at least one BCR-ABL+ cell in 500,000, in serial blood and bone marrow specimens we found decreases in transcript levels in 10/11 CP patients, but only in 1/8 of the AP patients. When present such decreases were gradual and became evident only after 3 months of STI571 treatment, and their kinetics in blood closely mirrored those seen in parallel marrow samples. Moreover, decreases were between 10- and 100-fold in 11/13 patients, with only two patients reaching residual disease levels below 10(-2) (a 900-fold decrease). Thus, no patient reached PCR negativity. We conclude that the RQ-PCR method is a highly suitable tool for following the effect of STI571 in CML and that further validation of the method, performed in a prospective manner, will contribute significantly to the elucidation of the proper role of STI571 in CML.

Adult↗
PubMed2002

Tumor suppressor genes in normal and malignant hematopoiesis.

Over the last decade, a growing number of tumor suppressor genes have been discovered to play a role in tumorigenesis. Mutations of p53 have been found in hematological malignant diseases, but the frequency of these alterations is much lower than in solid tumors. These mutations occur especially as hematopoietic abnormalities become more malignant such as going from the chronic phase to the blast crisis of chronic myeloid leukemia. A broad spectrum of tumor suppressor gene alterations do occur in hematological malignancies, especially structural alterations of p15(INK4A), p15(INK4B) and p14(ARF) in acute lymphoblastic leukemia as well as methylation of these genes in several myeloproliferative disorders. Tumor suppressor genes are altered via different mechanisms, including deletions and point mutations, which may result in an inactive or dominant negative protein. Methylation of the promoter of the tumor suppressor gene can blunt its expression. Chimeric proteins formed by chromosomal translocations (i.e. AML1-ETO, PML-RARalpha, PLZF-RARalpha) can produce a dominant negative transcription factor that can decrease expression of tumor suppressor genes. This review provides an overview of the current knowledge about the involvement of tumor suppressor genes in hematopoietic malignancies including those involved in cell cycle control, apoptosis and transcriptional control.

Cell Cycle↗
PubMed1986

[Bone marrow transplantation in chronic myeloid leukemia. Influence of gnotobiotic measures, especially antiviral prophylaxis].

Bone marrow from HLA-identical siblings was transplanted in 14 patients with chronic myeloid leukaemia (CML), including one patient in acceleration phase and one in chronic phase following 2 blast crises. Restoration of the bone-marrow occurred in all cases and Philadelphia chromosome could not be detected in any of the patients after the transplantation. Two patients died due to lung complications. Twelve patients who received antiviral prophylaxis (aciclovir per os, anti-CMV-hyperimmunoglobulin) after the transplantation are in very good condition with 140 to 790 days complete clinical and cytogenetic remission. Bone-marrow transplantation, as a curative measure for patients with CML up to the age of 45 (50), should be included in therapy schemes when an HLA-identical sibling is available.

Acyclovir↗
PubMed1983

In vitro culture of clonogenic leukaemic cells in acute myeloid leukaemia: growth pattern and drug sensitivity.

Bone marrow from 43 of 45 AML patients grew leukaemic colonies in culture with a technique using methyl-cellulose semi-solid medium and stimulation with PHA-leucocyte conditioned medium. Plating efficiency was significantly greater in M4FAB subtypes than in M1 or M2. The presence of Auer rods in cultured cells and the existence of cytogenetic abnormalities in both fresh and cultured blast cells in one patient confirmed the leukaemic origin of these colonies. These clonogenic cells were closely related to the growth fraction, as demonstrated by a high suicide index and a linear correlation between percentage of bone marrow blasts in S phase and plating efficiency. In vitro CFU-L sensitivity to cytosine-arabinoside (ARA-C) and to adriamycin (ADR) was tested in 22 patients treated with these two drugs. In the group sensitive in vitro to ARA-C (10 patients), 70% entered complete remission. In the resistant group (12 patients), only 25% had complete remission while 75% had resistant disease. Eight of 14 patients sensitive to ADR in vitro achieved complete remission, while five were resistant to chemotherapy. On the other hand, six of eight patients resistant in vitro were resistant in vivo. When drug sensitivities to ARA-C and ADR were cumulated, an excellent in vitro to in vivo correlation was found when the patient was sensitive or resistant to both drugs in vitro.

Bone Marrow↗
PubMed2003

Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia.

Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.

Adolescent↗
PubMed2003

Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells.

BCR-ABL fusion oncogene is the molecular hallmark of chronic myelogenous leukemia (CML), a condition characterized by a progression from a chronic to acute phase leukemia because of secondary genetic events, the nature of which remains largely unknown. Here, we report that the expression of the p210 BCR-ABL fusion protein leads to a down-regulation of BRCA1 protein, a gene product involved in the maintenance of genome integrity. BRCA1 protein is nearly undetectable in leukemia cells from patients with CML, both during the chronic phase and in blast crisis. Similarly, stable transfection-enforced expression of p210 protein in established hematopoietic cell lines leads to severe BRCA1 depletion. The lack of significant change in BRCA1 mRNA level in cells expressing p210 supports the hypothesis that the regulation of BRCA1 protein level occurs after transcription. It is abolished on exposure of the cells to STI571 and by mutation in the adenosine triphosphate (ATP) pocket of p210 and thus seems to require the tyrosine kinase activity of BCR-ABL. Cell lines expressing high levels of BCR-ABL display an increased rate of sister chromatid exchange and chromosome aberrations after ionizing radiation. These findings reveal a novel link between the oncoprotein BCR-ABL and the tumor-suppressor protein BRCA1.

Animals↗
PubMed2005

Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT.

This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.

Adolescent↗
PubMed2006

[Expression of Bcl-2 protein and the amplification of c-myc gene in patients with chronic myeloid leukemia].

BACKGROUND/AIM: Chronic myeloid leukemia (CML) represents a malignant myeloproliferative disease developed out of pluripotent hematopoietic stem cell that contains the fusion bcr-abl gene. Disorders that occur in the process of apoptosis represent one of the possible molecular mechanisms that bring about the disease progress. The aim of our study was to carry out the analysis of the presence of the amplification of the c-myc oncogene, as well as the analysis of the changes in the expression of Bcl-2 in the patients with CML. METHODS: Our study included 25 patients with CML (18 in chronic phase, 7 in blast transformation). Using an immunohistochemical alkaline phosphatase-anti-alkaline phosphatase (APAAP) method, we analyzed the expression of cell death protein in the mononuclear bone marrow cells of 25 CML patients. By a differential PCR (polymerase chain reaction) method, we followed the presence of amplified c-myc gene in mononuclear peripheral blood cells. RESULTS: The level of the expression of Bcl-2 protein was considerably higher in the bone marrow samples of the patients undergoing blast transformation of the disease. The amplification of c-myc gene was detected in 30% of the patients in blast transformation of the disease. CONCLUSION: The expression of Bcl-2 protein and the amplification of c-myc gene are in correlation with the disease progression.

Bone Marrow Cells↗
PubMed1998

Importance of mixed chimerism to predict relapse in persistently BCR/ABL positive long survivors after allogeneic bone marrow transplantation for chronic myeloid leukemia.

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.

Adult↗