Fludarabine Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant Despite Pharmacokinetic Dosing

Abstract Background: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two commonly used reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT). A recent analysis showed that both regimens had similar overall survival (OS) but relapse incidence (RI) was significantly higher with FB with a trend towards higher non-relapse mortality (NRM) in FM (Baron et al., Cancer 2015). However, that cohort included patients treated with oral and intravenous busulfan without pharmakokinetic targeting of intravenous which may impact anti-leukemic activity. Aim: Compare transplant related outcomes of FB vs. FM using intravenous (IV) busulfan targeted to the area under the curve (AUC). Methods: After due IRB approval, patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) receiving RIC-SCT from 2008-2014 were identified. All baseline and laboratory features were retrospectively extracted. Busulfan dose in FB was 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L (min). All patients received T-cell replete grafts. Categorical and continuous variables were compared using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier method and curves were compared using the log-rank test. Cumulative incidence was computed as competing events using Grey's model. Univariate and multivariate analyses were performed using Cox regression modeling. Results: A. Baseline characteristics and AUC monitoring: 134 pts were identified (47 FB and 87 FM). Median follow up of the entire cohort was 40 months (0-63.3) and at last follow up, 60% and 29% have died or relapsed, respectively. Baseline characteristics stratified according to conditioning regimen are shown in table 1. Younger age (60 yrs FB vs. 61 yrs FM, p = 0.015) and a trend towards a higher CMV R-/D- status (28% FB vs. 14% FM p = 0.064) were the only significant differences identified. All patients in the FB group received intravenous busulfan and 46/47 patients had evaluable AUC data with a range of 732-1354 mcmol/L (min). A total of 19 patients were outside of range, all <900 mcmol/L (min) and required a median dose increase of 28.1% (3.3-50.2%) B. Engraftment and toxicity data: The median time for platelet engraftment was 19 days (0-48) for FB vs. 16 days (14-183) for FM (p = 0.0023) whereas the median time to absolute neutrophil count (ANC) engraftment was 18 days (7-30) for FB and 15 days (11-40) for FM (p = 0.077). Cumulative incidence of grade II-IV, III-IV acute GVHD and chronic GVHD at 2-yr was 57.3%, 11% and 52.8% for FB and 48.6%, 17% and 63.4% for FM (p = 0.73, 0.4 and 0.21, respectively). Two patients in the FM group died of cardiac causes (heart failure and sudden cardiac arrest). No cases of sinusoidal obstructive syndrome were observed in either arm C. Transplant outcomes: A significantly higher 2-yr relapse incidence (RI) was associated with FB vs. FM at 35.6% vs 17.3%, respectively (p = 0.0058). 2-yr progression free survival (PFS) was also significantly lower in the FB vs. FM at 51.2% vs. 65.1%, respectively (p 0.031). However, 2-yr OS and NRM was similar for FB vs. FM (53.1% and 22.9% vs 63.9% and 21.9%, respectively p = 0.26 and 0.89). Necessitating a dose adjustment based on AUC did not increase the risk for relapse or affect NRM. In multivariate analysis, FB was associated with increased RI with hazard ratio (HR) 2.29 (1.07-4.88; p = 0.033). Other factors significantly associated with RI on multivariate analysis were secondary/therapy related disease with HR 2.84 (1.34-6.02; p = 0.0067) and CR1 vs. other with HR 0.39 (0.17-5.32; p = 0.019). The significance of the results remained unchanged after exclusion of MDS patients (data not shown) Conclusion: Despite AUC dose adjustment, FB compared to FM was associated with increased RI with a similar OS and NRM. AUC dose adjustment did not impact transplant outcomes and its routine use in RIC should be further evaluated. Given the wide use of FB as a conditioning regimen, these important observations should be prospectively studied in a randomized fashion. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding. Wolf:Janssen Scientific Affairs, LLC: Consultancy.

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Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽

10.1182/blood.v116.21.2353.2353 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2353-2353 ◽

Cited By ~ 1

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Stephane Morisset ◽

Nathalie Tedone ◽

Jacques-Olivier Bay ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Grade Ii ◽

Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/− and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/− (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Transplantation Following Reduced Intensity Conditioning with Fludarabine and Melphalan In Patients with Advanced Myelofibrosis Is Associated with Unacceptable Rates of Acute Graft-Vs-Host Disease and Non-Relapse Mortality.

Blood ◽

10.1182/blood.v116.21.4552.4552 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4552-4552

Author(s):

Samith Thomas Kochuparambil ◽

Kavita Natrajan ◽

Anand P. Jillella ◽

Sayed Mehdi Hamadani ◽

Farrukh Awan

Keyword(s):

Quality Improvement ◽

Median Time ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Allogeneic Hsct ◽

Prior Therapy ◽

Graft Vs Host Disease ◽

The Mean ◽

Reduced Intensity

Abstract Abstract 4552 Allogeneic hematopoietic stem cell transplant (HSCT) offers a potentially curative option for patients with primary myelofibrosis (PMF). The evidence for the utility of allogeneic HSCT originates from early reports documenting a graft-versus-myelofibrosis effect. The advent of reduced intensity conditioning (RIC) for patients undergoing allogeneic HSCT has resulted in significant improvements in outcomes primarily due to a reduction in non-relapse mortality (NRM). However, there is considerable variation in the outcomes of PMF patients undergoing RIC HSCT. EBMT has reported impressive 5-yr progression free (PFS) and overall survival (OS) of 51% and 67% with fludarabine, busulfan and anti-thymocyte globulin (ATG) based conditioning regimen. In contrast, a recent UK study reported more dismal outcomes with 3-yr OS of 31% and DFS of 24% when utilizing fludarabine, melphalan and ATG as their conditioning regimen. Similarly poor outcomes have also been reported for matched related donor (MRD) HSCT after the use of fludarabine and melphalan without ATG. We report here our experience of MRD Allogeneic HSCT after RIC in patients with PMF and attempt to identify issues in the management of these patients, and propose several quality improvement initiatives to improve HSCT outcomes in these patients. MRD Allogeneic HSCT with RIC regimen consisting of fludarabine (30mg/m2 day -6 to -3) and melphalan (70mg/m2 day -2 to -1) was performed in 6 patients from 2007–2009. The median age of the patients was 55 years (Range 31–66 years) and all had intermediate or high risk disease per the Lille score. The median time between diagnosis of PMF and HSCT was 5.5 months. Graft-vs-Host disease (GVHD) prophylaxis was with tacrolimus, methotrexate and steroids. 3 patients had Jak2 mutation and 2 had prior therapy with IMiDs. 4 patients had palpable splenomegaly at the time of transplant. The mean CD34+ cell dose was 3.5×106 and the mean CD3+ cell dose was 209.95×106. The median time to neutrophil engraftment was 10 days (Range 10–16) and the median time to platelet engraftment was 24 days (Range 16–42). None of our patients had graft failures or disease relapse. At a median follow up of 2 years, the Kaplan-Meier estimate of OS was 17%. Only one patient is alive after 3-years of follow up. The most common cause of death was severe infection or GVHD. Interestingly all patients developed ≥grade 2 GVHD of the gastrointestinal (GI) tract which was associated with significant morbidity. GI GVHD was also the primary form of GVHD in all our patients with limited involvement of other organ systems. Further analysis of patient characteristics revealed that 2 out of the 3 patients who developed ≥grade 2 oral mucositis after the RIC regimen subsequently developed >grade 2 GI GVHD. Interestingly both patients who had received prior therapy with IMiDs developed ≥grade 3 GI GVHD, however, all our analyses are hypothesis generating and our observations are limited by the small sample size. Our limited, single institution experience indicates a potentially higher risk of GI GVHD with the use of melphalan containing regimens, especially in patients who develop mucositis, don't receive ATG and have had prior treatment with IMiDs. As our quality improvement initiative we have introduced fludarabine and busulfan as the standard RIC regimen for patients with PMF. Further controlled studies are needed to establish the optimum RIC regimen for patients with PMF and the utility of ATG even in patients undergoing a MRD HSCT. Disclosures: No relevant conflicts of interest to declare.

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Comparison Of Unrelated Cord Blood (CB) and Peripheral Blood Stem Cell (PB) Transplantation In Adults With Myelodysplastic Syndrome (MDS) After Reduced Intensity Conditioning Regimen (RIC): A Collaborative Study From Eurocord and Chronic Malignancies Working Party (CMWP-EBMT)

Blood ◽

10.1182/blood.v122.21.3334.3334 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3334-3334

Author(s):

Marie Robin ◽

Annalisa Ruggeri ◽

Myriam Labopin ◽

Dietger Niederwieser ◽

Reza Tabrizzi ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Myelodysplastic Syndrome ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Unrelated Cord Blood ◽

Reduced Intensity

Abstract Background Outcome of patients with intermediate or high risk IPSS myelodysplastic syndrome (MDS) is poor in the absence of hematopoietic stem cell transplantation (HSCT). Choice of the best stem cell source is debated in this poor risk population. Unrelated cord blood transplantation (UCBT) has been used for patients lacking an HLA identical donor. This is the first study comparing well matched unrelated adult peripheral blood (PB) stem cell transplant to mismatched UCBT for patients with MDS. Method Patients with MDS transplanted from 2005 to 2011 with either unrelated CB or PB receiving a reduced intensity conditioning (RIC) were included. All PB donors were Human Leucocyte Antigens (HLA)-allele matched (10/10) or one allele mismatched (9/10) (-A, -B, -C, DRB1, -DQB1). Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier. Relapse incidence (RI), non-relapse mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD) were calculated using cumulative incidence (CInc) methods. Risk factors for outcomes were analyzed by Cox and Fine & Gray models. Results 502 patients transplanted with PB or 129 with CB (80 with double units) were compared. Among the PB recipients, 363 (72%) were 10/10 matched and 123 (25%) 9/10 matched. Most CB (98%) recipients had at least one HLA mismatch on 6 antigens tested (-A, -B antigen level and DRB1 allelic level), 32% had one mismatch and 66% had 2 mismatches. Median follow-up was 12 months for PB and 24 months for CB. MDS was transformed into AML in 416 patients. MDS WHO classification was: RA in 37, RCMD in 31, RAEB1 in 50 and RAEB2 in 87 and unclassified in 10 patients. Considering only patients with MDS, cytogenetic according to IPSS was: good in 96, intermediate in 57 and poor in 65 patients. PB and CB groups were different for age, gender, incidence of secondary AML (CB: 71% vs PB: 64%) and conditioning regimen. CInc of engraftment was lower in CB patients, 78 vs 96% (p<0.0001). Grade II to IV acute GVHD was 29% and 31% for PB and CB. Chronic GVHD was more frequent after PB (42% vs 23%, p=0.001). The unadjusted 2-year OS and DFS were better in patients transplanted with PB (46% vs 30% and 43% vs 28%, p=0.0001). There was no statistical difference for OS and DFS between single and double UCBT. RI was not significantly different (25 vs 30%, p=0.09) whereas NRM was higher in patients transplanted with CB (42 vs 33%, p=0.02). In multivariate analysis, OS (Hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.80) and DFS (HR: 0.57, 1.89, 0.79) were higher in patients transplanted with PB compared to CB. Furthermore, after adjustment, CB was also a risk factor for higher NRM ((PB, HR: 0.55, 95%CI: 0.37-0.80) and RI ((PB, HR: 0.62, 95%CI: 0.39-0.97). The analyses were performed using 3 groups of patients according to donor HLA type: PB 10/10, PB 9/10 and CB. The unadjusted 2-year OS and DFS were better with PB 10/10 than with PB 9/10 or CB: 49%, 37% and 30% (p=0.0001) and 45%, 36%, 28% (p<0.0001), respectively. NRM was not significantly different between CB and PB 9/10: 42% vs 36%. RI was similar after CB and PB 9/10: 28% vs 30%. Chronic GVHD was significantly lower after CB (PB 9/10: 37% vs CB 23%, p=0.004). The multivariate analysis showed an advantage of OS for PB 10/10 compared to PB 9/10 (HR: 1.45, 95%CI: 1.06-1.97, p=0.02) whereas there was no significant difference between PB 9/10 and CB (HR: 1.24, 95%CI: 0.84-1.83, p=0.29). Likewise, DFS was better after PB 10/10 (HR: 0.57, 95%CI: 0.43-0.77, p=0.05) and it was similar after PB 9/10 or CB (HR: 1.34, 95%CI: 0.92-1.97, p=0.13). In the 9/10 PB no differences in the results were observed according to the specific mismatched locus (A, B, DRB1, vs C, DQB1) Conclusion Despite the limitation of a retrospective registry based study and the short term follow up, our study shows that transplants with PB from matched unrelated donor gives the best outcomes. In the absence of a 10/10 unrelated matched PB donor, a 9/10 PB donor or mismatched CB give similar results. Therefore, for MDS patients without a HLA 10/10 unrelated donor a 9/10 regardless of the specificity of the locus where the mismatch occurs mismatched HLA locus or a HLA mismatched CB are both alternative options for transplantation. Disclosures: Gluckman: Cord use: Honoraria; gamida: Honoraria.

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Potential Increase in Graft Failure Risk after Reduced Intensity Conditioning Stem Cell Transplant (RIT) Using Umbilical Cord Blood for Children with Primary Immunodeficiency.

Blood ◽

10.1182/blood.v110.11.2006.2006 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2006-2006

Author(s):

Jessica Guarino ◽

Morris Kletzel ◽

Reggie Duerst ◽

David Jacobsohn ◽

Jennifer Schneiderman ◽

...

Keyword(s):

Stem Cell ◽

Cord Blood ◽

Median Time ◽

Primary Immunodeficiency ◽

Graft Failure ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Cd34 Cells ◽

Unrelated Donors ◽

Reduced Intensity

Abstract Allogeneic stem cell transplantation is curative for patients with primary immunodeficiency. A unique reduced intensity conditioning regimen has been developed to maximize cure rate and minimize transplant-related toxicity. Between 2000 and 2007, we performed 16 RIT in patients with hyper-IgM syndrome (n=2), severe combined immune deficiency (SCID) (n=10), immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) (n=2), Wiskott-Aldrich syndrome (n=1), and X-linked lymphoproliferative disease (n=1). There were 12 males and 4 females, with a median age at the time of RIT of 8.0 months (range 1.1 months to 8.9 years). Donor sources included peripheral blood stem cells (PBSCs) from matched related donors (n=7) or unrelated donors (n=2), and cord blood units (CBUs) (n=7). The median cell dose was 8.55 × 108 total nucleated cells (TNC)/kg and 6.7 × 106 CD34+cells/kg for the PBSC group, and 1.99 × 108 TNC/kg and 0.71 × 106 CD34+cells/kg for the CBU group. The conditioning regimen consisted of Fludarabine (Flu), days -10 through -5, intravenous Busulfan (Bu), days -5 and -4, and Anti-thymocyte globulin (ATG), days -4 through -1. GVHD prophylaxis included tacrolimus/prednisone (n=1), cyclosporine A (CSA) alone (n=2), and CSA/mycophenolate mofetil (n=13). All patients who received PBSCs from related and unrelated donors engrafted (9/9), whereas only 4/7 (57%) patients who received CBUs engrafted. The 3 patients who experienced primary graft failure had the following diagnoses; IPEX, T−B−NK+ SCID and T−B+NK+ SCID. Their cord blood doses were 0.78, 1.19 and 1.99 × 108 TNC/kg, and 0.11, 0.69, and 0.55 × 106 CD34+cells/kg, respectively. For the 13 patients who engrafted, median time to absolute neutrophil count (ANC) >1000 was 19 days (range 4 to 53) and median time to platelets >50K was 23 days (range 14 to 90). The ANC never dropped <500 for 8/13 (62%) patients, and platelets never dropped <20K for 9/13 (69%) patients who engrafted. VNTR analysis of donor cell contribution showed that full donor chimerism was achieved in 8/16 patients (50%; 6 received PBSCs and 2 received CBUs), and, partial donor chimerism was achieved in 5/16 patients (31%; 3 received PBSCs and 2 received CBUs). Toxicities within 100 days post-RIT included bacteremia (n=8), candidemia (n=1), and viral infection (n=6). All infections were effectively treated and patients fully recovered. No episodes of seizure or veno-occlusive disease were experienced. No mucositis or severe nausea/vomiting was reported. No grade III/IV acute graft-versus-host disease (GVHD) or chronic GVHD was seen. Three patients died within 100 days post-RIT from causes related to primary or secondary graft failure. The overall survival was 81.0% at 2 year post-RIT (95% CI 89.5–71.5). All deceased patients received CBUs as the donor source. One of these patients were considered high-risk with pre-RIT Lansky score =30%. If this patient was excluded from analysis, the 100 day RIT related mortality was 13.3%. This retrospective analysis revealed that RIT with Flu/Bu/ATG conditioning is well tolerated in children with primary immunodeficiency. The use of CBUs, however, appeared to increase the risk of graft failure. A larger study of the use of RIT in primary immunodeficiency could further examine this hypothesis.

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Lille Scoring System Rather Than DIPSS Is a Better Predictive of Overall Mortality After Allogeneic Hematopoietic Cell Transplantation (HCT) for Primary Myelofibrosis Using Reduced Intensity Conditioning: A Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽

10.1182/blood.v120.21.432.432 ◽

2012 ◽

Vol 120 (21) ◽

pp. 432-432

Author(s):

Vikas Gupta ◽

Kwang W Ahn ◽

Xiaochun Zhu ◽

Zhenhuan Hu ◽

Parameswaran Hari ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Scoring System ◽

Conditioning Regimen ◽

Primary Myelofibrosis ◽

Reduced Intensity Conditioning ◽

Donor Type ◽

Conditioning Regimens ◽

Reduced Intensity ◽

Overall Mortality

Abstract Abstract 432 The Dynamic International prognostic scoring system (DIPSS) is increasingly being used as a prognostic tool for determining the risk of mortality for primary myelofibrosis (PMF), and has largely replaced Lille scoring system. However, it is unclear whether this scale can predict mortality after reduced intensity conditioning (RIC) allogeneic HCT, a procedure that is increasingly being utilized, as demonstrated by data from the CIBMTR. Using the CIBMTR database, the impact of patient, disease and transplant related factors on outcomes of 222 patients, who underwent HCT for PMF using RIC was analyzed. Median follow-up of survivors was 50 months (range, 3–165). Median age at HCT was 55 years, and 56 (25%) were >60 years. Donors were matched related donor (MRD), well-matched unrelated (MUD), and partially/mismatched unrelated (MMUD) in 85 (38%), 94 (42%), and 43 (19%), respectively. Conditioning regimens were: Fludarabine (Flu) and Melphalan (Mel), 62 (28%); Flu and Busulphan (Bu), 81 (36%), Flu and total body irradiation (TBI), 49 (22%); and others 30 (14%). Disease-risk status at HCT according to Lille scoring system was: low 48 (22%), intermediate (Int) 105 (47%), and high 69 (31%); and according to DIPSS was: low 25 (11%), int-1 110 (50%), int-2 81 (36%), and high, 4 (2%). The cumulative incidences of acute graft versus host disease (GvHD) at 100 days and chronic GvHD at 5-years were 48% (95% confidence intervals [CI] 41–54) and 50% (95% CI 43–57), respectively. The cumulative incidence of relapse/progression and non-relapse mortality (NRM) at 5-years was 28% (95% CI 22–34) and 38% (95% CI 31–44), respectively. The corresponding disease-free and overall survival was 34% (95% CI 28–40), and 37% (95% CI 31–44), respectively. In multivariate analysis, high-risk disease defined by Lille scoring system was associated with two-fold higher mortality compared to low-risk disease (Table). Higher risk disease status as defined by DIPSS was not associated with a significant increase in mortality when compared to lower-risk disease (Table). MUD and MMUD use were associated with higher mortality risk compared to MRD with relative risk (RR) of 1.59 (95% CI 1.00–2.52) and 2.6 (95% CI 1.56–4.35), respectively. A comparison of conditioning regimens demonstrated a trend towards reduced mortality with FluMel when compared to FluBu (RR 0.56, 95% CI 0.33–0.92; overall p=0.11), or other regimens (RR 0.51, 95% CI 0.26–0.99; overall p=0.11). In conclusion, the current study highlights that the DIPSS was limited in predicting the mortality after RIC transplantation for PMF, while the Lille scoring system remained predictive of mortality in high risk patients. These findings underscore the need for transplant-specific scoring system. Compared to other conditioning regimens FluMel appears to be associated with a trend towards better survival, which needs to be confirmed in prospective randomized trials. Table. Multivariate Analysis (MVA) for overall mortality* Model 1. MVA of Lille scoring system Variable Relative Risk (RR) 95% CI Overall p-value Lille-risk score low-risk (n = 48) 1 0.02 Intermediate-risk (n = 105) 1.47 0.84-2.58 High risk (n = 69) 2.22 1.23-4.00 Conditioning regimen Flu TBI 1 0.11 Flu Mel 0.67 0.38-1.19 Flu Bu 1.20 0.73-1.97 Others 1.30 0.68-2.48 Donor type HLA-identical sibling/other related 1 0.001 Well-matched URD 1.60 1.01-2.53 Partially matched/mismatched URD 2.61 1.57-4.36 Contrast Flu Mel vs. Flu Bu 0.56 0.33-0.93 0.03 Flu Mel vs. Others 0.51 0.27-0.99 0.05 Flu Bu vs. Others 0.92 0.52-1.66 0.79 Intermediate vs. High 0.66 0.43-1.01 0.06 Well-matched URD vs. Partially matched/mismatched URD 0.61 0.38-0.98 0.04 Model 2. MVA of DIPSS DIPSS Low/Int-1 (n = 135) 1 0.10 Int-2/high (n = 85) 1.39 0.94-2.043 * Adjusted for age, sex, Karnofsky performance score, platelet count, spleen status, conditioning regimen, donor type, GVHD prophylaxis and year of transplant. Disclosures: No relevant conflicts of interest to declare.

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Thiotepa-based reduced intensity conditioning regimen: a 10 year follow up

Bone Marrow Transplantation ◽

10.1038/sj.bmt.1705863 ◽

2007 ◽

Vol 40 (11) ◽

pp. 1091-1093 ◽

Cited By ~ 11

Author(s):

A Bacigalupo ◽

A M Raiola ◽

T Lamparelli ◽

F Gualandi ◽

D Occhini ◽

...

Keyword(s):

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

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Ex Vivo Mesenchymal Precursor Cell-Expanded Cord Blood Transplantation Following Reduced Intensity Conditioning Regimens

Blood ◽

10.1182/blood.v126.23.1190.1190 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1190-1190 ◽

Cited By ~ 1

Author(s):

Rohtesh S. Mehta ◽

Rima M Saliba ◽

Kai Cao ◽

Indreshpal Kaur ◽

Katayoun Rezvani ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Cumulative Incidence ◽

Ex Vivo ◽

Patient Characteristics ◽

Reduced Intensity Conditioning ◽

Cd34 Cells ◽

Mesenchymal Precursor ◽

Reduced Intensity ◽

Neutrophil Engraftment

Abstract Introduction: Double-unit cord blood (CB) transplantation (DCBT) after myeloablative conditioning, where one CB unit is expanded ex-vivo with mesenchymal precursor cells (MPC)-co-culture led to significantly improved neutrophil and platelet engraftment compared to historical controls.1 Our aim was to determine the efficacy of this technique after reduced-intensity conditioning (RIC) regimens. Methods: We evaluated consecutive adult patients with hematological malignancies who received RIC regimens followed by DCBT where one unit was infused unmanipulated and second unit was expanded ex-vivo with MPC prior to infusion ("MPC group" n=27), as described previously,1 andcompared themwith historical cohort who received two unmanipulated CB units ("controls" n= 51) from 2003-2015. Two RIC regimens were used - Flu/Cy/TBI (flu 40 mg/m2, cy 50 mg/kg and TBI 200cGy) (n=40) and Flu/Mel (flu 40 mg/m2 and mel 140 mg/m2) (n=38) with rabbit ATG 3mg/kg. Tacrolimus and MMF were used for GVHD prophylaxis. Primary endpoint was median time to engraftment of neutrophils (≥ 0.5 X 109/L X 3 consecutive days) and platelets (≥ 20 X 109/L X 7 consecutive days without transfusion). Results: Diagnoses were AML/MDS (N=38; 49%), ALL (N=13; 17%),NHL (N=18; 23%), HD (N=3; 4%), CML (N=1; 1%), and CLL (N=4; 5%). Baseline patient characteristics were similar among the groups [Table 1]. Majority of CB units (66%) were 5-6/8 matched at HLA-A, B, C and DRB1 by high resolution testing. Infused median total nucleatedcells (TNC) (x107/Kg) were 4 and 8, and median CD34 cells (x105/Kg)were 4.3 and 19.7, respectively for control and MPC groups. Co-culture with MPCs led to expansion of TNC by a median of 11.1 and of CD34+ cells by a median of 49.3. Among engrafted patients, median time to neutrophil engraftment was 12 (range 1-28) days in MPC group as compared with 16 (range 5-48) days in controls (p=0.02); the median time to platelet engraftment was 31 days and 37 days, respectively (P=0.3). On day 26, the cumulative incidence of neutrophil engraftment was 78% in MPC group versus 67% in controls (P=0.1). On day 60, the cumulative incidence of platelet engraftment was 74% and 74%, respectively (P=0.7). [Figure 1] Conditioning regimen also affected the time to neutrophil recovery. Among patients with Flu/Mel, the median time to neutrophil engraftment was 14 days in MPC-group (n=13) compared with 22 days in controls (n=19) (p=0.001). Patients with Flu/Cy/TBI regimen had faster time to engraftment; median time to neutrophil engraftment was 6 days in MPC group (n=10) and 11 days in controls (n=27) (p=0.04). However, the median time to platelet engraftment was similar in MPC- and control groups in patients who received either Flu/Mel (37 vs 44 days, p=0.1) or Flu/Cy/TBI regimen (29 vs 31 days, p=0.5). There was no difference in the cumulative incidence of day 100 non-relapse mortality (4% vs. 11%, p=0.6), 6th month mortality (25% vs 24%, p=0.6), grade II-IV acute GVHD (28% vs 27%, p=0.9), 2-year chronic GVHD (29% vs 20%; p=0.9) and estimates of 2-year OS (32% vs. 34%) between patients with ex-vivo expanded and unmanipulated CB units. Conclusions: Transplantation of CB units expanded with MPC appeared to be safe and effective. Using MPC-expanded CB units significantly improved time to engraftment following Flu/Mel or Flu/Cy/TBI RIC regimens as compared with unmanipulated units. Table 1. Patient characteristics Control(N=51) MSC group(N=27) P value Age, years (median, interquartile range) 57 (48, 63) 59 (49, 67) 0.3 Disease Status CR1/CR2 20 (40%) 12 (45%) Advanced 31 (61%) 15 (56%) 0.7 Disease Risk Index, n (%) V. High/High 8 (16%) 9 (33%) Intermediate 38 (75%) 16 (59%) Comorbidity index 0-1 24 (47%) 13 (48%) 2-4 22 (43%) 11 (41%) >4 5 (10%) 3 (11%) 0.97 Flu/Mel regimen 22 (43%) 16 (59%) 0.2 References 1. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. NEJM. 2012;367(24):2305-2315 Disclosures Kaur: UT MD Anderson Cancer Center: Employment. Alousi:Therakos, Inc: Research Funding. Skerrett:Mesoblast: Employment. Burke:Mesoblast: Employment.

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Mismatched Family Member Donor Transplantation for Patients with Refractory Hematologic Malignancies: Long-Term Followup of a Prospective Clinical Trial.

Blood ◽

10.1182/blood.v108.11.3137.3137 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3137-3137 ◽

Cited By ~ 5

Author(s):

Gregory A. Hale ◽

Kimberly A. Kasow ◽

Renee Madden ◽

Usman Yusuf ◽

Edwin Horwitz ◽

...

Keyword(s):

Median Time ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Survival Rates ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Disease Recurrence ◽

Reduced Intensity Conditioning ◽

Reduced Intensity Conditioning Regimen ◽

One Year

Abstract Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Both disease recurrence and regimen-related toxicities contribute to the high mortality in this population. We designed a reduced intensity conditioning regimen using haploidentical donors in an effort to improve overall survival rates, by both decreasing disease recurrence and transplant-related mortality. From 2003 to 2005, we enrolled 25 patients with refractory hematologic malignancies. The median age was 11.9 years (range 2.8 to 26.5); 15 were male. Diagnoses included ALL (n= 9), AML (n= 10), MDS (n=1), NHL (n=3), CML (n=1), and JMML (n= 1). The majority (n=24) had persistent or refractory disease at the time of HSCT; only one was in remission (n= 1). Nine patients had no prior HSCT, 15 had 1 prior HSCT, and 1 had 3 prior HSCT. Donors were fathers (n=16), mothers (n=6), or siblings (n=3). Donor-recipient pairs matched at 3 (n=18), 4 (n=6), or 5 (n=1) of 6 HLA loci. All grafts were cytokine-mobilized peripheral blood stem cells, using GM-CSF and G-CSF. Grafts were depleted of T-lymphocytes on the CliniMACS device using the OKT3 antibody. Grafts contained a median of 14.89 X106 CD34+/kg (range, 2.23 to 51.20) and 1.4 X105 CD3+/kg (range, 0.1 to 4.5). The conditioning regimen consisted of fludarabine 40 mg/m²/day for 5 days, melphalan 60 mg/m²/day for 2 days, and thiotepa 10 mg/kg/day for 1 day. OKT3 was administered in an escalating and de-escalating fashion from day −9 to day +17. Rituximab was administered on day ) as EBV prophylaxis. MMF was initiated on day −2 for GVHD prophylaxis. The median time to engraftment of neutrophils was day +10 (range, 7–12); the median time to recovery of platelets to 20,000/mm3 and 50,000/mm3 was day +17 (range, 12–36) and day +17 (range, 12–76), respectively. 3 patients did not engraft: recovered with JMML, and were salvaged with grafts from their original HSCT donor. The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 44.0% and 8.0%, respectively; the cumulative incidence of chronic GVHD was 28.0%. No patient developed VOD. 13 patients died of disease recurrence with a median time to relapse of 105 days (range, 26–714). The cumulative incidence of relapse at 2 years post-HSCT was 50%. With only 4 patients dying of non-relapse causes, the cumulative incidence of non-relapse mortality plateaued at 20% at 11 months post-HSCT with 1 patient dying of each of the following: hemorrhage, infection, cardiomyopathy, and chronic GVHD. With a mean follow-up time of 387 days post-HSCT, the overall survival at one year and 2 years post-HSCT was 40% and 35%, respectively. The disease-free survival at one year and 2 years post-HSCT was 36% and 30%, respectively. Eight patients remain alive as outpatients with performance scores ≥90. Haploidentical HSCT with a reduced intensity conditioning regimen is safe and feasible in this high-risk patient population, resulting in prompt engraftment, acceptable GVHD rates, and promising survival rates. Measures to further prevent disease recurrence must be incorporated into future clinical trials to improve outcomes while maintaining low regimen-related toxicity rates.

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Allogeneic Hematopoietic Peripheral Blood Stem-Cell Transplantation From HLA-Identical Siblings Versus Allelic-Matched Unrelated Donors (10/10 high resolution) in Patients with Acute Myeloid Leukemia and Myelodyplasic Syndrome After Reduced Intensity Conditioning,

Blood ◽

10.1182/blood.v118.21.4132.4132 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4132-4132

Author(s):

Marie Robin ◽

Raphael Porcher ◽

Lionel Ades ◽

Emmanuel Raffoux ◽

Nicolas Boissel ◽

...

Keyword(s):

Cumulative Incidence ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Disease Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Sibling Donor ◽

Matched Sibling

Abstract Abstract 4132 Introduction: Although precise matching of the donor/recipient pairs has been made easier by HLA typing at the allelic level, several issues with respect to unrelated transplantation remain to be addressed. In particular, the impacts of allelic HLA matching in patients with Acute Myeloid Leukemia (AML) and myelodysplasic syndrome (MDS) who receive allogeneic Peripheral Blood Stem cells (PBSC) after a reduced intensity conditioning (RIC) regimen is still unclear. In the present study, we aim to compare the impact of the donor type in this setting: HLA identical sibling versus HLA matched 10/10 (high resolution) unrelated donor (MUD). Method and transplantation characteristics: From 01/2001 to 12/2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from HLA identical sibling (n=69) or MUD (n=39). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis consisted in cyclosporine plus mycophenolate in 79% of patients. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate and overall survival (OS) at 3 years were compared according to type of donor: HLA identical sibling donor and MUD. Disease characteristics: WHO classification for MDS at time of hematopoietic stem cell transplantation (HSCT) was RAEB1 (24%), RAEB2 (36%), MDS transformed into secondary AML (20%), CMML2 (9%), RA (4%), or other (7%). Disease risk was assumed by cytogenetic (MRC for AML, IPSS for MDS) and EBMT score (good risk: CR1 for AML or MDS or untreated MDS, intermediate risk: CR2 for AML, CR2 or partial remission for MDS, poor risk: all other status). Cytogenetic (no missing data) was poor, intermediate or good for 21, 74 and 5% of AML and 24, 36 and 40% of MDS, respectively. EBMT score at time of HSCT was poor, intermediate or good for 29, 7, 64% of MDS and 11, 21, 68% of AML, respectively. Results of the comparison: Patients characteristics according to type of donor were similar for age (median 57 years), gender and disease distribution. Particularly, disease risks were comparable in 2 groups. Conversely, conditioning regimen (more ATG in MUD: 69 vs. 43%, p=0.016), donor age (younger for MUD: 30 vs. 52 years, p<0.0001) and number of CD34+ cells infused (higher in MUD: 7 vs. 6.5 × 106/kg, p=0.022) were different. The median follow-up was 36 months (range 2 to 72). All patients engrafted. The cumulative incidence of acute GvHD was 40% with HLA matched sibling donor and 44% for MUD (p=0.58). The cumulative incidence of chronic GvHD at 3 years was 49% with HLA matched sibling donor and 45% with MUD (p=0.66). No risk factor was associated with acute GvHD but chronic GvHD was less frequent in patients with AML vs. MDS (41% vs. 59%, p=0.077) and in those patients who received ATG in conditioning regimen (54% vs. 43%, p=0.067). During follow-up, 47 patients died. The 3-year cumulative incidence of TRM was 17% and 22% with HLA matched sibling donor and MUD, respectively (p=0.55). Adjusting for age, MDS was the only factor increasing TRM (HR 3.4; 95% CI 1.2 to 9.5; p=0.02). The 3-year cumulative incidence of relapse was 46% with HLA matched sibling donor and 30% with MUD (p=0.28) knowing that there was no difference between both groups regarding disease risk (cytogenetic and EBMT score). The 3-year OS was 44% with HLA matched sibling donor (95%CI: 33–61) and 50% with MUD (95%CI: 35–71) (Figure 1). Disclosures: Fenaux: Celgene: Honoraria, Research Funding. Peffault de Latour:Alexion: Consultancy, Research Funding.

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Treatment of Relapsed AML and MDS After Allogeneic Stem Cell Transplantation: A Second Transplant From a Different Donor May Be the Most Effective Option

Blood ◽

10.1182/blood.v120.21.1963.1963 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1963-1963

Author(s):

Avichai Shimoni ◽

Noga Shem-Tov ◽

Yulia Volchek ◽

Ronit Yerushalmi ◽

Arnon Nagler

Keyword(s):

Supportive Care ◽

Median Time ◽

Patient Group ◽

Cumulative Incidence ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Matched Sibling ◽

Relapsed Disease ◽

Better Than

Abstract Abstract 1963 Salvage Therapy with Azacitidine Increases therapy for patients (pts) with AML and MDS. However, relapsed disease continues to be the most common reason for treatment failure. There is no standard treatment for relapsed disease after SCT. Treatment options range from supportive care alone to chemotherapy and donor lymphocyte infusion (DLI) and up to a second SCT from the same or a different donor. However, the most effective therapy is controversial and treatment results are often poor. We retrospectively analyzed the outcomes of 475 adult pts with AML (n=378) and MDS (n=97) given allogeneic SCT in a single institution over a 12 year period. The median age of this patient group was 54 years (range, 17–76), 279 men, 196 women. The donor was an HLA-matched sibling (n=246), 1-antigen mismatched related (n=10), or matched unrelated (n=219). Disease status at SCT was early (n=186), intermediate (n=87) or advanced (n=202) by CIBMTR criteria. The conditioning regimen was myeloablative (MAC, n=123), reduced-intensity (n=121) or reduced toxicity MAC (RTC, n=231).With a median follow-up of 40 months (range, 2 months – 12 years), 210 pts are alive, 103 died of non-relapse causes (NRM), 193 relapsed and 162 of them died. The cumulative incidence of relapse was 44% (95%CI, 39–49) and advanced disease at SCT was the only predicting factor for relapse, HR 2.3 (p< 0.001). Pts were given supportive care or low-dose chemotherapy alone (n=70), intensive chemotherapy ± DLI (including SCT from the same donor, n=99) or a second SCT from a different donor (n=24). In all, the median overall survival (OS) was 2.8 months, and the 2-year OS was 12% (95% CI, 7–17%). Among the 24 pts having a second SCT from a different donor, the median age at second SCT was 50 years (19–78). 18 pts were initially given SCT from a matched sibling, 12 were re-transplanted from a second sibling and 6 from an unrelated donor. Six pts were initially transplanted from an unrelated donor and re-transplanted from a different unrelated donor. The initial conditioning regimen was MAC (n=10), RTC (n=11) or RIC (n=3). The second regimen was most often fludarabine and treosulfan (FT, n=14) for those not previously given treosulfan, including all previously MAC recipients. Other regimens were fludarabine and busulfan (n=6) or FLAMSA (n=4). The median time from the first SCT to relapse was 14 months (2 months – 9 years), 6 within 6 months. The median time from first relapse to second SCT was 3 months (range, 1–41 months). 9 pts were in remission at second SCT with prior therapy, 9 were chemo-refractory, and 6 were re-transplanted with no attempts of re-induction. The median follow-up of surviving pts is 16 months (range, 2–74). 22 pts engrafted in a median of 13 days (range, 9–26). 2 pts died early from infections and 2 from GVHD and the cumulative incidence of NRM was 17% (95%CI, 7–42). 11 pts relapsed after second SCT, cumulative incidence 52% (95%CI, 34–79) 8 of them died. The estimated 2-year OS is 40% (95%CI, 16–63) and the 2-year disease-free survival is 31% (95%CI, 11–51). Pts re-transplanted in chemo-sensitive or untreated relapse had a better outcome than those with chemo-refractory relapse, 2 year OS 57% and 13%, respectively (p=0.02). Pts given FT for second SCT also fared better than the other regimens, 2-year OS 63% and 13%, respectively (p=0.02). 2 of 6 pts with relapse less than 6 months after SCT are long-term survivors after second SCT. The outcomes after second SCT seem better than the 12% 2 year OS of the entire relapsing patient group. To minimize the time bias of pts been able to have a second SCT, we compared their outcomes to the subgroup of 68 pts who were alive at least 3 months after relapse and theoretically been able to have a second SCT from a different donor. 14 pts in this subgroup are alive with an estimated 2-year OS of only 15% (95%CI, 4–22, p=0.02). Among these 68 pts, 37 achieved remission with re-induction, and were alive at least 3 months after relapse, and their 2-year OS was 26%, which is also inferior to the 2-year OS of 57% in pts re-transplanted in sensitive or untreated relapse (p=0.05). In conclusion, a second SCT from a different donor is feasible in a subset of pts with AML and MDS relapsing after SCT. Toxicity with the new RTC regimens, such as treosulfan-based is acceptable. This is a promising option for pts able to be successfully re-induced or re-transplanted early with a pre-identified second donor. These observations merit further confirmation in larger studies. Disclosures: No relevant conflicts of interest to declare.

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