Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.

Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.

A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence.

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

[Need for psychosocial care in in-patients with tumour disease. Investigations conducted in a clinic specializing in tumour surgery]. / Psychosozialer Betreuungsbedarf bei stationären Tumorpatienten. Untersuchungen an einer chirurgisch-onkologischen Schwerpunktklinik.

BACKGROUND: Patients with tumour disease are in particularly stressful situation at all times. The aim of the present study was to find what proportion of patients on a surgical oncology ward would also benefit from psycho-oncological care. PATIENTS AND METHOD: Within a period of 6 months (IIIrd and IVth quarters of 2004) 406 of our tumour patients were questioned with the aid of a method (Po-Bado) developed specifically for use with such patients. RESULTS: According to this inquiry, it can be assumed that 41.4% of tumour patients are in need of professional psycho-oncological support. Patients who are in hospital for diagnostic procedures to confirm or exclude the suspicion of tumour disease have a greater need for such support (48.7%) than do patients who have been admitted for a scheduled operation (37.3%). Correlations were found between the need for this therapy and different disease situations. The prevalence of need was highest among patients with a second tumour, in whom it was 66.7%. The type of tumour disease also had an influence whether psycho-oncological care was indicated. The study revealed that patients with malignant soft-tissue tumours (49%) and patients with tumours of the upper digestive organs (48.7%) find the mental stress more difficult to cope with than patients who are in hospital for treatment of malignant skin tumours (31.8%) or malignant tumours of the mammary gland (38.7%). CONCLUSION: These results suggest that an adequate psycho-oncologic diagnostic at the start of a stationary stay are reasonable. This is a precondition for a well-directed psycho-oncologic intervention in order to enhance the disease accomplishment but at the same time the target-oriented supply of psycho-oncologic care in hospitals is a limited resource.

A t(17;19)(q22;p13.3) Involving TCF3, a t(1;9)(p13;p13), and a 5' IGH Deletion in a Case of Adult B-cell Acute Lymphoblastic Leukemia.

TCF3 (19p13.3) abnormalities are relatively common in B-cell acute lymphoblastic leukemia (B-ALL). The t(1;19)(q23;p13) involving PBX1 is the most common of these rearrangements. The t(17;19)(q22;p13.3), resulting in the TCF3-HLF fusion gene, is also seen in B-ALL and is associated with an extremely poor prognosis. Herein, we present the case of a 25-year-old male diagnosed with B-ALL whose initial karyotype showed a t(17;19)(q22p13.3). FISH confirmed TCF3 involvement and also revealed a 5' IGH deletion. After treatment, the patient relapsed, at which point conventional cytogenetic studies showed a t(17;19), loss of the 5' IGH region, and a t(3;10) not seen in initial studies. After hematopoietic stem cell transplantation, the patient relapsed again, at which point conventional cytogenetic studies showed a complex karyotype with t(17;19), t(1;9)(p13;p13), and structural anomalies involving chromosomes 5, 7, and 14, but no IGH abnormalities by FISH. The t(1;9) has been shown to involve PAX5, which plays numerous regulatory roles in B-cell differentiation. Other PAX5 rearrangements have been detected in B-ALL cases of young adults and adolescents, but with unclear clinical significance. To the best of our knowledge, this is the first reported case of t(17;19)-ALL with concomitant 5' IGH deletion and t(1;9)(p13;p13) potentially involving PAX5, albeit at different time points in disease progression. This case provides insight into the clonal evolution of t(17;19)-ALL and the potential involvement of PAX5 and IGH aberrations in the evolution of this malignancy.

Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment.

Results of postremission chemotherapy for adults with acute myelogenous leukemia (AML) were assessed in two sequential prospective studies involving similar induction therapy and two courses of intensive consolidation treatment. Fifty-six patients achieving remission on the acute leukemia protocol (ALP3) study received high-dose cytarabine and daunorubicin as course one and standard-dose cytarabine and daunorubicin as course two. Results are compared with forty-six patients achieving remission on the ALP2 study who received azacitidine and doxorubicin as consolidation course one and standard-dose cytarabine, daunorubicin, and thioguanine as course two. The ALP3 regimen resulted in a significantly improved 5-year disease-free survival of 32% +/- 19% versus 20% +/- 11% for the ALP2 study (P = .03). Survival from remission was also improved, 40% +/- 14% versus 24% +/- 12% (P less than .01). Favorable prognostic factors for disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults less than or equal to 45 years of age was 58% +/- 19% with the ALP3 postremission chemotherapy regimen, comparable to most studies of BMT for AML in first remission. Actuarial 5-year survival for ALP3 patients greater than 60 years of age was 18% +/- 20% with no improvement compared with ALP2.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

PURPOSE: Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS: The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS: After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS: Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia.

PURPOSE: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. PATIENTS AND METHODS: Patients received ara-C 3 g/m(2)/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/m2/d [corrected]. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. RESULTS: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twenty-one patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m(2) of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P =.04). Daunorubicinol clearance decreased 3.3-fold (P =.016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. CONCLUSION: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Multiple myeloma clones are derived from a cell late in B lymphoid development.

We have previously demonstrated that the immunoglobulin (Ig) heavy chain variable region (VH) sequences expressed by the malignant clone in multiple myeloma (MM) contain a high degree of somatic mutation without clonal diversity. This sequence can be used to identify all members of the malignant clone in this B cell malignancy. We sequenced the variable regions expressed by patients with MM and generated primers from the complementarity determining region (CDR) sequences specific for each patient's tumor. Using these primers, we performed PCR amplification on highly purified subpopulations of cells separated by expression of CD10, CD34 and CD38. The results of these experiments demonstrate: 1) there is a small fraction of CD10-expressing tumor cells in MM patients, 2) CD34-bearing malignant cells do not exist in MM, and 3) although the vast amount of tumor is in the CD38-expressing cells, a small amount of tumor is in the CD38-negative population. We also used these primers to determine whether pre-class switch (i.e., Cmu-expressing lymphocytes) clonal cells exist in these patients. After PCR amplification with CDR1 and Cmu primers, colony hybridization was performed using both framework 3 (FR3) and CDR3 probes. Out of > 200 FR3-hybridizing colonies, < or = 5 colonies also hybridized with the CDR3 probe. Colonies which hybridized with both these probes were sequenced, and none of these sequences matched even closely the CDR3 expressed by the malignant clone. These results make the existence of a pre-class switch malignant cell unlikely in MM. Overall, these results suggest that the malignant clone in MM derives from a cell late in B lymphocyte development.

Postremission therapy of acute myeloid leukemia in older adults.

Acute myeloid leukemia (AML) in people over age 60 is characterized by adverse cytogenetic characteristics, prior myelodysplasia, and phenotypic features predictive of poor response to induction chemotherapy and brief leukemia-free survival. Because increased treatment-related toxicity complicates both induction and consolidation chemotherapy, most studies of AML in the elderly focus on induction regimens designed to reduce toxicity. Consolidation usually consists of a repeat cycle of conventional-dose induction chemotherapy. Older patients who achieve complete remission may represent a select population, clinically distinct from patients receiving induction therapy. Regardless of the consolidation regimen, the duration of complete remission is 3 months to 11 months, with long-term leukemia-free survival rates of 10 percent to 28 percent. In the UCLA experience, patients over age 60 who received consolidation, chemotherapy and pretreatment characteristics similar to elderly patients undergoing induction. Postremission treatment varied from standard-dose ara-C to high-dose ara-C consolidation followed by autologous stem-cell transplantation. Leukemia-free survival appears to be longer with high-dose ara-C and autologous stem-cell transplantation. Further randomized studies should be conducted to determine the feasibility of and response to postremission treatment.

Treatment of resistant disease.

Resistant AML encompasses two groups of patients: those with refractory leukemia and those whose leukemia has relapsed. Refractory leukemia is disease that does not respond to initial induction chemotherapy with cytarabine and an anthracycline. Patients with refractory leukemia are likely to have disease with adverse cytogenetics, a history of antecedent hematologic disturbance, adverse immunophenotypic features, and expression of multiple drug resistance. On the other hand, relapsed leukemia is leukemia that recurs following a CR. The duration of CR greatly affects the patient's prognosis and response to additional treatment. Patients with relapsed leukemia are heterogeneous with variable pretreatment characteristics.

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission.

In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.

Absence of microsatellite instability during the progression of chronic myelocytic leukemia.

Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. To test the occurrence of genetic instability in the progression of chronic myelocytic leukemia (CML), we studied microsatellite instability (MSI) in 17 patients with CML. The DNAs from both chronic phase and blast crisis were analyzed at 10 loci. No MSI was observed in any of the 17 cases of blast crisis. These results indicate that MSI is rare and is not associated with progression to blast crisis in most cases of CML.

Transplantation of autologous peripheral blood progenitor cells procured after high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia in first remission.

The purpose of the study was to evaluate the feasibility and efficacy of high-dose cytarabine-anthracycline consolidation chemotherapy followed by autologous transplantation of chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Fifty-nine consecutive patients (median age 45, range 18-69) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine-mitoxantrone consolidation chemotherapy used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 7 x 10(8) peripheral blood mononuclear cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-six patients received myeloablative chemo-radiotherapy followed by the infusion of chemotherapy/rHu-G-CSF-mobilized autologous peripheral blood progenitor cells. The median time to both neutrophil and platelet recovery from transplant was 15 days (range, 11-36 and 5-253+ days, respectively). After a median follow-up of 27 months, 31 patients remain alive with 27 in complete remission. Median remission duration for all eligible patients is 12 months, and actuarial leukemia-free survival at 3 years is 42 +/- 14%. The actuarial risk of relapse is 54 +/- 15%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in two patients and grade III/IV organ toxicity in six. Advanced age was a negative prognostic factor for leukemia-free survival. Our results demonstrate that autologous transplantation of chemotherapy-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission producing improved leukemia-free survival with minimal toxicity.

Transplantation of IL-2-mobilized autologous peripheral blood progenitor cells for adults with acute myelogenous leukemia in first remission.

In order to improve leukemia-free survival we evaluated the feasibility and efficacy of autologous transplantation of interleukin-2 (IL-2)-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Forty-nine consecutive patients (median age 49, range 21-70) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine/mitoxantrone consolidation chemotherapy with post-recovery IL-2 used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 2.08 x 10(6) CD34+ peripheral blood progenitor cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-one patients received myeloablative chemoradiotherapy followed by the infusion of IL-2-mobilized autologous peripheral blood progenitor cells. The median times to both neutrophil and platelet recovery were 16 days (range, 2-43) and 23 days (8-318+ days), respectively. Twenty-seven patients remain alive with 24 in continued first complete remission. Median remission duration for all eligible patients is 8 months, and actuarial leukemia-free survival is 49+/-15%. The actuarial risk of relapse is 43+/-16%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in three patients and serious organ toxicity in 12. Advanced age was a negative prognostic factor for leukemia-free survival. Results were compared to an age-matched historical control treated with autologous transplantation of chemotherapy-mobilized progenitor cells; no significant difference in favor of IL-2 mobilization could be demonstrated. Our results demonstrate that autologous transplantation of IL-2-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission with minimal toxicity but no clear evidence of benefit in leukemia-free survival.

Interferon-alpha induces dendritic cell differentiation of CML mononuclear cells in vitro and in vivo.

The ability of interferon-alpha (IFN-alpha) to induce dendritic cell (DC) differentiation in chronic myeloid leukemia (CML) was evaluated. Peripheral blood mononuclear cells from CML patients cultured with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) developed a dendritic morphology. Fluorescence in situ hybridization demonstrated that the DCs harbored the bcr/abl translocation. The DCs prepared with IFN-alpha/GM-CSF expressed significantly higher levels of class I and II HLA than those grown in interleukin-4 (IL-4) and GM-CSF. The DCs prepared from newly diagnosed CML patients using IFN-alpha/GM-CSF expressed immunoregulatory proteins at levels comparable to normal DCs. In contrast, DCs cultured from CML patients who did not achieve a cytogenetic response to IFN-alpha expressed significantly lower levels of class I HLA, CD40, CD54, CD80 and CD86 than normal DCs. The expression of CD86 by CML DCs was enhanced when they were cultured with IFN-alpha/IL-4/GM-CSF, or when IFN-alpha/GM-CSF-treated cells were induced to mature by CD40 ligand. The DCs from IFN-alpha failures were less stimulatory than normal DCs in the allogeneic mixed leukocyte reaction. CML patients who had a cytogenetic response to IFN-alpha initially had low numbers of bone marrow DCs that increased significantly with treatment, while nonresponders had more prevalent DCs at baseline that showed no consistent change with treatment. Therefore, IFN-alpha can induce DC differentiation from CML progenitor cells both in vitro and in vivo. The therapeutic activity of IFN-alpha in CML may be due to its ability to stimulate the generation of DCs that can present CML-specific antigens. Resistance to IFN-alpha may result when DC differentiation becomes impaired.

Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis.

The newly discovered member of the tumor necrosis factor superfamily, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), has been identified as an apoptosis-inducing agent in sensitive tumor cells but not in the majority of normal cells, and hence it is of potential therapeutic application. However, many tumor cells are resistant to Apo2L/TRAIL-mediated apoptosis. Various chemotherapeutic drugs have been shown to sensitize tumor cells to members of the tumor necrosis factor family. However, it is not clear whether sensitization by drugs and sensitivity to drugs are related or distinct events. This study examined whether an Adriamycin-resistant multiple myeloma (MM) cell line (8226/Dox40) can be sensitized by Adriamycin (ADR) to Apo2L/TRAIL-mediated apoptosis. Treatment with the combination of Apo2L/TRAIL and subtoxic concentrations of ADR resulted in synergistic cytotoxicity and apoptosis for both the parental 8226/S and the 8226/Dox40 tumor cells. Adriamycin treatment modestly up-regulated Apo2L/TRAIL-R2 (DR5) and had no effect on the expression of Fas-associated death domain, c-FLIP, Bcl-2, Bcl(xL), Bax, and IAP family members (cIAP-1, cIAP-2, XIAP, and survivin). The protein levels of pro-caspase-8 and pro-caspase-3 were not affected by ADR, whereas pro-caspase-9 and Apaf-1 were up-regulated. Combination treatment with Apo2L/TRAIL and ADR resulted in significant mitochondrial membrane depolarization and activation of caspase-9 and caspase-3 and apoptosis. Because ADR is shown to sensitize ADR-resistant tumor cells to Apo2L/TRAIL, these findings reveal that ADR can still signal ADR-resistant tumor cells, resulting in the modification of the Apo2L/TRAIL-mediated signaling pathway and apoptosis. These in vitro findings suggest the potential application of combination therapy of Apo2L/TRAIL and subtoxic concentrations of sensitizing chemotherapeutic drugs in the clinical treatment of drug-resistant/Apo2L/TRAIL-resistant multiple myeloma.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Treatment of resistant acute myeloid leukemia.

Although combination cytotoxic chemotherapy induces complete remission in 60-80% of adults with previously untreated acute myeloid leukemia, most patients will ultimately relapse and die from leukemia. Strategies which have been developed for patients with relapsed leukemia include the use of active non-cross-resistant chemotherapeutic agents, allogeneic or autologous bone marrow transplantation, or combined sequential therapy with hematopoietic growth factors and chemotherapy. Most salvage chemotherapeutic regimens use high-dose cytarabine; other agents which have activity include idarubicin, mitoxantrone, etoposide, and high-dose cyclophosphamide. Bone marrow transplantation represents the preferred approach for patients with resistant leukemia offering a likelihood of prolonged disease-free survival. Unique combinations of high-dose chemotherapy and growth factors may provide an alternative therapeutic role in the treatment of resistant leukemia.