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Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 37 records · Page 2Linked to original sources
PubMed2001

Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study.

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P =.0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P =.14), relapse-free survival (34% versus 9% at 2 years, P =.031) and overall survival (22% versus 12%, P =.046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P =.0089) and daunorubicinol (P <.0001) were significantly higher in CsA-treated patients. Survival (P =.0003) and induction response (P =.028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

The significance of bcr-abl molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation.

The bcr-abl chimeric messenger RNA is frequently detected in chronic myeloid leukemia (CML) patients after bone marrow transplantation. It was previously reported that the relapse risk of bcr-abl detection 6 to 12 months after transplantation was greater than 40%. This risk decreased as the time between transplantation and detection increased. To further define the relapse risk associated with bcr-abl molecular detection in "late" CML survivors, 379 consecutive CML patients alive at 18 months after transplantation or later were studied. Ninety of 379 patients (24%) had at least one positive bcr-abl test 18 months after transplantation or later; 13 of 90 bcr-abl-positive patients (14%) and 3 of 289 bcr-abl-negative patients (1.0%) relapsed. The median time from bcr-abl detection to relapse was 916 days (range, 251-2654 days). The hazard ratio of relapse associated with bcr-abl detection was 19.2 (P <.0001). The stage of disease, chronic graft-versus-host disease, and the donor type did not alter the association between bcr-abl and relapse. Quantification of bcr-abl was performed on 344 samples from 85 bcr-abl-positive patients by means of a real-time quantitative reverse transcriptase-polymerase chain reaction assay. The median bcr-abl change of patients who relapsed was significantly greater than those that remained in remission (P =.002). The median bcr-abl level at relapse was 40 443 bcr-abl copies per microg RNA (range, 960-299 552). Of 73 bcr-abl-positive patients who failed to relapse, 69% had only one positive test at a median of 24 copies bcr-abl per microg RNA. The detection of bcr-abl is common following transplantation. The prognostic significance of a qualitative bcr-abl can be refined by quantitative assays and thus may target patients who would benefit from early intervention.

Adolescent↗
PubMed2001

Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin.

Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33(+) relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P =.003) or 24% (P <.001) among samples from responders. In vitro gemtuzumab ozogamicin--induced apoptosis was also evaluated using an annexin V--based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted. (Blood. 2001;98:988-994)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

Administration, Oral↗
PubMed2001

Myeloablation and autologous peripheral blood stem cell rescue results in hematologic and clinical responses in patients with myeloid metaplasia with myelofibrosis.

Current therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 x 10(6) (range 0 to 410 x 10(6)) CD34(+) cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to > or = 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin > or = 100 g/L [10 gm/dL] without transfusion for > or = 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 x 10(9)/L (100 000/microL) responded with a durable platelet count more than 100 x 10(9)/L (100 000/microL). Symptomatic splenomegaly improved in 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation in most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted. (Blood. 2001;98:586-593)

Aged↗
PubMed2001

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

Acute Disease↗
PubMed2001

Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation.

Allogeneic peripheral blood stem cell grafts contain about 10 times more T and B cells than marrow grafts. Because these cells may survive in transplant recipients for a long time, recipients of blood stem cells may be less immunocompromised than recipients of marrow. Immune reconstitution was studied in 115 patients randomly assigned to receive either allogeneic marrow or filgrastim-mobilized blood stem cell transplantation. Between day 30 and 365 after transplantation, counts of most lymphocyte subsets were higher in the blood stem cell recipients. The difference was most striking for CD4 T cells (about 4-fold higher counts for CD45RA(high) CD4 T cells and about 2-fold higher counts for CD45RA(low/-)CD4 T cells; P <.05). On assessment using phytohemagglutinin and herpesvirus antigen-stimulated proliferation, T cells in the 2 groups of patients appeared equally functional. Median serum IgG levels were similar in the 2 groups. The rate of definite infections after engraftment was 1.7-fold higher in marrow recipients (P =.001). The rate of severe (inpatient treatment required) definite infections after engraftment was 2.4-fold higher in marrow recipients (P =.002). The difference in the rates of definite infections was greatest for fungal infections, intermediate for bacterial infections, and lowest for viral infections. Death associated with a fungal or bacterial infection occurred between day 30 and day 365 after transplantation in 9 marrow recipients and no blood stem cell recipients (P =.008). In conclusion, blood stem cell recipients have higher lymphocyte-subset counts and this appears to result in fewer infections. (Blood. 2001;97:3380-3389)

Adult↗
PubMed2001

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)

Adult↗
PubMed2001

FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia.

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RAS mutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P =.0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53 mutations were associated with a worse overall survival (median 1 versus 8 months, P =.0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes. (Blood. 2001;97:3589-3595)

Aged↗
PubMed2001

Haematopoietic cell transplantation as immunotherapy.

The graft-versus-tumour effect seen after allogeneic (genetically different) haematopoietic cell transplantation for human malignancies represents the clearest example of the power of the human immune system to eradicate cancer. Recent advances in our understanding of the immunobiology of stem-cell engraftment, tolerance and tumour eradication are allowing clinicians to better harness this powerful effect.

Animals↗
PubMed2001

Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation.

The experiences of 69 (38 marrow and 31 peripheral blood stem cell [PBSC]) donors participating in a randomized trial comparing allogeneic bone marrow with PBSC transplantation were studied. Marrow was collected by means of standard harvest techniques and general or regional anesthesia. PBSC donors were treated with 5 to 7 days of filgrastim at a dose of 16 microg/kg/d and underwent 1 to 3 days of apheresis to obtain 5 x 10(6) CD34(+) cells per kilogram recipient weight. Donors completed questionnaires describing their health experiences before, during, and then weekly after donation until return to baseline status. Both marrow and PBSC donors reported minimal fluctuation in symptoms measuring emotional status. In contrast, both groups of donors reported deterioration in physical status starting with administration of filgrastim (PBSC donors) or after the marrow collection procedure. The symptom burden reported was similar, with pain a prominent symptom for both groups. Equivalent mean levels of maximal pain, average pain, and pain duration through the day were reported, although toxicity peaks occurred at different time points during the harvest procedures. All PBSC donors but only 79% of marrow donors reported good physical status by 14 days after the harvest procedures. These data demonstrate similar levels of physical discomfort for hematopoietic stem cell donors regardless of the collection procedure used, but a quicker resolution of symptoms for PBSC donors.

Adolescent↗
PubMed2001

Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.

Adult↗
PubMed2001

Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.

BACKGROUND: In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS: Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS: The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS: In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.

Adolescent↗
PubMed2001

Perspectives on the future of chronic myeloid leukemia treatment.

Chronic myeloid leukemia (CML) is probably the best understood human malignancy at the molecular level, but among the hardest to explain to patients concerning appropriate treatment options. At present, we do not know the long-term outcome of promising new therapies such as the tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) and nonmyeloablative transplants. There is also no reliable way to predict which patients will respond to a particular therapy. The development of methods to predict therapeutic response will be of major benefit to patients, and the newly emerging science of gene array analysis may provide such a tool. In this context, given the proven likelihood of cure with allogeneic transplantation and the negative effects of delay, in Seattle we continue to suggest transplantation as the initial form of therapy for patients below age 55 years with matched sibling donors. For patients without matched donors below the age of 40, we would suggest an unrelated donor search and only proceed directly to transplant for those with allele-level matches. For younger patients without matches and those aged 40 to 55, an initial trial of imatinib mesylate might be preferred. For patients over age 55 with CML, initial therapy with imatinib mesylate, possibly an interferon-containing regimen or nonmyeloablative allogeneic transplantation may be considered.

Age Factors↗
PubMed2001

Blasts from elderly acute myeloid leukemia patients are characterized by low levels of culture- and drug-induced apoptosis.

Increasing evidence suggests that the biology of acute myeloid leukemia (AML) may differ between older and younger patients, with a higher incidence of antecedent myelodysplasia, unfavorable cytogenetic abnormalities, and multidrug resistance seen in the elderly. Abrogation of apoptosis in response to cytotoxic medications is associated with drug resistance in AML, as is expression of bcl-2, an important anti-apoptotic protein. We hypothesized that blasts from elderly (> or = 55 years) and young adult AML patients might have different levels of apoptotic and cell cycle responses to chemotherapeutic agents, as well as different levels of proliferation and of bcl-2 protein expression. Therefore, we cultured bone marrow leukemia samples from previously untreated elderly (n=33) and young (n=21) AML patients for 48 h and then measured apoptosis, bcl-2 protein levels, cell cycle distributions, and expression of a proliferation marker, proliferating cellular nuclear antigen (PCNA) in multi-parametric flow cytometry assays. In some experiments, leukemia samples were exposed to cytarabine (Ara-C) or daunomycin (DNR) for the last 16-18 h of the culture period. In comparison to samples from young patients, cultured samples from elderly AML patients had a higher fraction of viable cells, as measured by Trypan blue exclusion, higher PCNA expression, and significantly less culture-induced and drug-induced apoptosis. The mean apoptosis after culture was 13% for elderly AML samples, versus 20% for young AML samples (P=0.009). Similarly, the mean apoptosis after Ara-C was lower in elderly than in young AML samples, 13 versus 28% (P=0.001), as was the mean apoptosis after DNR, 15 versus 26% (P=0.012). Diminished apoptotic responses in elderly AML cells were not consistently associated with high bcl-2 levels at thaw or bcl-2 levels increased by culture. These data suggest that new therapies should be developed to overcome abrogated apoptosis, particularly in elderly AML patients.

Acute Disease↗
PubMed2001

Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5).

In vitro culture systems that parallel in vivo growth conditions are needed to study leukemia biology and to accurately test therapeutic efficacies. We investigated the effects of the HS-5 human bone marrow stromal cell line on cultured primary leukemia cell survival and chemosensitivity.A total of 30 bone marrow (BM) samples from untreated acute myeloid leukemia (AML) patients were cultured for 96 hours with serum and growth factors, without HS-5, or in direct contact with HS-5 monolayers, or with HS-5 separated from AML cells by transwell inserts. In some experiments, cytosine arabinoside or daunomycin was added for the last 18 hours of culture. Apoptosis frequencies, bcl-2 protein expression, proliferating cell nuclear antigen expression, and cell cycle distributions were determined in four-color flow cytometry analyses of CD45(+) leukemia cells. In comparison to control growth conditions, direct contact with HS-5 significantly inhibited culture-induced and drug-induced apoptosis of AML cells. Direct contact of AML cells with HS-5 significantly increased short-term proliferation and viability, and colony formation of primary AML cells. HS-5-mediated apoptosis inhibition was not consistently associated with increased bcl-2 protein in AML cells. Noncontact conditions inhibited drug-induced apoptosis significantly less than direct contact with HS-5. Coculture of AML cells on HS-5 monolayers improved in vitro leukemia cell survival and attenuated chemotherapy-induced leukemia cell killing. This has practical significance, increasing the fraction of primary AML samples that can be analyzed in vitro, and allows drug sensitivity testing in growth conditions more similar to the bone marrow microenvironment.

Antineoplastic Agents↗
PubMed2001

Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in adults 60 years of age and older.

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the optimal treatment for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). HDT, however, is often reserved for relatively younger patients due to limited data in older adults. We treated 53 patients aged 60 years and older (median age 62 years, range 60.3-67.7 years) with HDT and ASCT for NHL at our centers. Forty-four patients (83%) had aggressive histology, 75% had chemosensitive disease and all had failed anthracycline therapy. Conditioning regimens included busulfan, melphalan, and thiotepa (45%); cyclophosphamide (CY), etoposide (VP-16), and total body irradiation (TBI) (30%); CY and TBI (15%); and other regimens (10%). Estimated 4-year overall survival (OS), progression-free survival, and treatment-related mortality (TRM) were 33%, 24% and 22%, respectively. A multivariable analysis demonstrated that patients with chemosensitive disease (P = 0.03) and < or =3 prior regimens (P = 0.03) had superior survival. Four-year OS in patients with chemosensitive disease was 39% vs 15% in patients with chemoresistant disease. Reduced TRM was associated with the CY, VP-16 and TBI regimen (P = 0.02). HDT therapy with ASCT may result in prolonged survival and potential cure for about a quarter of elderly patients, and for almost 40% with chemosensitive disease. Optimal conditioning regimen selection may further improve outcome by reducing TRM. Age alone should not be used to exclude patients from receiving myeloablative therapy with ASCT.

Aged↗