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.

Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 661-661
Author(s):  
Jon J van Rood ◽  
Cladd E Stevens ◽  
Jacqueline Smits ◽  
Carmelita Carrier ◽  
Carol Carpenter ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hla Antigens ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Leukocyte Antigens ◽  
Grade Ii ◽  
The Impact ◽  
Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 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.

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.

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 Reduced Toxicity Conditioning Is Better Tolerated but Has Higher Graft Failure Compared to Myeloablative Conditioning in Children with Inherited Metabolic Disorders

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3352-3352
Author(s):  
Michael Downey ◽  
Ashish O. Gupta ◽  
Ryan Shanley ◽  
Weston P. Miller ◽  
Paul Orchard ◽  
...  
Keyword(s):  
Research Funding ◽  
Graft Failure ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
High Rate ◽  
Sinusoidal Obstruction Syndrome ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Post Transplant ◽  
Reduced Toxicity

Abstract Background: Hematopoietic stem cell transplantation (HCT) is a primary treatment option for various inherited metabolic diseases (IMDs). Successful engraftment is crucial for favorable survival and functional outcomes and correlates with optimal conditioning in these patients with an intact immune system. Traditional regimens have used myeloablative Busulfan and Cyclophosphamide (BuCy) which is associated with significant potential morbidity. Alternate reduced toxicity regimens, like Busulfan and Fludarabine (BuFlu), are often utilized to reduce treatment related toxicities. Objective: To compare outcomes and complications with BuCy and BuFlu based conditioning regimens in patients with IMDs. Methods: This is the largest single institution retrospective analysis of University of Minnesota's transplant database for patients with IMDs who underwent HCT using BuCy + campath or BuFlu + ATG based preparative regimen from March 2008 to September 2017. Incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary aplastic graft failure, primary graft failure with autologous recovery, secondary aplastic failure and secondary graft failure with autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined. Results: Total of 99 patients were studied who underwent HCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs transplanted and umbilical cord blood was the most common donor source (74%). One-year overall survival was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with a similar incidence of grade 3-4 acute GVHD (9% in BuCy vs. 6% in BuFlu; p=0.5) and chronic GVHD (9% in BuCy vs. 7% in BuFlu; p=0.67) in the two groups. Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu group (median 21 d vs. 34 d, p = 0.002). The cumulative incidence of graft failure was higher with BuFlu conditioning (29% vs 14%, p= 0.08, Figure 1a). Significantly higher rates of second HCT was noted following BuFlu conditioning (27% vs. 3%, p= 0.001; Figure 1b). The incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were notably higher in the BuCy group. Though donor myeloid engraftment was similar in both groups, donor T-cell engraftment occurred sooner with BuCy conditioning until 1-year post transplant (Figure 2). Conclusions: Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but is associated with a high rate of graft failure in patients with IMD. Alternate immune suppressive agents should be considered to reduce graft failure and minimize toxicities. Alternate donor options, including expanded UCB, should also be considered to improve engraftment in patients with IMDs. Disclosures Shanley: Magenta Therapeutics: Research Funding. Miller:Sangamo Therapeutics: Employment. Orchard:Magenta Therapeutics: Research Funding.

Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) for Patients with Severe Sickle Cell Disease (SCD)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 10-10 ◽  
Author(s):  
Matthew M Hsieh ◽  
Courtney D Fitzhugh ◽  
R. Patrick Weitzel ◽  
Wynona Coles ◽  
M Beth Link ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Organ Damage ◽  
Mixed Chimerism ◽  
Acute Chest Syndrome ◽  
Hematopoietic Stem ◽  
Total Body ◽  
Age Range ◽  
Simple Conditioning

Abstract Abstract 10 Allo-HSCT remains the only curative approach for patients with SCD, yet a high risk of procedural toxicities and graft-versus-host disease (GvHD) limit this approach in adult patients with end organ damage from SCD. We chose a low-dose radiation approach utilizing sirolimus based upon its unique ability to promote T cell tolerance. Entry criteria include irreversible SCD-related complications (stroke, nephropathy, or tricuspid regurgitant jet velocity >2.5 m/s), or reversible complications not ameliorated by a 6-month course of hydroxyurea (frequent vaso-occlusive crises or acute chest syndrome). Conditioning was achieved with 1mg/kg of alemtuzumab divided over 5 days, a single total body irradiation dose of 300cGy, and oral sirolimus targeting trough levels between 10–15 ng/ml. Donor chimerism was measured by microsatellite PCR among CD3 and CD14/15 positive white cells. Twenty-three patients have been transplanted to date, and their ages ranged from 17 to 64 years (median 28). All are alive at 2 months to 7 years post allo-HSCT. Conditioning was well-tolerated. All received unmanipulated G-CSF mobilized peripheral blood progenitors obtained from 8/8 HLA-matched siblings. CD34+ cell doses ranged from 5.5 to 31 × 10e6/kg (median 14.4), and CD3+ cell doses ranged from 1.6 to 5.4 × 10e8/kg (median 3.4). Three patients engrafted temporarily but lost their grafts between the 2nd and 3rd months post transplant and had recurrent SCD. Twenty patients engrafted with mean myeloid chimerism of 97.5% (median 89%) and CD3 chimerism of 42% (median 49%). Improvements in laboratory parameters of engrafted patients are as follows: pre vs post HSCT hemoglobin, 8.7 vs 12.1 g/dL; reticulocyte count, 181 vs 74 k/uL; LDH, 328 vs 202 units/L; total bilirubin, 2.87 vs 1.0 mg/dL. Hemoglobin electrophoresis revealed replacement by donor type hemoglobin in 19 patients by 1 year, with amelioration of the SCD phenotype allowing for therapeutic phlebotomy. In 17 patients at 1 year or more post allo-HSCT, 5 had CD3 chimerism >50% which allowed complete withdrawal of immunosuppression; they have maintained stable mixed chimerism. Two patients received preemptive treatment with ganciclovir or foscarnet for presumed CMV reactivation (blood PCR >300 genome/mL) before day 30. Treatment in both patients was discontinued 1 week later with negative blood PCR and prophylaxis with acyclovir was resumed. There were 2 patients with zoster at 2 and 3 years post allo-HSCT. Finally, no engrafted patient to date has developed any evidence of acute or chronic GVHD. Our results demonstrate that this relatively simple conditioning regimen is well-tolerated across a broad age range of adults with severe SCD, is effective in achieving stable mixed chimerism without the development of GVHD, and is sufficient to induce functional tolerance. Disclosures: No relevant conflicts of interest to declare.

An Observation On Clinical Outcomes of HLA-Haplotype Hematopoietic Stem Cell Transplantation with High-Dose and Post-Transplantation Cyclophosphamide for Children Malignancies Hematopathy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4547-4547
Author(s):  
Chunfu Li ◽  
Yuelin He ◽  
Xuedong Wu ◽  
Zhiyong Peng ◽  
Xiaoqin Feng ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
High Dose ◽  
Post Transplantation ◽  
Hematopoietic Stem

Abstract Abstract 4547 We retrospectively analyzed early clinical outcomes of HLA-haploidentical HSCT with high-dose post-transplantation cyclophosphamide (Cy). Between June 2009 and June 2012, 20 patients with high-risk acute lymphoblastic leukemias (ALL, n = 10, CR1=5, CR>1=2, NR=3), acute myeloid leukemia (AML, n=7, CR1=3, CR>1=1£¬NR=3), chronic myeloid leukemia (CML) (n=1, CR), and lymphoma (n=2, CR) received HLA-haploidentical HSCT. All patients were HLA-mismatched equal to and more than HLA (at antigen level). All patients received conditioning therapy consisted of Busulfan, Cytarabine, Cy, VP-16 (or CCNU, or TT), and/or TBI. GVHD prophylaxis consisted of Cy 50mg/kg (for first 10 cases) or 40mg/kg (for second10 cases) on day 3 and 4, FK506 and MMF. The median follow-up time was 507 days. Donor chimerism was ¡Ý80% on day +60 but there were one patient with bone marrow failure (BMF) and two without platelet engraftment after day 60. The median time to neutrophil and platelet engraftment were 23 days and 25 days respectively, and no significant deference was found out between first 10 cases and second 10 cases. No II-IV acute GVHD was observed. However, the cumulative incidences of grade I and above GVHD were 60% (garde 1–2 acute GVHD was 40%; garde 3–4 acute GVHD was 15%), and chronic GVHD was 20% after DLI because of relapse. The cumulative incidences of relapse and non-relapse mortality (NRM) were 30% and 40% respectively. Cytopenia occurred in most patients within 6 months after transplant. Three-year overall survival and event-free survival are 35% and 30% respectively. Thirteen patients have died. The causes of death included relapse (n=5), infection (n=3), cGVHD (n=1), BMF (n=1), hemorrhagic cystitis (n=1). Conclusions: HLA-haploidentical HSCT with high-dose, post-transplantation Cy for malignancies hematopathy is selection of treatment, with less aGVHD or cGVHD, but also with high relapse and NRM. Disclosures: No relevant conflicts of interest to declare.

Acceptable Results Of Allo-HSCT From Unrelated Donors In AML Patients Who Failed To Achieve The Complete Remission

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5520-5520
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Malwina Rybicka ◽  
Magdalena Gaj ◽  
Anna Koclega ◽  
...  
Keyword(s):  
Complete Remission ◽  
Conflicts Of Interest ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Clinical Problem ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Investigational Therapies ◽  
Preparative Regimen ◽  
Unrelated Donors

Abstract Introduction Despite the development of a variety of new investigational therapies for patients diagnosed with acute myeloblastic leukemia who either fail to achieve remission or who relapse thereafter, identifying suitable patients for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and choosing a best tolerable therapy that is most likely to succeed remains a difficult clinical problem. The rationale of this study was to evaluate results of allo-HSCT in AML patients who have failed to achieve complete remission pre-transplant. Patients and Methods 33 pts with refractory or relapsed AML with no (18) or with partial remission (15), aged 35 (15-64) years received allo-HSCT from 10/10 (19) or 9/10 (14) HLA-matched Unrelated Donors (UD) in Hematology and BMT Center in Katowice, Poland, from Dec 2000 to Jan 2013. The myeloablative preparative regimen consisted of busulfan 4x4 mg/kg plus cyclophosphamide (Cy) 4x30 mg/kg (18 pts), TBI (12 Gy) plus Cy 3x40 mg/kg (6 pts), or treosulfan 3x14 g/m2 plus either fludarabine 5x30 mg/m2 (7 pts) or Cy 3x40 mg/kg (2 pts). Standard GVHD prophylaxis consisted of cyclosporine-A, methotrexate and pre-transplant ATG or thymoglobulin. Source of cells was peripheral blood (22 pts) or bone marrow (11 pts) with median 6.8 or 3.9 x10(6)CD34+cells/kg, respectively. Results All but 4 pts engrafted. The 2-year estimated overall survival rate was 47%. 17 pts died 4 (0.3-16) months following allo-HSCT due to relapse (7) infection (5), GVHD (1) GF (1) and unknown cause (3). Acute GVHD grade I, II, III and IV was observed in 15, 6, 2 and 1 pt (serious aGVHD grade III-IV in 3 pts (9%)), limited or extensive chronic GVHD was present each in 5 (20%) of 25 evaluable pts. Other complications included CMV reactivation (13), hemorrhagic cystitis (7), serious 3-4 grade mucositis (8), SOS (3) and renal failure (1). 16 pts (48.5%) are alive 45 months (4 months-10 yrs) post-transplant. No difference in survival has been observed between pts transplanted in PR or NR stages nor between pts treated with variable preparative regimens. Conclusions Allo-HSCT from UD with myeloablative conditioning is a feasible and effective curative therapy providing acceptable rates of long-term remission or cure in refractory or relapsed AML in patients who fail to achieve CR with conventional treatment. Disclosures: No relevant conflicts of interest to declare.

Autologous Transplantation Followed by Reduced-Intensity Allogeneic Transplantation Is Feasible in Patients with High-Risk Non-Hodgkin's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3105-3105
Author(s):  
Roberto Crocchiolo ◽  
Luca Castagna ◽  
Sabine Furst ◽  
Jean El-Cheikh ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Chronic Gvhd ◽  
Autologous Transplantation ◽  
Salvage Regimen ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Abstract 3105 Introduction: relapse after ASCT remains the most important cause of treatment failure among high-risk lymphomas. In order to improve outcome, allogeneic hematopoietic stem cell transplantation (AlloSCT) is used to exploit graft-versus-lymphoma (GVL) effect; on the other hand, feasibility of AlloSCT is limited by the high risk of infections and graft-versus-host disease (GvHD), accounting for transplant-related mortality (TRM) up to 40% in some circumstances. Patients and Methods: we retrospectively analyzed data on 34 high-risk NHL patients who underwent ASCT followed closely by reduced-intensity AlloSCT (“tandem auto-allo”) from January 2002 to November 2010. The tandem transplantation decision relied on the high-risk disease, needing some consolidation therapy after ASCT, and on the hypothesis of a high GVL effect when a significant cytoreduction occurred after AlloSCT. The search for an allogeneic donor was started at the beginning of salvage regimen. Preparative regimen for reduced-intensity AlloSCT was an association of fludarabine-busulfan-ATG or fludarabine-cyclophosphamide with our without thiotepa. In one patient conditioning was BEAM regimen. GvHD prophylaxis included cyclosporine alone or in combination with methotrexate. Results: median patients' age at AlloSCT was 47 (27–68); hystotypes were as follows: diffuse large B-cell n= 5, follicular n= 14, transformed follicular n= 4, mantle-cell n= 5, lymphoplasmocytic lymphoma n=1, anaplastic large T-cell n= 2, peripheral T-cell n= 3. Donor were HLA-identical sibling (n= 29) or 10/10-matched unrelated (n=5). Peripheral stem cell was used in all patients but one. Median interval between ASCT and AlloSCT was 76 days (36–197). Median prior therapeutic lines before tandem transplantation were 2 (0–4). Overall, 16 patients were in complete remission, 13 were in partial remission and five were in progressive disease at time of AlloSCT. Successful allogeneic engraftment occurred in all patients. At a median follow-up of 46 (8–108) months since AlloSCT, 5-year overall survival (OS) is 77% (61–93) and progression-free survival (PFS) is 68% (51–85) (figure 1). Disease relapse or progression occurred in six patients (18%), 100-day TRM was 0%, overall TRM rate was 9%. Causes of TRM were: infection in two patients and severe extensive chronic GvHD in one patient. Ten patients developed grade >=2 acute GvHD and fifteen patients chronic GvHD, respectively. Conclusions: tandem transplantation is feasible in relapsed or refractory NHL patients having a HLA-identical allogeneic stem cell donor, with 0% early TRM and 9% overall TRM rate. This tandem approach, i.e. disease debulking by salvage therapy and ASCT followed by allogeneic GVL immunotherapy, could represent a suitable therapeutic option for those patients. This invites promptly starting a donor search in these situations. Disclosures: No relevant conflicts of interest to declare.

Haploidentical Stem Cell Transplantation (HAPLO-HSCT) With Reduced Intensity Conditioning (RIC) Regimens and High Dose Cylophosphamide Post-Transplant (HD-CY) As Gvhd Prophylaxis In Patients With Relapsed Or Refractory Hodgkin´s Disease: Multicentric Spanish Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3406-3406 ◽  
Author(s):  
Jorge Gayoso ◽  
Pascual Balsalobre ◽  
Cristina Castilla-Llorente ◽  
María Jesús Pascual ◽  
Mi Kwon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Immune Reconstitution ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Chronic Gvhd ◽  
High Dose ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Introduction Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor. This procedure has shown promissing results in patients diagnosed with relapsed or refractory Hodgkin´s disease (Burroughs LM et al. Biol Blood Marrow Transplant 2008; 14:1279-1287). Patients and Methods We retrospectively evaluate the results of HAPLO-HSCT with RIC regimens (Fludarabine 30 mg/m2 x5 days (-6 to -2), Cyclophosphamide14,5 mg/kg x2 days (-6 to -5), Busulfan IV 3,2 mg/kg x 1-2 days (BUX, days -3 to -2) or 200 cGy TBI on day -1) and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers to patients diagnosed with relapsed or refractory Hodgkin´s disease. Results From March-2009, 29 HAPLO-HSCT have been performed in patients diagnosed with relapsed or refractory Hodgkin´s disease in 11 GETH centers. Median age was 31 years (18-53), 19 were males and all were in advanced phases of their disease. Autologous HSCT was previously employed in 90% of them, and allogeneic HSCT in 10%. Disease status at HAPLO-HSCT evaluated by PET was complete remission in 8 (28%) and persistent disease in 21 (72%). Bone marrow was the stem cell source in 15 (52%) and peripheral blood in 14 (48%), without T-cell depletion in all cases. The haploidentical donor was the patient´s mother (13), father (2), brother (8), sister (5) or daughter (1). The RIC regimens employed included 1 dose BUX (11), 2 doses BUX (14) or 200cGy TBI (4). Median neutrophils engraftment was day +17 (11-44) and platelets >20K was day +26 (11-150). Main toxic complications were grade II-III muchositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a transplant related mortality rate of 7% (2/29) at day +100 and 17% (5/29) at 6 months post-transplant. Acute GVHD grade II-IV affected to 7/28 patients at risk (25%), with grade III-IV in 3/28 (11%). Chronic GVHD was present in 3/19 (16%), being extensive in 1/19 (5%). After a median follow-up of 9 months (0.3-49), 13/22 (59%) remain alive and in complete remission. Relapse or progression occured in 6/28 (21%). Immune reconstitution was fast and complete in those evaluated. Conclusions HAPLO-HSCT with HD-CY is a useful tool in the treatment of patients with relapsed or refractory Hodgkin´s disease, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution. Disclosures: No relevant conflicts of interest to declare.

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