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PubMed1998

Long term follow up after allogeneic stem cell transplantation for chronic myelogenous leukemia.

Between January 1983 and July 1997, 83 patients (35 female, 48 male) with a median age of 37 (19-57) years with chronic myelogenous leukemia (CML) were admitted for bone marrow transplantation (BMT) at the University hospital of Vienna. Fifty-six patients were in chronic phase, 17 in accelerated and 10 had blast crisis. Marrow donors were: HLA-identical siblings in 62 patients, 2-antigen mismatched related donor in 2, HLA-identical unrelated donors (MUD) in 17 and 1-antigen mismatched unrelated donor in 2 patients. The median time from diagnosis to BMT was 22 (2-91) months. Conditioning therapy consisted of cyclophosphamide (CY) and total body irradiation or CY and busulfan. For graft-versus-host disease (GVHD) prophylaxis methotrexate (MTX) alone, MTX and cyclosporine A (CSA), CSA alone or CSA and methylprednisone were given. Durable engraftment was documented in 75 of 77 patients (97%). As of July 31, 1997 48 patients are alive (58%), 36 (56%) after sibling transplantation with a median observation time of 77 months and 12 (63%) after MUD transplantation with a median observation time of 13 months. Overall survival for patients in chronic phase (CP) at time of BMT is 64%, 53% for patients in acceleration and 30% for patients in blast crisis (BC). Disease-free survival (DFS) after sibling BMT and unrelated donor transplantation is 53% and 58%, respectively. Ten patients (12%) experienced relapse of CML. Transplant-related mortality was 33% after sibling and 32% after MUD transplantation. Thus, sibling and unrelated donor BMT offer high cure rates with acceptable toxicity to patients with CML.

Adult↗
PubMed1983

Adenosine deaminase and terminal deoxynucleotidyl transferase: biochemical markers in the management of chronic myelogenous leukemia.

Serial determinations of adenosine deaminase (ADA) activity in 69 patients with chronic myelogenous leukemia provided a biochemical marker of disease activity. Eighty-nine % of patients in the accelerated phase had an elevation of ADA activity. This elevation was not a direct reflection of an increased absolute blast count. Furthermore, five of seven patients studied serially from the stable phase into the accelerated phase had an increase in ADA activity before the absolute blast count increased. This is the first investigation which clearly demonstrates the potential value of measuring serial ADA activities in a large number of patients with chronic myelogenous leukemia.

Adenosine Deaminase↗
PubMed1999

Enhanced expression of p16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

The tumor suppressor gene p16ink4a is homozygously deleted in numerous T as well as in some B lineage acute lymphoblastic leukemia (ALL). We therefore analyzed the clinical and biological implications of this feature by studying p16ink4a expression in 58 cases of childhood ALL. mRNA and protein were significantly correlated and both appeared more highly expressed in B than in T lineage ALLs: 13 out of the 15 T cell ALLs did not show any p16ink4a expression. The main result of this study is the strong prognostic value of p16ink4a expression. When stratifying the patients in three groups according to p16ink4a expression, we observed in univariate analysis: (1) the shortest disease-free survival for patients presenting a high p16ink4a level; (2) contrasting with the good prognosis in the group of patients expressing p16ink4a at low level; (3) while cases without any expression of the inhibitor were associated with a medium course of the disease (P=0.0165). This prognostic value was confirmed by the multivariate analysis showing therapeutic regimen and p16ink4a protein expression as the only variables retained in the model. A specific metabolic profile related to cellular survival and proliferation was observed in each of the three p16ink4a expression groups. Among the cell cycle-related proteins we analyzed, only p21waf1 bcl-2 and CDK4 were significantly and positively correlated to p16ink4a. Furthermore, CDK6 was also strongly expressed in the group of cases with high p16ink4a level. An enhancement of p16ink4a, p21waf1 and bcl-2 was previously described in prolonged cellular survival, while aging cells showed a decrease in CDK4 expression. The concomitant high expression of the oncogenic protein CDK4 (and of CDK6), we observed, may amplify the leukemic advantage of prolonged lifespan blast cells by favoring cell progression through G1 phase. These data suggest that at least two mechanisms may be associated in the oncogenesis of very aggressive ALLs, ie deregulation of cell multiplication and prolonged blast lifespan.

Adolescent↗
PubMed1990

A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders.

Platelet function and the clinical course of the disease were prospectively investigated in 29 patients with myeloproliferative disorders. Serial determinations (median: 5 investigations per patient within 17 months) of platelet aggregation, plasma and intraplatelet concentrations of beta-thromboglobulin (beta TG) and platelet factor 4 (PF4), and of fibrinopeptide A (FPA) plasma levels were carried out. In the chronic phase of polycythaemia vera, patients with thrombohaemorrhagic complications during the study period had higher platelet count, more severe platelet aggregation defects, and increased plasma levels of beta TG and FPA compared to patients without complications. However, thrombohaemorrhagic complications were not predicted by changes in these parameters in the individual patient during the chronic disease phase. When patients with chronic myelogenous leukaemia entered blast crisis, bleeding complications were related to thrombocytopenia, impaired platelet function and low intraplatelet concentrations of beta TG and PF4. Cytoreduction by chemotherapy in the chronic phase of CML did not alter beta TG and PF4 plasma levels, whereas treatment of polycythaemia rubra vera by venesection favourably influenced platelet alpha-granule secretion and increased intraplatelet concentrations of beta TG and PF4.

Adult↗
PubMed1995

Promyelocytic blast crisis of chronic myelogenous leukemia. A rare subtype associated with disseminated intravascular coagulation.

Two patients with chronic myelogenous leukemia (CML) developed blast crisis that morphologically appeared to be the microgranular variant of acute promyelocytic leukemia. This represented 8% of CML patients developing blast crisis from 1984 to 1993. Cytogenetic studies revealed translocation 15;17 in addition to translocation 9;22 that had been documented at initial diagnosis. Both patients had evidence of disseminated intravascular coagulation at the onset or during treatment of blast crisis, which was not documented in any other patients with CML blast crisis. One patient died of sepsis during intensive chemotherapy. The second returned to a chronic phase of the disease after therapy. Although rare, a promyelocytic blast crisis of CML can occur which, as in de novo acute promyelocytic leukemia, has a propensity to produce disseminated intravascular coagulation.

Adult↗
PubMed1984

Virologic, immunologic, and clinical observations on a patient during the incubation, acute, and convalescent phases of infectious mononucleosis.

One patient with infectious mononucleosis (IM) was studied from the probable time of Epstein-Barr virus (EBV) infection (38 days before the onset of clinically overt disease), during the incubation and acute phases, until 6 months after clinical remission. Analysis of spontaneous outgrowth of EBV-carrying lymphoblastoid cells, by limiting dilution on feeder layer cultures, showed that virus containing B lymphocytes are already present early during the incubation period. Also low interferon serum levels were detected early after infection, and only before the onset of clinical disease. All other studied clinical laboratory and virus-associated variables were within normal range during the incubation phase, but changed to a pattern characteristic of IM in parallel to the clinical symptoms. During the acute disease EBV-associated nuclear antigen (EBNA)-positive cells could be directly detected among the lymphocytes, and antibodies to EBV antigens appeared. Lymphocytes stained by monoclonal antibodies, detecting Ia-like determinants (activated cells) and suppressor cells, increased dramatically, in parallel to a strong increase of functional suppressor cell activity, measured by inhibition of blastogenesis and PWM-induced immunoglobulin production. During the acute phase there was also a decrease of spontaneous cytotoxicity against the NK-sensitive cell line K562, while cytotoxicity (spontaneous) against an autologous EBV-positive lymphoblastoid cell line (LCL) was detected only during this phase. These reactions correlated to the presence of blasts, and the autologous reaction was exerted mainly by Fc-receptor-negative cells. Lymphokine production in response to EBV antigens was also initiated during the acute phase. During the convalescence period the serological and cellular immune parameters adjusted to the pattern of a normal EBV-seropositive person.

Adolescent↗
PubMed1996

Long-term survival in advanced chronic myelogenous leukemia following bone marrow transplantation from haploidentical related donors.

From 1987 to 1991, 26 patients with CML and a median age of 31 years received allogeneic BMT from a partially mismatched related donor (PMRD) who shared at least one haplotype with the recipient. Nine patients were in accelerated phase (AP), and 11 patients were in blast crisis (BC) at the time of BMT. Patients were mismatched either in graft-versus-host or host-versus-graft directions for one antigen in 3 patients, two antigens in 14 patients, and three antigens in 9 patients. All patients were prepared with a regimen consisting of total body irradiation, etoposide, cytosine arabinoside, cyclophosphamide and methylprednisolone. All marrows were treated ex vivo with T10B91.A-31, a monoclonal antibody directed toward the alpha beta heterodimer of the CD3 receptor, and rabbit complement. Additional GVHD prophylaxis included either the anti-CD5 immunoconjugate XomaZyme-H65, cyclosporine, or both in combination with methylprednisolone. Eight patients did not have sustained engraftment. The 100-day survival was 42%. The incidence of > or = grade II acute GVHD was 29%. The incidence of chronic GVHD was 50% and was limited in all cases. The median survival at 4 years for all 26 patients was 27%. Seven patients (CP 1, AP 3, BC 3) remain in hematologic remission 1297-2241+ days after transplantation. AlloBMT from a PMRD may be considered for patients with advanced CML who lack a matched sibling or unrelated donor.

Adolescent↗
PubMed1993

In vitro and in vivo effects of 5-aza-2'-deoxycytidine (Decitabine) on clonogenic cells from acute myeloid leukemia patients.

5-Aza-2'-deoxycytidine (Decitabine) is an analog of deoxycytidine now entering clinical trials in acute myeloid leukemia (AML) owing to a defined antileukemic activity mediated at least in part by DNA hypomethylation, altered gene expression, and induction of cell differentiation. In the present study, we examined the relationship between the in vitro sensitivity to Decitabine of blast progenitors and the clinical outcome, in nine AML patients treated in vivo with Decitabine within a phase II trial carried out at two different institutions. Leukemic blast progenitors in acute myeloid leukemia (AML) undergo terminal divisions giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected by a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. Three out of four patients, in which clonogenic cells in methylcellulose were strongly suppressed by Decitabine and clonogenic growth of blasts cultured in suspension was only slightly affected, failed on Decitabine treatment in vivo. Two subjects, whose blast progenitors in suspension culture were significantly inhibited by Decitabine, obtained a positive hematological response (complete or partial remission, CR or PR) and an additional patient showing a similar in vitro pattern died in induction with an hypoplastic marrow without morphological evidence of persistant leukemia. Interestingly two patients displaying an unfavourable in vitro pattern (i.e. a minor suppression of self-renewal mitoses as evinced from suspension cultures) achieved a hematological response (CR and PR) upon in vivo therapy with Decitabine. The in vitro response to Decitabine of clonogenic progenitors from both these patients shifted to a favourable pattern (i.e. major suppression of self-renewal versus terminal mitoses) following manipulation of culture conditions by the addition or removal of exogenous growth factors. In addition, in a further patient refractory to treatment with Decitabine in vivo, similar alterations of the culture conditions were unable to modify the unfavourable pattern of response to the drug in vitro. Our results indicate that the sensitivity of blast progenitors in suspension cultures strongly correlates with the remission outcome of the patients. From our data, it also appears that alterations of culture microenvironment are able to modify the response of AML blasts to Decitabine, unveiling the 'hidden' sensitivity of leukemic progenitors to the drug in cases characterized by a discrepancy between in vivo and in vitro results, i.e. apparent in vitro resistance and favourable clinical outcome.

Acute Disease↗
PubMed2006

hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.

Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.

Adolescent↗
PubMed1991

Monitoring DNA cytometric parameters during the course of chronic myelogenous leukemia.

The prognostic value of three DNA cytometric parameters--stemline ploidy (STL), stemline shoulder fraction (SSF) and "proliferative" fraction (PRF)--for the prediction of disease transformation and survival was examined for 20 patients with chronic myelogenous leukemia (CML) during the course of their disease and compared with two commonly used hematologic parameters (degree of leukocytosis and percentage of circulating leukemic progenitor cells). With disease progression, STL and SSF increased significantly, whereas PRF showed a steady decrease from diagnosis to blast crisis. The most significant part of these changes took place during the chronic phase, before the clinical onset of disease transformation. Hematologic parameters, in comparison, revealed significant changes later, shortly before blast crisis. The remaining duration of the chronic phase diminished from 25.5 months at the time of diagnosis, when the median STL was 2.0c, to 19.6 months for patients showing an STL of 2.1c, to 15.0 months with an STL of 2.2c and to 1.0 months for those with an STL of greater than or equal to 2.3c. Prognostically relevant limits for SSF and PRF were at 20%. When the SSF passed this limit or the PRF fell below it, the mean remaining chronic phase of these patients amounted to only 14.1 and 10.1 months. Interactive cytometry allows analysis of the DNA cytometric equivalent of changes in leukemic progenitor cells, which are well known from cytogenetic and cell kinetic studies. These three DNA cytometric parameters reflect the "natural history" of CML with the development of a cytogenetically hyperdiploid clone during disease progression in most patients and a simultaneous loss of proliferative potential on the level of myelobasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Blast Crisis↗
PubMed1982

Selective effects of interferon on distinct sites of the T lymphocyte triggering process.

Lectin- and antigen-induced proliferation of murine T cells consists of two major events, namely, a rapid induction of susceptibility to growth factors and a later-occurring, accessory cell-dependent production of T cell growth factors (TCGF). The mechanism by which interferon (IFN) inhibits T cell responses was studied accordingly. A decrease of Con A-induced proliferation was observed in the presence of increasing amounts of IFN. The reduced proliferative response in such cultures was found to be due to an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, the results show that IFN did not inhibit the early events in T cell triggering, because the acquisition of responsiveness of resting T cells to TCGF was unaltered in the presence of IFN, nor did it interfere with production of TCGF. In contrast, IFN was found to interfere with the TCGF-dependent T cell blast growth. Cytofluorometric analysis of the proliferative phase revealed that IFN exerts its effect on T cells, which have entered the proliferative cycle, by a postmitotic accumulation in G0/G1, thus reducing the proliferating population. The results demonstrate that IFN primarily affects the later phase of proliferative activity after T cell triggering, leaving the helper cell functions untouched.

Animals↗
PubMed2007

Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study.

Following exposure to cytotoxic agents, acute myeloid leukemia (AML) blasts elevate cellular cholesterol in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/ (M2 x day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 x day) by CI, days 4-7] in 15 newly diagnosed and 22 salvage patients with unfavorable (n = 26) or intermediate (n = 10) prognosis cytogenetics. Compared with historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride and total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV + Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe, and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML.

Adult↗
PubMed1987

Fractionation of K-562 cells on the basis of their surface properties by partitioning in two-polymer aqueous-phase systems.

The K-562 cell line is a culture of human leukemia stem cells originally derived from a patient with chronic myelogenous leukemia in blast crisis. We have subjected such cells, in the log phase of growth, to countercurrent distribution in a charge-sensitive dextran-polyethylene glycol aqueous-phase system, a method that fractionates cells on the basis of subtle differences in their surface properties, and found that: (1) The cell population is heterogeneous since it is composed of cells with different partition ratios. (2) There is a correlation between increasing cell partition ratios and increasing cell electrophoretic mobilities. (3) Cells under different parts of the distribution curve have dissimilar ratios of cells in different parts of the cell cycle, a phenomenon that may, at least partially, be the basis for the subfractionation of these cells. There is a clear tendency for cells in G0 + G1 + early S to decrease and for those in late S + G2 + M to increase with increasing partition ratios. (4) Sialic acid is a major surface charge component of the cells as evidenced by a dramatic drop in their partition ratios after treatment with neuraminidase.

Cell Cycle↗
PubMed1976

Karyometric and cytophotometric studies on nucleic acids in the culture of human lymphocytes with phytohemagglutinin.

Lymphocyte transformation with phytohemagglutinin (PHA) was analyzed by karyometry and cytophotometry of single cells. The former showed the distribution of various-sized transforming cells, and the latter the increase of DNA and RNA. Two different types of karyograms were obtained; one with three peaks corresponding to 2c, 4c, and 8c, and the other with only a 2c peak. Although small in number (8%), karyometry showed that DNA synthesis took place in the extremely early stage of transformation, 1 h after stimulation with PHA, which was proved by cytophotometry and ultrastructural findings. An increasing curve of DNA and RNA revealed that a lymphocyte continued to enlarge from 2c to 4c and divide again through the normal cell cycle in a suitable condition. The largest blast cell, a polyploid cell, may be induced by the lack of a sufficient amount of RNA and protein in need of cell division, and may be a degenerative cell in the strict sense. Among the large cells with blastlike appearance, there were a considerable number of so-called degenerative cells with a low amount of DNA. The ratio of RNA to DNA increased steeply in the actively DNA synthesizing S phase, which supports the morphologic findings of blast cell, the appearance of basophilic cytoplasm, and active-looking nucleoli.

Adolescent↗
PubMed1993

Detection of P210bcr-abl in mature granulocytes from Ph1-positive chronic myelogenous leukemia patients by an immunoblotting method.

Previously, p210bcr-abl has been detected in Philadelphia-chromosome-positive chronic myelogenous leukemia (CML) blast crisis and established cells originating from blasts. It has not been detected in mature granulocytes in the chronic phase. Protein degradation tends to occur during protein extraction, due to the activities of protease and phosphatase within these cells. Protein was, therefore, extracted in a cell lysis buffer containing alpha 1-antitrypsin and a high concentration of Na3VO4 as inhibitors. In mature granulocytes in the chronic phase, p210bcr-abl was detected and the level of tyrosine phosphorylation estimated by immunoblotting, using the enzyme-labeled antibody method with anti-c-abl and anti-phosphotyrosine antibodies. p210bcr-abl was phosphorylated on tyrosine residues in blast crisis cells and K562 cells derived from CML blast crisis, whereas it was dephosphorylated in mature granulocytes from chronic phase CML patients. This suggests that p210bcr-abl in mature granulocytes has no tyrosine kinase activity, or it is extremely weak, and dephosphorylation of p210bcr-abl is associated with differential maturation of immature cells in the chronic phase of CML.

Blast Crisis↗
PubMed1986

Phase I-II trial of VP-16 in the treatment of acute nonlymphocytic leukemia and blast crisis of chronic granulocytic leukemia.

VP-16 was used to treat newly diagnosed elderly (greater than or equal to 65 yr) patients with acute nonlymphocytic leukemia (ANLL) and patients with blast crisis of chronic granulocytic leukemia (BI-CGL). Our pilot study indicated that VP-16 160 mg/m2 intravenously daily for 5 days was well tolerated and suggested a direct dose-response correlation. Thirty additional ANLL patients and 11 CGL patients were studied. Among 26 evaluable ANLL patients, we observed ten responses (38%) (seven complete remission and three partial remission), but none of 11 patients with CGL in blast crisis had meaningful responses. In patients who responded to treatment, myelosuppression was always reversed by day 25. Stomatitis was the major nonhematologic toxicity and appeared more severe with advancing age. We conclude that VP-16 is active against ANLL and is well tolerated at doses higher than have been previously described. It remains to be shown that the present schedule is superior to the intermittent high-dose or continuous low-dose infusion schedules, which have been recently described.

Adult↗
PubMed1980

Dynamic and morphological responses of draining lymph nodes to single and repeated applications of oxazolone to guinea-pig skin.

Auricular lymph nodes in guinea-pigs were studied for 3 weeks under continuous stimulation with oxazolone applied to the ear skin. Quantitation of 3H-Tdr labelled paracortical lymphocytes following pulse labeling, demonstrated a marked, but only transitory rise in the proportion of cells in DNA synthesis. In spite of this, the total number of cells in S-phase continued to rise during the remaining part of the observation time, as a result of a steady increase of the paracortical cell mass. The variation in the proportion of large, pyroninophilic blast cells, revealed a pattern similar to that of the labelling index. A high proportion of blast cells was found only in the initial phase of the reaction, while the chronic response was characterized by a low proportion, no different from the starting level. Paracortical enlargement appeared to be the most reliable morphological criterion on which a chronically stimulated paracortex could be distinguished from an "unstimulated". The initial paracortical response, similar to a primary reaction, was followed by an equally pronounced development of germinal centres and plasma cells. These were also persistent features under continued stimulation. The reported changes are most likely specific responses to oxazolone stimulation.

Administration, Topical↗
PubMed1988

Longitudinal study of serum ferritin concentrations in chronic granulocytic leukaemia.

In 60 patients with Ph1-positive chronic granulocytic leukaemia (CGL) the serum ferritin concentration was measured as a part of the initial evaluation of the disease. The mean value (+SD) was 285 +/- 368.6 ng/ml, normal or slightly increased values being obtained in most cases. In 38 patients serum ferritin was again determined in clinical remission following busulphan treatment. Although the levels generally remained within the normal range, a significant decrease was observed with respect to the initial values (p = 0.0000004), suggesting that serum ferritin at presentation of CGL may be partially influenced by the disease activity. Finally, a further determination of serum ferritin concentration was made in a subgroup of 21 patients when they were diagnosed as being in the accelerated or blastic phases of CGL. Although no substantial increase was found with respect to the values obtained at presentation, a significant increase (p = 0.0008) was observed when accelerated-blastic phase ferritin levels were compared with those obtained in clinical remission. Although in patients in blast crisis no correlation was found between blast cell mass and serum ferritin, the differences observed between the different phases could indicate that in CGL serum ferritin concentrations roughly parallel the disease activity.

Adolescent↗