The ?-chemokine, stromal-derived factor-1 (SDF-1), has been linked to the homing of circulating tumor cells to bone. SDF-1 is expressed by bone microvascular cells and osteoblasts and normally functions to attract blood-borne hematopoietic stem and progenitor cells to marrow. It has been shown that treatment of cancer cells with soluble SDF-1 results in a more aggressive phenotype; however, the relevance of the administration of the soluble protein is unclear. As such, a flow device was functionalized with P-selectin and SDF-1 to mimic the bone marrow microvasculature and the initial steps of cell adhesion. The introduction of SDF-1 onto the adhesive surface was found to significantly enhance the adhesion of lymphoma cells, as well as low-density bone marrow cells (LDBMC), both in terms of the number of adherent cells and the strength of cell adhesion. Thus, SDF-1 has a synergistic effect with P-selectin on cancer cell adhesion and may be sufficient to promote preferential metastasis to bone.
Multiple psychosocial factors appear to affect cancer progression in various populations; however, research investigating the relationship between psychosocial factors and outcomes following hematopoietic stem cell transplantation (HCT) is scarce. Subject to adverse immunological and psychological conditions, HCT patients may be especially vulnerable to psychosomatic health sequelae; therefore, we studied whether optimism and anxiety influence the pertinent clinical outcome of days to neutrophil engraftment (DTE).
Inappropriate activation of type I IFN plays a key role in the pathogenesis of autoimmune disease, including systemic lupus erythematosus (SLE). In this study, we report the presence of IFN activation in SLE bone marrow (BM), as measured by an IFN gene signature, increased IFN regulated chemokines, and direct production of IFN by BM-resident cells, associated with profound changes in B cell development. The majority of SLE patients had an IFN signature in the BM that was more pronounced than the paired peripheral blood and correlated with both higher autoantibodies and disease activity. Pronounced alterations in B cell development were noted in SLE in the presence of an IFN signature with a reduction in the fraction of pro/pre-B cells, suggesting an inhibition in early B cell development and an expansion of B cells at the transitional stage. These B cell changes strongly correlated with an increase in BAFF and APRIL expression in the IFN-high BM. Furthermore, we found that BM neutrophils in SLE were prime producers of IFN-? and B cell factors. In NZM lupus-prone mice, similar changes in B cell development were observed and mediated by IFN, given abrogation in NZM mice lacking type-I IFNR. BM neutrophils were abundant, responsive to, and producers of IFN, in close proximity to B cells. These results indicate that the BM is an important but previously unrecognized target organ in SLE with neutrophil-mediated IFN activation and alterations in B cell ontogeny and selection.
The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells.
The impact of pretransplant (hematopoietic cell transplantation [HCT]) cytarabine consolidation therapy on post-HCT outcomes has yet to be evaluated after reduced-intensity or nonmyeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia in first complete remission (CR1) reported to the Center for International Blood and Marrow Transplant Research who received a reduced-intensity or nonmyeloablative conditioning HCT from an HLA-identical sibling, HLA-matched unrelated donor, or umbilical cord blood donor from 2000 to 2010. We compared transplant outcomes based on exposure to cytarabine postremission consolidation. Three-year survival rates were 36% (95% confidence interval [CI], 29% to 43%) in the no consolidation arm and 42% (95% CI, 37% to 47%) in the cytarabine consolidation arm (P = .16). Disease-free survival was 34% (95% CI, 27% to 41%) and 41% (95% CI, 35% to 46%; P = .15), respectively. Three-year cumulative incidences of relapse were 37% (95% CI, 30% to 44%) and 38% (95% CI, 33% to 43%), respectively (P = .80). Multivariate regression confirmed no effect of consolidation on relapse, disease-free survival, and survival. Before reduced-intensity or nonmyeloablative conditioning HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant treatment-related mortality and is reasonable if required.
The isolation of hematopoietic stem and progenitor cells (HSPCs) is critical for transplantation therapy and HSPC research, however current isolation techniques can be prohibitively expensive, time-consuming, and produce variable results. Selectin-coated microtubes have shown promise in rapidly isolating HSPCs from human bone marrow, but further purification of HSPCs remains a challenge. Herein, a biomimetic device for HSPC isolation is presented to mimic the acidic vascular microenvironment during trauma, which can enhance the binding frequency between L-selectin and its counter-receptor PSGL-1 and HSPCs. Under acidic pH conditions, L-selectin coated microtubes enhanced CD34+ HSPC adhesion, as evidenced by decreased cell rolling velocity and increased rolling flux. Dynamic light scattering was utilized as a novel sensor to confirm an L-selectin conformational change under acidic conditions, as previously predicted by molecular dynamics. These results suggest that mimicking the acidic conditions of trauma can induce a conformational extension of L-selectin, which can be utilized for flow-based, clinical isolation of HSPCs.
A phase I study utilizing decitabine (DAC) followed by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, in patients with relapsed/refractory adult AML was undertaken to assess safety and feasibility. Patients received DAC 20mg/m(2) intravenously daily for 5 days followed by rapamycin from day 6 to day 25 at doses of 2mg, 4mg, and 6mg/day in a standard 3+3 dose escalation design. Twelve patients completed treatment for safety evaluation. Maximum tolerated dose (MTD) was not reached, and except for grade 3 mucositis in 4 patients, no other significant unexpected non-hematologic toxicities have occurred indicating safety of this regimen. This trial is registered at clinical trials.gov as NCT00861874.
Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.
Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ?400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated.
While psychosocial factors are known to affect cancer progression via biobehavioral pathways in many patient populations, these relationships remain largely unexplored in hematopoietic stem cell transplant (HCT) patients. The purpose of this paper is to critically review the literature regarding psychosocial and endocrine/immune aspects of HCT, with an emphasis on exploring pathways that may mediate the associations between psychosocial factors and disease outcomes. These include the roles of catecholamines, glucocorticoids, inflammation, vascular endothelial growth factor (VEGF), immune reconstitution and infectious susceptibility, as well as the new opportunities available in genomics research. We also discuss the implications for potential immunomodulating psychosocial interventions. Elucidating the biological pathways that account for the associations between psychosocial factors and clinical course could ultimately lead to improved outcomes for this psychologically and immunologically vulnerable population.
The natural history of the chronic phase (CP) of chronic myeloid leukemia (CML) and the high response rates achieved with BCR-ABL inhibitor therapy necessitate long-term evaluation of survival-based outcome measures. Prior to the availability of long-term BCR-ABL inhibitor data, short-term surrogate end points predictive of longer-term outcomes have been identified using data from clinical trials of patients with CML-CP treated with interferon-?-based therapy and approved BCR-ABL inhibitors. In patients with newly diagnosed CML-CP treated with imatinib, achieving a complete cytogenetic response (CCyR) by 12 months has been associated with more favorable outcomes, and both CCyR and major cytogenetic response have been used as surrogate end points for regulatory approval. Following approval of second-generation BCR-ABL inhibitors in the first-line setting (nilotinib, dasatinib), which have significantly faster and deeper response rates than imatinib, molecular-based surrogate markers at earlier time points of 3 and 6 months are also being explored, although longer follow-up is needed. As patients who achieve early responses show the greatest long-term benefit, these end points may help to identify patients with suboptimal responses early in treatment who might benefit from switching to a different, more effective therapy.
Hematopoietic-cell-transplantation-specific-comorbidity-index (HCT-CI) has been reported as a predictor of survival in allogeneic-transplant recipients; however its validity has recently been challenged. We evaluated the association of HCT-CI with survival of transplant recipients who underwent reduced-intensity-conditioning (RIC) with photopheresis, pentostatin, and total-body-irradiation. Median age of 103 patients selected was 55 years. Most patients (58.3%) had high (? 3) HCT-CI. Median OS was 298 days. Age, disease-type, disease-status, HCT-CI correlated with survival on bivariate analysis. On multivariate analysis, only HCT-CI was significantly associated with OS (low HCT-CI HR=0.29, CI 0.091-0.886; intermediate HCT-CI HR=0.41, CI 0.226-0.752). Our findings suggest HCT-CI as an independent predictor of survival in the setting of RIC transplants.
Older patients are increasingly undergoing allogeneic hematopoietic transplantation. A relevant question is whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD). Accordingly, transplants in leukemia/lymphoma patients age ?50 years were analyzed comparing outcomes for recipients of MSD ?50 (n = 1415) versus MUD <50 years (n = 757). Risks of acute graft-versus-host disease (GVHD) grade 2 to 4 (hazard ratio [HR], 1.63; P < .001), 3 to 4 (HR, 1.85; P < .001), and chronic GVHD (HR, 1.48; P < .0001) were higher after MUD compared with MSD transplants. The effect of donor type on nonrelapse mortality (NRM), relapse, and overall mortality was associated with performance score. For patients with scores of 90 or 100, NRM (HR, 1.42; P = .001), relapse (HR, 1.45; P < .001), and overall mortality (HR, 1.28; P = .001) risks were higher after MUD transplants. For patients with scores below 90, NRM (HR, 0.96; P = .76), relapse (HR, 0.86; P = .25), and overall mortality (HR, 0.90; P = .29) were not significantly different after MUD and MSD transplants. These data favor an MSD over a MUD in patients age ?50 years.
Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed "ROS-low"). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ?60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m(2) with once weekly idarubicin 10 mg/m(2) for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m(2) and idarubicin 10 mg/m(2)); idarubicin was reduced to 8 mg/m(2) without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m(2) and idarubicin 8 mg/m(2). Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.
The impact of rituximab on the outcome of high-dose therapy and autologous stem cell transplant (HD-ASCT) for transformed non-Hodgkin lymphoma (NHL) has not been previously described. We analyzed 18 consecutive patients with indolent NHL who transformed to diffuse large B-cell lymphoma (DLBCL), received rituximab-containing therapy either before or after transformation and underwent subsequent HD-ASCT. With a median follow-up of 40 months, the 2-year progression-free survival (PFS) was 59% and the 2-year overall survival (OS) was 82%. Six patients did not receive rituximab pre-transformation. This group had a significantly better PFS at 2 years post-HD-ASCT compared to 12 patients who were exposed to rituximab pre-transformation (p = 0.03). HD-ASCT remains an effective therapeutic option for transformed NHL in the rituximab era. However, patients exposed to rituximab pre-transformation appear to have inferior HD-ASCT outcomes, and thus may benefit from novel conditioning and maintenance regimens in the setting of HD-ASCT.
In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-?B expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-?B activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.
Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.
Salvage chemotherapy followed by high-dose autologous stem cell transplantation (HD-ASCT) is the standard of care for patients who have relapsed or refractory Hodgkins lymphoma (HL). Few trials have had long-term follow-up post-HD-ASCT in the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) era of treatment. We reviewed 95 consecutive patients who received HD-ASCT for relapsed or refractory HL following ABVD failure between 1990 and 2006 at the University of Rochester. Median follow-up for survivors was 8.2 years. All patients received HD-ASCT following upfront ABVD (or equivalent) failure. At 5 years, overall survival (OS) and event-free survival (EFS) were 54% and 37%, respectively. In total, 54 patients have died; 37 of these patients died directly of HL. Notably, there were 19 deaths >3 years post-HD-ASCT and 13 of these late deaths are directly attributable to HL. Furthermore, there were 51 documented relapses, 9 of which occurred >3 years post-HD-ASCT. In contrast to other studies, we did not observe a plateau in EFS following transplantation. Patients appear to be at continuous risk of recurrence beyond 3 years after HD-ASCT. Our results emphasize the importance of long-term follow-up for both toxicity and recurrence, and have important implications in defining success of posttransplantation maintenance strategies.
Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity. Among 37 evaluable patients, the median age was 74 years (range, 60-94), 21 (57%) were female, 19 (51%) had prior myelodysplastic syndrome, and 30 (81%) had pretreatment cytogenetic studies evaluated centrally. Six had isolated del(5q), 1 had del(5q) and +8, 23 had complex cytogenetics, and 7 others had del(5q) identified locally. Fourteen patients (38%) completed induction therapy: 7 patients died during induction therapy, 8 had disease progression, 7 had nonfatal adverse events, and 1 entered hospice. Eight patients started maintenance therapy. Five patients (14%) achieved a partial or complete response, 2 with isolated del(5q) and 3 with complex cytogenetics. Relapse-free survival was 5 months (range, 0-19). Median overall survival was 2 months for the entire population. In conclusion, lenalidomide as a single agent has modest activity in older del(5q) AML patients. Southwest Oncology Group Study S0605 is registered at www.clinicaltrials.gov as NCT00352365.
The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) can be challenging, owing to the absence of traditional lineage-specific markers, but is facilitated by CD4/CD56 co-expression and frequent skin involvement. Herein, we present our collective experiences with three BPDCN cases lacking cutaneous presentation and the inherent diagnostic pitfalls. Taken in context of similar historical cases, we suggest that BPDCN with "leukemic" presentation (L-BPDCN) otherwise presents no major distinguishing features and is at least as aggressive as its cutaneous-involved BPDCN counterpart.
Given the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m² days 1 and 4; rituximab 375 mg/m² day 1, and bortezomib 1.3 mg/m² days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.
Algae preparations are commonly used in alternative medicine. We examined the effects of algae extracts on normal hematopoietic cells and leukemia cells. Ethanol extracts were prepared of Dunaliella salina (Dun), Astaxanthin (Ast), Spirulina platensis (Spir), and Aphanizomenon flos-aquae (AFA). Cell viability effects were completed by Annexin staining. Ast and AFA inhibited HL-60 and MV-4-11 whereas Dun and Spir had no effect. Primary AML blasts demonstrated increased apoptosis in AFA. Primary CLL cells showed apoptosis at 24 hours after exposure to Dun, Ast, Spir, and AFA. High AFA concentrations decreased viability of normal marrow cells. Normal CD34+ viability was inhibited by Dun. Dun and AFA inhibited BFU-E, but all extracts inhibited CFU-GM. Cell-cycle analysis of AML cell lines showed G0/G1 arrest in the presence of AFA. These data suggest that algae extracts may inhibit AML cell lines and leukemia blasts, but they may also have potential inhibitory effects on normal hematopoiesis.
With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m², a substantial increase from the usual dose of 140 mg/m² in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned.
The incidence of excessive adiposity is increasing worldwide, and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myelogenous leukemia (AML) who underwent autologous (auto, n = 373), related donor (RD, n = 2041), or unrelated donor (URD, n = 1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using bone marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2004. Four weight groups by BMI (kg/m(2)) were defined: underweight <18 kg/m(2); normal 18-25 kg/m(2); overweight >25-30 kg/m(2); and obese >30 kg/m(2). Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (relative risk [RR], 1.92; 95% confidence interval [CI], 1.28-2.89; P = .002), but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, although this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT.
The survival rate for patients with metastases versus localized cancer is dramatically reduced, with most deaths being associated with the formation of secondary tumors. Circulating cancer cells interact with the endothelial lining of the vasculature via a series of adhesive interactions that facilitate tethering and firm adhesion of cancer cells in the initial steps of metastasis. TNF-related apoptosis-inducing ligand (TRAIL) holds promise as a tumor-specific cancer therapeutic, by inducing a death signal by apoptosis via the caspase pathway. In this study, we exploit this phenomenon to deliver a receptor-mediated apoptosis signal to leukemic cells adhesively rolling along a TRAIL and selectin-bearing surface. Results show that cancer cells exhibit selectin-mediated rolling in capillary flow chambers, and that the rolling velocities can be controlled by varying the selectin and selectin surface density and the applied shear stress. It was determined that a 1 h rolling exposure to a functionalized TRAIL and E-selectin surface was sufficient to kill 30% of captured cells compared to static conditions in which 4 h exposure was necessary to kill 30% of the cells. Thus, we conclude that rolling delivery is more effective than static exposure to a TRAIL immobilized surface. We have also verified that there is no significant effect of TRAIL on hematopoietic stem cells and other normal blood cells. This represents the first demonstration of a novel biomimetic method to capture metastatic cells from circulation and deliver an apoptotic signal.
Toll-like receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR-9 agonist (1018 ISS, 0.2 mg/kg sc weekly x 4 beginning day 8) with standard rituximab (375 mg/m(2) weekly x 4) in patients (n = 23) with relapsed/refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was well-tolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progression-free survival was 9 months. Biologically relevant increases in ADCC and circulating CD-3 positive T cells were observed in 35% and 39% of patients, respectively. Forty-five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post-therapy. Pre- and post-biopsies of tumour tissue demonstrated an infiltration of CD8(+) T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.
The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37-77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4.3-35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65-96%), with 54% complete responses. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI 63-96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.
To evaluate the patterns and timing of initial recurrence in patients with Hodgkins lymphoma (HL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplantation to enhance our understanding of the natural history of this disease and its modern treatment strategies and to direct approaches to disease surveillance.
For patients with recurrent or refractory large B-cell non-Hodgkins lymphoma, high-dose chemotherapy and autologous stem cell transplant (ASCT) is the treatment of choice. We evaluated the role of involved field radiation therapy (IFRT) post-ASCT for patients initially induced with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or, more recently, rituximab-CHOP (R-CHOP).
Most clinicians caring for patients with AML do not use the word "cure" casually, since for many patients diagnosed with AML, a state of cure or even of long term survival remains elusive. Analysis of prognostic factors may aid in defining the chance for cure in various AML subtypes, and improvements are required at all stages of AML treatment if cure is to be realized in a higher proportion of patients. In order to improve outcome, requirements will include targeting the mutation responsible for the leukemia emergence, suppressing the stem or progenitor cell which acquires the mutation, and the capability to deliver therapy to patients who themselves have adverse co-morbidities.
Unlike stem cells from solid tumors, the stem cells which initiate myelogenous leukemias arise in marrow, an organ with a unique circulation which allows ready access of leukemia cells, including leukemia stem cells (LSCs), to the vasculature. This poses unique problems in the targeting of LSCs since these cells are found circulating in the majority of leukemia cases at diagnosis and are usually not detectable during remission states. Because most cases of leukemia relapse, it is suggested that LSCs remain quiescent in the marrow until they eventually proliferate and circulate again. This indicates that effective targeting of LSCs must occur not only in peripheral circulation but in the micro-circulation of the marrow. Targeting such interactions may overcome cell adhesion-mediated treatment resistance, other multi-drug resistance mechanisms, and opportunities for clonal evolution in the marrow environment. Targeting selectins and integrins, signal transduction mediators, and chemokine/cytokine networks in the marrow micro-circulation may aid in abrogating leukemia-initiating stem cells which contribute to disease relapse. LSCs possess surface antigen profiles and signal transduction activation profiles which may allow differential targeting as compared with normal hematopoietic stem cells.
Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopags effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38-, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41-, CD34- CD41+, and CD34- CD41- cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34- C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.
Persistent thrombocytopenia after stem cell transplantation can lead to increased morbidity and mortality [1,2]. The underlying causes are often multifactorial in this patient population [3,4]. In autologous transplantation, thrombocytopenia is usually a result of poor engraftment or a sign of impending disease relapse. In allogeneic stem cell transplantation, the etiology is often more complex with engraftment deficits, medication effects, graft versus host disease (GVHD), and other immunologic processes potentially contributing. Eltrombopag is an orally available nonpeptide thrombopoietin (TPO) receptor agonist which interacts with the transmembrane domain of the receptor on bone marrow megakaryocytes and upstream progenitor/stem cells. It has been studied in patients with chronic idiopathic thrombocytopenic purpura  and in patients with thrombocytopenia secondary to hepatitis C infection . Unlike the case with recombinant human TPO, its use has not been associated with anti-platelet antibody production . We report two cases of post-transplantation thrombocytopenia, one allogeneic and one autologous, where eltrombopag was given to treat prolonged thrombocytopenia. The use of eltrombopag in these two cases was effective in elevating platelet counts to levels that eliminated the need for platelet transfusions.
Patients with recurrent or primary refractory Hodgkin lymphoma (HL) treated with high dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) commonly relapse post-ASCT in previous disease sites. We sought to evaluate involved field radiation therapy (IFRT) following ASCT and patterns of recurrence, overall survival (OS), and disease specific survival (DSS).
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