Favorable Results of Allo-HSCT from MRD in Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5934-5934
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Patrycja Zielinska ◽  
Agata Wieczorkiewicz-Kabut ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Collagen Type ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Graft Loss ◽  
Chronic Phase ◽  
Curative Treatment ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Introduction: Myelofibrosis (MF), chronic myeloid malignancy associated with shortened survival, in majority of patients develops de novo as Primary MF, but also polycythemia vera (PV) or essential thrombocythemia (ET) may progress into post-PV or post-ET MF. Although management of MF includes several treatment options, the only potentially curative treatment approach in MF is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim of this study was to evaluate the results of allo-HSCT in patients with MF treated in Katowice, Poland. Material and Methods: 27 pts (14 male and 13 female) with median age 51 years (range 21–63) were treated with allo-HCT due to PMF (20), post-PV (4) or post-ET (3) MF. 11,7,11,26 and 41% of pts had DIPSS 0,1,2,3 and 4, respectively. Median bone marrow cellularity was 70% (10-100%), fibrosis was collagen-type (14 pts including 2 with osteosclerosis), reticulin (10) or it was not specified (3). Splenomegaly was present in all pts: 13-20 cm (14 pts), > 20 cm (13 pts). JAK2V617F point mutation was present in 18 pts. Karyotype was available in 14 pts: in 9 normal, in 5 with variable abnormalities. Median time from diagnosis to allo-HCT was 1.5 (0.4–9.5) years. 16 pts (59.3%) received cells from HLA-matched related donor (MRD), 11 pts (40.7%) from unrelated donor: 10/10 (9) or 9/10 (2) HLA-A,B,C,DR,DQ alleles matched. Reduced intensity conditioning (RIC) was used in 26 pts, 1 patient received myeloablative conditioning (MC). Sources of stem cells were: peripheral blood (21), bone marrow (4) and both (2). All pts but one had chronic phase of MF at time of transplantation. Results: 14/27 (52%) pts are alive at median 3.4 (0.4-5.4) years after allo-HSCT: 11/16(69%) from MRD and 3/11(27%) from MUD, p=0.032. Graft failure, graft loss or PRCA were observed in 3, 5 and 1 pt, respectively. Absolute neutrophil count >0.5×109/L and platelet count >50×109/L were achieved at median 16 and 28 days, respectively. 12/27 (44%) pts reached complete blood count of Hb>10 g/dl, Plt>100 G/l and WBC>3.5 G/l; 11 of them (92%) are alive. 6/27 (22%) pts remained either RBC or PLT transfusions dependent post-transplant; 3 of them (50%) died. 9/27 (33%) pts remained both RBC and PLT transfusion dependent and all of them died. JAK2V617F mutation was completely eradicated in 11/16 evaluated previously positive patients (69%), decreased in 4 (25%) and stable in 1(6%) pt. Acute graft-versus-host disease (aGVHD) III-IV developed in 5/27 (19%) and extensive chronic GVHD in 5/19 (26%) pts. Relapse occurred in 4 pts and was treated with subsequent second transplant (in 1 pt thereafter by 3-rd allo-HSCT). Spleen length decreased at median by 5 (0.3-9.2) cm. Out of 7 pts with initial collagen fibrosis who were evaluated post-transplant, 1 had no fibrosis, 5 reticulin type and only in 1 pt collagen fibrosis was stable. Out of 3 pts with initial reticulin fibrosis it disappeared in 2 and progressed to collagen type in 1. Causes of death were GVHD (5 pts: 3 aGVHD, 2 cGVHD) and pancytopenia with either infection (7 pts) or CNS hemorrhage (1 pt). Conclusions: Allo-HSCT, the only curative treatment of myelofibrosis, provides chance of long survival, regression of the disease (lower stage of fibrosis, JAK2V617F eradication) and improved quality of life (transfusion independency, decreased splenomegaly). Transfusion independency may indicate good outcome. Favorable results are observed after allo-HSCT from MRD. Disclosures No relevant conflicts of interest to declare.

Chronic GVHD Is Not Increased with the Use of PBSC Instead of Bone Marrow for T-Replete HLA-Haploidentical Transplanation Using Post-Transplant Cyclophosphamide : A Multivartiate Analysis of 116 Consecutive Transplants from a Single Center

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3922-3922
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Katelin Connor ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Cox Model ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Increased Risk

Abstract HLA-haploidentical related donors (HID) are a potential option for patients who need an allogeneic haploidentical transplant but lack an optimally matched conventional donor (HLA-identical sibling or 8 of 8 HLA-A, B, C, DRB1 matched unrelated donor) (MRD and MUD respectively). The Baltimore approach to HID transplantation that uses T-replete grafts and post-transplant cyclophosphamide to control alloreactivity (HIDT-ptCy) has demonstrated promising outcomes and appears to be safe and effective. Bone marrow (BM) grafts have almost exclusively been used for HIDT-ptCy in Baltimore. Early studies from other centers have demonstrated that G-CSF mobilized PBSC may be safely used for HIDT-ptCy (Castagna et al BBMT 2014, Raj et al BBMT 2014). HIDT-ptCy using BM grafts has been associated with relatively low rates and severity of chronic GVHD. However, it is unclear whether the use of PBSC for HIDT-ptCy will be associated with higher rates of chronic GVHD than with BM grafts as has been demonstrated for MRD and MUD transplants. We analyzed 116 consecutive HIDT-ptCy first transplants (BM=64, PBSC=52) performed for hematologic malignancies at our center. Identical supportive care measures were utilized for BM and PBSC patients. GVHD was prospectively documented using established criteria by a single dedicated nurse. NIH consensus criteria were used for chronic GVHD. Gray's test was used to compare the cumulative incidences of GVHD. A Cox model was used in multivariate analysis of GVHD outcomes. Characteristics of the patients are demonstrated in Table 1. Patients undergoing HIDT-ptCy using PBSC were significantly more likely to receive myeloablative conditioning, were younger, were less likely to have been transplanted prior to 2007. Although the frequency of diagnoses differed, the Dana-Farber/CIBMTR Disease Risk Index (DRI) was not significantly different between the two groups. Median follow-up for BM and PBSC patients was 44 m and 25 m. Six month cumulative incidences of acute GVHD grades 2-4 were 39% and 42% and grades 3-4 were 14% and 21% for BM and PBSC grafts respectively. The two year cumulative incidences of extensive chronic GVHD were 38% and 45% and for severe chronic GVHD were 8% and 6% respectively (p=NS for all BM vs PBSC comparisons). In a multivariate analysis assessing effects of patient, disease and transplant variables on GVHD outcomes, graft type i.e. PBSC vs BM was not a significant predictive factor for acute or chronic GVHD. These data demonstrate that unlike the case following MRDT and MUDT, G-CSF mobilized PBSC grafts are not associated with an increased risk of chronic GVHD than BM grafts following HIDT-ptCy. Severe chronic GVHD is very uncommon with both types of graft following HIDT-ptCy and is an indication of the effectiveness of ptCy in controlling alloreactivity in this setting. Disclosures No relevant conflicts of interest to declare.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

Allogeneic Bone Marrow Transplantation From Unrelated Donors in Multiple Myeloma: A Study from the Italian Bone Marrow Transplantation Donor Registry

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2009-2009
Author(s):  
Benedetto Bruno ◽  
Roberto Passera ◽  
Francesca Patriarca ◽  
Francesca Bonifazi ◽  
Vittorio Montefusco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Cell Source ◽  
Reduced Intensity

Abstract Abstract 2009 To evaluate the role of allografting from unrelated donors in the treatment of myeloma we conducted a retrospective study through the Italian Bone Marrow Transplantation Donor Registry. Overall, from 2000 through 2009, 196 myeloma patients, median age 51 years (32–67), for a total of 199 allografts, were transplanted from an unrelated donor at 34 Centers in Italy. Fifty-two (28.1%%), 69 (37.3%), and 64 (34.6%) patients were prepared for transplant with a myeloablative, a reduced-intensity and a non-myeloablative conditioning respectively. Patient characteristics of the 3 cohorts are reported in Table 1.ConditioningMyeloablativeReduced-intensityNon-myeloablativePatient number (%)52/185 (28)69/185 (37)64/185 (35)Median Age455355Previous therapy lines < 2 (%)23 (27)33 (38)30 (35)Previous therapy lines ≥ 2 (%)29 (29)36 (37)34 (34)Stem Cell Source BM (%)24 (57)18 (43)0 (0)Stem Cell Source PBSC (%)28 (19)51 (36)64 (45) Cumulative incidence of acute grade II-IV graft-versus-host-disease (GVHD) was 46.4% whereas chronic GVHD was 45.1%. There was no difference in GVHD incidence among the 3 cohorts defined by type of conditioning. Complete and partial remissions in patients who survived at least 3 months post-transplant were 27% and 28% for an overall response rate of 55%. At a median follow up of 32 (0–118) months post-transplant, in the entire study population, median OS from diagnosis was 70.6 months while OS and EFS from the allograft were 18.9 and 14.9 months. Overall, the cumulative incidence of transplant related mortality (TRM) was 29.6% at 1 year and 32.4% at 5 years post-transplant. OS from diagnosis and EFS from transplant were 70.6 and 28.2 months; 66.8 and 9.1 months; and 111.9 and 22.4 months in patients who respectively underwent a myeloablative, a reduced-intensity and a non-myeloablative transplant. One-year and 5-year TRM was 33.3% and 35.7%, 32.2% and 34.4%, and 22.1% and 26.5% respectively. Univariate and multivariate analyses, assessed by multivariate Cox proportional hazards models, were performed for the following variables: number of previous chemotherapy lines (1,2 vs. ≥3), disease status at transplant, HLA- matched antigens (10/10 vs. 9/10 vs. ≤8/10), recipient/donor gender combinations, hematopoietic cell source (peripheral blood vs. bone marrow), conditioning (myeloablative vs. reduced-intensity vs. non-myeloablative), use of anti-thymoglobulin in the conditioning, acute GVHD, chronic GVHD, best response post-transplant, year of transplant (2000–02 vs. 2003–05vs. 2006–09). By univariate analysis, lower number of chemotherapy lines before the allograft, disease status at transplant, a fully HLA-identical donor, the use of peripheral hematopoietic cells rather than bone marrow were statistically significant variables for better OS whereas disease status at transplant, a fully HLA-identical donor, chronic GVHD (either limited or extensive) were statistically significant for better EFS. However, by multivariate analysis, only the development of chronic GVHD (HR 0.50; p<0.001) and a better response post-transplant (HR 2.11; p<0.03) were significantly associated with longer OS whereas chronic GVHD was the only variable associated with better EFS (HR 0.32; p<0.001). Acute GVHD was associated with both poorer OS (HR 2.35; p<0.001)) and EFS (HR 3.19; p<0.001). In conclusion, with a degree of caution given the retrospective nature of this study, there appears to be a strong association between both limited and extensive chronic GVHD and graft-vs.-myeloma effects. However, long term disease control remains an issue independent of the conditioning employed. Prospective trials may allow to define which patient category may most benefit from an unrelated donor allograft. Disclosures: Patriarca: Roche: Honoraria; Celgene: Honoraria; Schering-Plough: Honoraria; Janssen: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Favorable Results of Allo-HSCT in TKI-Resistant CML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4145-4145
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Katarzyna Wisniewska-Piaty ◽  
Andrzej Frankiewicz ◽  
Anna Koclega ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Hla Antigens ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Advanced Phase ◽  
Tki Treatment

Abstract Abstract 4145 Introduction: Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML). However, for patients who fail TKI or progress to advanced phase disease, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapeutic option. The rationale of this study was to evaluate results of allo-HSCT in CML patients who have failed TKI treatment. Patients and Methods: 48 CML pts aged 33 (19–52) years who failed previous treatment with TKI (imatinib-37 pts, imatinib+dasatinib-5, imatinib+dasatinib+nilotinib- 3, dasatinib-2, imatinib+nilotinib-1) received allo-HSCT from HLA-matched siblings (15) or from 10/10 (21) and 9/10 (12) HLA-antigens-Matched Unrelated Donors (MUD) in Hematology and BMT Center in Katowice, Poland, from 10.2002 to 03.2011. The myeloablative preparative regimen consisted of treosulfan 3×14 g/m2 plus fludarabine 5×30 mg/m2 (30 pts) or busulfan 4×4 mg/kg plus cyclophosphamide 4×30 mg/kg (18 pts). Standard GVHD prophylaxis consisted of cyclosporine-A, methotrexate and pre-transplant ATG or thymoglobulin in allo-HSCT from MUD. Source of cells was bone marrow (27 pts) or peripheral blood (21 pts) with median 2.6 or 6.7 x10(6)CD34+cells/kg, respectively. Results: All pts engrafted. 100% donor chimerism has been achieved in 40 (83.3%) pts, 97–99% in 4 pts, progressing mixed chimerism was observed in 4 pts. The 5-year estimated overall survival rate was 79%. 9 pts died 9 (1–21) months following allo-HSCT due to infection (5), GVHD (3) or relapse (1). Bio-molecular relapse or progressing mixed chimerism was observed in 6 pts and was treated with 3 to 5 donor lymphocyte infusions (3 pts), post-transplant imatinib (3 pts) or nilotinib (1 pt). Acute GVHD grade I, II, III and IV was observed in 15, 13, 2 and 1 pt (serious aGVHD grade III-IV in 3 pts (6.25%) only); limited and extensive chronic GVHD in 17 (35.4%) and 9 (18.75%) pts, respectively. Other complications in survivors included CMV reactivation (12), hemorrhagic cystitis (3), H. zoster (2), P. jiroveci (1) and cataract requiring surgery (1). 39 pts (81.25%) are alive 44 (3–92) months post-transplant. Conclusions: Allo-HSCT with myeloablative treo/flu or bu/cy conditioning is a feasible and effective curative therapy in TKI-resistant CML. The alternative therapy with allo-HSCT may overcome TKI resistance, providing long-term remission or cure from CML in patients who failed TKI treatment. Disclosures: No relevant conflicts of interest to declare.

Development and Preliminary Testing Of The Post-Transplant Multimorbidity Index (PTMI)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2076-2076 ◽  
Author(s):  
Sandra A. Mitchell ◽  
Steven Z. Pavletic ◽  
Ernst Holler ◽  
Philipp Y. Herzberg ◽  
Pia Heussner ◽  
...  
Keyword(s):  
Peptic Ulcer ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Measurement Properties ◽  
Comorbid Conditions ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Comorbidity Index

Abstract Background Comorbid health conditions, both those present before transplant and those acquired as late effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) and the treatment of chronic graft-versus-host disease (cGVHD), represent an important covariate. While the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror et al. Cancer, 2008; 112(9):1992-2001) has been developed to predict non-relapse mortality and overall survival in allo-HSCT recipients, many of the chronic comorbid conditions that develop in the allogeneic post-transplant setting are not represented in the HCT-CI, and its predictive validity has had limited study in long-term transplant survivors. The objectives of this study were to: (i) establish a new measure of multimorbidity for the post-transplant setting (Post-Transplant Multimorbidity Index [PTMI]), and (ii) explore its content validity. Methods Based on a review of the literature and the most commonly used comorbidity measures, the PTMI was developed to reflect a broad and inclusive list of comorbid conditions that may arise in the post-transplant setting. Preliminary definitions to establish the presence of each of these conditions were developed. To enhance longitudinal comparisons, the conditions and definitions from the HCT-CI were nested within the PTMI. The conditions and definitions were iteratively refined (SM and DW) through application in a cohort of 30 post-transplant patients. Subsequently, the PTMI, HCT-CI, Charlson Comorbidity Scale (CCS), and the Functional Comorbidity Index (FCI) were comparatively evaluated in a cohort of 50 alloHSCT survivors referred for comprehensive cGVHD consultation. The evaluation cohort was a mean age of 42 (range 23-68) years and a median of 33.5 (range 13-208) months post-transplant. All but two (late acute GVHD n=1; no cGVHD n=1) had active cGVHD that had been present for a median of 27 (range 3-197) months. A majority had severe cGVHD (NIH global severity score 1 n=4; 2 n=8; 3 n=36) and 90% were currently receiving systemic immunosuppression. Results Applying the PTMI, HCT-CI, CCS and FCI to our evaluation cohort yielded a mean of 5 (SD±2.5), 1.5 (SD±1.23), 1.39 (SD±0.78), and 2.18 (SD±1.16) co-occurring conditions, respectively. On average the HCT-CI, CCS, and FCI missed the identification of one or more comorbidities 71%, 75%, and 43% of the time. Conditions that were prevalent in the cohort but missed by the other comorbidity measures included osteoporosis, avascular necrosis, hypertriglyceridemia, hypothyroidism, BMI<22, and secondary solid malignancy (excluding nonmelanoma skin cancer) after transplant. Using the PTMI, the two most prevalent comorbid conditions were osteoporosis (64%) and underweight/sarcopenia (BMI<22) (46%), whereas the FCI identified osteoporosis and depression as most prevalent, and the HCT-CI psychiatric disturbance and peptic ulcer, and the CCS history of malignancy and peptic ulcer disease, as the two most prevalent comorbidities, respectively. Conclusions Our results offer preliminary evidence that the PTMI improves the identification of chronic comorbid conditions in long-term transplant survivors with cGVHD, and demonstrate that the choice of a measure is an important methodologic issue in the design of epidemiologic studies of comorbidity in post-transplant survivors with cGVHD. Prospective studies evaluating the measurement properties of the PTMI are ongoing in post-transplant survivors with and without active chronic GVHD. With continued testing and refinement, we anticipate that this new measure will have utility for risk-adjustment and stratification in both observational studies and clinical trials in the post-transplant setting. Disclosures: No relevant conflicts of interest to declare.

Allo-HCT from MUD/MRD for Paroxysmal Nocturnal Hemoglobinuria - 12 Years of Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5886-5886 ◽  
Author(s):  
Miroslaw Markiewicz ◽  
Malwina Rybicka-Ramos ◽  
Monika Dzierzak-Mietla ◽  
Anna Koclega ◽  
Krzysztof Bialas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclosporine A ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conflicts Of Interest ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Complete Disappearance ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Pnh Clone

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal abnormality of hematopoietic stem cell leading to lack of phosphatidylinositol glycoproteins, sensitizing cells to complement-mediated lysis. Despite the efficient symptomatic treatment of hemolytic PNH with eculizumab, allo-HCT is the only curative treatment for the disease, although outcomes presented in the past were controversial. Material and methods: We report 41 allo-HCTs: 37 from MUD and 4 from MRD performed for PNH in 2004-2016. Median age of recipients was 29(20-62) years and donors 30(19-53), median time from diagnosis to allo-HCT was 16(2-307) months. Median size of PNH clone was 80% granulocytes (0.5%-100%). Indication for allo-HCT was PNH with aplastic/hypoplastic bone marrow (19 pts), MDS (2 pts), overlapping MDS/aplasia (3 pts), severe course of PNH with hemolytic crises and transfusion-dependency without access to eculizumab (17 pts). Additional risk factors were Budd-Chiari syndrome and hepatosplenomegaly (1 pt), history of renal insufficiency requiring hemodialyses (2 pts), chronic hepatitis B (1 pt) and C (1 pt). The preparative regimen consisted of treosulfan 3x14 g/m2 plus fludarabine 5x30 mg/m2 (31 pts) or treosulfan 2x10 g/m2 plus cyclophosphamide 4x40 mg/kg (10 pts). Standard GVHD prophylaxis consisted of cyclosporine-A, methotrexate and pre-transplant ATG in MUD-HCT. 2 pts instead of cyclosporine-A received mycophenolate mofetil and tacrolimus. Source of cells was bone marrow (13 pts) or peripheral blood (28 pts) with median 6.3x108NC/kg, 5.7x106CD34+cells/kg, 24.7x107CD3+cells/kg. Myeloablation was complete in all pts with median 9(1-20) days of absolute agranulocytosis <0.1 G/l. Median number of transfused RBC and platelets units was 9(0-16) and 8(2-18). Results: All pts engrafted, median counts of granulocytes 0.5 G/l, platelets 50 G/l and Hb 10 g/dl were achieved on days 17.5(10-33), 16(9-39) and 19.5(11-34). Acute GVHD grade I,II and III was present in 16, 7 and 3 pt, limited and extensive chronic GVHD respectively in 11 and 3 pts. LDH decreased by 73%(5%-91%) in first 30 days indicating disappearance of hemolysis. 100% donor chimerism was achieved in all pts. In 1 patient donor chimerism decreased to 81% what was treated with donor lymphocytes infusion (DLI). 3 patients died, 1 previously hemodialysed pt died on day +102 due to nephrotoxicity complicating adenoviral/CMV hemorrhagic cystitis, two other SAA patients with PNH clone<10% died on days +56 due to severe pulmonary infection and +114 due to aGvHD-III and multi organ failure. Complications in survivors were FUO (10 pts), CMV reactivation (13), VOD (1), neurotoxicity (1), venal thrombosis (1), hemorrhagic cystitis (4) and mucositis (8). 38 pts (92.7%) are alive 4.2 (0.4-12) years post-transplant and are doing well without treatment. Complete disappearance of PNH clone was confirmed by flow cytometry in all surviving pts. Conclusions: Allo-HCT with treosulfan-based conditioning is effective and well tolerated curative therapy for PNH. Disclosures No relevant conflicts of interest to declare.

scholarly journals Haploidentical/Mismatched Hematopoietic Stem Cell Transplantation for Nonresponders to Immunosuppressive Therapy Compared with First-Line Rabbit Antithymocyte Immunoglobulin Treatment Against Acquired Severe Aplastic Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5508-5508
Author(s):  
Limin Liu ◽  
Xiuli Wang ◽  
Song Jin ◽  
Lin Hao ◽  
Yanming Zhang ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Immunosuppressive Therapy ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Similar Treatment ◽  
Treatment Failure Rate ◽  
Grade Ii ◽  
Immunoglobulin Treatment

Abstract We treated 86 patients with SAA, 31 patients who failed to respond to previous therapy underwent haploidentical hematopoietic SCT (haplo-HSCT, n=26) or mismatched unrelated donor HSCT (MMUD-HSCT, n=5). The other 55 patients were treated with immunosuppressive therapy (IST). At 6 months post-treatment, the treatment failure rates of HSCT and IST groups were 19.35% and 29.09% (P=0.320). Hematopoietic recovery time was shorter in the HSCT group than IST group (P > 0.05). The estimated OS at 3 years was 79.2% ± 7.7% in HSCT group and 89.7% ± 4.4% in the IST group (P=0.058). The estimated failure-free survival (FFS) at 3 years was 79.2% ± 7.7% in the HSCT group and 62.9% ± 8.0% in the IST group (P=0.391). The estimated FFS at 3 years in SAA that had progressed from non-SAA (NSAA) of HSCT was 71.6% ± 14.0% and 16.7% ± 13.6% of IST (P=0.021). Within the HSCT group, 38.71% of the patients developed grade II-IV acute GVHD, and 18.52% of the patients experienced moderate-severe chronic GVHD. These results suggest that haplo-HSCT/MMUD-HSCT and IST have similar treatment failure rate, OS and FFS. haplo-HSCT/MMUD-HSCT might provide a better chance of FFS than IST for SAA that had progressed from NSAA. Disclosures No relevant conflicts of interest to declare.

Tacrolimus, Mini-Methotrexate and Mycophenolate Mofetil Is Safe and Effective as Acute Gvhd Prophylaxis for Non-Myeloablative Unrelated Donor Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1172-1172
Author(s):  
Sanghee Hong ◽  
Thomas Martin ◽  
Lloyd E. Damon ◽  
Lawrence Kaplan ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mycophenolate Mofetil ◽  
Liver Toxicity ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Disease Relapse ◽  
Eligibility Criteria ◽  
Gvhd Prophylaxis

Abstract Abstract 1172 Poster Board I-194 Introduction: Acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) cause significant morbidity and mortality following nonmyeloablative unrelated donor transplantation (NMUDT). The incidence of severe aGVHD (grades II-IV) following non-myeloablative transplant and standard GVHD prophylaxis (cyclosporine or tacrolimus plus mini-methotrexate or mycophenolate mofetil (i.e. two drug prophylaxis)) ranges between 40-70%. The incidence of cGVHD ranges between 50-70%. In order to decrease the incidence and severity of acute and chronic GVHD following NMUDT, consecutive patients were given triple prophylaxis therapy with tacrolimus (TAC), mycophenolate mofetil (MMF) and mini-methotrexate (MTX). In addition, patients were given anti-thymocyte globulin (ATG, thymoglobulin 10 mg/kg) as part of preparative therapy. Patients and Methods: Thirty-five consecutive patients meeting eligibility criteria for NMUDT were prospectively enrolled. The majority of patients had advanced disease; 9AML, 4 MDS, 2CML, 2MPD, 4 MM, 3CLL, 9 Lymphoma and 2 with aplastic anemia. The mean age was 53 years (26-68); 18 males and 17 females. Preparative therapy consisted of Fludarabine (F) 150mg/m2, Busulfan (Bu) 6.4mg/kg IV and ATG. All patients received stem cells from allele-matched unrelated donors; 9/10 (n= 13) or 10/10 (n= 22) at HLA A, B, C, DR and DQ. Thirteen patients received bone marrow and 22 patients received G-CSF mobilized blood stem cells. All patients received TAC (target 5-10 ug/L), MTX (5mg/m2 d1,3,6,11) and MMF (15mg/kg bid day 0 to 60) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The F/Bu/ATG non-myeloablative regimen was well tolerated. On average, patients experienced little or no mucositis (15% > grade 1), enteritis (3%> grade 1), skin toxicity (3% >grade 1) or liver toxicity (29% > grade 1). No VOD was seen. The median total bilirubin, alkaline phosphatase, ALT, and AST values post-transplant were 1.4 mg/dL, 153 U/L, 91 U/L and 77 U/L, respectively. The incidence of Grades II-IV and III-IV aGVHD were 26% and 6% respectively. No difference in aGVHD for 9/10 vs. 10/10 allele matched donors or those receiving stem cells vs. bone marrow was detected. The 100 day non-relapse mortality (NRM) was 11% (2 GVHD, 1 infection, 1 neurotoxicity). The incidence of cGVHD was 52% (80% extensive cGVHD). The majority of these patients required immunosuppression for >1 year. The 1 year NRM was 20% (2 GVHD, 2 infection, 2 neurotoxicity). Disease relapse was the most common cause of mortality; 37% overall and 17% within the first year of transplantation. The overall survival at 4 years is 41%. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the GVHD prophylaxis regimen of TAC/MTX/MMF is safe and effective. The low incidence of aGVHD (26%) compares favorably to published results. Only two patients experienced Grade IV aGVHD within 100 days of transplantation. Chronic GVHD and disease relapse remain problematic. Better strategies to prevent and treat cGVHD and disease relapse are needed. Disclosures: No relevant conflicts of interest to declare.

Disruption Of The Hematopoietic Stem and Progenitor Cell Pool and Bone Marrow Microenvironment In a Murine Model Of Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2756-2756
Author(s):  
Sophia R Balderman ◽  
Benjamin J Frisch ◽  
Mark W LaMere ◽  
Alexandra N Goodman ◽  
Michael W. Becker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Murine Model ◽  
Bystander Effect ◽  
Conflicts Of Interest ◽  
Flow Cytometric Analysis ◽  
Bone Marrow Microenvironment ◽  
Hematopoietic Stem ◽  
Serial Blood ◽  
Post Transplant

Abstract Myelodysplastic Syndromes (MDS) are a group of clonal disorders characterized by ineffective hematopoiesis. Recently, data have emerged supporting a role of the bone marrow microenvironment (BMME ) in the initiation of MDS. We and others have previously shown that cells within the BMME play a central role in normal regulation of hematopoietic stem and progenitor cells (HSPCs). To determine if the HSPC compartment in MDS is defective and also if HSPC function in MDS is regulated by the BMME, we studied a transgenic murine model that expresses the Nup98/HOXD13 (NHD13) translocation product. As was previously reported, these mice develop ineffective hematopoiesis resulting in progressive cytopenias with dysmorphic cells, a phenotype similar to that of human MDS. We investigated the composition of the HSPC pool in these transgenic (TG) mice at 20 to 22 weeks from birth, a time when an MDS phenotype was evident but acute leukemia had not yet developed. Immunophenotypic analysis by flow cytometry on marrow cells from TG and wild type (WT) age-matched littermates demonstrated a severe defect in the TG HSPC pool, with a severe decline in Lin-Sca1+cKit+CD48-CD150+ long-term HSCs (WT vs. TG: 3.5 ± 1.2 x 104 vs 4.4 ± 3.4 x102, p =0.0025) and in Lin-Sca1+cKit+Flt3+Thy1.1- multipotent progenitors (WT vs. TG: 5.6 ± 1 x 105 vs 2.1 ± 0.4 x 104, p<0.0001), as well as in total Lin-Sca1+cKit+ cells and short-term HSCs. To determine if the numerical changes in phenotypic HSPCs corresponded with decreased HSPC function, we performed a competitive repopulation assay using whole bone marrow, and found relative loss of function of HSPCs by 9 weeks after transplantation of marrow from 22-week old TG vs littermate WT donor mice into lethally irradiated WT recipients as measured by percent of donor cells in the blood (WT vs. TG: 37.7 ± 3.4 vs 14.7 ± 1.7, p<0.0001). Serial blood cell flow cytometric analysis demonstrated myeloid skewing (marked by percent of CD11b positive cells) of HSPCs transplanted from TG mice at the expense of lymphocytes by 5 weeks (WT vs. TG: 44.0 ± 4.3 vs 64.9 ± 4.5, p=0.0047), which persisted at 9 weeks (WT vs. TG: 43.6 ± 3.6 vs 69.1 ± 5.9, p=0.0023) and 13 weeks post transplant, a feature which has been previously associated with HSPC aging. Curiously, despite robust engraftment of normal competitor marrow, serial blood counts of recipients after competitive transplant showed that mice receiving 22-week old TG marrow developed leukopenia (9 weeks, WT vs. TG: 7.3 ± 0.47 vs 4.6 ± 0.41, p=0.0008) and lymphopenia (9 weeks, WT vs. TG: 6.0 ± 0.42 vs 3.4 ± 0.37, p=0.0003), suggesting a bystander effect initiated by the TG marrow resulting in ineffective hematopoiesis in the recipients. To determine if the MDS microenvironment contributes to ineffective hematopoiesis, we transplanted NHD13 TG and normal competitor marrow into lethally irradiated TG or WT recipient mice. NHD13 TG marrow engrafted significantly better in WT compared to TG recipients as seen by 4 weeks post transplant (Percent of total cells, WT vs. TG recipient: 14.2 ± 2.3 vs 1.1 ± 0.1, p = 0.0049; Percent of CD11b positive cells, WT vs. TG recipient: 17.1 ± 4.2 vs 1.7 ± 0.1, p = 0.0208; Percent of B220 positive cells, WT vs. TG recipient: 2.7 ± 0.3 vs 0.1 ± 0.0, p = 0.0008). These aggregate results indicate (1) severe disruption of the immunophenotypic HSPC pool in this murine TG model of MDS, (2) a functional defect of HSPCs in this MDS model as evidenced by decreased engraftment and myeloid skewing, (3) contribution of the MDS BMME to ineffective hematopoiesis downstream of immature MDS cells and (4) MDS-dependent signals initiating such microenvironmental effects. Our data strongly suggest that the malignant clone in MDS initiates signals that disrupt the normal marrow microenvironment. Furthermore, these data provide support for a strategy where rejuvenation of the marrow microenvironment and/or interference with MDS-initiated signals may result in mitigation of ineffective hematopoiesis. Further understanding of the HSPC defect in this murine model of MDS and of the role of the BMME in MDS could therefore inform new therapeutic targets for this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The MEK/ERK Inhibitor Trametinib Reduces Fibrosis in a Transduction-Transplantation Model of Mutated Calreticulin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 635-635 ◽  
Author(s):  
Thanh Kim Nguyen ◽  
Prasanthi Tata ◽  
Stefan Brooks ◽  
Nilamani Jena ◽  
Sarah J Morse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Average Score ◽  
Spleen Weight ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact ◽  
Transplantation Model

Abstract Insertion or deletion mutations in calreticulin (CALR) are present in the majority of JAK2V617F-negative MPN patients. We utilized a murine retroviral transduction-transplantation model to express the 52bp CALR deletion mutation (CALRDEL) in both BALB/c and C57B/6 backgrounds. As described previously (Marty et al., Blood 2016;127:1317), recipients of CALRDEL-transduced marrow developed persistent thrombocytosis without leukocytosis or erythrocytosis by two months post-transplant. Mice were euthanized at six and nine months post-transplant to evaluate the tempo of disease progression. At six months CALRDEL mice had impressive expansion of megakaryocytes expressing the CALRDEL mutant protein in the bone marrow (BM) without fibrosis or significant splenomegaly. By nine months BM fibrosis and splenomegaly were present. Both whole BM and spleen cells were able to serially transplant the MPN phenotype into secondary recipients. When cultured in collagen-based media supplemented with thrombopoietin, CALRDEL BM cells produced an increased number of megakaryocyte colonies as compared to empty vector. The increased colony formation potential of CALRDEL bone marrow cells was limited to megakaryocytes, we found no increase in colony formation from CALRDEL hematopoietic stem and progenitor cells in methylcellulose with cytokines supporting erythroid and GM colony formation. However, CALRDEL enhanced the serial replating ability of LKS (lineageneg, c-kit+ Sca-1+) cells. Both pSTAT5 and pERK were increased in whole spleen lysates from CALRDEL mice as compared to wild-type BALB/c mice. Therefore, we tested the impact of ruxolitinib, a JAK1/2 inhibitor, and trametinib, a MAPK/ERK inhibitor, on the MPN phenotype of CALRDEL mice. At six months post-transplant mice were treated with either ruxolitinib (90mg/kg PO BID), trametinib (3mg/kg PO daily), or vehicle for 40 days. Ruxolitinib reduced pSTAT5 but caused a paradoxical increase in pERK in whole spleen lysates, while trametinib reduced pERK but not pSTAT5. Trametinib caused a transient increase in platelets and white cells. In spite of pharmacodynamic evidence of effective dosing, ruxolitinib had no significant effect on platelet or leukocyte count but did reduce hemoglobin slightly. Both ruxolitinib and trametinib reduced spleen weight. Ruxolitinib reduced the fraction of the mutant CALRDEL allele (inferred from percentage of GFP+ cells) in the spleen but not the bone marrow, while trametinib had no impact on disease allele burden in any organ. Neither ruxolitinib nor trametinib reduced the expansion of megakaryocytes in the bone marrow but trametinib significantly reduced marrow fibrosis (average score MF-2.5 for vehicle, MF-1.75 for ruxolitinib, MF-1 for trametinib). To assess the role of STAT5 in the pathogenesis of the ET-like MPN induced by the CALRDEL mutant, we transduced BM from syngeneic Balb/c donors carrying a floxed Stat5ab allele in combination with a Stat5ab null allele (Mx-Cre;Stat5abfl/-; Walz et al., Blood 2012;119:3550). Haploinsufficiency for Stat5ab significantly delayed the development of ET-like MPN and attenuated thrombocytosis, implicating JAK2-STAT5 signaling directly in the pathogenesis of this disease. In summary, this CALRDELmouse model results in an MPN phenotype resembling essential thrombocythemia followed by myelofibrosis. CALRDELresults in expansion of megakaryocytes and platelets without expansion of other myeloid cell types. Both pSTAT5 and pERK are increased in our CALRDEL model and pharmacologic inhibition of pERK results in reduction of fibrosis without reducing megakaryocytes. These studies implicate pERK as a potential anti-fibrosis therapeutic target in MPN. Disclosures No relevant conflicts of interest to declare.

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