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R Hehlmann

Publications and source records attributed to R Hehlmann.

At least 91 records · Page 5Linked to original sources
PubMed2000

HERV-IP-T47D, a novel type C-related human endogenous retroviral sequence derived from T47D particles.

A new type C retrovirus-related endogenous pol sequence (ERV-FTD) found to be occasionally copackaged in retrovirus-like particles released by the human mammary carcinoma cell line T47D was used to screen a human genomic library (Seifarth W, Skladny H, Krieg-Schneider F, Reichert A, Hehlmann R, and Leib-Mösch C: J Virol 1995;69:6408-6416). The DNA sequence of one full-length clone now reveals a human endogenous proviral sequence (HERV) of 4190 bp in length comprising a 5' LTR (489 bp) and regions with 37 and 74% overall amino acid homology to RTVL-Ia gag and pol genes, respectively. About 35 related elements were found to be distributed on all human chromosomes except 16, 17, and Y. Sequence comparisons with Mo-MuLV and various type C-related HERVs suggest that despite a proline primer-binding site this novel HERV element, now named HERV-IP-T47D, can be assigned to one family together with known HERV-I elements. Phylogenetic analyses of 5 proviral and 25 solitary LTR sequences confirmed the existence of two distinct but closely related subgroups of the HERV-IP superfamily in the primate genome. In contrast to most known HERV-families, the evolutionary age of HERV-IP elements dates back prior to the divergence of New and Old World monkeys. Despite their old age, members of the HERV-IP family are still transcriptionally active and were found to be highly expressed in specific human tissues such as liver and kidney.

Amino Acid Sequence↗
PubMed2000

Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group.

A substantial minority of patients with chronic myelogenous leukemia (CML) achieve a complete response (CR) to treatment with interferon-alpha (IFN), defined as the disappearance of Philadelphia chromosome-positive metaphases. Currently it is unclear how long IFN treatment should be continued for such patients. We used a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify levels of BCR-ABL transcripts in 297 peripheral blood specimens collected from 54 patients who had achieved CR with IFN. The median duration of observation was 1.9 years (range, 0.3-11.0 years). Total ABL transcripts were quantified as internal control and results were expressed as the ratio BCR-ABL/ABL. All 54 patients had molecular evidence of residual disease, although 3 patients were intermittently PCR negative. The median BCR-ABL/ABL ratio at the time of maximal response for each patient was 0.045% (range, 0%-3. 6%). During the period of observation 14 patients relapsed, 11 cytogenetically to chronic phase disease and 3 directly to blastic phase. The median ratio of BCR-ABL/ABL at maximal response was significantly higher in patients who relapsed than in those who remained in CR (0.49% versus 0.021%, P < 0.0001). Our findings show that the level of residual disease falls with time in complete responders to IFN, but molecular evidence of disease is rarely if ever eliminated. The actual level of minimal residual disease correlates with the probability of relapse. We suggest that for patients who reach CR, IFN should be continued at least until relatively low levels of residual leukemia are achieved. (Blood. 2000;95:62-66)

Adolescent↗
PubMed2000

Current trends in the management of chronic myelogenous leukemia.

The management of chronic myelogenous leukemia (CML) has become complex due to the availability of improved diagnostic procedures and life-prolonging or even curative treatment strategies that are more successful the earlier they are applied in the course of the disease. This is true for allogeneic bone-marrow transplantation, treatment with interferon alpha (IFN) and Philadelphia-negative stem-cell collections for autografting. Outcome differs according to risk profiles of patients at diagnosis. In addition, molecular techniques for the detection of the BCR-ABL fusion gene or its products, such as the reverse-transcriptase polymerase chain reaction (PCR), Southern blot analysis, or fluorescence in situ hybridization, facilitate accurate diagnosis and the monitoring of residual disease. They allow the individualization of treatment such as early infusion of donor lymphocytes if molecular relapse is detected after allografting, or discontinuation of IFN in the presence of very low BCR-ABL transcript levels). The availability of real-time PCR devices further improves and accelerates the diagnosis and monitoring of residual disease. This article addresses recent developments in drug therapy and allografting, including treatment intensification with low-dose ara C or intensive chemotherapy followed by autografting, introduction of new drugs (such as homoharringtonine or tyrosine kinase inhibitor STI571), progress with unrelated donor transplantations, use of peripheral blood stem cells for allografting, and transplantation without myeloablative conditioning. Tradeoffs between the treatment options will be discussed in the context of the evidence-based guidelines for treating CML, as recently published by the American Society of Hematology. Finally, the new competence network on acute and chronic leukemias will be introduced.

Bone Marrow Transplantation↗
PubMed2000

Interferon alpha in the treatment of polycythemia vera.

Interferon alpha (IFN) inhibits the growth of the abnormal clone in patients with myeloproliferative disorders, leading to a reduction of the clinical and laboratory signs of the pathologic myeloproliferation. The therapeutic efficacy of IFN in polycythemia vera (PV) is demonstrated by the summarized treatment results of 279 patients participating in 16 prospective nonrandomized studies and in three case reports. The initial IFN dose ranged from 3 to 35 million IU/week. In 82% of the patients the frequency of phlebotomies was reduced. In 50% a complete remission was achieved, defined as a stable hematocrit of 45% without concomitant phlebotomies. Reduction of splenomegaly was seen in 77% and control of pruritus in 81% of the patients. The median observation time of the studies was 13 months (ranging from 3 to 84 months). Individual cases were followed for up to 126 months. In 21% of the patients IFN was terminated, owing mostly to side effects. The selective suppression of the malignant clone by IFN was demonstrated by the induction of cytogenetic remissions in sporadic cases with a chromosomal marker and by the observation of unmaintained remissions that lasted up to 4.8 years. IFN has no known mutagenic or teratogenic effects. The data presently available demonstrate that IFN is an effective alternative to the present forms of treatment in PV. Controlled prospective studies are essential to clarify whether the favorable biologic properties are also reflected by a benefit in clinical course and survival, and whether IFN may reduce the rates of acute leukemia and myelofibrosis. A randomized study that compares IFN and hydroxyurea in patients with PV has recently been initiated by the Suddeutsche Hamoblastosegruppe (SHG) in Germany.

Acute Disease↗
PubMed2000

CD14+ peripheral blood mononuclear cells from chronic myeloid leukemia and normal donors are inhibitory to short- and long-term cultured colony-forming cells.

Monocyte-induced cell-cytotoxicity has been implicated in the mechanism of suppression of normal haematopoietic progenitors in chronic myeloid leukemia (CML). We examined here the in vitro effect of CML-derived and normal peripheral blood (PB) monocytes on short- and long-term cultured haematopoietic progenitor cells. Short-term coculture (5 days) of CML or normal monocytes with CML or normal peripheral blood mononuclear cells (PBMNC)/CD34+ cells as targets resulted in a significant inhibition of colony-forming cell (CFC) growth. Coculture conditioned medium (CCM) from 5-days cocultures of normal or CML CD14+ monocytes with CD34+ cells were likewise inhibitory to CFC. In 5-week long-term cocultures of monocytes in direct contact with normal bone marrow (BM) progenitors, CML monocytes reduced the proportion of long-term cultured CFC (LTC-CFC) significantly to 52% of the controls, while normal monocytes had a less pronounced inhibitory effect (89% of the controls) on LTC-CFC. Reduction of LTC-CFC was great when CML monocytes and target cells were separated by a transwell membrane as compared to control cultures in the absence of CD14+ cells (53.5 vs. 9%). CCM from 5-week cocultures of normal or CML CD14+ monocytes with CD34+ progenitors from bone marrow (BM) cells were also inhibitory to CFC. No difference in cytokine levels for TNF-alpha, IFN-gamma, G-CSF, IL-10, IL-6 was detectable between CML CD14+ CCM and control CCM derived from short- and long-term cocultures. Our results suggest that CML monocytes may play a role in the inhibition of normal haematopoiesis through a yet not defined soluble factor supporting the expansion of the malignant clone in CML.

Adult↗
PubMed2000

Aneuploidy precedes and segregates with chemical carcinogenesis.

A century ago, Boveri proposed that cancer is caused by aneuploidy, an abnormal balance of chromosomes, because aneuploidy correlates with cancer and because experimental aneuploidy generates "pathological" phenotypes. Half a century later, when cancers were found to be nonclonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result, aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer. However, we have recently proposed a two-stage mechanism of carcinogenesis that resolves the discrepancy between clonal mutation and nonclonal karyotypes. The proposal is as follows: in stage 1, a carcinogen "initiates" carcinogenesis by generating a preneoplastic aneuploidy; in stage 2, aneuploidy causes asymmetric mitosis because it biases balance-sensitive spindle and chromosomal proteins and alters centrosomes both numerically and structurally (in proportion to the degree of aneuploidy). Therefore, the karyotype of an initiated cell evolves autocatalytically, generating ever-new chromosome combinations, including neoplastic ones. Accordingly, the heterogeneous karyotypes of "clonal" cancers are an inevitable consequence of the karyotypic instability of aneuploid cells. The notorious long latent periods, of months to decades, from carcinogen to carcinogenesis, would reflect the low probability of evolving by chance karyotypes that compete favorably with normal cells, in principle analagous to natural evolution. Here, we have confirmed experimentally five predictions of the aneuploidy hypothesis: (1) the carcinogens dimethylbenzanthracene and cytosine arabinoside induced aneuploidy in a fraction of treated Chinese hamster embryo cells; (2) aneuploidy preceded malignant transformation; (3) transformation of carcinogen-treated cells occurred only months after carcinogen treatment, i.e., autocatalytically; (4) preneoplastic aneuploidy segregated with malignant transformation in vitro and with 14 of 14 tumors in animals; and (5) karyotypes of tumors were heterogeneous. We conclude that, with the carcinogens studied, aneuploidy precedes cancer and is necessary for carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Detection and quantification of residual disease in chronic myelogenous leukemia.

The degree of tumor load reduction after therapy is an important prognostic factor for patients with CML. Conventional metaphase analysis has been considered to be the 'gold standard' for evaluating patient response to treatment but this technique normally requires bone marrow aspiration and is therefore invasive. The frequency of cytogenetic analyses can be considerably reduced if patients are also monitored by molecular methods, which can be performed on peripheral blood specimens. Of the various techniques available, most attention has been paid to RT-PCR for BCR-ABL mRNA since this is by far the most sensitive. Simple, non-quantitative RT-PCR analysis gives only limited information on patients after treatment. Quantitative RT-PCR assays have been developed to monitor the kinetics of residual BCR-ABL transcripts over time. Variables in the quantitative PCR assay may be controlled for by quantification of transcripts of a normal gene (eg ABL or glucose-6-phosphate dehydrogenase, G6PD) as an internal standard. After allogeneic stem cell transplantation, most patients become RT-PCR negative, often after a period of low level positivity that may persist for several months. Those patients destined to relapse are characterized by the reappearance and/or rising levels of BCR-ABL transcripts. In contrast, for patients treated with interferon-alpha (IFN) residual disease is rarely, if ever, eliminated. The actual level of minimal residual disease in complete cytogenetic responders to IFN correlates with the probability of relapse. New quantitative real time procedures promise to simplify the protocols that are currently in use, but standardization and the introduction of rigorous, internationally accepted controls are required to enable RT-PCR to become a robust and routine basis for therapeutic decisions.

Fusion Proteins, bcr-abl↗
PubMed2000

Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group.

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16-60) years. The morphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were > or =5 x 10(9)/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was confirmed by karyotyping in 46 and by RT-PCR of the PML/RARalpha transcript in 45 cases. The rate of complete hematological remission was 92% and the early death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML/RARalpha (sensitivity 10(-4)) showed negativity in 29 of 32 (91%) evaluable cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 months after diagnosis, respectively. After a median follow-up of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% (79, 97), and the 2 years relapse-free survival 96% (90, 100). The high antileukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined with ATRA is one of the factors which may have a critical influence on the outcome of APL. A randomized trial should assess the value of an induction therapy including ATRA and high-dose ara-C in comparison to standard-dose ara-C.

Adolescent↗
PubMed2000

Trial of IFN or STI571 before proceeding to allografting for CML?

Ten-year survival of IFN-treated low risk CML patients is about 40%, and more in cytogenetic responders. Allografting has a cure rate of up to 75%, but is associated with considerable procedure related morbidity and mortality. One out of three or four is likely not to survive. A comparative quantification of survival after BMT and IFN treatment suggests that a trial of IFN (and possibly STI 571) before proceeding to allografting is a viable, and in low risk patients a probably preferable option.

Antineoplastic Agents↗
PubMed2000

Frequent polymorphism in BCR exon b2 identified in BCR-ABL positive and negative individuals using fluorescent hybridization probes.

Recently, a polymorphic base in exon 13 of the BCR gene (exon b2 of the major breakpoint cluster region) has been identified in the eighth position before the junctional region of BCR-ABL cDNA. Cytosine replaces thymidine; the corresponding triplets are AAT (T allele) and AAC (C allele), respectively, both coding for asparagine. Therefore, this polymorphism has no implication in the primary structure of BCR and BCR-ABL proteins. However, since the alteration is located close to the fusion region it may have a significant influence on the annealing of PCR primers, probes for real time PCR, and antisense oligonucleotides. We have developed a RT-PCR-based screening method to easily identify polymorphic BCR and BCR-ABL alleles in CML patients and normal individuals in order to estimate their frequency. After amplification from cDNA, a melting curve of a specific fluorogenic probe mapping to the 3' end of BCR exon b2 and spanning the polymorphism readily discriminates between normal and polymorphic BCR and BCR-ABL alleles. This reporter probe is 3' labeled with fluorescein and placed next to 5' LC Red640-labeled anchor probes mapping to the 5' ends of BCR exon b3 or ABL exon a2 so that resonance energy transfer occurs when the probes are hybridized (LightCycler technology). T and C alleles were discriminated by a melting temperature difference of the reporter probe of 3.2 K. We have investigated cDNAs derived from leukocytes from seven cell lines and a total of 229 individuals: normal donors, n = 15; BCR-ABL negative chronic myeloproliferative disorders, n=30; BCR-ABL negative acute leukemias, n= 11; b2a2BCR-ABL positive CML, n = 93; and b3a2BCR-ABL positive CML, n= 80. The frequency of the C allele was 33.0% in BCR-ABL negative individuals, 30.6% in b2a2BCR-ABL, and 23.8% in b3a2BCR-ABL positive CML. In CML patients, 27.7% of BCR-ABL and 27.2% of BCR alleles had the C allele (NS). In total, 132 of 458 (28.8%) exons b2 of BCR or BCR-ABL alleles demonstrated this polymorphism. We conclude that a thymidine/cytosine replacement occurs frequently in BCR exon b2. Probes for real time quantitative RT-PCR should be designed not to map to the critical region in order to avoid underestimation of the number of BCR-ABL transcripts.

Acute Disease↗
PubMed2000

Interferon-alpha-treated patients with chronic myelogenous leukemia show BCR/ABL-positive peripheral blood progenitor cells surviving long-term culture.

Several groups have shown that Ph-progenitors reappear in LTC of CML bone marrow or PBMNC when the cell preparations were derived from newly diagnosed Ph-positive patients or after induction chemotherapy. We have tested the hypothesis whether LTC may further decrease CML progenitors if the cells to be cultured were from IFN-treated patients. In our experiments, PBMNC were cultured from 7 IFN- and 5 HU-treated patients in stable chronic phase of the disease, and from 9 patients at diagnosis. Progenitor cells in PBMNC were quantitatively analyzed before and after 35 days of LTC by combining the clonogenic assay in semisolid medium with dual-color interphase FISH for identification of the BCR/ABL status of colony-forming progenitor cells. A median of 22 colonies (range 7-88) before and 30 colonies (5-71) after LTC were analyzed per patient. Our results show that the number of BCR/ABL-positive CFC before and after LTC was approximately the same. This was independent of IFN or HU therapy. In the IFN group there were 58% (median) BCR/ABL-positive CFC before and 54% (median) after LTC of PBMNC. In the HU group, 80% of CFC were BCR/ABL-positive before and 85% after LTC. A complete elimination of BCR/ABL-positive cells was not achieved. We conclude that CML early progenitors in PBMNC of IFN-treated CML patients may survive LTC.

Antineoplastic Agents, Alkylating↗
PubMed2000

BCR/ABL-negative clonogenic hematopoietic cells do not accumulate in the plastic-adherent fraction of peripheral blood mononuclear cells from patients with chronic myeloid leukemia in stable chronic phase.

PBMNC from patients with CML and healthy control persons were separated into plastic-adherent and nonadherent cell fractions. A colony assay in semi-solid medium was used to estimate the number and lineage commitment of CFC in each of the fractions. The CML blood-derived colonies were isolated and analyzed by FISH for BCR/ABL sequences. Thus, we were able to test the hypothesis whether a selective enrichment is possible of normal progenitor cells in the blood of CML patients in stable chronic phase after HU and/or IFN. Although the number of leukocytes differed considerably between patients at diagnosis and in stable chronic phase, the proportion of adherent and nonadherent cells was about the same in all preparations tested. There were also only minor differences of adherence between MNC of CML and normal origin. Furthermore, BCR/ABL-positive and negative colonies were equally distributed among unseparated, adherent, and nonadherent PBMNC fractions. In conclusion, an accumulation of BCR/ABL-negative CFC was not found in any of the PBMNC fractions. CFC from PBMNC of the same lineage commitment were simultaneously present in plastic-adherent and nonadherent cell fractions, indicating that their surface charges might be different and, on the other hand, that different lineage commitment precursors can be present in either of the fractions irrespective of CML or blood origin.

Antineoplastic Agents, Alkylating↗
PubMed1999

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Adolescent↗
PubMed1999

Mutator phenotype in human hematopoietic neoplasms and its association with deletions disabling DNA repair genes and bcl-2 rearrangements.

As mice carrying mutations of the DNA mismatch repair genes MSH2 and MSH6 often develop lymphoid neoplasms, we addressed the prevalence of the replication error (RER(+)) phenotype, a manifestation of an underlying defect of DNA mismatch repair genes, in human lymphoid tumors. We compared microsatellite instability (MSI) at 10 loci in 37 lymphoid tumors, including 16 acute lymphoid leukemias (ALL) and 21 non-Hodgkin's lymphomas (NHL), and in 29 acute myeloid leukemias (AML). Significant differences in MSI prevalence between AMLs and ALLs emerged, and MSI occurrence was more frequent in the NHLs versus AMLs. Indeed, only 3 of 29 (10%) AMLs exhibited MSI, thus confirming its paucity in myeloid tumors, while 10 of 37 (27%) lymphoid tumors, 6 ALLs and 4 NHLs, disclosed an RER(+) phenotype. In 1 ALL patient, the same molecular alterations were observed in correspondence with a relapse, but were not detected during remission over a 14-month follow-up; in another ALL patient, findings correlated with impending clinical relapse. These results suggest that the study of MSI in lymphoid tumors might provide a useful molecular tool to monitor disease progression in a subset of ALLs. To correlate MSI with other known genetic abnormalities, we investigated the status of the proto-oncogene, bcl-2, in the lymphoma patients and found that 4 of 4 NHL patients with MSI carried bcl-2 rearrangements, thus linking genomic instability to enhanced cell survival in NHL; moreover, no p53 mutations were found in these patients. Finally, we addressed the putative cause of MSI in hematopoietic tumors by searching for both mutations and deletions affecting DNA repair genes. A limited genetic analysis did not show any tumor-specific mutation in MLH1 exons 9 and 16 and in MSH2 exons 5 and 13. However, loss of heterozygosity (LOH) of markers closely linked to mismatch repair genes MLH1, MSH2, and PMS2 was demonstrated in 4 of 6 ALLs and 1 of 3 AMLs with MSI. These observations indicate that chromosomal deletions might represent a mechanism of inactivation of DNA repair genes in acute leukemia.

Adaptor Proteins, Signal Transducing↗
PubMed1999

An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology.

Because there are differing opinions regarding treatment of patients in the chronic phase of chronic myeloid leukemia (CML), the American Society of Hematology convened an expert panel to review and document evidence-based benefits and harms of treatment of CML with busulfan (BUS), hydroxyurea (HU), recombinant interferon-alpha (rIFN-alpha), and bone marrow transplantation (BMT). The primary measure for defining efficacy was survival. Analysis indicated a survival advantage for HU over BUS. Observational studies of rIFN-alpha suffer from numerous biases including sample size, variations in study populations, definitions of hematologic and cytogenetic remissions, and dose. That rIFN-alpha is more efficacious than chemotherapy is demonstrated by 6 prospective randomized trials. For patients with favorable clinical features in chronic phase, compared to HU and BUS, rIFN-alpha improves survival by a median of about 20 months. Most evidence suggests that rIFN-alpha is most effective when combined with other drugs and when given during the earliest stage of the chronic phase. Adding cytarabine to rIFN-alpha adds further survival benefit but increases toxicity. Limitations for evaluating the long-term benefits of allogeneic BMT include the retrospective nature of most studies, incomplete documentation of the clinical characteristics of the patients, paucity of the details on patient selection, lack of control groups, and limitations of survival calculations. Survival curves for BMT show that at least half of the patients transplanted remain alive 5 to 10 years after treatment, whereas similar curves for rIFN-alpha show a continuous relapse rate over time with the curves crossing at about 7 to 8 years. Estimates of long-term survival may be confounded by the selection biases mentioned and the analytic methods used. The magnitude of the incremental increase in benefit with BMT must be weighed against the potential serious harm and death that may accompany the procedure in the short term. The best results with BMT have been obtained when it is performed within 1 to 2 years from diagnosis. Since each treatment option involves tradeoffs between benefit and harm, patient choice must be based on the examination of facts presented in an unbiased fashion. Newly diagnosed younger patients and older patients who are candidates for BMT should also be offered information about IFN-based regimens, the tradeoffs involved, and, if possible, share in the treatment decision. Hopefully this analysis will provide the stimulus for evaluation of other important aspects of CML.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

[The 8p11 myeloproliferative syndrome].

CLINICAL MANIFESTATIONS: The 8p11 myeloproliferative syndrome is characterized by a chronic myelogenous leukemia-like myeloid hyperplasia, marked eosinophilia and a strikingly high incidence of non-Hodgkin's lymphoma, mostly of the T-lymphoblastic subtype. After a short chronic phase of 6 to 9 months it rapidly transforms into an acute myelogenous leukemia. The median survival time is less than 12 months. CYTOGENETICS: The leukemic cells of peripheral blood/bone marrow and the lymphoma cells have the same acquired, clonal abnormality of chromosome band 8p11 with the translocations t(8;13)(p11;q12), t(8;9)(p11;q34), and t(6;8)(q27;p11). MOLECULAR GENETICS: The molecular cloning of these translocations has shown the fusion of three unrelated genes (ZNF198 at 13p12, FAN at 9q34 and FOP at 6q27) to the fibroblast growth factor receptor-1 (FGFR1) gene at 8p11. The complete coding sequence of the tyrosine kinase domain of FGFR1 is retained in all three fusion genes and presumably activated by sequences of the different fusion partners by dimerization. CONCLUSION: Activation of tyrosinc kinase signal transduction pathways are of increasing interest in the pathogenesis of chronic myeloproliferative disorders and myelodysplastic syndromes. The development of tyrosine kinase inhibitors could represent a promising therapeutic tool.

Chromosomes, Human, Pair 8↗