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The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but this is not known for aHCT populations. We determined disease- and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 years and 50% at 10 years from aHCT. On the other hand, the 5-year relative survival was 70, 75, 81 and 88% after having survived 1, 2, 5 and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95% confidence interval (CI)=13.1-14.8). The risk of death approached that of the general population for 10-year survivors (standardized mortality ratio (SMR)=1.4, 95% CI=0.9-1.9), with the exception of female Hodgkin's lymphoma patients transplanted before 1995 at age 40 years (SMR=6.0, 95% CI=1.9-14.0). Among those who had survived 10 years, nonrelapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies. [ABSTRACT FROM AUTHOR]

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML. [ABSTRACT FROM AUTHOR]

IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM. [ABSTRACT FROM AUTHOR]

The Bone Marrow Transplant Survivor Study is a retrospective cohort study in which participants who received hematopoietic cell transplantation (HCT) between 1974 and 1998 and survived for 2 years completed a 255-item questionnaire on late effects occurring after HCT. There were 281 survivors with acute myeloid leukemia (AML) and 120 with acute lymphoblastic leukemia (ALL). Siblings of participants (n=319) were recruited for comparison. Median age at interview was 36.5 years for survivors and 44 years for siblings. Median follow-up after HCT was 8.4 years. Conditioning included total body irradiation in 86% of AML and 100% of ALL subjects. The frequencies of late effects did not differ between ALL and AML survivors. Compared with siblings, survivors had a higher frequency of diabetes, hypothyroidism, osteoporosis, exercise-induced shortness of breath, neurosensory impairments and problems with balance, tremor or weakness. In multivariable analysis, the risk of these outcomes did not differ by diagnosis. Survivors after allogeneic HCT had higher odds of diabetes (odds ratio (OR)=3.9, P=0.04), osteoporosis (OR=3.1, P=0.05), abnormal sense of touch (OR=2.6, P=0.02) and reported their overall health as fair or poor (OR=2.2, P=0.03). Ongoing surveillance for these late effects and appropriate interventions are required to improve the health status of ALL and AML survivors after HCT. [ABSTRACT FROM AUTHOR]

The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34(+) cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term culture-initiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a study on ex vivo propagation of genetically modified CD19-specific cytolytic T cells through a generated artificial antigen-presenting cells (aAPC) from K562 cells (human erythroleukemic cell line) as a platform.

Imatinib mesylate, a Bcr-Abl kinase inhibitor, has been very successful in the treatment of chronic myelogenous leukemia (CML). However, the majority of patients achieving cytogenetic remissions with imatinib treatment have molecular evidence of persistent disease, and residual BCR/ABL+ progenitors can be detected. There is a need to develop new approaches that enhance elimination of malignant progenitors in imatinib-treated patients. Here we show that CML CD34+ progenitors are sensitive to several apoptosis-inducing stimuli including the chemotherapeutic agents Ara-C and VP-16, radiation, arsenic trioxide, ceramide, growth factor withdrawal, and the death receptor activators TNFaand TRAIL. Bcr-Abl kinase inhibition by imatinib did not enhance sensitivity of CML progenitors to Ara-C, VP-16, ceramide, radiation or TRAIL-induced apoptosis but did enhance arsenic and TNFa-induced apoptosis. We further demonstrate that apoptosis was restricted to dividing cells, whereas nonproliferating BCR/ABL+ CD34+ cells were resistant to apoptosis induced by imatinib, Ara-C or arsenic, either alone or in combination. Resistance of quiescent CML progenitors to imatinib-induced apoptosis could contribute to persistence of residual malignant progenitors in imatinib-treated patients. Combination treatment with Ara-C or arsenic may not enhance targeting of nonproliferating CML progenitors. The assay described here may be useful for identifying agents targeting quiescent CML progenitors.Leukemia (2005) 19, 1034-1041. doi:10.1038/sj.leu.2403724 Published online 7 April 2005 [ABSTRACT FROM AUTHOR]

Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths. [ABSTRACT FROM AUTHOR]

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections. [ABSTRACT FROM AUTHOR]

The major cause of treatment failure in hematologic malignancies is the development of resistance to chemotherapeutic agents and the presence of clonogenic tumor cells in remission bone marrow. In the present study, we tested the optimal conditions for activation by interleukin-2 (IL-2) of endogenous bone marrow effector cells to develop cytotoxicity against solid tumor and leukemia cells and the effects of IL-2 treatment on eradication of malignant cells from the marrow product while preserving hematopoiesis. Normal donor bone marrow was contaminated with 10% A549 lung cancer cells, MCF-7 breast cancer, or EM2 leukemia cells, and then combined with peripheral blood-derived lymphokine-activated killer (LAK) cells which had been incubated in the presence of IL-2, 6000 IU/ml, for 5 days. Eradication (A549 and MCF-7) or >90% reduction in tumor cell number (EM2) was achieved upon exposure of the marrow to LAK cells but not to control, non-IL-2-exposed PBMC. The non-cross-resistance of chemotherapy and cell-mediated cytotoxicity were tested by using chemoresistant target cells for LAK cytotoxicity assays. Ara-C-resistant K562 cells were sensitive to LAK cytotoxicity, similar to sensitive controls. Similar effects were seen in daunomycin-resistant HL60 leukemia cells and VP-16-resistant K562 cells. The daunomycin-resistant K562 cells were also sensitive to LAK cell killing similar to sensitive controls. Activation of bone marrow mononuclear cells (BMMC) with IL-2, 6000 IU/ml for 24 h, significantly enhanced cytotoxicity against the NK-resistant, LAK-sensitive Daudi cell line. This procedure did not result in significant loss of total BMMC or hematopoietic colony-forming units. We then studied the possibility that the effector cell activity of the IL-2-activated BMMC which is diminished after removal of the IL-2 at 24 h could be recovered upon re-exposure of the marrow to IL-2. We found that the optimum conditions for preserving cytotoxicity were prolonged continuous exposures to IL-2 but that re-exposure of the 24-h IL-2-activated BMMC to IL-2 after a 1- or 2-week IL-2 withdrawal was associated with full recovery of cytotoxicity. These experiments also demonstrated that the overall recovery of viable cells from the BMMC was over 100%, possibly due to a proliferative effect of the IL-2 exposure on BMMC. These results demonstrate that the use of IL-2-activated marrow in patients with acute leukemia in remission undergoing autologous bone marrow transplantation (aBMT) may overcome the obstacles of clonogenic, drug-resistant minimal residual disease. The effector cell activity and hematopoietic capacity of the activated bone marrow product can also be maintained even if optimal clinical care requires an interruption in the in vivo exposure to IL-2. This therapeutic approach is currently being tested in acute leukemia patients undergoing IL-2-activated aBMT followed by prolonged IL-2 treatment before and after hematologic reconstitution. [ABSTRACT FROM AUTHOR]

Focuses on peripheral blood stem cells (PBSC) in autologous transplantation that has replaced marrow as a source of hematopoietic stem cells for autologous transplantation. Reason for the replacement of marrow by PBSC; Factors due to which the use of PBSC may not be associated with a higher incidence of graft-versus-host disease; Impact of relapse following PBSC.