scholarly journals Which Is the Best Mobilizing Regimen in POEMS Syndrome? a Retrospective Italian Study of Two Haematological Centres

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5692-5692
Author(s):  
Francesco Autore ◽  
Nicola Piccirillo ◽  
Andrea Nozza ◽  
Idanna Innocenti ◽  
Rossana Putzulu ◽  
...  
Keyword(s):  
Body Weight ◽  
Cell Count ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Laboratory Data ◽  
Case Series ◽  
Poems Syndrome ◽  
High Dose ◽  
Data Set ◽  
Hematopoietic Stem

Abstract Introduction. POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The use of alkylating agents and autologous peripheral blood stem cell transplantation (aPBSCT) seem to be the best strategy. At present aPBSCT should be considered the first line therapy in young patients with POEMS, eligible for high-dose Melphalan (HD-Mel), in absence of organ dysfunction. The best protocol to collect PBSC in patients affected by POEMS remains to be defined, because of the disease rarity and the heterogeneity of published case series. We therefore decided to combine the case series of our two institutions to describe and compare results and outcomes in order to contribute to the definition of the best CD34+ cell mobilization strategy. Patients and methods. We collected clinical and laboratory data of patients affected by POEMS syndrome undergoing hematopoietic stem cells (HSC) mobilization for aPBSCT from 2003 to 2018. Data were organized in order to perform a statistical analysis using "GraphPad Prism" GraphPad Software Inc., (5755 Oberlin Drive, #110, San Diego, CA 92121, USA). The COBE Spectra continuous flow cell separator (Terumo BCT, Shinagawa, Tokyo) was used for leukapheresis. Results. Our data set consisted of 25 patients, of whom 11 were mobilized using cyclophosphamide (CY) 4 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) 5 μg/kg and 14 patients were mobilized using G-CSF 10 μg/kg for 5 days. All patients submitted to mobilization underwent collection procedure. Three patients, because of low CD34+ cells after the administration of G-CSF alone, were submitted to plerixafor infusion achieving a median pre-apheresis CD34+cell count of 28 cells collecting a median of 4.5 CD34+cell/kg body weight. All patient underwent aPBSCT after HD-Mel conditioning regimen receiving an infusion of 4.7 CD34+cell/kg body weight (range 1.5-8.4) and achieved a successful engraftment. At present all the patients are alive and in remission. In order to compare mobilization schedule we performed a comparison analysis between 11 patients receiving chemotherapy as mobilizing regimen versus 14 patients receiving only G-CSF. Data analysis according to mobilization schedule was reported in Table 1. Analysing mobilization efficacy, chemo-mobilized patients achieved a higher pre-apheresis CD34+ cell count (57 vs 33 cells/µl, p<0.05). This result allowed a significantly shorter procedure (2.3 TBV vs 3 TBC, p<0001). Patients receiving only G-CSF showed a WBC count significantly higher than chemo-mobilized patients (40.000 vs 8.140, p<0.05). The incidence of poor mobilization was low (3 out of 25 patients, 12%) and not statistically different between the two mobilization schedules. Discussion. The collection of these data allowed us to achieve one of the major series published in literature and to perform a comparison between two different approaches. The data suggest that both schemes (CY plus G-CSF vs. G-CSF alone) were able to harvest a sufficient CD34+ cell dose. Disclosures No relevant conflicts of interest to declare.

Population Pharmacokinetics of Cyclophosphamide in Patients with Thalassaemia Major Undergoing HSCT Shows Body Weight, CYP450, GST and ALDH Polymorphisms as Covariates Explaining Inter-Individual Variation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1182-1182 ◽  
Author(s):  
Poonkuzhali Balasubramanian ◽  
John Carl Panetta ◽  
Salamun Desire ◽  
Shaji R Velayudhan ◽  
Vikram Mathews ◽  
...  
Keyword(s):  
Body Weight ◽  
Individual Variation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Thalassaemia Major ◽  
Hematopoietic Stem ◽  
Beta Thalassaemia ◽  
Population Pk

Abstract Abstract 1182 Poster Board I-204 Cyclophosphamide (Cy) in combination with busulfan is an important component of myeloablative conditioning regimen used prior to hematopoietic stem cell transplantation (HSCT) for both malignant and non-malignant conditions. We have previously reported up to 20 fold inter-individual variation in the pharmacokinetics (PK) of Cy in patients with beta thalassaemia undergoing HSCT [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 99]. PK parameters of Cy have been shown to be associated with regimen related toxicity and outcome of transplant. To explain the basis of the inter-individual variation in Cy PK, we have developed a population PK model. We analyzed the PK of Cy in consecutive children with beta thalassaemia major who received HSCT from HLA identical matched sibling donor at the Christian Medical College, Vellore from 2001 till 2004. A total of 900 cyclophosphamide concentration measurements from 55 patients were included and correlated with age, sex, body weight and 10 polymorphisms in enzymes involved in the metabolism or biotransformation of Cy namely GST A1, M1, T1, P1, CYP2B6, CYP2C9, CYP2C19 and ALDH genes. Non-linear mixed effects modeling analysis was performed with Monolix (version 2.4, www.monolix.org) to investigate the effect of patient covariates on PK, and to estimate the relative magnitude of inter-individual and inter-occasion variability. A two-compartment pharmacokinetic model was used to describe the data. The pharmacokinetic parameters estimated included elimination rate constant and volume (ke (1/hr), V (L or L/kg)), and the inter-compartmental parameters (k12 and k21 (1/hr)). The distribution of the parameters was assumed log-normal. Body weight was the main covariate which explained the largest portion of the IIV (28% and 20% of V and ke IIV, respectively). In addition, the following genotypes showed differences in the pharmacokinetics: GSTP1*B (1.7X higher ke in MUT versus WT or HET; p<0.05), CYP3A4*1B (2X higher ke in HET versus WT; p<0.05), and ALDH1A1*2 (2X higher ke in HET versus WT; p<0.05). We have developed a population PK model for Cy in thalassaemic children by considering morphological and biological covariates, which explains more than 45% and 22% (V and ke IIV, respectively) of the variation in Cy PK in these patients. This model-based algorithm may be used to design and plan targeted dose therapy in this group of pediatric patients and to predict the risk of toxicity and outcome of HSCT. Disclosures: No relevant conflicts of interest to declare.

Rapid Immune Reconstitution Following Unmanipulated Haploidentical BMT with Post-Transplant High Dose Cyclophosphamide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3050-3050 ◽  
Author(s):  
Alida Dominietto ◽  
Anna Maria Raiola ◽  
Barbara Bruno ◽  
Maria Teresa van Lint ◽  
Francesco Frassoni ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd4 Counts ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Unrelated Cord Blood

Abstract Abstract 3050 Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for the majority of hematological malignancies. Early and successful immunologic reconstitution after HSCT reduces morbidity and mortality due to infection complications and improves survival. Aim of the study. We analyzed immune recovery after HSCT in 444 patients according to donor source. Patients and Methods. From January 2005 to June 2011 176 patients were grafted from HLA identical siblings (MSD), 125 from alternative donors (1 antigen mismatched family or unrelated donors) (ALT), 103 from unrelated cord blood grafted intra bone (CBIB) and 40 from haplo-identical mismatched family donors (HAPLO). All patients received unmanipulated bone marrow: 283 after a myeloablative (MA) conditioning regimen (CY-TBI or BU-CY) and 161 after a fludarabine based reduced intensity regimen (RIC). Graft versus host disease (GvHD) prophylaxis was cyclosporin methotrexate (CyA+MTX) for all patients except for CBIB (CyA and mycophenolate, MMF) and for HAPLO transplants which consisted of CyA+MMF and post-transplant high dose cyclophosphamide (HDCY) according to the Baltimore protocol (Lutznik et al BBMT 2008). Anti-thymocyte globulin (ATG) was used only for ALT transplants. Results. We compared immune reconstitution in MA and RIC transplants according to donor type at different time points post BMT. CD3+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 477, 565, 700; in ALT donors were 146, 404, 470; in CBIB were 30, 57, 196; for HAPLO transplants they were 195, 182, 499. CD3+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 301, 660, 700; in ALT donors were 506, 186, 721; in CBIB 234, 399, 522; in HAPLO were 178, 276, 1300. CD4+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 166, 170, 198; in ALT donors were 36, 86, 111; in CBIB 7, 36, 106; for HAPLO transplants they were 45, 127, 211. CD4+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 89, 189, 274; in ALT donors were 131, 210, 220; in CBIB 52, 110, 130; for HAPLO transplants they were 41, 205, 385. CD8+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 280, 389, 500; in ALT donors were 102, 278, 413; in CBIB 42, 16, 51; in HAPLO transplants were 73, 424, 408. CD8+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 196, 432, 300; in ALT donors were 366, 65, 494; in CBIB 71, 167, 199; for HAPLO transplants they were 137, 129, 900. CD3, CD8, and CD4 counts in HAPLO transplants were not statistically different from MSD with the only exception of day +30, both for MA and RIC conditioning. Platelet median counts/μl on day+30, +90, +180 in MA conditioning were in MSD 142, 129, 180, in ALT 75, 101, 147, in CBIB were 19, 77, 128 and for HAPLO transplants were 67, 126, 128; in RIC conditioning platelets counts were in MSD 137, 156, 168, in ALT 33, 134, 142, in HAPLO were 77, 95, 188. Acute GvHD II-IV developed in 29% (MSD) 38% (ALT) 16% (CBIB) and 12% (HAPLO) (p=0.004) in MA conditioning and 40% (MSD) 18% (ALT) 25% (CBIB) and 10% (HAPLO) (p=0.07). Overall Cumulative Incidence of Non-Relapse Mortality (CI-NRM) was respectively 18% (MSD), 35% (ALT), 34% (CBIB), 22% (HAPLO) (p=0.02) in MA conditioning (p=0.02) and was 30% (MSD), 33% (ALT), 45% (CBIB), 0% (HAPLO) (p=0.02) in RIC conditioning (p=0.02). Day+100 CI-NRM was respectively 10% (MSD), 21% (ALT), 19% (CBIB), 12% (HAPLO) in MA conditioning (p=0.01) and 11% (MSD), 19% (ALT), 26% (CBIB), 0% (HAPLO) in RIC conditioning (p=0.02). Death due to infections were respectively 6% (MSD), 26% (ALT), 30% (IBCB), 17% (HAPLO) in MA conditioning and for RIC were 15 (MSD), 36% (ALT), 32% (IBCB), 0% (HAPLO). Conclusions. HAPLO transplant with HDCY post transplant as proposed by the Baltimore group, is associated with (1) rapid immunologic (CD3, CD4, CD8) recovery (2) low infectious death rate, (3) low overall and Day+100 CI-NRM, (4) rapid hematologic recovery. These results are comparable with those achieved with MSD and warrant further studies with HDCY post transplant as a GvHD prophylaxis. Figure: absolute CD4+ counts/μl on day+30, +90, +180, according to donor type in MA conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

The Roel of High Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT) In PATIENTS with POEMS SYNDROME: A Retrospective study of the MM Subcommittee of the Chronic Leukemia Working Party of the EBMT,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4115-4115 ◽  
Author(s):  
Gordon Cook ◽  
Laurent Garderet ◽  
Anja van Biezen ◽  
Anja Henseler ◽  
Véronique Leblond ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Working Party ◽  
Poems Syndrome ◽  
Plasma Cell Dyscrasia ◽  
Bone Lesions ◽  
High Dose ◽  
Engraftment Syndrome ◽  
The Impact

Abstract Abstract 4115 Introduction: Polyneuropathy, organomegaly, endocrinopathy, skin changes associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment, including ASCT, of the underlying plasma cell dyscrasia can control the disease and often dramatically control symptoms. Limited data is available for ASCT in POEMS. Specific Aim: The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. The incidence of engraftment syndrome and the presentation of relapse were examined. Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Results: 116 patients underwent an ASCT between 1997–2009 and satisfied the entry criteria. The median age was 50 yrs (range 26–69) with 56.8% of patients '50 year of age. 58.6% had peripheral neuropathy, 66.2% volume overload, 48.3% had organomegaly, 19.8% had papiloedema, 46.6% had dermopathies and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.8 mns (range 1–346) with 34.5% of patients receiving an ASCT >12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 32% CR/PR, 30% SD/MR/untreated and 5 in PD. Missing information on stage in 33% of the cases. The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan <200mg/m2 in 9.3% (38.1 of data on dose is missing) and TBI-containing only 1 patient. Engraftment was seen in 112 (96.6%) patients with failed engraftment reported in 3 patients (2.5%). Details of the occurrence of engraftment syndrome are currently under collection and analysis though peri-engraftment fever was reported in 23.4% and pulmonary infiltrates in 4.8%. Haematological response was characterized as CR in 31%, PR in 20.7%, <PR in 20.7% and currently unknown in 27.6%. Best disease response, in terms of end-organ response is under evaluation. With a median follow-up of 30.1 mns (range 0.1–161), 90.5 % of patients are alive and only 8.6% of patients have relapsed. The non-relapse mortality was 6.9%. Causes of death: 5 died of infection, 2 from graft failure, 1 from cardiac toxicity. The 3-year probabilities of PFS and OS are 82% and 94%, respectively. The 5-year probabilities of PFS and OS are 80% and 92%, respectively. The data analyzed in this study, to-date, demonstrates that ASCT can be an effective and safe therapeutic modality for patients with POEMS syndrome. The role of high dose therapy compared with more conventional dose therapies warrants further investigation. Disclosures: No relevant conflicts of interest to declare.

Effect of Obesity on Outcomes after Autologous Hematopoietic Stem Cell Transplantation (Auto HCT) for Multiple Myeloma (MM): An Analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3333-3333
Author(s):  
Dan T. Vogl ◽  
Waleska S. Peréz ◽  
Tao Wang ◽  
Edward A. Stadtmauer ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analyses ◽  
Autologous Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Obese Patients ◽  
Hematopoietic Stem ◽  
Severely Obese ◽  
High Dose Melphalan ◽  
Univariate Analyses

Abstract Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure

Comparative Analysis of the Value of Consolidation with Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Versus High-Dose Cytarabine (HDAC) Based Chemotherapy in Patients (pts) with Acute Myeloid Leukemia (AML) with Chromosome Seven Abnormalities

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2029-2029
Author(s):  
Elias J. Jabbour ◽  
Hagop M. Kantarjian ◽  
Betul Oran ◽  
Farhad Ravandi ◽  
Hady Ghanem ◽  
...  
Keyword(s):  
Complete Remission ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Response To Therapy ◽  
Chromosome 7 ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Hematopoietic Stem ◽  
Platelet Recovery

Abstract Abstract 2029 Background: The karyotype of leukemic cells in pts with AML is one of the most pronounced prognostic factors determining response to therapy and overall outcome. Pts with AML and chromosome 7 abnormalities have poor prognosis and AHSCT is highly indicated for such pts. Aims: To determine to what extent AHSCT reduces relapses and improve survival in pts with AML with chromosome 7 abnormalities compared with alternative post remission therapy. Methods: We reviewed 2167 consecutive pts with AML referred to our department between 2000 and 2011. Among them, 325 were diagnosed with chromosome 7 abnormalities as a single abnormality (n=53, 16%) or complex (n=272, 84%). Of these, 126 pts (39%) were induced with IA based regimen and 49 (39%) of them achieved a complete remission (CR) or complete remission without platelet recovery (CRp) and pursued consolidation therapy. These pts were matched with 33 pts with available donors who were referred to receive an ASHCT in first CR. Results: Median age for pts receiving consolidation chemotherapy versus AHSCT was 56 (range, 19–78) and 49 (range, 22–71) years, respectively (<0.001). Of the 33 pts who received an AHSCT, 17 received their stem cells from related siblings, 15 from unrelated matched donors, and 1 from a haplo-identical donor. Conditioning regimen were fludarabine and busulfan in 26 pts and fludarabine and melphalan in 7 pts. Graft versus host disease (GVHD) prohylaxis consisted mainly of tacrolimus and short methotrexate. Median time to engraftment was 12 days for neutrophils (range, 9–20) and 19 days for platelets (range, 10–53). Acute Grade 3/4 and chronic GVHD were observed at the rate of 3% and 45%, respectively. With a median follow-up of 29 weeks (range, 14–239) for pts receiving consolidation chemotherapy and of 168 weeks (range, 5–454) for pts receiving AHSCT, the 4-year event-free survival (EFS) rates were 4% and 51%, respectively (p<0.001). The median EFS for pts receiving consolidation chemotherapy and AHSCT were 17 (range, 1–330) and 51 (range, 1–456) weeks (Figure 1), respectively. The 4-year OS rates were 7% and 62%, respectively (p<0.001), with the median survival being 35 (range, 1–568) and 389 (range, 1–456) weeks, respectively (Figure 2). Conclusion: AHSCT applied as a consolidation in first CR in pts with chromosome 7 abnormalities is associated with a significant reduction of the relapse rate and improvement of OS compared to alternative post remission therapy. Disclosures: No relevant conflicts of interest to declare.

T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3387-3387
Author(s):  
Izaskun Ceberio ◽  
Patrick Hilden ◽  
Sean M. Devlin ◽  
Molly Maloy ◽  
Jenna D Goldberg ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Case Series ◽  
Myelogenous Leukemia ◽  
Low Grade ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Increased Risk

Abstract Intro Allogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. Methods A retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. Results Pt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and <10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7). Female gender was significantly associated with decreased OS and DFS (p<0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p<0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1). Conclusion These results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Post-Transplant Cyclophosphamide Versus MTX-CSA As Gvhd Prophylaxis in HLA-Identical Sibling HSCT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3394-3394
Author(s):  
Rebeca Bailén ◽  
Maria-Jesús Pascual ◽  
Pascual Balsalobre ◽  
Anabel Gallardo-Morillo ◽  
Abel García-Sola ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA). Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Symptom Burden of Busulfan and Melphalan Versus Melphalan Alone for Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 681-681
Author(s):  
Loretta A. Williams ◽  
Muzaffar H. Qazilbash ◽  
Qiuling Shi ◽  
Qaiser Bashir ◽  
Huei K. Lin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Muscle Weakness ◽  
Symptom Severity ◽  
Conditioning Regimen ◽  
Symptom Burden ◽  
Phase Iii ◽  
Dry Mouth ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Background: High-dose melphalan 200 mg/m2 (Mel) is the standard for autologous hematopoietic stem cell transplantation (autoHSCT) for multiple myeloma. Retrospective analyses suggested that a combination of busulfan and melphalan (Bu-Mel) may be associated with a longer progression-free survival (PFS). A secondary aim of a randomized, phase III trial that compared the safety and efficacy of Bu-Mel vs Mel was to compare the symptom burden of the two regimens. Symptom burden is the combined impact of disease- and therapy-related symptoms on patient functional ability. Methods: Patients were randomized to Bu-Mel (Bu 130 mg/m2 daily for 4 days, either as a fixed dose or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel 70 mg/m)2or Mel (Mel 100 mg/m2 daily for 2 days). A subset of patients completed the 20 symptom severity and 6 interference items of MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM) prior to the start of the treatment regimen and weekly for 4 weeks post autoHSCT. Symptoms and interference are rated on 0-10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Differences in individual symptom severity and interference between the two arms were assessed by t-tests and mixed modeling. Results: As previously reported, 204 (Bu-Mel: 104, Mel: 100) were enrolled between October 2011 and March 2017. At last evaluation, 52 (51%) and 49 (49%) patients achieved a CR (p=0.88), and 69 (68%) and 67 (67%) patients achieved a CR+nCR (p=0.88) in Bu-Mel and Mel arms, respectively. Median PFS was 64.7 months and 34.4 months (p=0.013) in Bu-Mel and Mel arms, respectively. There was no difference in OS between the two arms. One hundred sixty-five of the patients (Bu-Mel: 81, Mel: 84) completed at least one MDASI-MM assessment. Median ages at autoHSCT were 57.2 and 57.0 years in Bu-Mel and Mel groups, respectively (p=0.86). At baseline, t-tests showed significantly higher mean severity of constipation (1.80, standard deviation [SD] = 2.87 vs 0.98, SD = 1.94; p=0.036), muscle weakness (2.38, SD=2.49 vs 1.44, SD=1.87; p=0.034), diarrhea (1.45, SD=2.43 vs 0.60, SD=1.10; p=0.005), and global symptom interference (2.96, SD=2.81 vs 1.77, SD=2.00; p=0.003) in the Bu-Mel arm than the Mel arm. The Bu-Mel patients had a significantly higher mean severity of pain (5.67, SD=2.65 vs 3.17, SD=3.07; p=0.0043) and mouth sores (7.35, SD=2.41 vs 1.25, SD=2.22; p &lt;0.0001) than the Mel patients 7 days post autoHSCT. Longitudinal analysis using mixed modeling showed that the Bu-Mel arm had a significantly higher mean severity of pain (ED = 1.102, p=0.003), drowsiness (ED = 0.674, p=0.040), dry mouth (ED = 0.904, p=0.009), constipation (ED = 0.695, p=0.006), muscle weakness (ED = 0.815, p=0.006), mouth sores (ED = 1.683, p &lt;0.0001), rash (ED = 0.362, p=0.019), and interference with physical functions (general activity: ED = 1.015, p=0.010; working: ED=1.229, p=0.006; walking: ED=0.920, p=0.009) than the Mel arm during the 4 weeks following autoHSCT. Conclusions: Patients receiving Bu-Mel vs Mel prior to autoHSCT report some differences in symptom severity, with Bu-Mel patients experiencing more severe sore mouth, pain, and symptom interference with daily functioning. The greater intensity of the double-alkylating agent conditioning regimen of Bu-Mel likely led to these differences. The increased severity of drowsiness, dry mouth, constipation, and muscle weakness may be due to an increased need for opioids to control severe pain and mouth sores. The effect of significant differences in symptom severity and interference at baseline between these two groups, despite randomization, is not clear. However, the longer time to progression of myeloma with the Bu-Mel regimen may offset the greater symptom burden early post autoHSCT. Systematic measurement of symptom burden during clinical trials can provide useful information for clinicians and patients in evaluating the full impact of different treatment regimens and enhance treatment decision making and discussion between clinicians and patients. Disclosures No relevant conflicts of interest to declare.

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