JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Cyclosporine in Combination with Mycophenolate Mofetil versus Methotrexate for Graft versus Host Disease Prevention in Myeloablative HLA-identical Sibling Donor Allogeneic Hematopoietic Cell Transplantation.
Am. J. Hematol.
PUBLISHED: 06-03-2014
Show Abstract
Hide Abstract
Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA +MTX. Patients receiving MMF+CSA had rapid neutrophil (median 11 versus 19 days with MTX+CSA), and platelet recovery (median 19 versus 25 days), lower incidence of severe mucositis by OMAS (19% versus 53%), and shorter length of hospital stay (median 25 versus 36 days) (p<0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF+CSA 37% versus MTX+CSA 39%) or 3-4 acute GVHD (17% versus 12%), chronic GVHD (46% versus 56%), relapse (28% versus 27%), non-relapse mortality (20% versus 27%) or overall survival (47% versus 44%) (p=NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, p=0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed.
Related JoVE Video
SWOG0919: a Phase 2 study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia.
Br. J. Haematol.
PUBLISHED: 04-02-2014
Show Abstract
Hide Abstract
Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia (AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group (SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission (CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin. This study closed to accrual after meeting the defined criterion for a positive study. Thirty-six patients with a median age of 59 years (range 23-78) were enrolled. The median time from diagnosis to registration was 18 months. Relapse status was first relapse, 17 patients (47%); second relapse, 15 patients (42%); third relapse, two patients (5·5%) and fourth relapse, two patients (5·5%). The response rate was 75% [95% confidence interval: 58-88%; 20 CRs, 7 CR with incomplete count recovery (CRi)], and the median overall survival was 12 months. The P-value comparing 75-30% (the null response rate based on prior SWOG experience) was 3·356 × 10(-4) . Given the encouraging CR/CRi rate, this regimen should be considered for testing in a prospective randomized trial against best conventional therapy.
Related JoVE Video
Risk for developing myelodysplastic syndromes in prostate cancer patients definitively treated with radiation.
J. Natl. Cancer Inst.
PUBLISHED: 02-27-2014
Show Abstract
Hide Abstract
Exposure to ionizing radiation has been linked to myelodysplastic syndromes (MDS); it is not clear whether therapeutic radiation doses used for prostate cancer pose an increased MDS risk.
Related JoVE Video
Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes: Lingering Uncertainties and Emerging Possibilities.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-05-2014
Show Abstract
Hide Abstract
The landscape of transplantation in myelodysplastic syndrome (MDS) has evolved rapidly in the last decade, driven mostly by advances in patient selection through better risk stratification, increasing age of allogeneic recipients, introduction of reduced-intensity conditioning regimens, increased availability of unrelated donors, new donor sources, and improvements in transplant technology and supportive care. Despite these advances, several issues, mostly centering on approaches to improve post-transplant survival while minimizing transplant-related mortality, continue to present significant challenges. Advances in understanding the molecular pathogenesis of MDS have made it feasible to construct clinically useful risk models that integrate prognostic genes with conventional risk parameters for better selection of patients likely to benefit from hematopoietic cell transplantation. Simultaneous research efforts in several areas, including comorbidity assessment, novel preparative regimens, optimal pretransplant cytoreductive strategy, and post-transplantation therapies, are expected to improve long-term disease-free survival and quality of life.
Related JoVE Video
Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI.
Blood
PUBLISHED: 09-24-2013
Show Abstract
Hide Abstract
Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.
Related JoVE Video
Providing personalized prognostic information for adult leukemia survivors.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-28-2013
Show Abstract
Hide Abstract
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.
Related JoVE Video
Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient Outcomes: Consensus Guidelines and Recommendations.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-26-2013
Show Abstract
Hide Abstract
Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.
Related JoVE Video
Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-21-2013
Show Abstract
Hide Abstract
The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score ?90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score ?90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.
Related JoVE Video
Related JoVE Video
Defining incidence, risk factors, and impact on survival of central line-associated blood stream infections following hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-23-2013
Show Abstract
Hide Abstract
Central line-associated blood stream infections (CLABSI) commonly complicate the care of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition that attempts to exclude pathogens usually acquired because of disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (N = 73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16 to 70); 34 had a high (?3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2 to 12) for UCB and 78 days (range, 7 to 211) for BM/PSC (P < .001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (P = .030). Risk factors for OCLABSI in univariate analysis included CBC (P < .001), human leukocyte antigen (HLA)-mismatch (P = .005), low CD34(+) count (P = .007), low total nucleated cell dose (P = .016), and non-Caucasian race (P = .017). Risk factors for OCLABSI in multivariable analysis were UCB (P < .001) and high HCT-CI (P = .002). There was a significant increase in mortality for both OCLABSI (hazard ratio, 7.14; CI, 3.31 to 15.37; P < .001) and MCLABSI (hazard ratio, 6.44; CI, 2.28 to 18.18; P < .001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition, given its greater precision for identifying preventable infection in HCT patients.
Related JoVE Video
Risk factors for 30-day hospital readmission following myeloablative allogeneic hematopoietic cell transplantation (allo-HCT).
Biol. Blood Marrow Transplant.
PUBLISHED: 06-13-2011
Show Abstract
Hide Abstract
Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n = 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR](Adj) = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation.
Related JoVE Video
Cytomegalovirus reactivation after matched sibling donor reduced-intensity conditioning allogeneic hematopoietic stem cell transplant correlates with donor killer immunoglobulin-like receptor genotype.
Exp Clin Transplant
PUBLISHED: 05-25-2011
Show Abstract
Hide Abstract
Cytomegalovirus reactivation is common after reduced-intensity conditioning allogeneic hematopoietic stem cell transplant. Natural killer and T cells mediate immunity against viruses including cytomegalovirus. The alloreactivity of natural killer cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors with target cell ligands. This study sought to assess whether donor inhibitory or activating killer immunoglobulin-like receptor genotypes may influence post-transplant cytomegalovirus reactivation in transplant recipients.
Related JoVE Video
Can G-CSF cause leukemia in hematopoietic stem cell donors?
Biol. Blood Marrow Transplant.
PUBLISHED: 03-18-2011
Show Abstract
Hide Abstract
A large majority of allogeneic hematopoietic stem cell donations are achieved using granulocyte-colony stimulating factor (G-CSF). G-CSF use has been associated with later development of myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML) in several clinical circumstances. Although clinical data to date have failed to identify any increased incidence of MDS/AML in G-CSF mobilized donors, the quality of these data are insufficient to exclude a long-term risk. Physicians should explain the potential risk to donors, and where appropriate, offer donors the option of marrow donation.
Related JoVE Video
Autologous stem cell transplant for early relapsed/refractory Hodgkin lymphoma: results from two transplant centres.
Br. J. Haematol.
PUBLISHED: 03-16-2011
Show Abstract
Hide Abstract
Prior series have demonstrated that early relapsed (within 1 year) or refractory Hodgkin lymphoma (HL) is associated with poor prognosis. To determine the outcome for patients with early relapsed/refractory HL in the modern era, we combined data from two large transplant centres, Cleveland Clinic Taussig Cancer Institute (CCTCI) and Memorial Sloan-Kettering Cancer Center (MSKCC), and analysed consecutive patients transplanted for relapsed/refractory HL following induction failure or remission durations of <1 year. Two hundred and fourteen patients were analysed and the event-free survival (EFS) and overall survival (OS) at 6 years for all patients were 45% and 55%, respectively. Factors significant for prognosis in multivariate analysis were extranodal disease and bulky disease (?5 cm). Patients with 0, 1, or 2 risk factors achieved 6 year EFS of 65%, 47%, and 24% and 6 year OS of 81%, 55%, and 27%, respectively. Patients with the sole risk factor of early relapsed/refractory disease achieved good outcomes in this large series; however the presence of bulk and/or extranodal disease significantly reduced EFS and OS. Patients with these additional risk factors are best suited for clinical trials investigating novel salvage regimens and post-transplant maintenance strategies.
Related JoVE Video
Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-11-2011
Show Abstract
Hide Abstract
We compared the outcomes of patients age 60-70 years with acute myelogenous leukemia receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (n = 94) with the outcomes in patients treated with induction and postremission chemotherapy on Cancer and Leukemia Group B protocols (n = 96). All patients included had been in CR1 for at least 4 months. The HCT recipients were slightly younger than the chemotherapy patients (median age, 63 years vs 65 years; P < .001), but there were no significant between-group differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for the HCT recipients (median, 44 days vs 38 days; P = .031). Allogeneic HCT was associated with significantly lower risk of relapse (32% vs 81% at 3 years; P < .001), higher nonrelapse mortality (36% vs 4% at 3 years; P < .001), and longer leukemia-free survival (32% vs 15% at 3 years; P = .001). Although overall survival was longer for HCT recipients, the difference was not statistically significant (37% vs 25% at 3 years; P = .08). Our findings suggest that reduced-intensity conditioning allogeneic HCT in patients age 60-70 with acute myelogenous leukemia in CR1 reduces relapse and improves leukemia-free survival. Strategies that reduce nonrelapse mortality may yield significant improvements in overall survival.
Related JoVE Video
Treatment with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate results in poor mobilization of peripheral blood stem cells in patients with mantle cell lymphoma.
Leuk. Lymphoma
PUBLISHED: 02-14-2011
Show Abstract
Hide Abstract
Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate) is an intense chemotherapy regimen frequently used for hematologic malignancies including mantle cell lymphoma. To address whether treatment with hyper-CVAD impairs mobilization of peripheral blood stem cells, we retrospectively analyzed mobilization data from 77 consecutive adult patients with mantle cell lymphoma who underwent peripheral blood stem cell (PBSC) mobilization for planned autologous stem cell transplant (ASCT). Compared to patients treated with alternative regimens, patients treated with hyper-CVAD collected fewer CD34+?cells, required more total days of pheresis, and more frequently required a second mobilization attempt, despite being more likely to have undergone mobilization with a VP16-containing regimen. In multivariable linear regression analysis, treatment with hyper-CVAD was associated with a significant reduction in total CD34+?cells mobilized (p?
Related JoVE Video
The non-relapse mortality rate for patients with diffuse large B-cell lymphoma is greater than relapse mortality 8 years after autologous stem cell transplantation and is significantly higher than mortality rates of population controls.
Br. J. Haematol.
PUBLISHED: 01-12-2011
Show Abstract
Hide Abstract
High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the preferred treatment modality for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes of these patients, we retrospectively analysed data from 309 consecutive patients who underwent ASCT for DLBCL between 1994 and 2006. We found that non-relapse mortality (NRM) became the major cause of death beginning approximately 8 years after ASCT. The most common causes of NRM during the study period were respiratory failure (31%), infection (13%), cardiac toxicity (15%) and secondary malignancy (15%). The strongest predictor of relapse mortality (RM) was disease status at transplant: patients who were in second or greater complete or partial remission had a higher risk of RM than those in first complete or partial remission [hazard ratio (HR) 3·7, P<0·001], as did those who were relapsed or refractory (HR 4·9, P<0·001). We describe the longest reported follow-up of a large cohort of DLBCL patients uniformly-treated with ASCT. Although relapse was initially the more likely cause of death, NRM exceeded RM after 8 years. After ASCT, surviving patients have significantly increased risk mortality rates relative to the general population and this excess risk persists over time.
Related JoVE Video
Predicting hematopoietic stem cell mobilization failure in patients with multiple myeloma: a simple method using day 1 CD34+ cell yield.
J Clin Apher
PUBLISHED: 01-06-2011
Show Abstract
Hide Abstract
Early and reliable prediction of the likelihood of achieving adequate stem cell collection for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) would improve collection efficiency, prevent unnecessary aphereses, and permit appropriate treatment alterations. No previous study has reported a threshold CD34+ cell collection quantity on Day 1 or 2 of leukapheresis that could predict successful stem cell collection. We performed a retrospective analysis of all MM patients undergoing first attempt of stem cell collection at our institution from 2001 through 2008. Recursive partitioning analysis was used to identify Day 1 or Day 1+2 CD34+ collection quantity that predicted failure to reach target ? 2 × 10(6) CD34+ cells/kg within five days of collection. Totally, 172 patients were included in the analysis. Patients underwent mobilization with G-CSF or G-CSF+ chemotherapy. 23 of 172 patients (13.4%) failed to collect sufficient (? 2 × 10(6) CD34+ cells/kg) CD34+ cells after five days of apheresis: 22 of 29 who collected ? 0.70 × 10(6) CD34+ cells/kg and 1 of 143 who collected > 0.70 × 10(6) CD34+ cells/kg (75.9% vs. 0.7%, P < 0.001) on Day 1. Collection failure occurred in 23 of 30 patients who collected ? 1.54 × 10(6) CD34+ cells/kg and 0 of 142 who collected >1.54 × 10(6) CD34+ cells/kg (76.7% vs. 0%, P < 0.001) on Days 1 + 2. Day 1 CD34+ cell collection quantity identifies patients unlikely to achieve adequate collection for ASCT. Patients who collect ? 0.70 × 10(6) CD34+ cells/kg on day 1 could be considered for treatment modifications to improve CD34+ collection, such as early administration of plerixafor or large volume apheresis.
Related JoVE Video
Vitamin D level after allogeneic hematopoietic stem cell transplant.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-19-2010
Show Abstract
Hide Abstract
Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted.
Related JoVE Video
Effect of post-remission chemotherapy preceding allogeneic hematopoietic cell transplant in patients with acute myeloid leukemia in first remission.
Leuk. Lymphoma
PUBLISHED: 07-16-2010
Show Abstract
Hide Abstract
Patients with acute myeloid leukemia (AML) with intermediate or high risk cytogenetics are often considered for allogeneic hematopoietic stem cell transplant (AHSCT) in first remission. Between attainment of remission and AHSCT, post-remission chemotherapy is frequently administered, though there is no evidence for its effectiveness. This study was performed to determine the impact of post-remission chemotherapy on outcome after AHSCT. A subset analysis was performed to determine whether the influence of post-remission chemotherapy might be different in those with intermediate compared to high risk cytogenetics. There was no significant difference in relapse mortality (RM) (p = 0.70), non-relapse mortality (NRM) (p = 0.12), or survival (OS) (p = 0.15) between post-remission chemotherapy groups. There was no difference in RM, NRM, or OS between cytogenetic groups according to whether they received post-remission chemotherapy. No differential effect between intermediate and high risk cytogenetics was detected (RM, p = 0.80; NRM, p = 0.23; OS, p = 0.26). These data do not show a benefit of post-remission chemotherapy before AHSCT.
Related JoVE Video
Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure.
J. Clin. Oncol.
PUBLISHED: 07-12-2010
Show Abstract
Hide Abstract
Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis.
Related JoVE Video
Impact of weekend admissions on quality of care and outcomes in patients with acute myeloid leukemia.
Cancer
PUBLISHED: 06-22-2010
Show Abstract
Hide Abstract
Hospital services are expectantly reduced over the weekend, which may result in a delay in treatment or in obtainment of medical procedures. The authors investigated quality of care and clinical outcomes of newly diagnosed acute myeloid leukemia (AML) patients who were hospitalized on weekends versus weekdays and treated with induction chemotherapy.
Related JoVE Video
Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis.
Blood
PUBLISHED: 06-10-2010
Show Abstract
Hide Abstract
We compared the outcomes of unrelated donor (URD, n = 358) with human leukocyte antigen (HLA)-matched sibling donor (MSD, n = 226) transplantations in patients with acute myeloid leukemia (AML) in first complete remission (CR1) having unfavorable cytogenetics at diagnosis. Unfavorable cytogenetic abnormalities were: complex (? 3 abnormalities), 32%; and noncomplex involving chromosome 7, 25%; chromosome 5, 9%; 11q or MLL rearrangements, 18%; t(6;9), 5%; and other noncomplex, 10%. URDs were HLA-well-matched (n = 254; 71%) or partially-matched (n = 104; 29%). Three-year leukemia-free survival (LFS) for MSD was 42% (95% confidence interval [CI], 35%-48%) compared with 34% (95% CI, 28%-41%) for HLA-well-matched URD and 29% (95% CI, 20%-39%) for partially-matched URD (P = .08). In multivariate analysis, HLA-well-matched URD and MSD yielded similar LFS (relative risk [RR] = 1.1, 95% CI, 0.86-1.40, P = .44) and overall survival (OS; RR = 1.06, 95% CI, 0.83-1.37, P = .63). LFS and OS were significantly inferior for HLA-partially-matched URD recipients, those with prior myelodysplastic syndrome, and those older than 50 years. All cytogenetic cohorts had similar outcomes. Patients with chronic graft-versus-host disease had a significantly lower risk of relapse (RR = 0.68, 95% CI, 0.47-0.99, P = .05). Hematopoietic cell transplantation (HCT) using HLA-well-matched URD and MSD resulted in similar LFS and OS in AML patients in CR1 with unfavorable cytogenetics. Outcomes of HCT from HLA-partially- matched URD were inferior.
Related JoVE Video
Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus.
Mol. Cancer Ther.
PUBLISHED: 05-25-2010
Show Abstract
Hide Abstract
The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation.
Related JoVE Video
Race and intensity of post-remission therapy in acute myeloid leukemia.
Leuk. Res.
PUBLISHED: 05-04-2010
Show Abstract
Hide Abstract
In many cancers, including AML, blacks have poorer overall survival. We investigated whether differences in post-remission therapy (PRT) were a contributing factor.
Related JoVE Video
Acute myeloid leukemia: when to transplant in first complete remission.
Curr Hematol Malig Rep
PUBLISHED: 04-29-2010
Show Abstract
Hide Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly used to treat acute myeloid leukemia (AML) because it is potentially curative when other therapies have a low likelihood of success. Although most patients with newly diagnosed AML will achieve a first complete remission (CR1) with standard induction chemotherapy, obtaining a durable remission necessarily requires either further (postremission) chemotherapy or allogeneic HSCT. The decision of which of these options to choose is complex and depends on both clinical and molecular variables as well as the availability and histocompatibility of donor stem cells. Important clinical factors include the individual patients age, performance status, and comorbidities. Molecular and cytogenetic factors are increasingly important in stratifying patients into favorable, intermediate, and unfavorable risk categories. Whereas patients with favorable-risk cytogenetics fare better with postremission chemotherapy, allogeneic HSCT provides superior long-term survival for most non-elderly patients with intermediate-risk or unfavorable-risk AML. Because of the expanded use of umbilical cord blood as a source of hematopoietic stem cells and the use of reduced-intensity conditioning regimens, allogeneic HSCT is an option for an increasing number of patients with AML.
Related JoVE Video
The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission.
Blood
PUBLISHED: 04-19-2010
Show Abstract
Hide Abstract
We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.
Related JoVE Video
Nonmyeloablative second transplants are associated with lower nonrelapse mortality and superior survival than myeloablative second transplants.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-10-2010
Show Abstract
Hide Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) for patients who have previously undergone allogeneic or autologous SCT is potentially curative, but dangerous. To identify patient, disease, and treatment characteristics associated with outcome, we analyzed prognostic factors in 98 consecutive patients who underwent second transplants using allogeneic donors at the Cleveland Clinic between May 1987 and October 2008. Inclusion criteria included age ?18 years, first SCT either autologous or allogeneic, and second SCT allogeneic. Patients whose second transplant was myeloablative (MA) had shorter survival (median 3.2 versus 14.7 months, P < .001) than patients whose second transplant was nonmyeloablative (NMA). In multivariable analysis, MA second transplant was associated with a higher risk of NRM (hazard ratio [HR] 2.01, P = 0.022) and death (HR 2.13, P = 0.002). Improved survival after NMA second transplant occurred primarily in patients without acute leukemia and when the first transplant was allogeneic. Among 17 patients transplanted within 3 months of first transplant, mortality was 100% and median survival was 2.3 months. MA transplantation within 3 months of prior SCT carries an unacceptably high rate of NRM. NMA second transplants were associated with substantially less NRM and despite a higher incidence of relapse, significantly improved survival compared to MA second transplants.
Related JoVE Video
A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia.
Leuk. Res.
PUBLISHED: 01-17-2010
Show Abstract
Hide Abstract
The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.
Related JoVE Video
Superior survival after replacing oral with intravenous busulfan in autologous stem cell transplantation for non-Hodgkin lymphoma with busulfan, cyclophosphamide and etoposide.
Br. J. Haematol.
PUBLISHED: 10-11-2009
Show Abstract
Hide Abstract
Autologous stem cell transplantation (ASCT) with cyclophosphamide, etoposide and oral busulfan (BuCyVP) is an effective therapy for relapsed or refractory non-Hodgkin lymphoma (NHL). Substituting intravenous for oral busulfan reduces variability in drug exposure, potentially improving the safety and efficacy of the BuCyVP regimen. We retrospectively compared the outcomes of 604 consecutively treated patients who underwent ASCT for NHL with BuCyVP using oral (n = 468) or IV (n = 136) busulfan, without measurement of busulfan levels for pharmacokinetic (PK) analysis. Patients who received oral busulfan experienced more severe oral mucositis and a higher incidence of nonrelapse mortality. Median overall survival (OS) after ASCT was 72 months with oral busulfan but was not reached for the IV busulfan group. IV busulfan was associated with a lower rate of relapse, and superior relapse-free survival (RFS) and OS. In multivariate models, the route of busulfan administration was an independent prognostic factor for relapse (P = 0.01), RFS (P = 0.002) and OS (P = 0.001). IV busulfan appears to provide better efficacy and lower toxicity than oral busulfan in ASCT with BuCyVP for NHL. Whether PK-based busulfan dosing can achieve further improvements in this setting is worthy of study.
Related JoVE Video
Incidence and reasons for late failure after allogeneic haematopoietic cell transplantation following BuCy2 in acute myeloid leukaemia.
Br. J. Haematol.
PUBLISHED: 10-11-2009
Show Abstract
Hide Abstract
The long-term follow-up is presented for 317 patients with acute myeloid leukaemia who underwent human leucocyte antigen-identical sibling marrow transplants between 1984 and 1995 following preparation with busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. Among the 142 (45%) who were alive and leukaemia-free 3 years following transplantation, the leukaemia-free survival at 15 years was 72.8%. The cumulative incidence of late (>3 years beyond transplant) non-relapse mortality at 15 years was 12.9% and of late relapse was 16.5%. None of the variables considered (including age, disease stage, and graft-versus-host disease) were predictive of late failure.
Related JoVE Video
Allogeneic hematopoietic cell transplant for prolymphocytic leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-28-2009
Show Abstract
Hide Abstract
The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case series. We reviewed the database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range: 30-75 years). With a median follow-up of 13 months, progression-free survival (PFS) was 33% (95% confidence interval [CI] 20%-47%) at 1 year. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality (TRM) at 1-year posttransplant was 28%. The small patient population prohibited prognostic factor analysis, but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit.
Related JoVE Video
A prognostic scoring system for adult patients less than 60 years of age with acute lymphoblastic leukemia in first relapse.
Leuk. Lymphoma
PUBLISHED: 06-27-2009
Show Abstract
Hide Abstract
The outcome of patients with acute lymphoblastic leukemia (ALL) in first relapse is poor. We retrospectively evaluated patients with ALL in first relapse, 18-60 years of age, to define a prognostic score. For all patients, a scoring system of 0-3 was developed with 1 point for each of the following: age at diagnosis >or=45 years, lactate dehydrogenase (LDH) at the time of relapse >or=1.5 times upper limits of normal (ULN), not proceeding to allogeneic bone marrow transplant (BMT). A similar scoring system was developed for patients proceeding to BMT. LDH >or=1.5 times ULN at the time of relapse predicted poor overall survival. Patients with a prognostic score of greater than 1 have a poor prognosis, even with BMT, and should be considered for treatment with innovative approaches such as Phase 1 clinical trials.
Related JoVE Video
Elevated pretransplant ferritin is associated with a lower incidence of chronic graft-versus-host disease and inferior survival after myeloablative allogeneic haematopoietic stem cell transplantation.
Br. J. Haematol.
PUBLISHED: 06-08-2009
Show Abstract
Hide Abstract
Elevated pretransplant serum ferritin levels have been associated with an increased incidence of morbidity and mortality after allogeneic haematopoietic stem cell transplantation (HCT). We studied 222 patients who underwent myeloablative allogeneic HCT in whom pretransplantation serum ferritin levels were available. Pretransplantation ferritin > 1910 microg/l was associated with lower overall survival (P = 0.003), lower relapse-free survival (P = 0.003), decreased chronic graft-versus-host disease (GVHD) (P = 0.019) and increased non-relapse mortality (NRM) (P = 0.042). Similar results were obtained when pretransplantation ferritin was analysed as a continuous variable and by quartiles. Our results indicate that an elevated pretransplant ferritin level adversely impacts transplantation outcomes. The adverse impact of elevated ferritin on NRM and survival was despite its association with lower incidences of acute and chronic GVHD, which are major causes of NRM. The association of ferritin with iron overload and its influence on HCT outcomes requires further prospective validation.
Related JoVE Video
Treatment of acute myeloid leukemia with hematopoietic stem cell transplantation.
Future Oncol
PUBLISHED: 05-20-2009
Show Abstract
Hide Abstract
Allogeneic hematopoietic stem cell transplantation provides the most powerful antileukemic effect in the treatment of acute myeloid leukemia. Due to its significant morbidity and mortality, it should be used in first remission patients whose relapse risk is substantial. Reduced intensity transplantation is safer and extends the application of early transplantation to older patients and those with comorbidities. In patients with advanced disease, allotransplantation provides a lower chance for cure, but is often the only curative treatment available. Advances in histocompatibility typing and supportive care have improved results of allogeneic transplantation in acute myeloid leukemia.
Related JoVE Video
Sibling versus unrelated donor allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia: refined HLA matching reveals more graft-versus-host disease but not less relapse.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-06-2009
Show Abstract
Hide Abstract
Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor-recipient histoincompatibility can augment the graft-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA matching. Here, we used our recently refined HLA-matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new matching criteria identifies substantially more frequent mismatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-matching scheme in analyzing retrospective data sets when fully informative, allele-level typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD, but does not improve protection against relapse; thus the best donor remains the most closely matched donor.
Related JoVE Video
Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients.
Blood
PUBLISHED: 02-07-2009
Show Abstract
Hide Abstract
Acute myeloid leukemia (AML) is considered an oncologic emergency. Delaying induction chemotherapy until molecular testing results return, may benefit some patients but harm others. We examined the effect of time from AML diagnosis to treatment (TDT) on complete remission (CR) and overall survival (OS), using patient characteristics available at diagnosis. Regression models were applied to older (> or = 60 years) and younger (< 60 years) adults, controlling for age, baseline white blood cell count, secondary AML (sAML), and performance status. Median patient age was 60 years (range, 17-87 years), TDT 4 days (range, 1-78 days), and 45% had sAML. Cytogenetic risk distribution was: favorable, 8%; intermediate, 66%; unfavorable, 26%. CR rate was 67% and median OS was 68 weeks in patients younger than 60 years; 55% and 33 weeks in older patients, respectively. In univariate and multivariate analyses, longer TDT was associated with worse CR and OS in younger (univariate: P < .001 in both; multivariate: P < .001 and P = .001, respectively), but not older patients (univariate: P = .45, P = .19; multivariate: P = .63, P = .30, respectively). Results did not change with inclusion of cytogenetic data or in risk group subsets. AML therapy should be initiated immediately in younger patients. Delaying treatment does not seem harmful in older patients, allowing individualized approaches.
Related JoVE Video
Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.
Case Rep Transplant
Show Abstract
Hide Abstract
Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.
Related JoVE Video
Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.
PLoS ONE
Show Abstract
Hide Abstract
We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.
Related JoVE Video
SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes.
Blood
Show Abstract
Hide Abstract
Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation.
Related JoVE Video
Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia.
Am. J. Hematol.
Show Abstract
Hide Abstract
We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ?350 cells/?L at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/?L (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ?350 cells/?L on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/?L (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/?L vs. ?350 cells/?L, P ? .0004 for OS and EFS) along with WBC at diagnosis (?6.0 or >30.0 K/?L vs. >6.0-30.0 K/?L, P ? 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.
Related JoVE Video
Related JoVE Video
Concise review: the role of hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia.
Stem Cells
Show Abstract
Hide Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with acute myeloid leukemia (AML). Our understanding of the biology of leukemic stem cells has continued to improve over the last decade and risk stratification using cytogenetics and molecular markers have improved our ability to select patients who would benefit from allogeneic transplantation. Results of HSCT have also improved substantially, extending the potential application of allogeneic transplant to more patients. This review discusses the theoretical aspects of transplant, analyzes clinical results, and provides recommendations for the use of HSCT in AML. Further study of the biology of leukemic stem cells and the role for HSCT is necessary to optimize outcomes in AML patients.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.