Biomedical subjects

M D Minden

Publications and source records attributed to M D Minden.

At least 37 records · Page 2Linked to original sources

PubMed1999

Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach.

We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of de novo cholesterol synthesis, was a potential mediator of the biological effects of retinoic acid on human neuroblastoma cells. The HMG-CoA reductase inhibitor, lovastatin, which is used extensively in the treatment of hypercholesterolemia, induced a potent apoptotic response in human neuroblastoma cells. This apoptotic response was triggered at lower concentrations and occurred more rapidly than had been previously reported in other tumor-derived cell lines, including breast and prostate carcinomas. Because of the increased sensitivity of neuroblastoma cells to lovastatin-induced apoptosis, we examined the effect of this agent on a variety of tumor cells, including leukemic cell lines and primary patient samples. Based on a variety of cytotoxicity and apoptosis assays, the 6 acute lymphocytic leukemia cell lines tested displayed a weak apoptotic response to lovastatin. In contrast, the majority of the acute myeloid leukemic cell lines (6/7) and primary cell cultures (13/22) showed significant sensitivity to lovastatin-induced apoptosis, similar to the neuroblastoma cell response. Of significance, in the acute myeloid leukemia, but not the acute lymphocytic leukemia cell lines, lovastatin-induced cytotoxicity was pronounced even at the physiological relevant concentrations of this agent. Therefore, our study suggests the evaluation of HMG-CoA reductase inhibitors as a therapeutic approach in the treatment of acute myeloid leukemia.

Acute Disease↗

PubMed1999

Three decades of allogeneic bone marrow transplants at the Princess Margaret Hospital.

A total of 1,122 patients with various hemopoietic disorders were transplanted at the Princess Margaret Hospital since 1970. The majority suffered from acute or chronic myeloid leukemia. Improvements in support strategies permitted a gradual escalation of the upper age limit for transplant candidates and resulted in better survival. The overall survival at 10 years of all patients transplanted consecutively either before or after 1986 increased from 30 to 50%. This change was observed independent of other transplant related risk factors and is predominantly attributable to the use of cyclosporine and ganciclovir. An improvement of similar magnitude was seen for transplant recipients presenting with good risk features. The 10-year survival of patients with acute and chronic myeloid leukemia transplanted from a fully matched sibling donor in first complete remission or first chronic phase increased from 40 to approximately 70%. The quality of life of surviving patients may not return to normal but appears to improve with time after the transplant.

Bone Marrow Transplantation↗

PubMed1998

Phosphorylation of BCL-2 after exposure of human leukemic cells to retinoic acid.

Serine phosphorylation of bcl-2 has been reported after treatment of cells with protein kinase C, okadaic acid, taxol, and other chemotherapeutic agents that attack microtubules. We report here that bcl-2 is phosphorylated on serine in acute myeloblastic leukemia (AML) blasts exposed to all trans retinoic acid (ATRA). Two-dimension gels (isoelectric focusing followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) disclosed a novel acidic isoform of bcl-2 in ATRA-treated blast cells from a continuous line and from two AML patients; when the cell lysates were digested with lambda-phosphatase, bcl-2 reverted to the control position, indicating that it was phosphorylated. Metabolic labeling experiments using 32Pi showed that, while control bcl-2 was labeled, incorporation was greatly increased when cells were treated with ATRA. A comparison of bcl-2 from blasts treated with ATRA or taxol showed that bcl-2 was phosphorylated on serine in cells treated with either agent; however, both qualitative and quantitative differences were seen. Qualitatively, the phosphorylated isoform from taxol-treated cells was slightly larger than the native isoform and could be distinguished on 10% to 20% SDS-polyacrylamide gradient gels, while the phosphorylated bcl-2 after ATRA ran as a single band on gradient gels at the same position as control bcl-2. Quantitatively, all bcl-2 from ATRA-treated cells was in the phosphorylated isoform, while after taxol, both phosphorylated and native bcl-2 was present; incorporation of 32Pi into bcl-2 was stimulated to greater extent in ATRA-treated compared with taxol-treated cells. We used immunoprecipitation experiments to ask if bcl-2 phosphorylated after ATRA or taxol had altered capacity to dimerize with bax. No change in dimerization was demonstrated. We conclude that: bcl-2 is phosphorylated on serine after treatment of AML blasts with ATRA; bcl-2 phosphorylation after ATRA is different from that seen after taxol; bcl-2 phosphorylated after either agent retains capacity to dimerize with bax. The ATRA or taxol-induced phosphorylation of bcl-2 can also be seen in blast cells obtained from AML patients.

Dimerization↗

PubMed1998

Antileukemic action of buthionine sulfoximine: evidence for an intrinsic death mechanism based on oxidative stress.

The glutathione-depleting agent buthionine sulfoximine (BSO) was found to be toxic to some AML blast populations. This toxicity was manifested as the appearance of high levels of reactive oxygen generation in GSH-depleted cells, and later by the loss of mitochondrial membrane potential and an increase in intracellular calcium. Striking heterogeneity in BSO sensitivity was observed in a series of four human AML cell lines, and in fresh leukemic blasts obtained from eight AML patients. In some cases, toxicity was seen at BSO concentrations as low as 1 microM; approximately 100-fold less than the plasma levels achieved in patients treated with BSO as a drug resistance reversing agent. Based on these results we propose that some AML blast populations are unusually dependent on GSH-based antioxidant mechanisms, due to high intrinsic rates of reactive oxygen generation. The mitochondrial respiratory chain is the most likely source of this reactive oxygen. Because toxicity is seen at clinically achievable concentrations of BSO, this agent might have antileukemic activity in patients.

Adult↗

PubMed1997

Transcriptional activation of human LIM-HOX gene hLH-2 in chronic myelogenous leukemia is due to a cis-acting effect of Bcr-Abl.

DNA methylation plays an important role in gene regulation. A human LIM-HOX gene, namely hLH-2, was highly expressed in chronic myelogenous leukemia (CML) and located on chromosome 9q33-34.1, in the same region as the reciprocal translocation that creates the Bcr-Abl chimera of Philadelphia chromosome [Wu et al. (1996) Oncogene 12, 1205]. To elucidate the mechanism of hLH-2 transcriptional activation, we studied the methylation status of hLH-2 in normal bone marrow and CML cells. When blots containing genomic DNA digested with Hpa II or Msp I were hybridized with full-length cDNA probe, it was discovered that hLH-2 was methylated in normal bone marrow cells in which hLH-2 was not expressed; in contrast, both alleles of hLH-2 locus in CML cells were heavily hypomethylated. Furthermore, using the sensitive RT-PCR technique, we examined the expression of LH-2 in mouse x human hybrids and a wide array of mouse cell lines containing Abl or Bcr-Abl and failed to identify a consistent expression pattern in the cell lines tested. These results suggest that the transcriptional activation of hLH-2 in CML is likely due to a cis-acting effect, but not a trans-acting effect of the Bcr-Abl fusion protein. Because hypomethylated genes generally are transcribed more efficiently than hypermethylated genes, the high level of hLH-2 mRNA in CML cells probably is a consequence of the low level of methylation of the gene in the leukemic cells.

Animals↗

PubMed1997

Transcriptional activation of human LIM-HOX gene, hLH-2, in chronic myelogenous leukemia is due to a cis-acting effect of Bcr-Abl.

DNA methylation plays an important role in gene regulation. A human LIM-HOX gene, namely hLH-2, was highly expressed in chronic myelogenous leukemia (CML) and located on chromosome 9q33-34.1, in the same region as the reciprocal translocation that creates the Bcr-Abl chimera of Philadelphia chromosome (H.-K. Wu et al., 1996, Oncogene 12, 1205-1212). To elucidate the mechanism of hLH-2 transcriptional activation, we studied the methylation status of hLH-2 in normal bone marrow and CML cells. When blots containing genomic DNA digested with Hpa II or Msp I were hybridized with full-length cDNA probe, it was discovered that hLH-2 was methylated in normal bone marrow cells in which hLH-2 was not expressed; in contrast, both alleles of the hLH-2 locus in CML cells were heavily hypomethylated. Furthermore, using a sensitive RT-PCR technique, we examined the expression of LH-2 in mouse x human hybrids and a wide array of mouse cell lines containing Abl or Bcr-Abl, and we failed to identify a consistent expression pattern in the cell lines tested. These results suggest that the transcriptional activation of hLH-2 in CML is likely due to a cis-acting effect, but not a trans-acting effect, of the Bcr-Abl fusion protein. Because hypomethylated genes generally are transcribed more efficiently than hypermethylated genes, the high level of hLH-2 mRNA in CML cells probably is a consequence of the low level of methylation of the gene in the leukemic cells.

Animals↗

PubMed1997

Defects of the mismatch repair gene MSH2 are implicated in the development of murine and human lymphoblastic lymphomas and are associated with the aberrant expression of rhombotin-2 (Lmo-2) and Tal-1 (SCL).

Mutations in the DNA mismatch repair (MMR) gene hMSH2 underlie a novel pathway of tumorigenesis for some cancers of epithelial origin. Mice deficient in MSH2 are susceptible to lymphomas but defects in this gene have not been identified in human lymphoid tumors. To determine if the lymphomas these mice develop are related to a particular subtype of human lymphoma we evaluated 20 clinically ill homozygous MSH2-/- mice ranging in age from 2 to 13 months. The murine tumors comprised a single histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembled human precursor T-cell lymphoblastic lymphoma (LBL). Evaluation of the expression of three T-cell malignancy associated genes showed that Rhombotin-2 (RBTN-2 also known as Lmo-2), TAL-1 (also known as SCL), and HOX-11 were expressed in 100%, 40%, and 0% of the murine tumors, respectively. The MSH2-/- murine model of precursor T-cell LBL was substantiated by the finding of a nearly identical expression profile of RBTN-2, TAL-1, and HOX-11 in 10 well-characterized cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was established by sequence analysis of exon 13 of hMSH2, which revealed coding region mutations in 2 of 10 cases. Our findings implicate defects in the MMR system with the aberrant expression of T-cell specific proto-oncogenes and define a new pathway of human lymphomagenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Loss of imprinting of human insulin-like growth factor II gene, IGF2, in acute myeloid leukemia.

Genomic imprinting is a non-Mendelian form of gene regulation resulting in differential allelic expression of a gene and plays an important role in the development of certain types of cancer and genetic diseases. Imprinting of IGF2 was demonstrated in normal placenta and fetal kidney by showing monoallelic paternal expression. In contrast, several kinds of tumor showed biallelic expression of IGF2, suggesting that relaxation of the normal imprinting of this growth cytokine may be a feature of some tumors. In this study we wished to determine whether relaxation of IGF2 imprinting was also common in human leukemias. An intragenic Apa I polymorphism within the 3' untranslated region of the gene was used to examine allele-specific transcription in leukemic blasts derived from 24 primary patients with acute myeloid leukemia by RT-PCR. Leukemic samples from 12 of the 24 leukemia patients were identified as heterozygous for IGF2 and potentially informative for the RT-PCR assay. RNA-PCR from these informative leukemia samples studied showed biallelic expression of IGF2, indicating loss of normal imprinting of this gene to be very frequent. In conclusion, constitutional loss of monoallelic expression in 50% of the leukemia samples tested suggests that abnormal imprinting of IGF2 could play an important role in either leukemogenesis or cytokine dysregulation for leukemic cells.

Alleles↗

PubMed1997

Quality of life following bone marrow transplantation: a comparison of patient reports with population norms.

All surviving patients who had received an allogeneic bone marrow transplant at the Princess Margaret Hospital were asked to participate in a health-related quality of life (HQL) study using the Medical Outcomes Survey-Short Form 36 (MOS SF-36), the Satisfaction with Life Domains Scale-Bone Marrow Transplantation (SLDS-BMT) and a current symptoms checklist. The main objective was to compare the health status of BMT survivors with age-adjusted population norms. Of the 251 patients contacted, 93% returned questionnaires. The median follow-up after BMT was 40 months, ranging from 1-253 months. On average, survivors had some diminished HQL relative to the health status of the population in general. Time since transplant had a significant influence on HQL; those less than 3 years from transplant experienced considerable impairment while those who had survived beyond this point were indistinguishable from the normal population in most domains and significantly better in certain psychosocial aspects of health. Many patients still reported symptoms months after BMT; some were mildly affected while others experienced more troublesome symptoms. However, 81% of patients were satisfied with the HQL outcome that they had achieved and 94% would recommend a transplant for someone in similar circumstances.

Adult↗

PubMed1997

A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia.

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin and P-gp antigen expression (Xie et al, Leukemia 1995; 9:1882-1887). This discordance suggests that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Cloning, expression, and chromosomal localization to 11p12-13 of a human LIM/HOMEOBOX gene, hLim-1.

We have identified a putative transcription factor, designated hLim-1, from human fetal brain using degenerate polymerase chain reaction (PCR) and cDNA library screening. The deduced open reading frame, derived from sequencing a 3.0-kb hLim-1 cDNA, encodes a protein of 384 amino acids with two cysteine-rich LIM domains and one homeobox (HOX) DNA-binding domain. The nucleotide sequence of hLim-1 cDNA is 87% identical to mouse Lim-1 and the predicted amino acid sequence is greater than 97% conserved. Expression patterns of hLim-1 were evaluated by Northern analysis and reverse transcription (RT)-PCR coupled with Southern blotting. HLim-1 expression was observed in human brain, thymus, and tonsillar tissue. Expression of hLim-1 was also observed in 58% of acute myelogenous leukemia (AML) cell lines and in four of five primary samples from patients with chronic myeloid leukemia (CML) in myeloid blast transformation. The gene encoding hLim-1 was mapped using fluorescence in situ hybridization (FISH) to human chromosome 11p12-13. The expression pattern and structural characteristics of the hLim-1 gene suggest that it encodes a transcriptional regulatory protein involved in the control of differentiation and development of neural and lymphoid cells. Its expression in CML in blast crisis suggests that it may be involved with progression in this disease; a prospective study is required to confirm this.

Amino Acid Sequence↗

PubMed1997

Retroviral mediated gene transfer of Flt3 ligand enhances proliferation and MAP kinase activity of AML5 cells.

Flt3/flk-2 ligand (Flt3-L) co-stimulates and synergizes with cytokines such as granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor (G-CSF), interleukin-3 (IL-3), and erythropoietin in the proliferation of bone marrow and cord blood hematopoietic stem and progenitor cells. To study the biological effects of Flt3-L on the Flt3-L responsive AML5 cell line, the retroviral vector L(Flt3-L)SN was constructed based on the vector LXSN, but containing the human Flt3-L cDNA transcriptionally regulated by the Mo-MLV LTR. High-titer amphotropic producer cells that generated 10(6) cfu/mL after shuttle packaging through ecotropic packaging cells were isolated. AML5 cells were cultured overnight with L(Flt3-L)SN retroviral supernatant, 8 micrograms/mL polybrene, and 100 U/mL G-CSF, and expanded 1 week in medium with G-CSF. Transduced cells were selected in medium containing 0.4 mg/mL G418 and then in medium with 1.0 mg/mL G418. Retroviral mediated gene transfer in G418-resistant cells was confirmed after amplification by PCR of neo-specific sequences in genomic DNA. Northern blot analysis demonstrated L(Flt3-L)SN mRNA expression. Soluble Flt3-L was undetectable (< 100 pg/mL) by ELISA assay of conditioned medium from transduced cells, but Flt3-L was detected on the surface of AML5 cells by FACS analysis. Cells were plated in colony assay with and without 100 ng/mL Flt3-L, 100 U/mL G-CSF, and the combination. Gene transfer or growth factor treatment increased somewhat the clonogenicity of the nontransduced AML5 cells. More strikingly, L(Flt3-L)SN and each growth factor combination greatly increased the size of the resultant colonies such that the size of colonies from AML5/Flt3-L cells without added growth factor approximated that of the AML5 cells stimulated by exogenous soluble Flt3-L. Moreover, MAP kinase activity in L(Flt3-L)SN-transduced cells cultured without soluble Flt3-L was increased to the level induced in control cells by soluble Flt3-L. These results indicate that retroviral mediated gene transfer and autologous expression of the Flt3-L enhances growth and intracellular signaling of AML5 cells, information that should be of value for studying the effects of Flt3-L on immature subsets of primary hematopoietic stem and progenitor cells.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1996

Shiga-like toxin purges human lymphoma from bone marrow of severe combined immunodeficient mice.

Shiga-like toxin-1 (SLT-1) is a bacterial toxin that kills cells by inhibiting protein synthesis. SLT-1 is composed of one cytotoxic A-subunit and five B-subunits that bind to CD77, a cell-surface glycolipid. In the human hematopoietic system, CD77 expression is restricted to a subset of activated B cells and derived cancers. Here we report that SLT-1 treatment of murine bone marrow ex vivo effectively cures severe combined immunodeficient mice of a human B-cell lymphoma xenograft while sparing normal hematopoietic precursor cells. Flow cytometry results using fluorescein isothiocyanate-labeled SLT-1 B-subunit show the high prevalence of expression of SLT-1 receptors (CD77) in human non-Hodgkin's lymphomas, especially follicular lymphomas. These results suggest the use of SLT-1 for the purging of human bone marrow before autologous bone marrow transplant in the case of CD77+ B-cell lymphomas as just one of many possible uses.

Animals↗

PubMed1996

Translational regulation of human p53 gene expression.

In blast cells obtained from patients with acute myelogenous leukemia, p53 mRNA was present in all the samples examined while the expression of p53 protein was variable from patient to patient. Mutations in the p53 gene are infrequent in this disease and, hence, variable protein expression in the majority of the samples cannot be accounted for by mutation. In this study, we examined the regulation of p53 gene expression in human leukemic blasts and characterized the p53 transcripts in these cells. We found control both at the level of RNA abundance and at the level of translation. Four experiments point towards translational control of human p53 gene expression. First, there is no correlation between the level of p53 mRNA and the level of p53 protein expression in blast cells. Second, in two cell lines with similar levels of p53 protein expression but with different levels of p53 mRNA, we find that there is preferential association of p53 mRNA with large polysomes in the cells with less p53 RNA. Third, translation of synthetic human p53 transcripts in cell-free extracts is inhibited by the p53 3'UTR. Fourth, the p53 3'UTR, when present in cis, can repress translation of a heterologous transcript. These observations raise the possibility that human p53 mRNA translation may be regulated in vivo by RNA binding factors acting on the p53 3'UTR.

Acute Disease↗

PubMed1996

Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic myelogenous leukaemia and located on 9q33-34.1.

We describe the isolation of human LH-2, a putative transcription factor containing two cysteine-rich regions (LIM domains) and a homeobox (Hox) DNA-binding domain. High levels of hLH-2 expression were observed in all cases of chronic myelogenous leukaemia (CML) tested, regardless of disease status. hLH-2 was mapped to chromosome 9Q33-34.1, in the same region as the reciprocal translocation that creates the BCR-ABL chimera of the Philadelphia chromosome (Ph'), the hallmark of CML; hLH-2 was retained on the derivative 9 chromosome and is therefore centromeric of c-ABL. The proximity of hLH-2 to the breakpoint on chromosome 9 raises the possibility of cis-activation by the t(9;22)(q34;q11) translocation. In addition to finding hLH-2 expression in all cases of CML, expression was observed in lymphoid malignancies and myeloid cell lines, but not in primary cases of acute myelogenous leukaemia. The role of hLH-2 in the development or progression of leukaemia is not known. However, hLH-2 may prove useful as a marker of CML for monitoring residual disease.

Amino Acid Sequence↗

PubMed1996

Expression of rhombotin 2 in normal and leukaemic haemopoietic cells.

The rhombotin 2 gene was identified by its association with a recurrent chromosome translocation (11;14)(p13;q11), occurring in T-cell acute lymphoblastic leukaemias (ALLs). High levels of RBTN2 have been found in T-cell leukaemias carrying the translocation and in some T-cell ALLs that lack, by cytogenetic and molecular techniques, translocations involving 11p13. In normal murine tissues RBTN2 has been found to be widely expressed, with high levels present in brain and early B cells. Studies carried out in mice lacking RBTN2 have demonstrated the importance of this gene in erythropoiesis. We have investigated the expression of RBTN2 in human leukaemic cells, and in human and murine normal myeloid progenitor cells. RBTN2 is expressed in the leukaemic cells of patients with pre-B ALL, T-ALL and acute myeloblastic leukaemia (AML). By cytogenetic and molecular techniques no abnormalities were noted in 11p13. Using clonogenic assays and single cell PCR we found that RBTN2 is expressed strongly in the precursors of mixed erythrocyte/macrophage/mast, erythrocyte, megakaryocyte, neutrophil and macrophage colonies. In contrast, RBTN2 message was low to undetectable in the mature progeny. These findings indicate that RBTN2 is expressed in leukaemias of both the myeloid and lymphoid lineages. Further, these studies show that in normal myeloid and lymphoid cells the expression of RBTN2 is present in progenitor cells and is lost as the cells terminally differentiate. This latter finding further illustrates that the detection of a RNA in a population of cells should not be interpreted to mean that all of the cells in that population express the RNA.

Base Sequence↗

PubMed1996

A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies.

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA-C) and all-trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA-C. In contrast to ARA-C, paclitaxel dose responses were independent of cell culture method, the growth factors G-CSF and GM-CSF, and the ligands all-trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of pacliataxel and ATRA on the ARA-C dose responses of OCI/ AML-5; paclitaxel exposure was either before or after ARA-C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA-C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA-C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA-C. The studies justify trials combining ARA-C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.

Adult↗

PubMed1996

Intensive remission induction therapy for chronic myeloid leukemia in blast phase with a goal of post-remission bone marrow transplant--a pilot study.

An intensive protocol utilizing mitoxantrone, high-dose cytarabine, vincristine, etoposide and methylprednisolone as induction therapy for chronic myeloid leukemia in blast transformation is described. Fourteen patients were treated, with a remission/second chronic phase achieved in 64%. None of the 3 patients older than 50 yr responded. Complete hematological responses were seen in 9 of the 11 younger patients, 4 of whom also became BCR-ABL negative by Southern Blot analysis. Four patients went on to allogeneic bone marrow transplant. Median remission durations were 4.5 (1-5) and 8.5 (5-16) months in the non-transplanted and transplanted cohorts, respectively. Median survival is 1.5 (0.5-3), 9.5 (7-14) and 17 (14-61+) months in the non-responding, responding non-transplanted and transplanted cohorts, respectively. Toxicity, particularly gastrointestinal, was significant. This represents an aggressive protocol that should be reserved for patients who are potential transplant candidates.

Adolescent↗