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PubMed1994

Autologous peripheral stem cell transplantation of the blastic phase of chronic myeloid leukemia following sequential high-dose cytosine arabinoside and melphalan.

Blast-phase chronic myelogenous leukemia (CML) is the terminal phase in CML and is uniformly fatal. We treated 12 patients with blast-phase CML with a program of high-dose cytarabine 3.0 g/m2 and melphalan 140 mg/m2, followed by reinfusion of stem cells obtained from peripheral blood during the chronic phase. Seven patients achieved either a partial or complete hematologic remission, while five patients showed no response to therapy. One patient returned to chronic phase features with loss of a chromosomal abnormality acquired at blast phase, restoration of hematopoiesis, and a decrease in the amount of bone marrow blasts to less than 10%. Six patients cleared their peripheral blasts and showed recovery of their myeloid and platelet lineages, but all six required treatment for acceleration within 3 months. Of the five nonresponding patients, three died with aplastic bone marrow, one patient never cleared peripheral blasts after chemotherapy, and one patient had evidence of peripheral blasts 3 weeks after the autologous stem cell reinfusion. None of the patients returned to a normal karyotype. The ablative regimen was effective in eradicating bone marrow blasts to < 10% in 8 of 10 patients in whom interpretable bone marrow samples were performed following chemotherapy. Overall, the median survival for all patients from the time of stem cell reinfusion was 5.5 months. We conclude that autotransplants with peripheral blood can successfully be used to support hematopoiesis during high-dose therapy for CML blast crisis, however, has no role by itself in the curative therapy of blast crisis CML. A small number of patients can be restored to chronic phase features, and this may provide an opportunity to administer subsequent alternative treatments designed to eradicate the malignant stem cell population. Autotransplants with stem cells may also be used as therapy for patients without a histocompatible marrow donor. However, the autotransplant may be more effective when used during the chronic phase of CML, with the use of hematopoietic growth factors, and with reinfusion of stem cells depleted of the malignant Philadelphia chromosome-positive clone.

Adult↗
PubMed2004

Immunohistochemical detection of VEGF in the bone marrow of patients with chronic myeloid leukemia and correlation with the phase of disease.

We studied expression of vascular endothelial growth factor (VEGF) in paraffin-embedded bone marrow sections obtained from 15 patients with chronic myeloid leukemia (CML) in chronic phase (CP), 3 in accelerated phase (AP), 7 in myeloid blast phase (BP(M)), 6 in lymphoid blast phase (BP(L)), and in 3 normal bone marrow samples. VEGF expression was determined immunohistochemically by using an anti-VEGF antibody. In CML-CP, the distribution of VEGF showed a pattern similar to that of normal marrow. VEGF was expressed in myeloid progenitors and megakaryocytes and less abundantly in mature granulomonocytic cells, whereas erythroid cells did not stain positively for VEGF. In CML-BP(M), myeloblasts expressed substantial amounts of VEGF. By contrast, little if any VEGF was detectable in blast cells in CML-BP(L). VEGF messenger RNA (mRNA) was detected in leukemic cells in CML-BP(M) by reverse transcriptase-polymerase chain reaction, whereas blast cells in CML-BP(L) did not express substantial amounts of VEGF mRNA. Our data show that VEGF is expressed in immature myeloid cells in CML. The extent of VEGF expression depends on the phase of disease and the cell type involved in disease progression.

Adolescent↗
PubMed1990

The maintenance of busulphan-induced remissions in chronic granulocytic leukaemia with recombinant interferon alpha-2b.

Interferon (IFN) shows no specificity in inhibiting the growth of colonies of myeloid leukaemia blasts in culture as compared to normal haemopoietic precursors, but does reduce the self-renewal capacity of myeloblasts. We have tested the ability of IFN to slow the leukocyte doubling time (Ldt) and to prolong remissions induced by busulphan in 14 patients with chronic granulocytic leukaemia (CGL). Patients served as their own controls; the Ldt during relapse from a busulphan-induced remission on no therapy was determined and compared with the Ldt on IFN maintenance therapy. The initial dose of IFN (2 x 10(6) U M-2 subcutaneously, three times per week) was adjusted up, or down, to prevent the leukocyte count from rising and the platelet count from falling below 75 x 10(9) l-1. The dose of IFN required to prevent relapse in seven patients ranged from 1 x 10(6) U M-2 three times per week to 5.2 x 10(6) U M-2 daily, with a median of 2 x 10(6) U M-2 three times per week. IFN maintenance therapy has prevented relapse in six patients for more than 22 months to more than 68 months. In five patients the Ldt was slowed initially but the disease later progressed in four patients to enter the accelerated (three patients) or blast phase (one patient). The Ldt during IFN therapy did not change from the Ldt on no therapy in one patient; this patient later progressed to the blast phase. In two additional patients the leukaemia progressed during the first course of IFN, with shortening of the Ldt; both of these patients entered the blast phase. In the four patients who have discontinued IFN following relapse in the chronic phase, the Ldt remained prolonged for at least one relapse after the IFN was stopped. IFN maintenance therapy failed to control the leukocyte count in the six patients with a control Ldt of less than 40 days and five of these have progressed to enter the accelerated or blast phase. The early survival of this group of patients resembles the survival of 'good risk' CGL patients reported by others. We conclude that IFN maintenance therapy does alter the relapse pattern of a subset of CGL patients, either slowing the Ldt or preventing relapse.

Adult↗
PubMed2006

Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis.

The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

In vitro culture studies of blood and marrow cells in chronic myeloid leukemia at different phases of the disease.

The in vitro culture growth of peripheral blood (PB) and bone marrow (BM) cells were studied simultaneously from 100 adult patients with chronic myeloid leukemia at different phases. Sixty-five patients were investigated at initial diagnosis, 30 patients in control phase, and 41 patients in blast phase. In untreated chronic phase, the relative concentrations of granulocyte-macrophage progenitor cells (CFU-GM) in BM were not significantly different from those of normal controls, but there was generally a marked increase in circulating CFU-GM. The 6 Ph1-negative patients did not show different growth characteristics. We were unable to correlate the CFU-GM number to any of the hematologic parameters as well as to the response to busulfan therapy. Pretreated patients with excessive cluster formation did not necessarily indicate impending blast crisis. In hematologic remission, the numbers of CFU-GM in both BM and PB were well within the ranges of normal controls. Culture results in blast phase revealed a spectrum of abnormal growth. In myeloid crisis, 14/29 BM and 12/29 PB samples showed increased colony and cluster formations which were composed predominantly of immature cells with variable degeneration. Marrow cells in lymphoid crisis produced low numbers of both colonies and clusters in 5 out of 8 patients, while blood cells from 8 out of 10 patients formed large amount of colonies of normal morphology. This study indicates that the in vitro CFU-GM assay may have diagnostic utility in differentiating lymphoid crisis from myeloid crisis.

Adult↗
PubMed2006

Absence of the JAK2 mutation V617F in CD34+ hematopoietic stem and progenitor cells from patients with BCR-ABL-positive CML in chronic phase and blast crisis.

In this study, we examined highly enriched CD34+ cells from patients with BCR-ABL-positve CML in chronic phase or blast crisis for the JAK2 V617F activation mutation by sequencing. The cells examined did not bear the mutation irrespective of the disease stage. This finding suggests that the previously described increase of expression and kinase activity of JAK2 in CML cells does not result from the JAK2 V617F activation mutation and that transformation into blast crisis is not associated with the occurrence of this mutation.

Amino Acid Substitution↗
PubMed1989

Granulocyte-macrophage colony-stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia.

A strategy designed to stimulate myeloid leukemic blasts into active cell cycle may increase the effectiveness of S phase-specific agents such as cytosine arabinoside (ARA-C). Since recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) is known to stimulate the growth of myeloid leukemic cells in vitro, we have evaluated the ability of this growth factor to enhance leukemic clonogenic cell kill in the presence of ARA-C. In seven patients studied, GM-CSF increased the fraction of myeloid leukemic blasts in S phase as measured by propidium iodide DNA staining, bromodeoxyuridine incorporation, or ARA-C suicide techniques. Six of these seven patients demonstrated clonogenic cell growth in agar in response to GM-CSF. In five of these six patients, the combination of GM-CSF and ARA-C treatment in vitro resulted in a significant increase in leukemic clonogenic cell kill when compared to treatment with ARA-C in the absence of GM-CSF. Similar results were observed with the combination of GM-CSF and hydroxyurea, another S phase specific agent, further suggesting that the observed enhancement of cytotoxicity was due to the ability of GM-CSF to increase the number of leukemic cells in S phase. These data provide a rationale for investigating the toxicity and efficacy of combined GM-CSF and ARA-C therapy in patients with high-risk myeloid leukemia.

Blast Crisis↗
PubMed1976

Terminal deoxynucleotidyl transferase as a biological marker for human leukemia.

High levels of terminal deoxynucleotidyl transferase have been observed in leukocytes of 7 out of 20 patients with chronic myelogenous leukemia in acute blast phase of the disease. These levels are comparable to the levels observed in human and calf thymus gland and cell lines with some T cell characteristics (Molt 4 and 8402). Negligible levels of this activity were observed in chronic myelogenous leukemia not in an acute blast phase of the disease, chronic lymphocytic leukemia, human B cells, mature T cells, and the mixed population of lymphocytes present in normal human blood. The detection of this enzyme in some patients with chronic myelogenous leukemia in acute blast phase of the disease suggests that the blast proliferation may involve primitive stem cells which have more lymphoid than myelogenous characteristics. This enzyme assay may be of use as a biological marker for following patients during treatment and in remission.

Cations, Divalent↗
PubMed1977

Ultrastructural cytochemical analysis of blastic transformation of chronic myelocytic leukemia.

Ultrastructural cytochemical changes occurring during the blast phase of chronic myelocytic leukemia (CML) are described. Normal developing promyelocytes contain myeloperoxidase (MPO) -positive rough endoplasmic reticulum, nuclear envelope, and Golgi apparatus. All secretory granules of normal promyelocytes are also MPO-positive. In this study we have found abnormal promyelocytes with MPO-positive as well as MPO-negative secretory granules in blast phase CML patients which contrast with the normal pattern of MPO distribution in most CML patients not in the blast phase or in nonleukemic controls. Alkaline phosphatase activity was found in the nuclear envelope of blasts and promyelocytes of one of the blast transformation patients who had a markedly increased leukocyte alkaline phosphatase score. The cytochemical changes in the distribution of MPO suggest that immature leukemic cells may alter their patterns of secretory granule production. Such processes may reflect the emergence of an abnormal clone of cells during the blastic transformation of CML.

Alkaline Phosphatase↗
PubMed1975

[Results of combined chemotherapy in treatment-resistant leukaemia of adults (author's transl)].

In 21 patients with acute leukaemia not or no longer responsive to conventional chemotherapy, and in four patients with chronic myeloid leukaemia in the blast phase, intensive combination treatment was started with thioguanine, daunomycine, cytarabine, methotrexate, prednisone, cyclophosphamide, and vincristine. Six patients with acute leukaemia went into complete remission, three into partial remission. The mean duration of remission was relatively short at 11 weeks. Of the four patients in the blast phase of chronic myeloid leukaemia two had objective and subjective remission. The toxicity of the combined treatment was not marked and subjective tolerance good. Such combined treatment is a realistic means of managing treatment-resistant acute leukaemia and chronic myeloid leukaemia in the blast phase.

Acute Disease↗
PubMed2006

Coding sequence and intron-exon junctions of the c-myb gene are intact in the chronic phase and blast crisis stages of chronic myeloid leukemia patients.

The c-myb gene encodes a transcription factor required for proliferation, differentiation and survival of normal and leukemic hematopoietic cells. c-Myb has a longer half-life in BCR/ABL-expressing than in normal cells, a feature which depends, in part, on PI-3K/Akt-dependent regulation of proteins interacting with the leucine zipper/negative regulatory region of c-Myb. Thus, we asked whether the stability of c-Myb in leukemic cells might be enhanced by mutations interfering with its degradation. We analyzed the c-myb gene in 133 chronic myeloid leukemia (CML) patients in chronic phase and/or blast crisis by denaturing-high performance liquid chromatography (D-HPLC) and sequence analysis of PCR products corresponding to the entire coding sequence and each exon-intron boundary. No mutations were found. We found four single nucleotide polymorphisms (SNPs) and identified an alternatively spliced transcript lacking exon 5, but SNPs frequency and expression of the alternatively spliced transcript were identical in normal and CML cells. Thus, the enhanced stability of c-Myb in CML blast crisis cells and perhaps in other types of leukemia is not caused by a genetic mechanism.

Base Sequence↗
PubMed1991

Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase.

Four patients with Philadelphia chromosome positive CML were treated with 18-42 x 10(6) IU of purified natural leukocyte IFN-alpha per week, after high-dose chemotherapy for blast phase and attainment of 2nd chronic phase. The second blast phase occurred within 3 months in 3 patients, but one patient is still in second chronic phase after 22 months of treatment. Treatment consisted of interferon only during the first year, and interferon in combination with hydroxyurea during the second year. During the second year suppression of the Philadelphia chromosome was seen in one patient, with 20% Philadelphia negative bone marrow metaphases. The toxicity of purified natural leukocyte IFN-alpha was similar to the toxicity of recombinant IFN-alpha. Antibodies to IFN-alpha were not detected in any patient.

Adult↗
PubMed1995

Changing p53 mutations with the evolution of chronic myeloid leukaemia from the chronic phase to blast crisis.

The frequent involvement of chromosome 17p abnormalities in the progression of chronic myeloid leukaemia (CML) led us to investigate the involvement of the p53 tumour suppressor gene located on chromosome 17p. We analysed 31 samples from four patients sequentially, and 16 patients in blast crisis only, using single stranded conformational polymorphism (SSCP) analysis of exons 5-8, followed by cloning and sequencing. The sequential samples ranged from diagnosis through to late disease. We found that 15% of our blast crisis samples had p53 abnormalities. In our sequential studies we found two of the four patients analysed in more detail had p53 mutations in the late chronic phase of disease (11 and 5 months prior to blast crisis becoming apparent). These chronic phase mutations differed from the p53 abnormalities found in the blast crisis samples from these patients. One patient also had the same chronic phase mutation at post bone marrow transplant relapse. Our results suggest that, in some cases, sequential investigations through CML disease progression of p53 mutations and other oncogenes/proto-oncogenes may provide early indications of the routes of disease progression to blast crisis.

Base Sequence↗
PubMed1996

Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis.

Progress in understanding the abnormal regulation of hematopoiesis in chronic myelogenous leukemia (CML) would be facilitated if neoplastic cells, at all stages of the disease, could be studied in an animal model. In this report, we show that irradiated severe combined immunodeficient (SCID) mice can be transplanted with both normal (Philadelphia chromosome [Ph]-negative) and neoplastic (Ph+) cells from CML patients with either chronic or blast phase disease. Mice transplanted with peripheral blood (PB) or bone marrow (BM) cells from 9 of 12 chronic phase CML patients were well engrafted with human cells including multilineage colony-forming progenitors and CD34+ cells for at least 90 days posttransplantation. Repeated posttransplant injections of cytokines did not enhance the number of engrafted human cells. Interestingly, approximately 70% of the human progenitors found in the engrafted SCID BM were Ph-, suggesting that the growth of primitive normal cells is favored in this in vivo transplant model. A similar number of normal cells were found in mice transplanted with either PB or BM cells, suggesting that elevated numbers of primitive normal cells are present in CML PB. When cells from patients with CML in either myeloid or lymphoid blast crisis were transplanted into SCID mice, the BM of these mice was more rapidly repopulated and to a higher level than that observed with transplants of chronic phase cells. Moreover, all human colony-forming progenitors present in the BM of mice transplanted with blast crisis cells were Ph+, and the majority of cells showed the same morphological features of the blast crisis cells originally transplanted. These experiments provide a starting point for the creation of an animal model of CML and establish the feasibility of using this model for the future characterization of transplantable CML stem cells during disease progression.

Animals↗
PubMed1999

Chronic myeloid leukemia with expression of ALL-type BCR/ABL transcript: a case-report and review of the literature.

CML with exclusive expression of ALL-type bcr/abl has only been rarely described. In some cases, the presence of this fusion gene has been associated to a differentiated subtype of CML that share some features with CMML, while in another case this molecular hallmark has been associated to a bad prognosis of the disease with a blast phase as clinical presentation or an early transformation to blast phase. We report a case of a 30-year-old woman who was diagnosed of CML in chronic phase in May 1989. She received treatment first with busulfan, achieving hematological remission and afterwards with interferon and Hydroxiurea. In February 1998, she was admitted at our hospital for an ABSCT. Then, molecular studies were performed. Multiplex PCR revealed the presence of a 481 bp product identified as the ela2 bcr/abl transcript and confirmed by sequencing. After 9 years from diagnosis, the patient remains in hematological remission and in good clinical condition.

Adult↗
PubMed1992

Use of cell-free retroviral vector preparations for transduction of cells from the marrow of chronic phase and blast crisis chronic myelogenous leukemia patients and from normal individuals.

Marrow cells were exposed to the LNL6 or G1N safety-modified variants of the N2 retrovirus, which contain the G418 bacterial resistance gene neo. The frequency of acquisition of the G418 resistance phenotype following exposure to LNL6 or G1N was compared among hematopoietic progenitor cells from the marrow of patients with chronic phase chronic myelogenous leukemia (CML), blast crisis CML, or from nonleukemic individuals. Under the conditions of our experiments, the myeloid committed progenitor cells from 3 of 6 nonleukemic individuals, 9 of 18 chronic-phase CML patients, and 2 of 4 blast crisis CML patients acquired resistance to at least 1 mg/ml G418 following incubation with cell-free supernatants from the PA317 LNL6 or PA317 G1N producer cell lines. Ten of the 32 colonies growing up in 0.8 mg/ml G418 from chronic-phase marrow exposed to LNL6 were shown to contain the neo gene by polymerase chain reaction (PCR) assay of DNA. These results were consistent with estimates of the transduction frequency based on acquisition of resistance to G418 as the number of colonies growing under G418 selection was always greater at 0.8 mg/ml G418 than at higher concentrations of G418 (1.0-1.4 mg/ml). The average transduction frequency at each G418 concentration (1.0, 1.2, and 1.4 mg/ml) in cells from blast crisis CML cells ranged from 2 to 14%, as measured by acquisition of G418 resistance. Chronic-phase CML showed slightly lower average frequencies of transduction (0.6-2.8% of the colonies are G418 resistant). The average transduction frequency of cells from nonleukemic marrow was as high as that seen from the marrow of chronic-phase CML individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2006

Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal.

BACKGROUND: Several staging classification systems, all of which were designed in the preimatinib era, are used for chronic myeloid leukemia (CML). The World Health Organization (WHO) recently proposed a new classification system that has not been validated clinically. The authors investigated the significance of the WHO classification system and compared it with the classification systems used to date in imatinib trials ("standard definition") to determine its impact in establishing the outcome of patients after therapy with imatinib. METHODS: In total, 809 patients who received imatinib for CML were classified into chronic phase (CP), accelerated phase (AP), and blast phase (BP) based on standard definitions and then were reclassified according to the new WHO classification system. Their outcomes with imatinib therapy were compared, and the value of individual components of these classification systems was determined. RESULTS: With the WHO classification, 78 patients (10%) were reclassified: 45 patients (6%) were reclassified from CP to AP, 14 patients (2%) were reclassified from AP to CP, and 19 patients (2%) were reclassified from AP to BP. The rates of complete cytogenetic response for patients in CP, AP, and BP according to the standard definition were 72%, 45%, and 8%, respectively. After these patients were reclassified according to WHO criteria, the response rates were 77% (P = 0.07), 39% (P = 0.28), and 11% (P = 0.61), respectively. The 3-year survival rates were 91%, 65%, and 10%, respectively, according to the standard classification and 95% (P = 0.05), 63% (P = 0.76), and 16% (P = 0.18), respectively, according to the WHO classification. Patients who had a blast percentage of 20-29%, which is considered CML-BP according to the WHO classification, had a significantly better response rate (21% vs. 8%; P = 0.11) and 3-year survival rate (42% vs. 10%; P = 0.0001) compared with patients who had blasts > or = 30%. CONCLUSIONS: Different classification systems had an impact on the outcome of patients, and some prognostic features had different prognostic implications in the imatinib era. The authors believe that a new, uniform staging system for CML is warranted, and they propose such a system.

Adolescent↗
PubMed2005

Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate.

Sudden blastic transformation (SBT) has been reported in 0.5% to 2.5% of patients treated with interferon-alpha (IFN-alpha) during the first 3 years of therapy. Imatinib is now standard therapy for patients with chronic myeloid leukemia in chronic phase. We investigated the occurrence of SBT among patients treated with imatinib. Among 541 patients treated with imatinib in chronic phase, 23 developed blast phase, which was of sudden onset (ie, occurring in patients previously in complete cytogenetic remission) in 4 patients (17%; 0.7% of the total), 2 lymphoid and 2 myeloid. Patients with SBT were found to have low-risk features more often at the time of presentation and had achieved optimal response with imatinib. Three of the 4 patients underwent allogeneic stem cell transplantation and achieved a molecular remission. SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory.

Adult↗