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M Talpaz

Publications and source records attributed to M Talpaz.

At least 199 records · Page 11Linked to original sources
PubMed1993

Ubiquitous expression of cytokines in diverse leukemias of lymphoid and myeloid lineage.

It has recently been suggested that autocrine production of hematopoietic regulatory molecules can modulate the cardinal features of many leukemic states: excessive proliferation of the neoplastic cells and suppression of the normal elements. We therefore analyzed samples obtained from 57 patients with a variety of hematologic malignancies (21, acute myelogenous leukemia; 14, acute lymphoblastic leukemia; 12, Philadelphia chromosome-positive chronic myelogenous leukemia [blast phase] or acute leukemia; 5, chronic lymphocytic leukemia; and 5, chronic myelomonocytic leukemia) for expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) transcripts on Northern blots. TNF-alpha mRNA was discerned in almost half of the samples (47%), and was expressed in some patients with every type of leukemia, except T-cell acute lymphoblastic leukemia (ALL). Expression occurred with great frequency in samples (12 of 15 [80%]) from monocytic (acute or chronic) leukemias, and from advanced chronic lymphocytic leukemia (4 of 5 samples [80%]). IL-1 beta transcripts were detected in 20 of 57 samples (35%). Its presence, like that of TNF-alpha, was ubiquitous, and only chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia cells consistently failed to produce IL-1 beta message. Therefore it appears that TNF-alpha and/or IL-1 beta mRNA can be found in the leukemic cells from a substantial subset of patients with B cell-derived acute lymphoblastic leukemia as well as with chronic and acute myeloid, monocytic or lymphocytic leukemias. Because these cytokines have potent direct and indirect effects on normal and malignant hematopoiesis, their widespread constitutive expression by neoplastic blood cells may play a fundamental role in driving the leukemic process.

Blotting, Northern↗
PubMed1993

Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis.

PURPOSE: To determine the clinical and laboratory characteristics and outcomes of patients with chronic myelogenous leukemia (CML) in the lymphoid blastic phase. PATIENTS AND METHODS: Data from 296 patients with CML blastic-phase disease who were referred to our institution between 1967 and 1991 were analyzed. Sixty-eight patients had CML lymphoid blastic-phase disease. Pretreatment characteristics, responses to different therapies, and survival rates were evaluated. RESULTS: Compared with patients having myeloid or undifferentiated blastic-phase disease, those with lymphoid morphology were significantly younger, presented with significantly lesser degrees of anemia, lower white blood cell and peripheral blast counts, higher percentages of marrow blasts, lower lactic dehydrogenase levels, and higher albumin levels. Accelerated-phase CML preceded the blastic phase in 40% of patients with lymphoid disease, compared with 54% of those with other morphologic findings (p = 0.03). The common acute lymphocytic leukemia antigen (CALLA) was expressed on lymphoid blasts in 97% of patients. The incidence of chromosomal abnormalities was similar in the three morphologic categories, although patients with lymphoid disease tended to have a lower incidence of trisomy 8 (17% versus 27%; p = 0.10) and of isochromosome 17 abnormalities (10% versus 17%; p not significant). The incidence of lymphoid blastic phase disease has not increased over the past decade, and it is not higher in patients with the chronic phase of the disease treated with alpha interferon. Patients with lymphoid disease had a significantly higher response rate to chemotherapy during the first salvage (49% versus below 20% for other morphologies; p < 0.001), particularly with vincristine, Adriamycin, and dexamethasone therapy (complete response rate of 61%). Survival during the blastic phase of the disease was also significantly longer in patients with lymphoid morphology than in those with other morphologies (median survival of 9 months versus 3 months; p = 0.01). The benefit associated with lymphoid blastic-phase morphology is brief, and plans for allogeneic bone marrow transplantation or experimental maintenance or consolidation programs should be implemented rapidly. CONCLUSIONS: Patients with CML lymphoid blastic-phase disease have different clinical and laboratory features than patients with other blastic-phase morphologies. In patients developing CML blastic-phase disease, distinguishing those with lymphoid transformation is extremely important because of the different therapeutic requirements (acute lymphocytic leukemia-type therapy) and prognostic implications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Suppression of chronic myelogenous leukemia colony growth by interleukin-4.

Interleukin-4 (IL-4) is a cytokine with pleiotropic activities. In normal bone marrow cultures grown in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), IL-4 suppresses granulocyte-macrophage colony-forming unit (CFU-GM) proliferation but it enhances the colony-stimulatory effect of granulocyte colony-stimulating factor (G-CSF). We studied the effect of IL-4 on chronic myelogenous leukemia (CML) bone marrow or peripheral blood cells from 30 patients using the CFU-granulocyte-erythrocyte-monocyte-megakaryocyte colony culture assay. In several repetitive experiments, IL-4 inhibited CFU-GM colony replication by 24 to 65% in a dose-dependent fashion at concentrations ranging from 0.01 to 10 micrograms/ml when patients' cells were cultured in the presence of erythropoietin alone or with phytohemagglutinin-conditioned medium, GM-CSF, or IL-3. The addition of 100 U/ml of IL-1 beta to the CML cultures partially reversed the inhibitory effect of IL-4. Incubation of CML low-density peripheral blood cells with IL-4 resulted in down-regulation of IL-1 beta and IL-6 production in three of four samples, suggesting that the suppressive effect of IL-4 is mediated by inhibition of IL-1 and by other mechanisms including inhibition of IL-6 production. In contrast to the stimulatory effect exerted by IL-4 on G-CSF-dependent CFU-GM progenitor proliferation in normal marrow, the addition of IL-4 to CML cultures grown in the presence of G-CSF resulted in a divergent effect: suppression of CML CFU-GM in two, stimulation in three, and no significant effect in two CML patients' samples. It is therefore possible that IL-4 may have an in vivo antiproliferative effect in a subpopulation of CML patients.

Adult↗
PubMed1992

Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors.

Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1-inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Adult↗
PubMed1992

Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy.

The significance of the polymerase chain reaction (PCR) in the detection of minimal residual disease in Philadelphia chromosome (Ph')-positive chronic myelogenous leukemia (CML) following interferon therapy was investigated. Forty remission blood samples obtained at various remission time points from 29 patients in complete cytogenetic remission were analyzed. All 40 samples showed minimal residual Ph'-positive cells by PCR: 22 in remission for less than 12 months, 12 in remission for 12 to 24 months, four in remission for 25 to 60 months, and two in remission for more than 60 months. Of these 29 patients, seven relapsed at 4, 6, 9, 14, 17, 19, and 50 months after their first PCR-positivity during remission. One developed extramedullary myelopoiesis at 49 months after PCR-positivity. The remaining 21 patients remained in complete hematologic and cytogenetic remission with median follow-up of 13 months (range, 4 to 36 months) after PCR analysis. These findings indicate that PCR-positivity is not associated with immediate disease recurrence. Long-term follow-up is essential to determine the relevance of PCR-positivity, since late recurrence is observed in our study.

Biomarkers, Tumor↗
PubMed1992

Interferon-stimulated genes in interferon-sensitive and -resistant chronic myelogenous leukemia patients.

alpha-Interferon induces hematological and cytogenetic remissions in some individuals with newly diagnosed Philadelphia-positive chronic myelogenous leukemia. However, interferon-resistant disease occurs in a consistent patient subset (primary resistance) and develops during therapy in additional patients (secondary resistance). Several alpha-interferon-inducible genes have been characterized. In interferon-resistant cell line variants, defects in these genes have been implicated in the mechanisms mediating resistance. We have, therefore, evaluated mRNA expression of four interferon-stimulated genes (ISGs) following alpha-interferon therapy. Twenty-seven chronic myelogenous leukemia patients (ten interferon-sensitive patients, 17 interferon-resistant patients) were studied. Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts. Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon. The ISG-15 message was detected in eight of nine interferon-sensitive and in 15 of 16 interferon-resistant patients, as well. Overall, no consistent defect in the ISG system could be identified. Therefore, lack of induction of these genes cannot explain resistance to alpha-interferon in chronic myelogenous leukemia patients. Other mechanisms such as posttranslational modification, leading to defects in the ISG corresponding proteins, may play a role in the development of resistance.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Polyclonal hematopoiesis in interferon-induced cytogenetic remissions of chronic myelogenous leukemia.

Interferon (IFN) therapy of early chronic myelogenous leukemia (CML) frequently produces partial or complete cytogenetic remission of the disease. Patients with complete cytogenetic remission often continue on therapy for several years with bone marrow showing only diploid (normal) metaphases. We studied hematopoiesis in five female patients with major cytogenetic remissions from CML during IFN therapy. Clonality analysis using the BstXI PGK gene polymorphism showed that granulocytes were nonclonal in all patients during cytogenetic remission. BCR region studies showed rearrangement only in the one patient whose remission was incomplete at the time of sampling. Granulopoiesis is nonclonal in IFN-induced remissions of CML and may be derived from normal hematopoietic stem cells.

Clone Cells↗
PubMed1992

Bone marrow hypoplasia and aplasia complicating interferon therapy for chronic myelogenous leukemia.

In four patients with Philadelphia chromosome-positive (Ph1) chronic myelogenous leukemia (CML), bone marrow hypoplasia (three patients) and aplasia (one patient) developed during or after therapy with either alpha-interferon (IFN) or gamma-IFN. The predominant clinical characteristic of this complication was protracted pancytopenia, which required 2 to 5 months recovery time after treatment and did not resolve in one patient. Bone marrow cytogenetic analysis in two of the patients demonstrated 100% Ph1 metaphases despite the profound bone marrow suppression. Overall, this complication was uncommon, occurring in less than 2% of the patients with CML treated with various IFN. The possible underlying causes include previous therapy with alkylating agents, lack of "reservoir" or normal stem cells, or pronounced sensitivity of the malignant cell clone to the suppressive effect of IFN.

Adult↗
PubMed1992

Very low doses of GM-CSF administered alone or with erythropoietin in aplastic anemia.

UNLABELLED: PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy. PATIENTS AND METHODS: We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously). RESULTS: In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin. CONCLUSIONS: Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.

Adolescent↗
PubMed1992

Identification of a complex formed between nuclear proteins and the transcriptional enhancer of interferon-inducible genes that is present in the peripheral blood myeloid cells of CML but not normal individuals.

Interferon-alpha (INF-alpha) induces cytogenetic remissions in 20% of chronic myelogenous leukemia (CML) patients. To clarify the mechanisms through which this antiproliferative action of IFN is mediated in the CML cell, a modification of the mobility-shift assay was used to follow the formation of complexes between nuclear proteins and IFN-inducible transcriptional enhancers involved in mediating the cellular effects of IFN-alpha. These studies identified a complex that was present in the myeloid cells of 18/24 (75%) of chronic-phase CML patients tested whose cells contained 100% Philadelphia chromosome positive (Ph+) cells, while the proteins of none of the samples tested from normal peripheral blood samples and only 22% (2/9) of the CML patients in an IFN-induced major cytogenetic remission (less than 30% Ph+ cells) contained these complexes. These studies suggest that the mobility-shift assay detects changes in the CML myeloid cell that distinguish it from the normal myeloid cell.

Base Sequence↗
PubMed1992

Detection of minimal residual disease by polymerase chain reaction of bcr/abl transcripts in chronic myelogenous leukaemia following allogeneic bone marrow transplantation.

The prognostic significance of detecting minimal residual disease by polymerase chain reaction (PCR) amplification of bcr/abl mRNA transcripts was investigated in 27 bone marrow samples from 20 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukaemia (CML) in complete cytogenetic remission following allogeneic bone marrow transplantation. Sixteen were transplanted in first chronic phase, two were in second chronic phase, one was in accelerated phase and one was in blast crisis. All 20 achieved complete cytogenetic remission post transplant and 15 patients had detectable bcr/abl mRNA by PCR from 2 to 22 months following the procedure. One of these patients had graft failure and one died from graft-versus-host-disease at 7 months. Of the remaining 13 PCR-positive patients, only one (8%) relapsed after 23 months; the other 12 were alive and still in remission after a median follow-up of 16+ months (ranging 5+ to 29+ months). Five patients were PCR negative; all are alive in complete clinical and cytogenetic remission at 10+, 11+, 19+, 25+ and 25+ months post transplant. In this study, detection of subclinical Ph1-positive cells by PCR was not associated with imminent clinical or cytogenetic relapse. Since late recurrence may potentially occur, long-term follow-up is required to definitely determine the prognostic value of the PCR assay.

Adult↗
PubMed1992

Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor.

PURPOSE: The study was undertaken to improve the results of intensive chemotherapy in chronic myelogenous leukemia (CML) in accelerated (CML-AP) and blastic phases (CML-BP) by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) as supportive therapy. PATIENTS AND METHODS: Forty-eight patients were treated with daunorubicin 120 mg/m2 intravenously on day 1, cytarabine (ara-C) 1.5 g/m2/d by continuous infusion over 24 hours for 4 days, and Solu-Medrol (methylprednisolone; The Upjohn Co, Kalamazoo, MI) 100 mg/d for 5 days, followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters. Twenty-four patients had CML-BP, and 24 had CML-AP. RESULTS: During remission induction, 45 patients (94%) developed febrile episodes (fever of unknown origin, 23 patients [48%]; documented infections, 22 patients [46%]). The median time to recovery of granulocyte count above 0.5 x 10(3)/microliters was 29 days and to platelet count above 30 x 10(3)/microliters, 28 days. Overall, 14 of 48 patients (29%) achieved a complete hematologic remission (CHR), and seven (15%) reverted to a second chronic phase. CHR was noted in eight of 24 patients with CML-BP (33%), and in six of 24 patients with CML-AP (25%). Cytogenetic responses were observed in 11 patients (23%), but were transient. Sixteen patients developed either fluid retention, hypotension, pleuropericardial effusions, or pericarditis, or a combination of these side effects. These side effects were severe in four patients and are likely to be disease-associated, as a similar regimen of intensive chemotherapy and GM-CSF at the same dose and schedule in acute lymphocytic leukemia was not associated with these side effects. CONCLUSIONS: The results pertinent to remission rates, induction mortality, myelosuppression profile and related complications, and overall survival were not significantly improved compared with previous experience. In summary, the results of intensive chemotherapy in CML-transformed phases remain poor, despite the addition of GM-CSF as a supportive measure.

Adult↗
PubMed1992

Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of interferon-alpha (IFN-A) and low-dose cytarabine (ara-C) combination chemotherapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Sixty patients with advanced phases of Philadelphia chromosome (Ph)-positive CML received combination therapy with IFN-A 5 x 10(6) U/m2 daily, and low-dose ara-C 15 mg/m2 daily for 2 weeks every 4 weeks until remission, then for 1 week every month as maintenance. Forty patients were in late chronic-phase CML, and 20 were in accelerated-phase CML (16 with clonal evolution only, four with other criteria). Their outcome was compared with 58 patients (39 late chronic-phase CML and 19 accelerated-phase CML) who had been previously treated with IFN-A alone in the same dose schedule. RESULTS: In late chronic-phase CML, patients receiving IFN-A plus ara-C had a better complete hematologic response (CHR) rate compared with those treated with IFN-A alone (55% v 28%; P = .02), a trend for better Ph suppression (15% v 5%; P = .13), and a longer survival (3-year survival rate 75% v 48%; P less than .01). These differences do not seem to be caused by imbalances in prognostic factors between the two treatment groups. In accelerated-phase CML, the addition of ara-C to IFN-A did not improve the response rate of treated patients, and the difference in survival was accounted for by different patient characteristics. Suppression of clonal evolution was observed in five patients (25%). Patients with clonal evolution as the only criterion for disease acceleration had a longer survival than those with other or additional accelerated-phase criteria (3-year survival rate 67% v 22%; P less than .01). CONCLUSION: The results with the combination of IFN-A plus ara-C in late chronic-phase CML are encouraging, and suggest the need for its evaluation in early chronic-phase CML.

Adult↗
PubMed1992

The modulatory hematopoietic activities of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a multi-potential cytokine which has been implicated in the hematopoietic regulatory machinery. For example, we have found that LIF is constitutively expressed in marrow stroma. Other investigators have reported that LIF affects remodeling of bone, and that, in concert with other growth factors, it stimulates hematopoietic stem cell proliferation. Moreover, in vivo animal trials reveal that, at high doses, administration of LIF induces myelosclerosis whereas, at lower doses, megakaryocytosis and thrombocytosis with reduced bone marrow cellularity and marrow lymphopenia are observed. Therefore, the role of LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and sclerosis merits investigation. Further, its megakaryocytic stimulatory properties suggest that LIF may be exploitable in the clinic to enhance platelet production.

Animals↗
PubMed1992

Comparison of in vivo and in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with acute myeloid leukemia.

We studied the in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in 13 patients with acute myeloid leukemia (AML) and one patient with refractory anemia with excess of blasts in transformation using the AML blast (AML colony-forming units, AML-CFU) and mixed (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) colony culture assays. In parallel, these patients received GM-CSF s.c. at 125 micrograms/m2/day, or in escalated doses starting with 10 micrograms/m2/day for a week or until circulating blast counts reached 50 x 10(9)/liter, in an effort to sensitize leukemic blasts to cell-cycle-specific agents. Results of in vivo GM-CSF treatment were correlated with those of in vitro assays. In 9 of 12 patients (75%), GM-CSF treatment increased peripheral blood blast counts (in vivo effect). GM-CSF also stimulated in vitro AML blast colony proliferation in these nine patients and increased the S+G2M phases of the cell cycle in five out of five of these patients' samples. Two of three patients in whom an in vivo response could not be demonstrated also failed to have a detectable in vitro response. These observations suggest that the AML blast colony culture assay may be useful in predicting the response of AML to cytokine therapy. Finally, GM-CSF stimulated granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) and erythroid (erythroid burst-forming units, BFU-E) colony proliferation in 14 and 11 patients, respectively, including the 3 individuals who demonstrated no clinical effect on blast counts. It is, therefore, possible that GM-CSF may be used to stimulate proliferation of progenitors that differentiate into mature granulocyte, monocyte-macrophage, and erythroid cells.

Acute Disease↗
PubMed1992

The effect of granulocyte-macrophage colony-stimulating factor on undifferentiated and mature acute myelogenous leukemia blast progenitors.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used recently to recruit undifferentiated acute myelogenous leukemia (AML) blasts into the S-phase of the cell cycle and increase the fraction of cells killed by cell cycle-specific drugs. Using three AML blast colony assays combined with a suspension culture (delta assay), we determined the in vitro effect of GM-CSF on mature and undifferentiated AML blast progenitors obtained from bone marrow aspirates of six AML patients. GM-CSF stimulated AML blast colony proliferation at a concentration of 5 ng/ml in the methylcellulose and the agar clonogenic assays in six of six AML marrow samples. However, in the delta assay, which selects for immature AML progenitors, GM-CSF did not affect AML blast colony-forming cells in five of six AML marrow samples at concentrations ranging from 5 to 300 ng/ml. Our data imply that GM-CSF stimulates mature but not undifferentiated AML blast progenitors. It is therefore possible that GM-CSF may not be beneficial as a recruiting agent in most AML patients.

Adult↗
PubMed1992

Minimal residual disease in interferon-treated chronic myelogenous leukemia: results and pitfalls of analysis based on polymerase chain reaction.

Therapy with interferon-alpha results in complete cytogenetic remission in 15-20% of patients with chronic myelogenous leukemia. Even during prolonged clinical follow-up, most of these patients do not relapse. However, because of the limited sensitivity of cytogenetic techniques (approximately 5%) and Southern blots (approximately 1%), it is uncertain whether the residual malignant clone becomes extinct or persists below the limit of detection in these patients. We used polymerase chain reaction to amplify the chimeric BCR-ABL transcripts in 18 patients with chronic myelogenous leukemia who became Ph1 chromosome negative while receiving treatment with interferon-alpha, either alone or in combination with interferon-gamma. At the time of study, these patients had been Ph1-negative for a median of 22+ months. Fifteen patients were positive for residual BCR-ABL transcripts. No residual BCR-ABL message was detected on analysis of multiple serial samples in three patients. In order to confirm these results, the samples from these three patients, along with positive and negative controls, were analyzed by two independent laboratories in a blinded fashion. In the first laboratory, RNA specimens from all three patients were considered negative using chemiluminescent acidinium-ester-labeled probes. In the second laboratory, samples from all three patients were also negative by conventional polymerase chain reaction (PCR). However, when a second round of amplification was carried out on the amplified samples using a different combination of primers, samples from two of the three patients were positive. The results confirm the presence of a small proportion of BCR-ABL-positive cells in the majority of patients who are in complete remission and highlight some of the potential problems of PCR-based analysis. There is a need to standardize PCR methodology and potential confounding factors need to be addressed before PCR can be generally applied to analysis of minimal residual disease in CML. The implications of BCR-ABL positivity for these patients are discussed.

Adult↗