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.
Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation.
J. Clin. Oncol.
PUBLISHED: 08-25-2014
Show Abstract
Hide Abstract
Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown.
Related JoVE Video
Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients.
J. Clin. Invest.
PUBLISHED: 08-08-2014
Show Abstract
Hide Abstract
Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.
Related JoVE Video
Preoperative MRI improves prediction of extensive occult axillary lymph node metastases in breast cancer patients with a positive sentinel lymph node biopsy.
Acad Radiol
PUBLISHED: 08-08-2014
Show Abstract
Hide Abstract
To test the ability of quantitative measures from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict, independently and/or with the Katz pathologic nomogram, which breast cancer patients with a positive sentinel lymph node biopsy will have four or more positive axillary lymph nodes on completion axillary dissection.
Related JoVE Video
A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation.
Haematologica
PUBLISHED: 08-01-2014
Show Abstract
Hide Abstract
The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).
Related JoVE Video
Gallstones in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up.
J. Pediatr. Hematol. Oncol.
PUBLISHED: 07-19-2014
Show Abstract
Hide Abstract
To determine risk factors for the development of gallstones and the prevalence of related cholecystectomy in children following hematopoietic cell transplantation (HCT).
Related JoVE Video
Impact of donor age on outcome after allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-11-2014
Show Abstract
Hide Abstract
As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-vs.-host disease (GVHD), and non-relapse mortality (NRM) among 1,174 consecutive patients undergoing myeloablative and 367 patients undergoing non-myeloablative HCT from HLA-matched related or unrelated donors with G-CSF-mobilized peripheral blood mononuclear cell (G-PBMC) allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and non-myeloablative conditioning, respectively, for grafts from donors <60 years old (younger; n=1,416) and 98% and 100%, respectively, for those from donors ?60 years old (older; n=125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = 0.04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and non-myeloablative recipients with older sibling donors had significantly less grade II-IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III-IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ?60 years old do not adversely affect outcomes of allogeneic HCT compared to grafts from younger donors.
Related JoVE Video
Number of Courses of Induction Therapy Independently Predicts Outcome after Allogeneic Transplantation for AML in First Morphological Remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-11-2014
Show Abstract
Hide Abstract
Whether the number of chemotherapy cycles required to obtain a first morphological remission affects prognosis of patients with acute myeloid leukemia (AML) remains controversial. To clarify how achievement of early remission might influence outcome of allogeneic hematopoietic cell transplantation (HCT), we studied 220 consecutive adults with AML in first morphological remission who were transplanted following myeloablative or nonmyeloablative conditioning to investigate how the number of standard- or high-dose induction courses required to achieve remission influenced post-HCT outcome. Three-year estimates of overall survival were 65% (56-73%), 56% (43-67%), and 23% (6-46%) for patients requiring 1 course, 2 courses, or >2 courses of induction therapy; corresponding relapse estimates were 24% (17-31%), 43% (31-55), and 58% (30-78%), respectively. After covariate adjustment (MRD status, conditioning, age, cytogenetic disease risk, type of consolidation chemotherapy, pre-HCT karyotype, and pre-HCT peripheral blood count recovery), the hazard ratios for 2 or >2 induction courses vs. 1 induction were 1.16 (0.73-1.85, P=0.53) and 2.63 (1.24-5.57, P=0.011) for overall mortality, and 2.10 (1.27-3.48, P=0.004) and 3.32 (1.42-7.78, P=0.006), respectively, for relapse. These findings indicate that the number of induction courses required to achieve morphological remission in AML adds prognostic information for post-HCT outcome that is independent of other prognostic factors.
Related JoVE Video
Metabolic syndrome appears early after hematopoietic cell transplantation.
Metab Syndr Relat Disord
PUBLISHED: 07-09-2014
Show Abstract
Hide Abstract
Improved survival after allogeneic hematopoietic cell transplantation (allo-HCT) enables us to learn more about potential late complications after HCT, one of which is metabolic syndrome. There are no studies investigating the prevalence or development of metabolic syndrome within the first year post-HCT in adult myeloablative transplant recipients.
Related JoVE Video
Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease.
Haematologica
PUBLISHED: 07-04-2014
Show Abstract
Hide Abstract
The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients' mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.
Related JoVE Video
Simultaneous transplantation of hematopoietic stem cells and a vascularized composite allograft leads to tolerance.
Transplantation
PUBLISHED: 06-12-2014
Show Abstract
Hide Abstract
We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. We test the hypothesis that tolerance to a VCA in our dog leukocyte antigen-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT).
Related JoVE Video
Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multicenter Trial.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-09-2014
Show Abstract
Hide Abstract
Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
Related JoVE Video
Failure-free survival after initial systemic treatment of chronic graft-versus-host disease.
Blood
PUBLISHED: 05-29-2014
Show Abstract
Hide Abstract
This study was designed to characterize failure-free survival (FFS) as a novel end point for clinical trials of chronic graft-versus-host disease (GVHD). The study cohort included 400 consecutive patients who received initial systemic treatment of chronic GVHD at our center. FFS was defined by the absence of second-line treatment, nonrelapse mortality, and recurrent malignancy during initial treatment. The FFS rate was 68% at 6 months and 54% at 12 months after initial treatment. Multivariate analysis identified 4 risk factors associated with treatment failure: time interval <12 months from transplantation to initial treatment, patient age ?60 years, severe involvement of the gastrointestinal tract, liver, or lungs, and Karnofsky score <80% at initial treatment. Initial steroid doses and the type of initial treatment were not associated with risk of treatment failure. Lower steroid doses after 12 months of initial treatment were associated with long-term success in withdrawing all systemic treatment. FFS offers a potentially useful basis for interpreting results of initial treatment of chronic GVHD. Incorporation of steroid doses at 12 months would increase clinical benefit associated with the end point. Studies using FFS as the primary end point should measure changes in GVHD-related symptoms, activity, damage, and disability as secondary end points.
Related JoVE Video
Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens.
Oncologist
PUBLISHED: 05-05-2014
Show Abstract
Hide Abstract
Reduced intensity conditioning (RIC) regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients and up to 2 years for 311 patients who underwent a RIC HCT at two institutions from January 2008 to December 2010. Multiple linear regression was used to analyze the association between clinical variables, center effect, and costs. Patient and transplant characteristics were comparable between the sites, although differences were seen in pretransplant performance scores. Significant predictors for lower costs for the first 100 days included a diagnosis of lymphoma/myeloma and use of human leukocyte antigen-matched related donors. Grade II-IV acute graft-versus-host disease (GVHD) was associated with higher costs. The overall short-term costs between the two institutions were comparable when adjusted for clinical variables (p = .43). Late costs between 100 days and 2 years after HCT were available for one cohort (n = 311); median costs during this period were $39,000 and accounted for 39% of costs during the first 2 years. Late costs were not associated with any pretransplant variables, but were higher with extensive chronic GVHD and death. After adjustment for clinical characteristics, the overall costs of the RIC transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/alternative donors, transplant for diseases other than lymphoma or myeloma, and acute GVHD were predictors for higher early costs, and extensive chronic GVHD and death were associated with higher late costs.
Related JoVE Video
Langerhans cell homeostasis and turnover after nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation.
Transplantation
PUBLISHED: 04-11-2014
Show Abstract
Hide Abstract
Langerhans cells (LCs) are self-renewing epidermal myeloid cells that can migrate and mature into dendritic cells. Recipient LCs that survive cytotoxic therapy given in preparation for allogeneic hematopoietic cell transplantation may prime donor T cells to mediate cutaneous graft-versus-host disease (GVHD). This possible association, however, has not been investigated in the setting of nonmyeloablative allografting.
Related JoVE Video
Autologous transplant for relapsed follicular lymphoma: impact of pre-transplant rituximab sensitivity.
Leuk. Lymphoma
PUBLISHED: 04-09-2014
Show Abstract
Hide Abstract
Patients with rituximab-refractory follicular lymphoma (FL) have limited options. Before the rituximab era, autologous stem cell transplant (ASCT) was shown to improve outcomes in chemotherapy-sensitive, relapsed FL, but the impact of rituximab-sensitivity on these results is unknown. We analyzed 194 consecutive relapsed patients with FL who underwent ASCT at out center and categorized them as rituximab-sensitive (RS, n = 35), rituximab-refractory (RR, n = 65) or no rituximab (NoR, n = 94) if transplanted before rituximab was used. Progression-free survival at 3 years was 85% in RS and 35% in RR patients (p = 0.0004). Only rituximab-sensitivity was significant on multivariate analysis with improved overall survival (OS) (hazard ratio [HR] 0.24, p = 0.01) and progression-free survival (PFS) (HR 0.35, p = 0.006) in RS patients and increased relapse in RR patients (HR 2.11, p = 0.01). Pre-transplant rituximab-sensitivity is a strong independent predictor of post-transplant outcomes in relapsed FL, although one-third of RR patients achieved a PFS of over 3 years with ASCT.
Related JoVE Video
Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-12-2014
Show Abstract
Hide Abstract
A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.
Related JoVE Video
Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma.
J. Am. Acad. Dermatol.
PUBLISHED: 02-09-2014
Show Abstract
Hide Abstract
The effects of primary tumor size on nodal involvement and of number of involved nodes on survival have not, to our knowledge, been examined in a national database of Merkel cell carcinoma (MCC).
Related JoVE Video
Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-28-2014
Show Abstract
Hide Abstract
Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients.
Related JoVE Video
Treosulfan, fludarabine, and 2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-10-2014
Show Abstract
Hide Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n = 36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n = 60: 35 first complete remission [CR], 18 second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14 g/m(2)/day treosulfan i.v. on days -6 to -4, 30 mg/m(2)/day fludarabine i.v. on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n = 27) or unrelated (n = 69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n = 10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2 years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse.
Related JoVE Video
Plasma CXCL9 elevations correlate with chronic GVHD diagnosis.
Blood
PUBLISHED: 12-20-2013
Show Abstract
Hide Abstract
There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential ELISA to compare 17 patients with treatment-refractory de novo onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify five candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2R?, Elafin, CD13 and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n=109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source and degree of HLA matching (71% vs. 20%, p<0.001). A separate validation cohort from a different transplant center (n=211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs. 60%; p=0.001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD.
Related JoVE Video
p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility.
Am. J. Clin. Pathol.
PUBLISHED: 11-15-2013
Show Abstract
Hide Abstract
To determine the clinical utility of p63 expression, which has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma (MCC).
Related JoVE Video
Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease.
Haematologica
PUBLISHED: 09-20-2013
Show Abstract
Hide Abstract
We evaluated short-term response endpoints for acute graft-versus-host disease treatment trials. We postulated that response endpoints should correlate with reduced symptom burden and decreased subsequent treatment failure defined as nonrelapse mortality, recurrent malignancy, or additional systemic treatment. The cohort included 303 consecutive patients who received initial systemic steroid treatment for acute graft-versus-host disease. Response was evaluated at day 28 after initial treatment, which in all cases preceded the onset of chronic graft-versus-host disease. At day 28, 36% of patients had complete response, 26% very good partial response, 10% other partial response and 28% no response. As expected, the symptom burden was lower in patients with very good partial response compared to those with other partial response. The frequencies of subsequent treatment failure were similar in patients with complete and very good partial response, but lower than in patients with other partial response or no response at day 28. The frequency of second-line treatment was lower in patients with very good partial response than in those with other partial response. Risk factors associated with a lower probability of complete or very good partial response at day 28 were unrelated or human leukocyte antigen-mismatched related donor grafts and liver or gastrointestinal involvement at onset of initial treatment. Taken together, these results suggest that endpoints in acute graft-versus-host disease treatment trials should distinguish between very good partial response and other partial response. Our results support the use of complete or very good partial response at day 28 as an appropriate short-term primary endpoint.
Related JoVE Video
Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow-up.
Pediatr Blood Cancer
PUBLISHED: 07-22-2013
Show Abstract
Hide Abstract
Kidney stones have been reported to occur after childhood cancer, but little is known about kidney stones in children following hematopoietic cell transplantation (HCT). The objective of this retrospective study was to determine risk factors for the development of kidney stones and to describe the prevalence among survivors.
Related JoVE Video
Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission.
Blood
PUBLISHED: 07-11-2013
Show Abstract
Hide Abstract
Minimal residual disease (MRD) before myeloablative hematopoietic cell transplantation (HCT) is associated with adverse outcome in acute myeloid leukemia (AML) in first complete remission (CR1). To compare this association with that for patients in second complete remission (CR2) and to examine the quantitative impact of MRD, we studied 253 consecutive patients receiving myeloablative HCT for AML in CR1 (n = 183) or CR2 (n = 70) who had pre-HCT marrow aspirates analyzed by 10-color flow cytometry. Three-year estimates of overall survival were 73% (64%-79%) and 32% (17%-48%) for MRDneg and MRDpos CR1 patients, respectively, and 73% (57%-83%) and 44% (21%-65%) for MRDneg and MRDpos CR2 patients, respectively. Similar estimates of relapse were 21% (14%-28%) and 58% (41%-72%) for MRDneg and MRDpos CR1 patients, respectively, and 19% (9%-31%) and 68% (41%-85%) for MRDneg and MRDpos CR2 patients, respectively. Among the MRDpos patients, there was no statistically significant evidence that increasing levels of MRD were associated with increasing risks of relapse and death. After multivariable adjustment, risks of death and relapse were 2.61 times and 4.90 times higher for MRD(pos) patients (P < .001). Together, our findings indicate that the negative impact of pre-HCT MRD is similar for AML in CR1 and CR2 with even minute levels (? 0.1%) as being associated with adverse outcome.
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
Comparing high and low total body irradiation dose rates for minimum-intensity conditioning of dogs for dog leukocyte antigen-identical bone marrow grafts.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-24-2013
Show Abstract
Hide Abstract
We tested the hypothesis that total body irradiation (TBI) given at a high dose rate would be more immunosuppressive and lead to a higher incidence of stable hematopoietic cell engraftment after suboptimal levels of conditioning irradiation compared with TBI at a low dose rate. We assessed the engraftment success of dog leukocyte antigen-identical bone marrow transplantation in recipients of 100, 150, and 200 cGy TBI administered at a rate of 7 or 70 cGy/min. Dogs received donor marrow on the same day as TBI and were subsequently treated with postgraft immunosuppression consisting of mycophenolate mofetil (for 28 days) and cyclosporine (for 37 days). Donor chimerism was monitored until the end of study and was characterized by either graft rejection or stable engraftment. Increasing the radiation dose rate from the traditional 7 cGy/min to 70 cGy/min did not lead to increased engraftment success at any of the irradiation doses tested. The dose rate of 70 cGy/minute was no more hematotoxic than the rate of 7 cGy/minute. TBI delivered at a high dose rate was well tolerated but was not associated with a better rate of allogeneic hematopoietic cell engraftment compared with TBI delivered at a lower dose rate.
Related JoVE Video
Costs of second allogeneic hematopoietic cell transplantation.
Transplantation
PUBLISHED: 05-23-2013
Show Abstract
Hide Abstract
A second allogeneic transplantation after a prior allogeneic (allo-allo) or autologous (auto-allo) hematopoietic cell transplantation (HCT) is usually performed for graft failure, disease recurrence, secondary malignancy, and, as planned, auto-allo transplantation for some diseases.
Related JoVE Video
Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-16-2013
Show Abstract
Hide Abstract
The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m(2) fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation.
Related JoVE Video
Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-05-2013
Show Abstract
Hide Abstract
Targeted busulfan ((T)BU) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/(T)BU conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. Compared with (T)BU/CY-conditioned patients, CY/(T)BU-conditioned patients had greater exposure to CY (P < .0001) and less exposure to 4-hydroxycyclophosphamide (P < .0001). Clinical outcomes were compared between cases and controls (n = 271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (T)BU/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% versus 13%; P = .01). CY/(T)BU conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.
Related JoVE Video
Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease.
Blood
PUBLISHED: 04-01-2013
Show Abstract
Hide Abstract
Sclerotic chronic graft-versus-host disease (GVHD) can result in disability after allogeneic hematopoietic cell transplantation. We assessed the incidence and risk factors of sclerosis and its association with transplant outcomes among 977 consecutive patients treated with systemic immunosuppression for chronic GVHD. Sclerosis was defined when cutaneous sclerosis, fasciitis, or joint contracture was first documented in the medical record. Seventy (7%) patients presented with sclerosis at the time of initial systemic treatment for chronic GVHD, and the cumulative incidence of sclerosis increased to 20% at 3 years. Factors associated with an increased risk of sclerosis included the use of a mobilized blood cell graft and a conditioning regimen with > 450 cGy total body irradiation. Factors associated with a decreased risk of sclerosis included the use of an HLA-mismatched donor and a major ABO-mismatched donor. Development of sclerosis was associated with longer time to withdrawal of immunosuppressive treatment but not with risks of overall mortality, nonrelapse mortality, or recurrent malignancy. We found a substantial incidence of sclerosis in patients with chronic GVHD. Development of sclerosis can cause disability but does not affect mortality or recurrent malignancy in patients with chronic GVHD.
Related JoVE Video
Relationship of body mass index and arm anthropometry to outcomes after pediatric allogeneic hematopoietic cell transplantation for hematologic malignancies.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-19-2013
Show Abstract
Hide Abstract
Although nutritional status may adversely affect various health outcomes, the relationship between anthropometry and outcomes after hematopoietic cell transplantation (HCT) has not been fully studied in children. We analyzed the impact of pre-HCT body mass index (BMI), arm muscle area, and arm fat area on outcomes in 733 patients age 2-18 years who underwent allogeneic HCT for a hematologic malignancy between 1985 and 2009. We evaluated these 3 variables according to patient group based on age- and sex-adjusted percentiles for BMI, arm muscle area (<5th, 5th-24th, 25th-94th, and ?95th), and arm fat area (<25th, 25th-94th, and ?95th). Cox proportional hazards regression models for event-free survival (EFS), relapse, and nonrelapse mortality (NRM) at 100 days and 3 years after HCT, as well as grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD, were performed using the 3 major variables and adjusted for covariates. BMI was <5th percentile in only 3% of patients and ?95th percentile in 15% of patients, but outcomes for both groups were similar to those for the BMI 25th-94th percentile group. The BMI 5th-24th percentile group had lower EFS (P = .01) and higher relapse (P = .003) at day +100 post-HCT, but these associations did not hold at 3 years post-HCT. Arm muscle area was <5th percentile in 8% of patients, and arm fat area was <25th percentile in 10%. Analysis of arm muscle area showed that the <5th percentile group had lower EFS and higher NRM and relapse rate at day +100 (P = .002, .04, and .01, respectively) and 3 years (P = .0004, .008, and .01, respectively) post-HCT. Arm fat area <25th percentile was associated with lower EFS at day +100 (hazard ratio, 1.5; P = .05), but not at 3 years post-HCT. Anthropometry variables were not associated with acute or chronic GVHD. In conclusion, arm muscle area <5th percentile appears to be a stronger predictor than BMI of poor outcomes after HCT in children with hematologic malignancies.
Related JoVE Video
Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation.
J. Clin. Oncol.
PUBLISHED: 03-11-2013
Show Abstract
Hide Abstract
We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.
Related JoVE Video
A novel soluble form of Tim-3 associated with severe graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-08-2013
Show Abstract
Hide Abstract
The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry-based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.
Related JoVE Video
Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3+ T cell dose.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-06-2013
Show Abstract
Hide Abstract
The impact of donor lymphocyte infusion (DLI) initial cell dose on its outcome is known in patients with chronic myeloid leukemia but limited in patients with other hematological malignancies. In this retrospective study, we evaluated the effect of initial DLI CD3(+) cell dose on graft-versus-host disease (GVHD) and overall survival after DLI given for relapse of any hematological malignancies after allogeneic hematopoietic cell transplantation (HCT) with high- or reduced-intensity conditioning. The cohort included 225 patients. Initial DLI CD3(+) cell dose per kilogram of recipient body weight was ? 1 × 10(7) (n = 84; group A), >1.0 to <10 × 10(7) (n = 58; group B), and ? 10 × 10(7) (n = 66; group C). The initial cell dose was unknown for the remaining 17 patients. Cumulative incidence rates of GVHD at 12 months after DLI were 21%, 45%, and 55% for groups A, B, and C, respectively. Multivariate analysis showed that initial DLI CD3(+) cell ? 10 × 10(7) dose per kilogram is associated with an increased risk of GVHD after DLI (P = .03). Moreover, an initial DLI CD3(+) cell dose of 10 × 10(7) or higher did not decrease the risk of relapse and did not improve overall survival. Thus, these results support the use of less than 10 × 10(7) CD3(+) cell per kilogram as the initial cell dose of DLI for treatment of persistent or recurrent hematological malignancy after HCT.
Related JoVE Video
Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-06-2013
Show Abstract
Hide Abstract
We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 ?g/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 ?g/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.
Related JoVE Video
Failure-free survival after second-line systemic treatment of chronic graft-versus-host disease.
Blood
PUBLISHED: 01-15-2013
Show Abstract
Hide Abstract
This study attempted to characterize causes of treatment failure, identify associated prognostic factors, and develop shorter-term end points for trials testing investigational products or regimens for second-line systemic treatment of chronic graft-versus-host disease (GVHD). The study cohort (312 patients) received second-line systemic treatment of chronic GVHD. The primary end point was failure-free survival (FFS) defined by the absence of third-line treatment, nonrelapse mortality, and recurrent malignancy during second-line treatment. Treatment change was the major cause of treatment failure. FFS was 56% at 6 months after second-line treatment. Lower steroid doses at 6 months correlated with subsequent withdrawal of immunosuppressive treatment. Multivariate analysis showed that high-risk disease at transplantation, lower gastrointestinal involvement at second-line treatment, and severe NIH global score at second-line treatment were associated with increased risks of treatment failure. These three factors were used to define risk groups, and success rates at 6 months were calculated for each risk group either without or with various steroid dose limits at 6 months as an additional criterion of success. These success rates could be used as the basis for a clinically relevant and efficient shorter-term end point in clinical studies that evaluate agents for second-line systemic treatment of chronic GVHD.
Related JoVE Video
Allogeneic hematopoietic cell transplantation following minimal intensity conditioning: predicting acute graft-versus-host disease and graft-versus-tumor effects.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-12-2013
Show Abstract
Hide Abstract
Most patients with hematologic malignancies have received extensive chemotherapy before hematopoietic cell transplantation (HCT), resulting in neutropenia, lymphocytopenia, and use of antibiotics. Accordingly, patients have a wide range of neutrophil counts, lymphocyte counts, and previous antibiotic use. The minimal toxicity of the current conditioning regimen allowed us to ask whether peritransplantation neutrophil or lymphocyte levels influences the risks of acute graft-versus-host disease (GVHD) or relapse. We analyzed outcomes in 459 patients age 7-75 years (median, 57 years) who received conditioning with fludarabine and low-dose total body irradiation for HLA-matched HCT. We report 2 key findings. First, low neutrophil nadirs within the first 3 weeks post-HCT had significant associations with increased risks of acute GVHD and 5-year nonrelapse mortality, but showed no association with the risk of relapse. Second, high lymphocyte counts immediately before HCT had significant associations with reduced risks of relapse and overall mortality, but no association with the risks of GVHD or nonrelapse mortality. These findings suggest that the immunologic mechanisms involved in acute GVHD might differ from those that initiate graft-versus-tumor effects.
Related JoVE Video
Nonmalignant late effects and compromised functional status in survivors of hematopoietic cell transplantation.
J. Clin. Oncol.
PUBLISHED: 12-05-2011
Show Abstract
Hide Abstract
Our objective was to describe the incidence of nonmalignant late complications and their association with health and functional status in a recent cohort of hematopoietic cell transplantation (HCT) survivors.
Related JoVE Video
Durable donor engraftment after radioimmunotherapy using ?-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation.
Blood
PUBLISHED: 12-01-2011
Show Abstract
Hide Abstract
To reduce toxicity associated with external ?-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the ?-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 ?Ci/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 ?Ci/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 ?Ci/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/?L), lymphopenia (0-270 cells/?L), and thrombocytopenia (1500-6560 platelets/?L) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 ?Ci/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning.
Related JoVE Video
Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras.
Transplantation
PUBLISHED: 11-16-2011
Show Abstract
Hide Abstract
Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a reproducible strategy for the induction of tolerance toward solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of antigenic vascularized composite allografts.
Related JoVE Video
Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study.
Haematologica
PUBLISHED: 11-04-2011
Show Abstract
Hide Abstract
The National Institutes of Health Consensus Conference proposed the term "overlap" graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present.
Related JoVE Video
Evaluation of oral beclomethasone dipropionate for prevention of acute graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-28-2011
Show Abstract
Hide Abstract
Results from two randomized trials have shown that oral beclomethasone dipropionate (BDP) is effective for treatment of acute gastrointestinal graft-versus-host disease. Here, we report results of a double-blind, randomized placebo-controlled phase II study designed to test the hypothesis that acute graft-versus-host disease could be prevented by administration of oral BDP, beginning before hematopoietic cell transplantation and continuing until day 75 after hematopoietic cell transplantation after myeloablative conditioning. Study drug (BDP or placebo) was administered as 1-mg immediate-release formulation plus 1-mg delayed-release formulation orally four times daily. According to the primary endpoint, systemic glucocorticoid treatment for graft-versus-host disease was given to 60 of the 92 participants (65%) in the BDP arm, versus 31 of 46 participants (67%) in the placebo arm. The secondary efficacy endpoints showed no statistically significant differences between the two arms. The proportion of participants who took at least 90% of the prescribed study drug during the first 4 weeks after hematopoietic cell transplantation was 54% overall. Lower severity of mucositis strongly correlated with higher adherence to the schedule of study drug administration. Inconsistent adherence related to mucositis during recovery after myeloablative conditioning may have obscured a beneficial therapeutic effect in the current study.
Related JoVE Video
Cytopenias after day 28 in allogeneic hematopoietic cell transplantation: impact of recipient/donor factors, transplant conditions and myelotoxic drugs.
Haematologica
PUBLISHED: 08-31-2011
Show Abstract
Hide Abstract
Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.
Related JoVE Video
Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia.
Br. J. Haematol.
PUBLISHED: 08-18-2011
Show Abstract
Hide Abstract
This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 ?g/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.
Related JoVE Video
Immunomodulatory effects induced by cytotoxic T lymphocyte antigen 4 immunoglobulin with donor peripheral blood mononuclear cell infusion in canine major histocompatibility complex-haplo-identical non-myeloablative hematopoietic cell transplantation.
Cytotherapy
PUBLISHED: 08-17-2011
Show Abstract
Hide Abstract
BACKGROUND AIMS. Previously, cytotoxic T lymphocyte antigen 4 (CTLA4) immunoglobulin (Ig) has been shown to allow sustained engraftment in dog leukocyte antigen (DLA)-identical hematopoietic cell transplant (HCT) after non-myeloablative conditioning with 100 cGy total body irradiation (TBI). In the current study, we investigated the efficacy of pre-transplant CTLA4-Ig in promoting engraftment across a DLA-mismatched barrier after non-myeloablative conditioning. METHODS. Eight dogs were treated with CTLA4-Ig and donor peripheral blood mononuclear cells (PBMC) prior to receiving 200 cGy TBI followed by transplantation of granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from DLA haplo-identical littermates with post-grafting immunosuppression. A control group of six dogs was conditioned with 200 cGy only and transplanted with grafts from DLA haplo-identical littermates followed by post-grafting immunosuppression. RESULTS. In vitro and in vivo donor-specific hyporesponsiveness was demonstrated on day 0 before TBI in eight dogs that received CTLA4-Ig combined with donor PBMC infusions. Four of five dogs treated with increased doses of CTLA4-Ig achieved initial engraftment but eventually rejected, with a duration of mixed chimerism ranging from 12 to 22 weeks. CTLA4-Ig did not show any effect on host natural killer (NK) cell function in vitro or in vivo. No graft-versus-host disease (GvHD) was observed in dogs receiving CTLA4-Ig treatment. CONCLUSIONS. Non-myeloablative conditioning with 200 cGy TBI and CTLA4-Ig combined with donor PBMC infusion was able to overcome the T-cell barrier to achieve initial engraftment without GvHD in dogs receiving DLA haplo-identical grafts. However, rejection eventually occurred; we hypothesize because of the inability of CTLA4-Ig to abate natural killer cell function.
Related JoVE Video
Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria.
Blood
PUBLISHED: 07-26-2011
Show Abstract
Hide Abstract
In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.
Related JoVE Video
Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation.
Blood
PUBLISHED: 06-16-2011
Show Abstract
Hide Abstract
Monosomal karyotype (MK), defined as ? 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK(+) patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK(+). The 4-year overall survival of patients after HCT was 25% for MK(+) AML and 56% for MK(-) AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK(+) patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK(+) patients remains worse than that for MK(-) patients in the transplantation setting, HCT appears to improve the overall outcome of MK(+) patients, especially patients without a complex karyotype. However, the 28% of MK(+) patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients.
Related JoVE Video
Late effects among pediatric patients followed for nearly 4 decades after transplantation for severe aplastic anemia.
Blood
PUBLISHED: 06-07-2011
Show Abstract
Hide Abstract
Aplastic anemia (AA), a potentially fatal disease, may be cured with marrow transplantation. Survival in pediatric patients has been excellent early after transplantation, but only limited data are available regarding late effects. This study evaluates late effects among 152 patients followed 1-38 years (median, 21.8 years). Transplantation-preparative regimes were mostly cyclophosphamide with or without antithymocyte globulin. Survival at 30 years for the acquired AA patients is 82%, and for the Fanconi anemia patients it is 58% (P = .01). Multivariate analysis demonstrated that chronic GVHD (P = .02) and Fanconi anemia (P = .03) negatively impacted survival. Two Fanconi patients and 18 acquired AA patients developed a malignancy that was fatal for 4. There was an increased incidence of thyroid function test abnormalities among those who received total body irradiation. Cyclophosphamide recipients demonstrated normal growth, basically normal development, and pregnancies with mostly normal offspring. Quality-of-life studies in adult survivors of this pediatric transplantation cohort indicated that patients were comparable with control patients except for difficulty with health and life insurance. These data indicate that the majority of long-term survivors after transplantation for AA during childhood can have a normal productive life.
Related JoVE Video
Prognostic impact of discordant results from cytogenetics and flow cytometry in patients with acute myeloid leukemia undergoing hematopoietic cell transplantation.
Cancer
PUBLISHED: 06-01-2011
Show Abstract
Hide Abstract
Cytogenetics and multicolor flow cytometry (MFC) are useful tools for monitoring outcome of treatment in acute myeloid leukemia (AML). However, no data are available regarding the meaning of results when the 2 tests do not agree.
Related JoVE Video
Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation.
Blood
PUBLISHED: 06-01-2011
Show Abstract
Hide Abstract
This study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.
Related JoVE Video
Association between calcineurin inhibitor blood concentrations and outcomes after allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-31-2011
Show Abstract
Hide Abstract
To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versus-host disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n = 634) or unrelated (n = 547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n = 774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD (aGVHD, cGVHD). After nonmyeloablative HCT (n = 407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 aGVHD (hazard ratio [HR] per 100 ng/mL change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95% CI, 0.49-0.9, respectively), nonrelapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95% CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of cGVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against aGVHD that translates into reduced risks of nonrelapse and overall mortality.
Related JoVE Video
Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia.
Haematologica
PUBLISHED: 04-20-2011
Show Abstract
Hide Abstract
Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia.
Related JoVE Video
Limiting the daily total nucleated cell dose of cryopreserved peripheral blood stem cell products for autologous transplantation improves infusion-related safety with no adverse impact on hematopoietic engraftment.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-15-2011
Show Abstract
Hide Abstract
Cryopreserved peripheral blood stem cell (PBSC) products can induce a number of infusion-related adverse reactions, including life-threatening cardiac, neurologic, and other end-organ complications. Preliminary analyses suggested limiting the daily total nucleated cell dose infused might decrease the incidence of these adverse effects. A policy change implemented in December 2007, limiting the total nucleated cell (TNC) dose to <1.63 × 10(9) TNC/kg/day, allowed us to assess the impact of this intervention on infusion-related safety, infusion schedules, engraftment, and costs in cohorts of patients undergoing autologous stem cell transplants (ASCTs) 2 years before (325 ASCTs in 288 patients) and 2 years after the policy change (519 ASCTs in 479 patients). The percentage of autologous transplant patients requiring multiple day infusions increased from 6% to 24%. Concurrently, the incidence of infusion-related grade 3-5 severe infusion-related adverse events (SAEs) decreased significantly, from 4% (13 of 325) prepolicy change to 0.6% (3 of 519) postpolicy change (P < .0004). Multiday infusions were not associated with increased time to neutrophil or platelet engraftment or the costs of transplantation. We conclude that limiting the daily TNC dose improved the safety of this procedure without compromising engraftment or increasing the costs of the procedure.
Related JoVE Video
Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma.
Blood
PUBLISHED: 04-13-2011
Show Abstract
Hide Abstract
Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.
Related JoVE Video
Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-12-2011
Show Abstract
Hide Abstract
Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ?0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ?0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.
Related JoVE Video
A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients.
Cancer Chemother. Pharmacol.
PUBLISHED: 03-18-2011
Show Abstract
Hide Abstract
Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
Related JoVE Video
Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-08-2011
Show Abstract
Hide Abstract
We tested the hypothesis that changes in the phenotype of CD8(+) T cells from patients with chronic graft-versus-host disease (cGVHD) correlate with disease activity, and resolve or normalize in clinically tolerant patients successfully withdrawn from immunosuppression therapy (IST). No significant difference was found in the absolute CD8(+) T cell counts among cGVHD patients, tolerant patients, and healthy controls. However, compared with healthy normal controls, CD8(+) T cells from cGVHD patients had decreased expression of the IL-7 receptor and an increase in effector T cells, Ki-67, and perforin expression and apoptosis, suggesting that activation, differentiation, and proliferation of host-reactive CD8(+) effector T cells is a mechanism by which cGVHD is sustained and persists. The increase in effector T cells was most prominent in older patients and patients who were cytomegalovirus seropositive before transplantation. Use of IST was associated with a decreased number of CD45RA(-) CD8(+) effector T cells, a decreased expression of Ki-67, and an increased expression of CD95 (Fas). Together, these results demonstrate that CD8(+) T cells in patients with cGVHD are characterized by an increased level of activation and proliferation, and an expansion of effector cells that appear to be selectively sensitive to IST compared with other CD8(+) T cells. In GVHD-free tolerant patients, CD8(+) T cells showed an increased expression of granzyme and HLA-DR molecules compared with CD8(+) T cells from healthy controls, indicating that clinical tolerance in these patients can occur without full normalization of the CD8(+) T cell phenotype.
Related JoVE Video
Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-24-2011
Show Abstract
Hide Abstract
Peripheral blood stem cell (PBSC) products contain more T cells and monocytes when compared with bone marrow (BM), leading to fewer bacterial and fungal infections. Cytomegelovirus (CMV) viral load and disease as well as CMV-specific immune reconstitution were compared in patients enrolled in a randomized trial comparing PSBC and BM transplantation. There was a higher rate of CMV infection and disease during the first 100 days after transplantation among PBSC recipients (any antigenemia/DNAemia: PBSC, 63% vs BM, 42%, P = .04; CMV disease: PBSC, 17% vs BM, 4%, P = .03). By 2 years, CMV disease rates were similar. The early increase in CMV events correlated temporarily with lower CMV-specific CD4(+) T helper and CD8(+) cytotoxic T lymphocyte function at 30 days after transplantation in PBSC recipients. By 3 months after transplantation and thereafter, CMV-specific immune responses were similar between BM and PBSC recipients. In conclusion, higher CMV infection and disease rates occurred in PBSC transplant recipients early after transplantation. These differences may be because of a transient delay in CMV-specific immune reconstitution following PBSC transplantation.
Related JoVE Video
Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria.
Blood
PUBLISHED: 01-24-2011
Show Abstract
Hide Abstract
Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.
Related JoVE Video
A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-13-2011
Show Abstract
Hide Abstract
This retrospective study was performed to compare results with tacrolimus versus cyclosporine in combination with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation (HCT) with granulocyte colony-stimulating factor-mobilized blood cells. The cohort included 456 consecutive patients who received first allogeneic T cell-replete HCT with mobilized blood cells from related or unrelated donors after high-intensity conditioning for treatment of hematologic malignancies. Study endpoints included grades II-IV acute graft-versus-host disease (aGVHD), grades III-IV aGVHD, chronic GVHD (cGVHD), end of treatment for cGVHD, overall mortality, disease-free survival (DFS), recurrent malignancy, and nonrelapse mortality (NRM). Adjusted multivariate Cox regression analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested. Although the size of the cohort is not sufficient to exclude clinically meaningful differences in outcomes, these results support the continued use of cyclosporine at centers that have not adopted tacrolimus as the standard of care after HCT with mobilized blood cells after high-intensity conditioning regimens. A larger registry study should be performed to provide more definitive information comparing outcomes with the 2 calcineurin inhibitors.
Related JoVE Video
Comparison of short-term response and long-term outcomes after initial systemic treatment of chronic graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-08-2010
Show Abstract
Hide Abstract
Clinical trials of chronic graft-versus-host disease (cGVHD) often use early endpoints, such as clinical response at 3 or 6 months, as the primary endpoint instead of measures of long-term treatment success, such as the ability to discontinue immunosuppressive treatment after development of immune tolerance and resolution of active disease. We evaluated the ability of defined overall and organ-specific response categories at 3 and 6 months to predict the subsequent success or failure of primary treatment. The analysis included 116 patients evaluated at 3 months after enrollment and 94 patients evaluated at 6 months after enrollment. Success was defined as withdrawal of systemic treatment after resolution of cGVHD without secondary therapy. Failure was defined as secondary systemic treatment, or death or development of bronchiolitis obliterans during primary treatment. With most definitions, response at 3 months and response at 6 months were not statistically significantly correlated with subsequent success of primary treatment. With some definitions, the absence of response at 6 months had a statistically significant correlation with subsequent failure of primary treatment. These findings suggest that early response to the agents currently used for primary treatment does not necessarily predict subsequent tolerance, an important endpoint in the management of cGVHD. Rigorously defined clinical response is an appropriate primary endpoint for studies of cGVHD, but future clinical trials should provide for extended follow-up to ascertain late outcomes that are not necessarily predictable by evaluation of response before 6 months.
Related JoVE Video
Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia.
J. Clin. Oncol.
PUBLISHED: 05-03-2010
Show Abstract
Hide Abstract
Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients.
Related JoVE Video
Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-03-2010
Show Abstract
Hide Abstract
We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had hematopoietic cell transplantation (HCT) from HLA-identical siblings (n = 630) or HLA-matched unrelated donors (n = 576) at a single institution between 2001 and 2007 for a correlation between recipient statin use and risk of graft-versus-host disease (GVHD). Among recipients with cyclosporine-based postgrafting immunosuppression (n = 821), statin use at the time of transplant (6%) was associated with a decreased risk of extensive chronic GVHD (cGVHD) (multivariate hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.4-1.0; P = .05) and an increased risk of recurrent malignancy (HR, 1.75; 95% CI, 1.0-3.0; P = .04). Recipient statin use, however, had no apparent impact on the risks of cGVHD and recurrent malignancy among recipients given tacrolimus-based immunosuppression (n = 385; 8% statin treated). Risks of acute GVHD, nonrelapse mortality, and overall mortality were not significantly affected by recipient statin use. Hence, recipient statin treatment at the time of allogeneic HCT may decrease the risk of cGVHD in patients with cyclosporine-based immunosuppression, but at the expense of a compromised graft-versus-tumor effect.
Related JoVE Video
Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study.
Br. J. Haematol.
PUBLISHED: 03-16-2010
Show Abstract
Hide Abstract
Immunosuppressive therapies have proven valuable in treating patients with myelodysplastic syndromes (MDS). We evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble tumour necrosis factor receptor, etanercept (Enbrel), in a phase II trial. Twenty-five patients with MDS [4-refractory anaemia (RA), 2-RA with ring sideroblasts, 15-refractory cytopenia with multilineage dysplasia (RCMD), 3-RCMD and ring sideroblasts, 1-RA with excess blasts type 1] in International Prognostic Staging System risk groups low (n = 11) or intermediate-1 (n = 14) were enrolled. All patients were platelet or red cell transfusion-dependent. Nineteen patients completed therapy with ATG at 40 mg/kg per day for four consecutive days, followed by etanercept, 25 mg subcutaneous twice a week for 2 weeks, every month for 4 months. Thirteen patients had haematological improvement (HI)-erythroid, 2 HI-neutrophil, and 6 HI-platelet. One patient with a co-existing diagnosis of multiple sclerosis and rheumatoid arthritis had a complete remission. The overall response by intent to treat analysis among the 25 patients was 56% (95% confidence interval 35-56%). Four patients did not complete their first course of therapy and one patient did not survive to the 8-week post-treatment assessment. Among patients who completed treatment and survived to the 8-week assessment, 70% had at least haematological responses lasting for at least 5 to more than 36 months. Thus, combination therapy with ATG and etanercept was active and safe in patients with MDS.
Related JoVE Video
Validation and comparison of pharmacogenetics-based warfarin dosing algorithms for application of pharmacogenetic testing.
J Mol Diagn
PUBLISHED: 03-12-2010
Show Abstract
Hide Abstract
Warfarin is a widely prescribed drug that is difficult to use because of its narrow therapeutic window. Genetic polymorphisms associated with warfarin metabolism have been identified, but the clinical utility of genetic testing in warfarin dosing has not been established. External validation of published algorithms is critical to determine the best prediction for warfarin dosing in prospective trials. We used two independent datasets totaling 1095 patients to evaluate four published algorithms and a simple prediction algorithm developed in this study based on the CYP2C9*2, CYP2C9*3, and VKORC1 -1639 polymorphisms in 150 patients taking warfarin. Predicted warfarin doses were calculated and compared for accuracy with actual maintenance doses. All evaluated pharmacogenetics-based dosing algorithms performed similarly for both datasets. The proportion of variation explained (R(2)) was high (60% to 65%) in the small white-only Connecticut dataset but low (36% to 46%) in the large dataset on a diverse ethnic population from the International Warfarin Pharmacogenetics Consortium (IWPC). When comparing the percentage of patients whose predicted dosage are within 20% of actual, the IWPC algorithm performed the best overall (45.9%) for the two datasets combined while other algorithms performed nearly as well. Because no algorithm could be considered the best for all dosing ranges, it may be important to consider the nature of a local service population in choosing the most appropriate pharmacogenetics-based dosing algorithm.
Related JoVE Video
A preclinical model of double- versus single-unit unrelated cord blood transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-15-2010
Show Abstract
Hide Abstract
Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 x 10(7)/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained
Related JoVE Video
Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation.
J. Clin. Oncol.
PUBLISHED: 01-11-2010
Show Abstract
Hide Abstract
PURPOSE Hematopoietic cell transplantation can cure hematologic malignancies and other diseases, but this treatment can also cause late complications. Previous studies have evaluated the cumulative effects of late complications on survival, but longer-term effects on life expectancy after hematopoietic cell transplantation have not been assessed. PATIENTS AND METHODS We used standard methods to evaluate mortality, projected life expectancy, and causes of death in a cohort of 2,574 patients who survived without recurrence of the original disease for at least 5 years after allogeneic or autologous hematopoietic cell transplantation from 1970 through 2002. Sex- and age-specific comparisons were made with US population data. Results Estimated survival of the cohort at 20 years after transplantation was 80.4% (95% CI, 78.1% to 82.6%). During 22,923 person-years of follow-up, 357 deaths occurred. Mortality rates remained four- to nine-fold higher than the expected population rate for at least 30 years after transplantation, yielding an estimated 30% lower life expectancy compared with that in the general population, regardless of current age. In rank order, the leading causes of excess deaths were second malignancies and recurrent disease, followed by infections, chronic graft-versus-host disease, respiratory diseases, and cardiovascular diseases. CONCLUSION Patients who have survived for at least 5 years after hematopoietic cell transplantation without recurrence of the original disease have a high probability of surviving for an additional 15 years, but life expectancy is not fully restored. Further effort is needed to reduce the burden of disease and treatment-related complications in this population.
Related JoVE Video
Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept.
Br. J. Haematol.
PUBLISHED: 01-07-2010
Show Abstract
Hide Abstract
Combination therapy with azacitidine and etanercept was hypothesized to lead to improved responses in myelodysplastic syndrome (MDS) patients. Thirty-two patients with MDS/chronic myelomonocytic leukaemia were treated with azacitidine + etanercept; 30 completed at least three therapy cycles. At 3 months, nine patients had achieved complete response (CR), two had partial response, 10 had marrow CRs, seven had stable disease, two patients had haematological improvement without marrow response and two patients had disease progression. The overall response rate was 72%; median duration of response was not reached at 2 years. Marrow response rates and duration were improved with azacitidine + etanercept compared to azacitidine alone.
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.