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PubMedDate not supplied

Repeated blast crisis (BC) of changing morphology, immunologic phenotype and cytogenetics in chronic myeloid leukemia (CML).

The clinical course of a 66 year old male with CML who experienced several " relapse " BC of changing morphology, immunologic phenotype and cytogenetics is reported. The first BC was of lymphoblastic phenotype, the second of myeloid, the third again of lymphoblastic, and the fourth, terminal BC was not further characterized or treated. Whereas a phenotypic switch from lymphoblastic to myeloid has been documented twice, the sequence of myeloid followed by a lymphoblastic BC has, to our knowledge, not been reported so far. Lymphoblastic BC responded to a combination of vindesine/prednisone and 6-mercaptopurin. Myeloid BC was controlled by an AML-type induction regimen consisting of daunorubicin and cytosine arabinoside. This unusual case demonstrates that relapse BC is not necessarily of the same morphologic and phenotypic lineage as the preceding BC. Moreover, treatment should be adjusted to the predominant cell type in order to prolong survival.

Aged↗

PubMed1978

Production of mesenchymal tumors in nude mice by Ph1 negative fibroblasts obtained from a Ph 1 positive CML patient: a preliminary report.

An experimental model system is presented for the investigation in humans of the role of hematopoietic stromal elements in the regulation of hematopoiesis as well as in the pathogenesis of myelofibrosis in myeloproliferative disorders. The model is based on the simultaneous application of three experimental techniques: (1) growth of bone-marrow derived fibroblastic colonies in vitro, (2) cytogenetic demonstration of marker chromosomes associated with hematopoietic malignancies, and (3) the transplantation of isolated stromal elements into athymic (nude) mice. Using this model, we describe the induction of mesenchymal tumors in nude mice by Ph1 negative fibroblasts obtained from the bone marrow of a patient with a Ph1 positive chronic myelogenous leukemia. Mesenchymal tumors also were induced in nude mice with bone marrow-derived fibroblasts from a patient with aplastic anemia, who was successfully treated with bone marrow transplantation, and from a normal human volunteer. Morphologic, cytogenetic and electron microscopic studies of bone marrow mesenchymal elements in culture and of tumors induced in nude mice from the CML patient indicate the cells composing the tumor are of human origin and are negative for the Ph1 chromosome. The results provide the first in vivo morphological and cytogenetic support using human materials, of the hypothesized relationship of progenitors of in vitro fibroblastic colonies to marrow stromal elements.

Animals↗

PubMed1987

[Indirubin in the treatment of chronic myelocytic leukemia (CML)--estimation of labelling index of bone marrow cells by 3H-TdR].

Using 3H-TdR labelling radioautography in vitro, labelling index (LI) of the bone marrow cells from patients with CML was estimated before and after treatment by indirubin, and compared with myleran. The results showed that LI of the bone marrow cells was prone to decline after treatment by indirubin or myleran, and it was most marked on the myelocyte and polychromatophilic erythroblast. The LI reduction was less by indirubin than myleran. It suggests that the inhibition of indirubin on the bone marrow cells be weaker than that of myleran. However, long-term administration of indirubin would inhibit not only the granulocytic series but also the red cell series to a certain degree.

Adolescent↗

PubMed1985

Cytogenetics and flow cytometry may predict phenotype of CML blast crisis.

Twenty-eight patients with chronic myelocytic leukemia (CML) and the Philadelphia chromosome (Ph1) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. These abnormal populations fell into two categories based on the presence or absence of HLA.DR. Patients with HLA.DR+ abnormal cells showed no clonal evolution and progressed to lymphoid blast crisis. Patients with HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase.

Adult↗

PubMed1980

[Adenopathies in chronic myeloid leukemia (CML). Study of 161 cases].

161 cases of CML have been studied. Clinically significant adenopathies were present in 3,2% of the patients at the moment of diagnosis, and in the subsequent course they appeared in 7% of them. The behaviour of adenopathies showed to be unrelated to: --splenomegaly; --blastic metamorphosis in the peripheral blood or in the marrow (which they often preceded from 3 to 26 months); --hematological sensibility to cytostatic therapy; and furthermore they often acted as the most important clinical and therapeutic problem. From the cyto-histological point of view three features have been observed: 1) blastic metamorphosis in a lymphnode showing features of myeloid metaplasia; 2) blastic invasion in a lymphnode without any sign of myeloid metaplasia; 3) malignant lymphoma. Cytological examination of imprints and ultrastructural studies, besides the usual histological investigations, proved to be useful for the definition of the above mentioned features. In lymphomatous forms, together with the study of the cariotype and the research of the Ph' chromosome, the performance of immunocytological investigations is also necessary.

Adult↗

PubMed1994

Bcr-abl-positive and -negative clonogenic cells in CML patients undergoing long-term interferon treatment.

Bone marrow (BM) and peripheral blood cell (PBC) samples of 11 Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) patients in long-lasting hematologic remission induced by interferon (IFN) treatment were examined for the presence of leukemic hematopoietic precursor cells. Southern blot analysis revealed residual leukemic cells in BM samples of four patients, whereas seven patients showed no aberrant bands. Reverse transcription polymerase chain reaction (RT-PCR), however, amplified bcr-abl-specific cDNA in unfractionated BM or PBC samples in all 11 patients. The patients demonstrating bcr rearrangements in Southern blots had either a mosaic pattern (three patients) of bcr-abl-negative and positive colony-forming precursors (CFU-GEMM, BFU-E, CFU-GM, CFU-Mega), or all colonies were derived from leukemic precursors (one patient). However, in soft agar cultures of four patients without aberrant bands in Southern blots, only colonies without amplifiable bcr-abl transcripts were detectable. In another patient, few bcr-abl-positive colonies were found after 44 months of treatment, but not after 53 and 56 months of therapy. In these patients, therefore, residual disease detectable by PCR analysis of unfractionated cell samples does not appear to reside in the colony-forming cell compartment. The prognostic implications of these observations and the nature of the remaining bcr-abl-positive cells within unfractionated cell samples remain to be determined.

Adult↗

PubMed1994

Biological characterization of stem cell present in mobilized peripheral blood of CML patients.

Peripheral blood stem cell grafts are now frequently used for autologous transplantation of patients with malignancies. In this report we address the question of whether true long-term repopulating pluripotent hematopoietic stem cells (PHSC) are mobilized into peripheral blood and whether stem cells isolated from CML patients are depleted of Philadelphia chromosome positive cells. The presence of stem cells in mobilized peripheral blood (MPB) was examined by staining the CD34+Lineage- (Lin-) population for the expression of the Thy-1 antigen. The extent and kinetics of mobilization of CD34+Thy-1+ Lin- cells into peripheral blood were studied. In our analysis the percentage of these cells was found to vary widely depending on the day of leukapheresis and the individual patient. Fluorescence activated cell sorting (FACS) was used to isolate Thy-1 subsets from MPB which were analyzed for activity in in vitro long term cultures and in two in vivo models in which SCID-hu mice were implanted with human fetal bone or thymus grafts. The long term culture assay shows that the cells which express Thy-1 are enriched for cobblestone area forming activity (CAFC), an assay which can be used as a measure of detecting PBSC's in vitro. This CD34+Thy-1+ Lin- cell population was capable of producing both B and myeloid cells, and maintaining CD34+Lin- cells in these long term cultures. Moreover, the CD34+Thy-1+Lin- cell subset possessed a higher ability to engraft and to produce multilineage hematopoietic lineages in the SCID-hu bone assay and T cells in the SCID-hu thymus assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗

PubMed1995

Allogeneic BMT in a patient with CML and prior disseminated infection by mycobacterium avium complex.

A patient with chronic myeloid leukemia (CML) who developed a disseminated infection by mycobacterium avium complex (MAC) was successfully treated with rifampin, ethambutol, isoniazid, cycloserin and ciprofloxacin. Diagnosis was proven by histologic examination of hepatic biopsy and culture of the liver biopsy material. Two years later the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor. Antimycobacterial prophylaxis to MAC with ethambutol, cycloserin and ciprofloxacin was given throughout the immediate post-transplant period. On day +25 post-BMT secondary prophylaxis was changed to ciprofloxacin and clarithromycin due to hepatic toxicity. Treatment was maintained until day 100 without side effects. There was no evidence of recurrent mycobacteriosis. Eight months after BMT the patient is well, with a good performance status and chronic graft-versus-host disease (GVHD) limited to the oral mucosa. Thus, MAC infection prior to transplant need not be a contraindication to successful BMT.

Adult↗

PubMedDate not supplied

Interferon-alpha 2a therapy in CML: disappearance of BCR/ABL transcript in a case of long-lasting continuous cytogenetic conversion.

Seventy months after diagnosis, minimal residual disease is undetectable in a patient with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in long-lasting continuous cytogenetic conversion (CCC), achieved through alpha 2a-interferon (IFN-alpha) therapy. Fluctuating molecular remission, evaluated with the two-stage reverse transcriptase-polymerase chain reaction (RT-PCR) with nested primers, has persisted for two years at the maximum tolerable dose of IFN alpha (1.5 x 10(6) IU per day).

Adult↗

PubMed1978

[Varying course of pancytopenia after busulfan treatment of chronic myelocytic leukemia (CML)].

In 84 patients with chronic myeloid leukaemia receiving a cytostatic monotherapy with busulfan, an aplastic syndrome developed which was confirmed by a biopsy of the pelvis crest and examination of the sternal marrow. The time interval until pancytopenia was detected varied considerably in each case, ranging between 6 and 126 months. There are no correlations to the initial doses of busulfan. 3 patients died of the immediate effects of the bone-marrow damage caused by busulfan. In 4 from 6 of the following pancytopenic patients the leukocyte values lay between 12,800/microliter and 80,400 microliter when busulfan adminstration was interrupted. Thus, it is scarcely possible to give any reliable informations about a leukocyte limit value as a standard for an interruption of therapy in order to prevent bone-marrow aplasia. Taking this into account, the conclusion may be drawn that relatively short control intervals have to be made in this monochemotherapy of CML which often can be used successfully for many years.

Adolescent↗

PubMed1993

Frequent detection of BCR-ABL specific mRNA in patients with chronic myeloid leukemia (CML) following allogeneic and syngeneic bone marrow transplantation (BMT).

We performed a two-step polymerase chain reaction (PCR) to detect bcr-abl-specific mRNA in 440 peripheral blood and/or bone marrow samples of 30 chronic myeloid leukemia (CML) patients (mean 15, range 2-50 samples) following non T-cell-depleted allogeneic (n = 28) or syngeneic (n = 2) bone marrow transplantation (BMT). Median follow-up after BMT is 40 months (range 2-116 months), the median observation time 29 months (range 2-40 months). In 15 patients (50%), bcr-abl-specific mRNA could be detected following BMT. Bcr-abl positivity was rare in patients who were in hematological remission for at least 40 months (2/11). In five patients, PCR positivity was observed only once; all five patients are in complete hematological remission. Ten patients showed bcr-abl specific mRNA in two or more consecutive samples. Hematological relapse occurred in five of the latter patients. Bcr-abl positivity preceded hematological relapse in all cases. Bcr-abl positivity was detected more frequently in patients without graft-versus-host disease (GVHD) (11/15), than in patients with GVHD (4/15) (p < 0.02). Our data indicate that transient bcr-abl positivity is not usually followed by hematological relapse, while patients, who are positive in serial samples have a high risk of relapse.

Adult↗

PubMed1993

Molecular characterization of a variant Ph1 translocation t(9;22;11) (q34;q11;q13) in chronic myelogenous leukemia (CML) reveals the translocation of the 3'-part of BCR gene to the chromosome band 11q13.

We performed cloning and sequence analysis of translocation junctions at 11q- and 22q- (Ph1) chromosomes and the corresponding germline DNAs of a variant Ph1-positive CML with t(9;22;11)(q34;q11;q13). Southern blot analysis using probes for different regions of bcr mapped the translocation break near the 5'-side of bcr exon 4. Cloning, Southern blot analysis and restriction map analysis of both bcr fragments showed that the part of bcr 3'- to the translocation break moved to 11q13. Sequence analysis of the translocation junction on the Ph1 chromosome showed that the translocation break occurred 63 bp upstream of exon 4. Compared to the germline sequence, bcr sequence from the translocated partners showed deletion of seven basepairs at the site of translocation. A probe derived from the 5'-region of the clone isolated from the 11q- chromosome identified clonal rearrangements in the leukemic DNA. Restriction map and sequence analysis showed that this clone consisted of the 3'-half of the glutathione S-transferase Pi (GST-Pi) gene and the 3'-part of bcr. We identified two point mutations in the GST-Pi allele involved in translocation. Northern blot analysis showed that the GST-Pi gene was expressed in the leukemic cells at blast crisis but not at chronic phase; however, no fusion mRNA between GST-Pi and bcr was identified. We did not find any sequence homology between 11q13 DNA and 22q11 DNA around the translocation breakpoints; however, sequences homologous to ALU repeats were identified close to the sites of translocation breaks at 22q11 and 11q13. This study supports our hypothesis that variant Ph1 translocations may occur as primary cytogenetic changes similar to the classical Ph1 translocations.

Base Sequence↗

PubMed1993

Hematopoietic recovery from host progenitors with normal karyotype devoid of Philadelphia chromosome in a patient with CML after allogeneic BMT.

A male patient with CML received a BMT from his sister and developed chronic GVHD. The host-origin normal karyotype (46,XY) was identified for the first time in the 60th month after BMT. Detection of Y-chromosome-specific DNA in BM and peripheral blood (PB) showed that all BM samples obtained 6 months from BMT were positive for Y-specific DNA, while PB became positive in the 60th month after BMT. The BCR-ABL mRNA derived from leukemic cells was detected in the 36th month post-BMT, but not in the 60th month or thereafter. Fluorescence in situ hybridization revealed that 1.5% and 0.6% in BM and PB cells were Y-positive in the 70th month post-BMT, respectively. DNA analysis of hematopoietic progenitor colonies revealed 1 of 42 erythroid colonies to be host derived. These results indicate that host-origin hematopoietic cells survive chronic GVHD, while the Ph1 clone was eliminated.

Adult↗

PubMed1993

Successful allogeneic bone marrow transplantation in juvenile CML: conditioning or graft-versus-leukaemia effect?

Allogeneic BMT is the treatment of choice for juvenile CML (JCML). This has been successful following conditioning with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (10-15.75 Gy). However, busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) (Bu/Cy) conditioning has been reported to be insufficient to eradicate the malignant clone in JCML. We report successful BMT and eradication of the disease at 18 months follow-up in a child 15 months old at presentation, who was conditioned with busulphan 20 mg/kg and cyclophosphamide 200 mg/kg, with the addition of splenic irradiation. Despite using higher than conventional doses of busulphan, pharmacokinetic analysis revealed very low busulphan peak levels and rapid excretion. As a possible consequence, only partial chimerism was achieved, but full engraftment ensued following the discontinuation of cyclosporin A, rebound donor lymphocytosis and the onset of acute GVHD. We suggest that host resistance to engraftment and tumour elimination was overcome by removing a suppressive effect on donor lymphocytes, allowing a graft-versus-leukaemia effect.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Detection of BCR/ABL fusion gene in CML: a preliminary report.

The BCR/ABL fusion gene in 31 patients with chronic myeloid leukemia (CML) was detected by RT/PCR. In 18 cases of Ph' positive patients, 13 had BCR 3/ABL II rearrangement, 1 had BCR 2/ABL II rearrangement and 4 had both rearrangements. One case with complex translocation: 46,XY,t(9;9;22), had BCR 3/ABL II rearrangement. In 8 cases of Ph' negative patients, 4 had BCR 3/ABL II rearrangement, 3 had both rearrangements while 1 had no BCR/ABL rearrangement. Interestingly, in 4 patients who had no cytogenetic result, we could observe BCR 3/ABL II rearrangement in 3 cases and both rearrangements in 1 case. The results suggest that this procedure is sensitive and independent of the presence or absence of an identifiable Ph' chromosome.

Bone Marrow↗

PubMed1996

Reconstitution with Philadelphia chromosome-negative recipient haematopoiesis early after allogeneic BMT for CML.

We report a 33-year-old man with Ph chromosome-positive CML who underwent an allogeneic BMT from an unrelated donor. DNA microsatellite studies showed complete donor chimaerism immediately after BMT followed by mixed chimaerism; by day + 45 haematopoiesis was exclusively of recipient origin. Throughout the first year post-transplant all marrow metaphases were Ph negative but with non-clonal rearrangements consistent with autologous recovery. Cytogenetic relapse of leukaemia was first detected 15 months post-transplant. This case is unusual in that non-malignant stem cells of recipient origin survived the transplant and reconstituted haematopoiesis very early after BMT. Later the leukaemic cells reasserted their 'proliferative' advantage.

Adult↗

PubMed1996

Lymphoblastoid human interferon and low dose IL-2 combined with donor lymphocyte infusion as therapy of a third relapse of CML--a case report.

A patient, who was treated twice with donor lymphocyte infusions for relapse of CML after an allogeneic BMT was given lymphoblastoid human alpha-IFN after a third relapse. Further donor lymphocyte infusions were followed by repeated courses of 30 days treatment with a low dosage of IL-2 subcutaneously, alternately with alpha-IFN. This treatment resulted in a hematologic and cytogenetic remission. He also developed a limited degree of chronic GVHD. At the latest follow-up at 20 months after the third course of lymphocyte infusions he is in continuous hematologic and cytogenetic remission. Furthermore, a qualitative PCR analysis for the bcr/abl translocation is negative.

Adult↗

PubMed1996

Allogeneic bone marrow and peripheral stem cell transplantation from a haplo-identical mother and CD34 positive selection for CML.

A 6-year-old boy with CML in blastic crisis was transplanted with BM and PBSC from his HLA-mismatched MLC-positive mother following CD34-positive selection. Preconditioning for transplant was with thiotepa, cyclophosphamide, rabbit anti-human thymocyte globulin, and TBI followed by infusion of 2.6 x 10(6)/kg of CD34-positive BM and PBSC. Engraftment was confirmed by FISH analysis, and GVHD was not observed. On day 50, he relapsed and died despite three transfusions of donor lymphocytes without GVHD prophylaxis. CD34-positive cell selection for HLA-mismatched transplantation may prevent severe acute GVHD.

Animals↗