The biology of chronic myeloid leukemia.
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Cell Transformation, Neoplastic↗
Biomedical subjects
R Kurzrock
Publications and source records attributed to R Kurzrock.
Autocrine interleukin-1beta production in leukemia: evidence for the involvement of mutated RAS.
Interleukin (IL)-1beta is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-1beta and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NFkappaB, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1beta promoter and IL-1beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21Ras and IL-1beta protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1beta to the cultures. Our observations suggest that mutated RAS genes may mediate autocrine IL-1beta production in some leukemias by stimulating signal transduction pathways that activate the IL-1beta promoter.
Alkyl and Aryl Transferases↗
Prognostic factor analysis in mycosis fungoides/Sézary syndrome.
BACKGROUND: The influence of prognostic factors on survival in patients with mycosis fungoides/Sézary syndrome (MF/SS) is less well described than for other lymphomas. OBJECTIVE: Our purpose was to evaluate the prognostic value of diverse clinicopathologic and laboratory characteristics in patients with MF/SS. METHODS: All 115 patients with MF/SS seen at the Mycosis Fungoides clinic at M. D. Anderson Cancer Center during the study period who had slides available for pathologic review were analyzed. Univariate and multivariate methodologies were used. RESULTS: Age (> or = 60 years; P = .0002), advanced stage (P < 10(-5)), tumor (T3) stage disease (P < or = 10(-5)), lymphadenopathy (P = .006), bone marrow infiltration (P = .03), high lactate dehydrogenase (LDH; P = .0002), high beta2-microglobulin (> 2 mg/L; P = .009), and transformation to large-cell lymphoma (P = .004) were significant prognostic factors in the univariate analysis and correlated with a poorer survival. The outcome of patients staged as IIB was significantly worse than that of those staged as I or IIA or III (P < .001) and was comparable to that of the patients staged as IV (P = .8). In the multivariate analysis, the factors selected include stage (I to IIA and III vs IIB and IV; P < .0001), LDH (P = .006), and age (> or = 60 vs < 60 years; P = .02). The actuarial median survival of patients with advanced stage, high LDH, or age 60 years or more was 2.5 to 3.5 years, whereas that of patients without any of these parameters was more than 13 years. CONCLUSION: Our results suggest that patients with MF/SS who are staged as IIB or IV, who have a high LDH, or who are 60 years of age or older have an aggressive course and poor survival.
Bone Marrow↗
RAS inhibitors in hematologic cancers: biologic considerations and clinical applications.
As the molecular mechanisms responsible for the development and propagation of cancer are becoming elucidated, the nascent field of gene-directed therapy is emerging. Recently, several investigators have described inhibitors of the Ras protein. This molecule has been targeted because RAS is one of the most commonly mutated oncogenes in human neoplasia. In this review, we will discuss the role of Ras in the pathogenesis of hematologic neoplasms, and the biology behind the development of novel compounds which specifically suppress Ras function.
Animals↗
A pilot study of recombinant human interleukin-4 therapy of myelofibrosis.
Twelve patients with myelofibrosis were treated with recombinant human interleukin-4 (IL-4) administered subcutaneously thrice weekly. Dosage ranged from 1 microg/kg to 4 microg/kg. Median patient age was 65 years (range 36-74). Five patients had transient minor responses, and 5 patients had progressive disease. One patient had a transient minor response, rapidly followed by progressive disease. One patient suffered angioneurotic edema with first injection. Other significant toxicities included fever, flu-like symptoms, peripheral edema, and ascites. IL-4 at this schedule was toxic and had no significant activity in myelofibrosis.
Adult↗
2-chlorodeoxyadenosine-associated transient acantholytic dermatosis in hairy cell leukemia patients.
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Acantholysis↗
Pentostatin therapy of T-cell lymphomas with cutaneous manifestations.
PURPOSE: To determine the side effects of and response to pentostatin in patients with T-cell lymphomas with cutaneous manifestations. PATIENTS AND METHODS: Pentostatin was administered to 28 patients who had relapsed cutaneous T-cell lymphoma or peripheral T-cell lymphoma with prominent cutaneous disease. The starting dose was between 3.75 to 5.0 mg/m(2)/d intravenous for 3 days every 3 weeks. RESULTS: Of the 24 patients assessable for response, 17 (71%) achieved a partial remission (46%) or complete remission (25%). The patients had a median number of three (range, one to 12) prior therapies. Of the 86 courses of pentostatin given, 39 were administered at doses of 5.0 mg/m(2)/d and 30 at doses of 3. 75 mg/m(2)/d. Dose escalation to 6.25 mg/m(2)/d was possible in only five courses, and toxicity necessitated dose reduction to 2.8 mg/m(2)/d in 12 courses. The most common side effects were granulocytopenia, nausea, and nonneutropenic fever. Most patients developed significant lowering of CD4 counts. Herpes zoster was seen within 1 year after pentostatin in five patients (19%). CONCLUSION: Pentostatin is an active agent in heavily pretreated T-cell lymphomas with cutaneous manifestations.
Adult↗
RAS and leukemia: from basic mechanisms to gene-directed therapy.
PURPOSE AND DESIGN: The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 was performed. RESULTS: A wealth of data has been published on the role of Ras pathways in cancer. To be biologically active, Ras must move from the cytoplasm to the plasma membrane. Importantly, a posttranslational modification--addition of a farnesyl group to the Ras C-terminal cysteine--is a requisite for membrane localization of Ras. Farnesylation of Ras is catalyzed by an enzyme that is designated farnesyltransferase. Recently, several compounds have been developed that can inhibit farnesylation. Preclinical studies indicate that these molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells. CONCLUSION: An increasing body of data suggests that disruption of Ras signaling pathways, either directly through mutations or indirectly through other genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfere with the function of Ras may be exploitable in leukemia (as well as in solid tumors) as novel antitumor agents.
Alkyl and Aryl Transferases↗
Minimal residual disease in hematologic disorders.
In almost no other area of medical oncology has the introduction of new drugs, combinations of chemotherapeutic agents, and novel biologic treatments caused such dramatic responses as it has in the treatment of malignant hematologic disorders. However, despite some therapeutic success, many patients relapse and die from recurrence of their disease. The implications of minimal residual disease (MRD), a term referring to disease that is undetectable by conventional morphologic methods, have therefore attracted increasing attention in recent years. New and powerful laboratory tools such as polymerase chain reaction assays have extraordinary sensitivity and provide exciting new insights into the detection, nature, quantification, and kinetics of MRD. This article summarizes methods used in the identification of MRD and its importance as exemplified in the case of acute leukemias and chronic myelogenous leukemia.
Adult↗
A phase I study of recombinant interferon-beta in patients with advanced malignant disease.
To evaluate the safety, toxicity, and maximum tolerated dose (MTD) of IFN beta-1a (Rebif, Serono Laboratories, Inc.) in patients with malignant diseases unresponsive to standard therapies and to assess the pharmacodynamics and pharmacokinetics associated with IFN beta-1a administration, an open-label, single-center phase I study was designed. Thirty-four patients were enrolled and treated with IFN beta-1a. All had measurable solid neoplasms or evaluable hematological malignancies. All patients received a single i.v. bolus dose of IFN-beta-1a on day 1, followed 7 days later by daily s.c. injections for 28 consecutive days. Successive groups of three patients received increasingly higher doses (in geometric progression from 1.5 million international units (MIU)/m2 to 24 MIU/m2) until dose-limiting toxicities were noted. Pharmacokinetic and biological studies, including measurement of the activity of 2',5'-oligoadenylate synthetase (2',5'-OAS) in peripheral blood mononuclear cells and serum levels of soluble Tac (CD 25) and beta-2 microglobulin, were performed on patients who agreed to participate. i.v. and s.c. doses of IFN beta-1a up to 24 MIU/m2 were administered. The most frequent adverse events (AEs) were constitutional symptoms. Grade III AEs during i.v. dosing included fever, elevation of bilirubin, and infection unrelated to therapy. No grade IV events were seen. AEs noted during continuous s.c. therapy included fever, liver transaminase increase, albuminuria, fatigue, nausea, myalgia, and rigors. Dose-limiting toxicities were encountered during s.c. dosing at the 24-MIU/m2 and 18-MIU/m2 dose levels and included gastrointestinal toxicity, elevations of aspartate aminotransferase and alanine aminotransferase, and albuminuria. The s.c. MTD was determined to be 12 MIU/m2, although there was great variability in the individual patient's ability to tolerate IFN beta-1a. 2',5'-OAS activity, thought to be indicative of IFN activity, increased within hours after i.v. and s.c. dosing, with the level remaining persistently elevated during the s.c. daily injections. The highest peak level was attained in the 6-MIU/m2 group. There was no evidence that the increase in 2',5'-OAS activity decayed with repetitive dosing, nor was there evidence of accumulation in this pharmacodynamic marker. Serum beta-2-microglobulin levels showed a modest time- and dose-dependent increase after s.c. administration of IFN beta-1a, with the largest increase seen at the 24-MIU/m2 dose level. There were no clear dose-dependent responses noted in soluble Tac serum levels. IFN beta-1a was well-tolerated when administered by a single i.v. bolus injection at doses up to and including 24 MIU/m2. Daily s.c. injections for at least 28 days were well-tolerated at doses up to and including 12 MIU/m2, with some patients tolerating doses twice as high as this. The MTD for the i.v. route could not be clearly determined according to the guidelines of the protocol. However, i.v. bolus doses up to 24 MIU/m2 were relatively well-tolerated. For the s.c. route, the MTD was determined to be 12 MIU/m2, but there was great interpatient variability, with some patients able to tolerate higher doses.
2',5'-Oligoadenylate Synthetase↗
Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis.
The occurrence of large cell transformation has been well documented in a subgroup of patients with mycosis fungoides/Sezary syndrome (MF/SS). However, because of the rarity of MF/SS, little is known about the influence of clinicopathologic features in predicting large cell transformation and about outcome in the transformed cases. We evaluated all patients with MF/SS who were registered in our clinic during the study period and for whom pathologic slides for review were available or could be obtained. Disease was classified as transformed if biopsy showed large cells (>/=4 times the size of a small lymphocyte) in more than 25% of the infiltrate or if they formed microscopic nodules. Twenty-six patients with transformation were identified from a total of 115 evaluable cases with a diagnosis of MF/SS. The actuarial cumulative probability of transformation reached 39% in 12 years. The median time from diagnosis of MF/SS to transformation was 12 months (range, 0 to 128 months). Thirty-one percent of all patients with stage IIB-IV disease at presentation eventually transformed versus 14% of those with stage I-IIA (P = . 03), with transformation being especially common in patients with tumors (T3), 46% of whom transformed. Combining elevated beta2 microglobulin and lactic dehydrogenase (neither elevated v one or both elevated) was also predictive for transformation (P = .009). The median survival from initial diagnosis of MF/SS for the transformed patients was 37 months versus 163 months for the untransformed group (P = .0029). The median survival from transformation was 19.4 months (range, 2+ to 138 months). The following characteristics were associated with an inferior survival in transformed patients: (1) early transformation (<2 years from the diagnosis v >/=2 years; P = .011) and (2) advanced stage (IIB-IV v I-IIA; 2-year survival, 23% v 86%; P = .0035). We conclude that MF/SS patients with stages IIB-IV disease and, in particular, those with tumors have a high incidence of large-cell transformation. Patients with transformation have a relatively poor survival, especially if transformation occurs early (within 2 years) in the course of disease or if they are staged as IIB or higher.
Actuarial Analysis↗
Interleukin-1 increases expression of the LYT-10 (NFkappaB2) proto-oncogene/transcription factor in renal cell carcinoma lines.
The LYT-10 gene was initially cloned by virtue of its disruption by the translocation breakpoint in some t(10;14) lymphoid neoplasms. LYT-10 is now known to encode a component of the NF-kappaB family of transcriptional activators and has therefore also been designated NFkappaB2. Activation of NF-kappaB is generally associated with its transfer to the nucleus and is followed by a rapid increase in expression of its target genes, which include cytokines such as interleukin-6 (IL-6). IL-6 can also be induced by other transcription factors such as NF-IL6. We studied the interaction of IL-1 and these transcription factors in two renal cell carcinoma cell lines (ACHN and Caki-1). These lines produce high levels of IL-6, show endogenous chloramphenicol acetyltransferase activity for the IL-6 promoter, and have high basal levels of transcripts encoding the NF-kappaB components Lyt-10, p50, and p65 as well as the NF-IL6 transcription factor. IL-1alpha and IL-1beta markedly increased steady-state levels of LYT-10 (NFkappaB2) transcripts and nuclear Lyt-10 protein in both cell lines. Levels of the NFkappaB1 (p50-encoding), p65, and NF-IL6 transcripts also increased after IL-1 exposure. These changes were accompanied by a 20-fold or greater increase in levels of IL-6 messenger ribonucleic acid (mRNA) and protein. Our observations suggest that the mechanism by which IL-1alpha or IL-1beta induces IL-6 may be mediated through increases in LYT-10 mRNA and protein levels as well as increases in expression of other transcription factors (NFkappaB1, p65, and NF-IL6), in addition to the known ability of IL-1 to post-translationally activate NF-kappaB.
Blotting, Northern↗
Z-138: a new mature B-cell acute lymphoblastic leukemia cell line from a patient with transformed chronic lymphocytic leukemia.
We describe a new mature B-cell acute lymphoblastic leukemia (ALL) cell line designated Z-138 that was derived from a patient with chronic lymphocytic leukemia (CLL) whose disease underwent transformation to a rare, aggressive form of mature B-cell ALL. This cell line has an L3 morphology, ultrastructural characteristics of lymphoblasts, B-lineage surface markers and an immunoglobulin heavy-chain gene rearrangement identical to the rearrangement observed in the patient's blasts from whom the cell line was derived. Z-138 cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and high levels of granulocyte-CSF (G-CSF), but they do not exhibit a proliferative response to either cytokine. Both the patient's lymphoblasts and Z-138 cells exhibited cytogenetic abnormalities including t(8;14), t(14;18) and a chromosome 11 abnormality similar to the t(11;14) of the parental cells, resulting in marked overexpression of cyclin D1 (BCL-1 (PRAD1)) mRNA in Z-138 cells. Since these karyotypic anomalies have been associated with low grade (t(14;18)), intermediate grade (t(11;14)) and high grade (t(8;14)) lymphomas, their development may be involved in the unusual aggressive transformation of this patient's CLL.
Aged↗
DNA in situ hybridization of individual colonies to determine lineage derivation in leukemia.
The degree of lineage commitment of the hematopoietic stem cell in chronic myelomonocytic leukemia (CMML) and in acute myelogenous leukemia (AML) remains debatable and may be heterogeneous depending on the patient subgroup. In this study, we have used a modification of DNA in situ hybridization which adapts this technique to the analysis of karyotype in single hematopoietic colonies. By utilizing a digoxigenin-labeled chromosome 7 probe, we demonstrate that, in patients with monosomy 7, both erythroid and myelomonocytic progenitors can be karyotypically aberrant. In addition, significant levels of diploid clonogenic cells persist (as reflected by the presence of between 14% and 43% diploid colonies) despite the detection of only monosomy 7-bearing bone marrow metaphases as assessed by standard cytogenetic techniques. Our observations demonstrate that digoxigenin-based DNA in situ hybridization (DISH) can be performed on individually microaspirated colonies for determination of lineage derivation. This technique may also be applicable to the detection of minimal residual disease with clonogenic potential and for assessing the interaction between normal and leukemic precursors.
Aged↗
GM-CSF can improve the cytogenetic response obtained with interferon-alpha therapy in patients with chronic myelogenous leukemia.
Patients with chronic myelogenous leukemia (CML) who achieve a major cytogenetic remission when treated with interferon-alpha (IFN-A) have a survival advantage when compared to patients with no cytogenetic response. We investigated the effect of combining granulocyte-macrophage colony-stimulating factor (GM-CSF) with IFN-A in the cytogenetic response of patients with minor responses to IFN-A alone. CML patients were eligible if they had shown sensitivity to IFN-A as determined by achievement of a hematologic or cytogenetic response, but failed to achieve or lost a major cytogenetic response after a minimum of 12 months of therapy with IFN-A alone. Patients received GM-CSF 30 microg/m2 daily, subcutaneously and the dose was escalated to 60 microg/m2 if tolerated. IFN-A was continued at the same dose being received by the patient and escalated when possible. Fourteen evaluable patients were included, 13 in chronic phase and one in accelerated phase. The best response prior to GM-CSF was a transient major cytogenetic response in two patients (14%), minor cytogenetic response in nine (64%), and complete hematologic response in three (22%). The median time on IFN-A prior to the start of GM-CSF was 39 months (range 12-72 months). Four patients achieved a significant cytogenetic response, including two complete (14%) and two partial (14%) cytogenetic remissions during therapy. One partial cytogenetic remission converted to complete shortly after therapy was discontinued. Two other patients had a significant reduction in the percentage of Philadelphia chromosome-positive metaphases. The dose of IFN-A could be escalated in half of the patients treated. No toxicity could be attributed to the addition of GM-CSF. We conclude that the addition of GM-CSF to the treatment with IFN-A in CML patients who are sensitive to IFN-A alone but fail to achieve a major cytogenetic response may be beneficial in some patients and should be further investigated.
Adult↗
Conversion of interferon-induced, long-term cytogenetic remissions in chronic myelogenous leukemia to polymerase chain reaction negativity.
PURPOSE: Interferon alfa (IFN-alpha) induces complete cytogenetic remission in a significant minority of patients with chronic myelogenous leukemia (CML). To date, use of the polymerase chain reaction (PCR) has suggested that residual disease is present in virtually all these individuals at median follow-up intervals of approximately 1 year after initial achievement of cytogenetic remission. We sought to determine the PCR status of CML patients with very long continuous complete cytogenetic remissions on IFN-alpha. PATIENTS AND METHODS: Blood and/or bone marrow samples from 18 CML patients maintained in continuous cytogenetic remission by IFN-alpha for at least 1 year were studied for residual BCR-ABL mRNA by single-step reverse-transcriptase (RT)-PCR methodology, followed by detection of the amplification product by the hybridization protection assay (HPA). RESULTS: Ten of 18 patients showed RT-PCR negativity for BCR-ABL. The median duration of continuous complete cytogenetic remission at the time of sample collection for the negative patients was 42 months versus 21 months for the patients whose tests remained positive (P = .05). CONCLUSION: Very long-term follow-up of IFN-alpha-treated CML patients in continuous complete cytogenetic remission is associated with a decrease in the number of BCR-ABL transcripts to a level below that detectable by the RT-PCR assay used in this study.
Adult↗
Thrombopoietin stimulates myelodysplastic syndrome granulocyte-macrophage and erythroid progenitor proliferation.
Thrombopoietin (TPO) has been successfully used to stimulate megakaryocyte progenitor proliferation and platelet production both in vitro and in vivo. We and other investigators have found that TPO also stimulates normal marrow colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth. In contrast to its effect on normal marrow precursors, TPO stimulates acute myelogenous leukemia (AML) progenitor proliferation in only 25% of the cases. Because the hematopoietic cells in Myelodysplastic syndrome (MDS) originate from both the normal and leukemic clones, we hypothesized that TPO may be a useful therapeutic agent for MDS. To test this hypothesis, we used fresh marrow samples taken from 14 MDS patients. We found that in the presence of fetal calf serum (FCS) and erythropoietin (EPO) TPO (5 to 40 ng/ml) MDS CFU-GM and BFU-E colony-forming cell proliferation were stimulated in a dose-dependent fashion by up to 103% and 93% respectively. This effect was similar to the stimulation obtained with optimal concentrations of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3). Furthermore, TPO increased the colony-stimulatory effects of G-CSF, GM-CSF, IL-3, and stem cell factor (SCF) on MDS marrow cells. However, depletion of either T lymphocytes or adherent cells abrogated the effect of TPO, suggesting that the effect is not a direct one but is mediated through interaction with cytokines produced by accessory cells. Taken together, our data suggest that the therapeutic role of TPO in the management of MDS warrants further investigation.
Aged↗
High serum interleukin-6 levels correlate with a shorter failure-free survival in indolent lymphoma.
Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic and prognostic significance in a number of disorders. The objective of this study was to examine the correlation between serum IL-6 levels and phenotypic characteristics, as well as failure-free survival of patients with low-grade non-Hodgkin's lymphomas (NHL). Using a sensitive enzyme-linked immunoabsorbent assay (ELISA), we measured IL-6 in frozen sera from 55 healthy controls and in the pre-treatment frozen sera from 100 low-grade lymphoma patients who were enrolled on protocols at MD Anderson Cancer Center. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free survival. The serum IL-6 levels were > or =2 pg/mL in 9% (median, <0.91 pg/mL; range, <0.91-4.31 pg/mL) of controls versus 25% of the indolent lymphoma patients (median, <0.91 pg/mL; range <0.91 to 225.97) (p = 0.0118). Serum IL-6 levels were higher in patients with B-symptoms (p = 0.02), an elevated P2-microglobulin level (> or =3.0 mg/L) (p = 0.00013), and unfavorable International Index (p = 0.03). Patients with elevated serum IL-6 levels had an inferior failure-free survival (log rank p = 0.008) compared with those with normal serum IL-6 levels (three-year-failure-free-survival = 55% versus 81%, respectively). In conclusion a minority (25%) of patients with indolent non-Hodgkin's lymphomas have elevated serum levels of IL-6 at diagnosis. In these individuals, high IL-6 levels are associated with adverse disease features, and predictive of a shorter failure-free survival.
Adult↗