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  • 1
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 16, No. 12 ( 2010-12), p. 1707-1717
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
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  • 2
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 19 ( 2021-10-12), p. 3789-3793
    Abstract: Treatment with CD19-directed (CAR) T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune effector cell–associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30% to 40% of patients treated with axicabtagene-ciloleucel (axi-cel), usually within the first 4 weeks after administration of the dose and usually responding well to steroids. We describe a case of progressive central neurotoxicity occurring 9 months after axi-cel infusion in a patient with r/r LBCL who had undergone a prior allogeneic hematopoietic cell transplant. Despite extensive systemic and intrathecal immunosuppression, neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T-cell DNA copy numbers and elevated levels of interleukin-1 (IL-1) and IL-6 were found in the cerebral spinal fluid as clinical symptoms emerged, and CAR T-cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected, devastating, late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 3
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4523-4523
    Abstract: Background Chronic graft-versus-host disease (cGVHD) is the major cause of treatment related morbidity and mortality after allogeneic stem cell transplantation (allo-HSCT). Recently Paul Martin et al. reported that treatment success at 1 year (defined as a patient being in partial (PR) or complete remission (CR) of cGVHD, in ongoing remission of underlying disease and not requiring any secondary treatment for cGVHD) was the only endpoint associated with clinical benefit. Strikingly this robust endpoint was only achieved in less than 20% of patients undergoing primary treatment for cGVHD. Therefore, although most patients show initial response to first-line therapy, long-term clinically meaningful treatment success remains rare. Methods: We conducted a prospective multicentre phase II trial in 6 transplant centres across Germany (ClinicalTrials.gov Identifier: NCT01862965). Patients aged 18 years or older with newly diagnosed moderate or severe cGVHD were included. All patients received prednisone (1mg/kg BW) and everolimus (target level 3-8 ug/l). Study treatment was scheduled for 12 months followed by a one-year follow-up period. Primary endpoint was treatment success at 6 months defined as patient being alive, achieving PR or CR of cGVHD, having no relapse of underlying disease and requiring no secondary treatment for cGVHD. Secondary endpoints included time to treatment failure, overall survival at one and 2 years, time to response, incidence of PR /CR at 6 months, incidence of relapse, thrombotic microangiopathy, pneumonitis and osteonecrosis. Results: A total of 38 patients were included between March 2013 and February 2018 in the study. Four patients were excluded from the efficacy analysis because of screening failure. Of the 34 patients, 61% had moderate and 39% severe cGVHD. Of these 19 (56%) patients showed treatment success at 6 months with 22% and 52% of the patients in a CR and PR respectively. Overall 30 patients (88%) had a CR or PR as best response, nearly all responses (29/30) occurring within the first 6 weeks of treatment (figure 1). Median time to treatment failure was 24.7 weeks. The cumulative incidence of treatment failure at one year was 63%, resulting in a treatment success incidence of 37% (figure 2). Relapse of underlying disease was diagnosed in 2 (5.9%) patients. Other predefined side effects (thrombotic microangiopathy, pneumonitis and osteonecrosis) were not observed in any patient. Conclusion: This, to the best of our knowledge, is the first prospective study analysing the endpoint treatment success as defined by Paul Martin et al. Our results indicate that addition of everolimus to prednisolone is well tolerated and may help improve long-term outcome of patients with cGVHD. Acknowledgements: This study was supported by a research grant from Novartis to Nicolaus Kröger and Francis Ayuk Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Wagner:MEDAC: Other: Travel support; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; MSD: Other: Advisory board. Wolff:Neovi: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Mallinckrodt: Honoraria. von Harsdorf:Novartis: Other: none. Koenecke:Novartis: Other: none. Sayer:Novartis: Other: none. Kroeger:Novartis: Honoraria, Other: Advisory Board, Travel Costs, Research Funding. OffLabel Disclosure: Everolimus used for Treatment of chronic GVHD
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 4
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 42-42
    Abstract: The NIH staging and response criteria offer for the first time the chance for uniform documentation and evaluation of physical functioning and quality of life aspects of chronic graft-versus-host disease (cGVHD) as well as its response to immunosuppressive treatment. Here we present the interim analysis of a prospective Germany multicenter study on the NIH staging criteria in cGVHD. Methods: Seventy-six patients (median age 46 years, range 19–64) after allogeneic hematopoetic stem cell transplantation (HSCT) for hematologic malignancies were evaluated according to the NIH criteria based cGVHD activity assessment, the Lee Chronic GVHD Symptom-Scale, FACT-BMT, human activity profile (HAP), SF 36, Berliner Social Support Scale (BSSS), 24 item Adjective Measure (24 - AM), Hospital Anxiety and Depression Scale (HADS) and the NCCN-Distress-Thermometer. Enrolment occurred between day 100 and 1 year after HSCT or in the presence of active cGVHD also at later time points. Follow-up surveys were conducted at 1, 2, 3, 5, 8, 12 and 18 months after baseline survey. At all time points disease status, comorbidities and medication were documented. Additionally the NIH-Symptom-Scale was applied for clinician rating of cGVHD symptoms. Results: Fifty-one patients had cGVHD (mild n=15, moderate n=32, severe n=4) while 25 patients did not have cGVHD. The cGVHD NIH consensus grading as well as the 10 point scale correlated with impairment of physical functioning (p 〈 0.01, r=.48), the FACT-G total score (p=0.02, r=.33) and mental health (p 〈 0.01, r=.41). The HAP maximum activity score correlated inversely with severity of cGVHD (p=0.028, r=.44), with the physical functioning (p 〈 0.01, r=.53) and with role limitation due to physical problems (p 〈 0.01, r=.43) evaluated by the SF36. In addition an impaired physical functioning correlated with role limitations due to emotional problems (p 〈 0.01, r=.52) and with impaired mental health (p 〈 0,01, r=.63). Moreover the HAP maximum activity score correlated with emotional well being as evaluated by the FACT (p 〈 0.01, r=.39). Depression as measured by the HADS depression score correlated with pain (p 〈 0,01, r=.35) and impaired physical functioning (p=0.03, r=.26) while the HADS anxiety score did not. The results demonstrate, that severity of cGVHD as assessed by the NIH consensus grading and the 10 point scale correlate with impairment of physical functioning as well as daily activities and quality of life. Moreover reduction of daily activities lead to impairment of emotional well being.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 5
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2255-2255
    Abstract: Hematopoietic stem cell transplantation (HSCT) associated thrombotic microangiopathy (TA-TMA) is a frequent and prognostic important complication of HSCT and may affect 20-30% of recipients. One third of these patients suffer from severe TA-TMA with a devastating prognosis. TA-TMA is a systemic small vessel disease affecting predominantly the kidney and the CNS but can affect any other organ. There is currently no accepted standard therapy for TA-TMA. The most commonly used therapeutic approaches such as plasma exchange and defibrotide are ineffective in severe TA-TMA with mortality rates of 〉 80%. Recent data have suggested that TA-TMA, like most other forms of atypical Haemolytic-Uraemic Syndrome (aHUS) is caused by systemic activation of the alternative complement pathway. Given the high success rate of treatment of aHUS with the anti-C5 monoclonal antibody eculizumab (EC), this suggests that EC might be an effective treatment of TA-TMA. Initial reports in pediatric transplant patients seem to support this hypothesis, but the experience in adult patients is very limited and contradictory. Materials and Methods: We performed a retrospective analysis of 13 patients (table 1) treated with EC in our center. Inclusion criteria were diagnosis of TA-TMA according to the Choi-criteria, significant organ damage, evidence of systemic or local complement activation by measurement of serum sC5-9 levels or tissue biopsy. The patients were treated according to the approved dosing schedule of a weekly application of 900mg EC for 4-6 weeks followed by a maintenance phase with 1200mg biweekly. EC therapy was guided by monitoring CH50 activity and serum sC5-9 concentrations as proposed by Jodele et al 2015. The EC dosing schedule was thus adjusted to maintain CH50 activity below 10% and a normal sC5-9 concentration. Clinical response was defined as improvement of organ function (e.g. no neurological residues; termination of kidney dialysis) and independence of red blood cell and platelet transfusions. All patients received ciprofloxacin prophylaxis and the majority antifungal prophylaxis with posaconazole. Results: All patients were in remission of their underlying disease at the time of TA-TMA diagnosis a median of 9 months (from 2 to 29) after HSCT. At diagnosis 12 patients were receiving either tacrolimus (n=6), cyclosporine A (n=1) or sirolimus (n=5), which was withdrawn promptly. The median C5b-C9 level was 461 U/ml (127-810). Most patients presented with multiple organ involvement, combined CNS and kidney affection was the most common (n=8). In 9 patients EC was the primary therapy, in the other 4 patients EC was initiated after treatment failure of plasma exchange and defibrotide. The median time from TA-TMA diagnosis until EC initiation was 10 days (1-16). All patients showed sufficient blockade of the terminal complement pathway after the second EC application (CH50 〈 10%). A median of 9 (1-23) EC infusions were given. Clinical response was seen in 11 patients (85%) and correlated with a successful and durable normalization of sC5-9 levels. However, 9 patients (70%) died during EC therapy (4 during induction, 5 during maintenance phase) with a median survival of 3.7 months (CI95% 1.2-6.7). The main causes of death were infections (n=7) with 3 cases of aspergillosis. Progressive TA-TMA caused death in 2 patients. Multiple organ involvement (p=0.003) and active GvHD (p=0.005) at diagnosis were identified as adverse prognostic factors. Conclusion: In our analysis we are able to show that EC shows a high response rate in severe TA-TMA patients. However, the prognosis remains very poor due to the high rate of infection related mortality which may be partially related to EC therapy. Since most patients presented with advanced, severe TA-TMA, we hypothesize that earlier diagnosis and treatment of TA-TMA and more effective prevention and treatment of infections will improve the outcome of patients with this complication. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1209-1209
    Abstract: Abstract 1209 Poster Board I-231 Background: The prognosis of patients with cytogenetically normal acute myeloid leukemia (CN-AML) ranges from relatively favorable to extremely poor. Recently, based on the presence or absence of well defined mutations, molecular subgroups have been identified, which allow an estimate of a patient's prognosis at the time of diagnosis. Allogeneic stem cell transplantation (SCT) is the only curative treatment for the majority of these patients. However, only limited data is available to describe the role of alloSCT in different molecular subgroups of CN-AML, particularly in advanced stages of the disease. Methods: We retrospectively analyzed the data on 247 patients with CN-AML, who uniformly had received the FLAMSA-RIC conditioning regimen for alloSCT in 14 European centers between 1996 and 2008. Results: Patients suffered from de novo AML (76%), sAML/MDS (21%), and tAML (4%). Median age was 52.1 (19-71) years. Donors were matched or mismatched family, and matched or mismatched unrelated donors in 30%, 2%, 50% and 18%, respectively. SCT was performed in untreated disease (6%), after primary induction failure (PIF, median time from diagnosis to transplantation 134 days; 23%), in first complete remission (CR1, 14%), and beyond CR1 (57%). Median follow-up of survivors was 19 months. Overall survival (OS) and leukemia-free-survival (LFS) of the entire cohort at 2 years from SCT was 51% and 47%, respectively. The disease stage at transplant was the most important variable for outcome (p=.001 for OS, 〈 .001 for LFS): Encouraging results were achieved in patients transplanted in CR1 (2y OS and LFS: 76%), and in patients with PIF (2y OS and LFS: 69%), whereas results were inferior after transplantation in previously untreated disease (2y OS and LFS: 34%), or beyond CR1 (2y OS: 42%, LFS: 34%). Age, sex, de novo vs. secondary leukemia, donor type and CD34+ cell counts showed no influence on outcome. Information on molecular markers was available in 183 patients (74%). As suggested by Schlenk et al. (NEJM 2008), analysis was based on two subgroups: 22 patients with isolated NPM1 mutation (NPM1mut), and 161 patients with other genotypes (FLT3 internal tandem duplication [FLT3-ITD], n=66; or wildtype FLT3/wildtype NMP1 [FLT3wt/NPM1wt] , n=95). Patients with NPM1mut had a 4y OS/LFS of 75/63%. Results were not significantly different, when these patients were transplanted in PIF, CR1, or beyond CR1. Patients with other genotypes showed an OS/LFS of 51%/48% at 2y and of 40%/39% at 4y, without differences among patients with FLT-ITD and FLT3wt/NPM1wt. However, in this subgroup, outcome was highly dependent on the disease stage at SCT, with excellent results after transplantation in PIF (2y OS/LFS: 75%/74%) or in CR1 (2y OS and LFS: 76%), but inferior outcome after transplantation beyond CR1 (2y OS/LFS 38%/33%; p=.004 for OS and .001 for LFS). Conclusion: Allogeneic SCT following the FLAMSA-RIC conditioning produces excellent survival rates in patients with CN-AML, particularly when performed in CR1. Encouraging results in PIF support an early transplant, regardless of molecular subgroup, when CR is not reached after double induction therapy. In patients with an NPM1 mutation, transplantation in advanced disease achieved identical results as in early stage, which supports the strategy not to transplant these patients in CR1, but to delay alloSCT until relapse has occurred. In contrast, patients with FLT3-ITD or FLT3wt/NPM1wt achieved significantly worse results when transplanted beyond first relapse, arguing in favor of transplantation in CR1 for this molecular subgroup. Disclosures: Mayer: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1233-1233
    Abstract: Introduction The role of allogeneic stem cell transplantation (allo-HSCT) in the treatment algorithms for patients with multiple myeloma remains controversial although it is the only potentially curative approach currently available. Here we present the retrospective analysis of 95 allo-HSCT performed between 1994 and 2013 at Ulm University Hospital. We focused on the impact of cytogenetics, graft-versus-host disease (GvHD) and intensity of conditioning on overall survival (OS), progression- free survival (PFS), relapse and non-relapse mortality (NRM). Study population Median age at initial diagnosis was 49 years (range 25-64), median age at time of allo-HSCT was 51 years (range 26-65). Median time from initial diagnosis to allo-HSCT was 13 months (range 3-106). Indications for allo-HSCT were 1) primary allo-HSCT after induction therapy (11 pts), 2) planned tandem auto-allo-HSCT (44 pts), 3) relapse after single allo-HSCT (25 pts), 4) relapse after tandem-auto-HSCT (15 pts). The conditioning regimen in 60 pts was a reduced intensity conditioning (RIC), in 35 pts myeloablative conditioning (MAC). In 68 pts cytogenetic data were available: 13 pts were stratified into standard-, 39 pts into the intermediate- and 16 pts into the high-risk group according to the mSMART recommendations. Results: Median follow-up was 70 months (95% CI, 64,5-75,5). The estimate 1-, 2- and 5-year OS was 87,4 %, 74,7 % and 46,4 % with a median OS of 36 months (95 % CI, 19,7 -52,2). For both, RIC and MAC median OS was 36 months (95% CI, 24,4–47,6 versus 95% CI, 0-108,4). The cumulative incidence of TRM was not different for RIC and MAC but there was a trend for lower relapse in patients receiving MAC (p=0,0612). With respect to the indication for allo–HSCT outcomes were as follows: Median OS was 89 months for primary allo-HSCT, 47 months for tandem auto-allo-HSCT, 20 months for relapse after auto-HSCT and 26 months for relapse after double auto-HSCT. OS did not differ significantly. Median OS in the standard risk group was 20 months (95% CI, 6,7-33,3), in the intermediate group 41 months (95% CI, 17,3-64,7) and in the high-risk group 7 months (95% CI, 0-14,8), showing no statistical significance. 1-year OS was 61,5% vs 66,7% vs 43,8%, 2-year OS was 35,9% vs 66,7% vs 43,8% and 5-year OS was 35,9% vs 43,2% vs 11,7% (standard vs intermediate vs high risk). The median PFS was 12 months (95% CI 8,4-15,6). 1-year PFS was 49,2%, 2-year PFS 32,9% and 5-year PFS was 21,8%. PFS according to the cytogenetic aberration showed a median PFS of 20 vs 14 vs 5 months, 1-year PFS was 53,8% vs 51,3 % vs 30 %, 2-year PFS with 35,9% vs 30,8% vs 7,5%, and 5-year PFS with 26,9% vs 11,5 % vs 7,5% (standard vs intermediate vs high risk). These differences are not statistically significant. Considering the impact acute GvHD, OS significantly differed between the groups with no aGvHD or aGvHD grade I and aGvHD grade II-IV with inferior survival for patients suffering from aGvHD grade II-IV. Chronic GvHD had no impact on outcome. Conclusion Our data of a 19 year experience in treatment of patients with advanced multiple myeloma with allo-HSCT showed an effective treatment option with a curative potential even for patients after intensive pretreatment including autologous stem cell transplantation. Patients who received MAC had a trend for lower cumulative incidence of relapse compared to RIC without increasing TRM in our study. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 8
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 46, No. 10 ( 2008-05-15), p. e96-e105
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Issue
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2008
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  • 9
    In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 143, No. 8 ( 2017-8), p. 1613-1619
    Type of Medium: Online Resource
    ISSN: 0171-5216 , 1432-1335
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 1459285-X
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  • 10
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3059-3059
    Abstract: Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens offers a potential curative therapy to patients with advanced NHL. RIC HCT induces potent graft-versus-lymphoma effects with best results in patients with low tumor burden at time of HCT. Combined use of radioimmunotherapy (RIT) with RIC may increase anti-lymphoma activity of RIC while HCT provides rescue from hematologic toxicity of RIT. This may allow dose escalation of RIT. A multicenter phase I/II study of allogeneic HCT combining RIT using yttrium-90-ibritumomab tiuxetan (Y90-CD20) with two RIC regimens for treatment of patients with NHL has been initiated. Patients with indolent NHL (Arm A) receive RIT with Y90-CD20 (0.4 mCi/kg) on day −14 combined with RIC using fludarabine (30 mg/m^2 day −4 to−2) and 2 Gy TBI (day 0). Patients with aggressive NHL (Arm B) receive an escalated dose of Y90-CD20 (0,6–0,8 mCi/kg) on day −14 combined with RIC using fludarabine (30 mg/m^2 day −8 to−4), melphalan (140 mg/m^2 day −3) and campath (20–30 mg day −3 to−2). For postgrafting immunosuppression either CSA/MMF (Arm A) or CSA alone (Arm B) is used. To date, 31 patients have been enrolled (Arm A=23, Arm B=8). Diagnoses in Arm A were FL (n=12), MCL (n=6), CLL (n=4) and Immunocytoma (n=1). Diagnoses in Arm B were DLBCL (n=6), blastoid MCL (n=1) and transformed CLL (n=1). Median age was 55 (range, 34–67) years. PBSC grafts were either from matched related (n=10) or matched unrelated donors (n=21). All patients were high risk with refractory disease or relapse after preceding HCT. Disease status after salvage therapy at time of HCT was in Arm A: CR=1, PR=18, SD=4 and in Arm B: PR=8. No additional toxicity due to RIT was observed. Engraftment was rapid and sustained with no graft rejections. In Arm A median time to 〉 500 granulocytes/μL was 13 (range, 0–69) days and to 〉 20000 platelets/μL 3 (range, 0–69) days (in 11 patients platelets never dropped 〈 20000/μL). In Arm B median time to 〉 500 granulocytes/μL was 17 (range, 9–23) days and to 〉 20000 platelets/μL 11 (range, 8–29) days. TRM in the first 100 days was 3%, overall 19%. Incidence of grade II-IV GVHD in Arm A was 35% (II=3, III=4, IV=1) and in Arm B 25% (II=2). Best disease response observed was in Arm A: CR=18, PR=5 and in Arm B: CR=3, PR=5. To date, 16/23 patients in Arm A and 6/8 patients in Arm B are alive with a median follow-up of 271 (range, 20–390) days, resulting in a Kaplan-Meier 1 year survival estimate of 65% in Arm A and 62% in Arm B. Causes of death were infection=5, GVHD=1, relapse=1 in Arm A and relapse=2 in Arm B. A combination of RIT with RIC is feasible with no additional toxicity due to RIT and stable engraftment in all patients. Preliminary response data suggest that this strategy may improve early post-transplant disease control, but long-term disease-free survival remains to be determined.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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