Pilot Study of Telmisartan (Micardis) for Prevention of Acute Graft Vs. Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: Interim Analysis

Telmisartan (TMS) is an angiotensin receptor blocker with anti-inflammatory properties and little or no clinical immunosuppressive effect. We undertook an unblinded, single arm, pilot study of TMS (160 mg/d p.o.) for prevention of acute graft vs. host disease (aGvHD) in recipients of HLA matched allogeneic hematopoietic stem cell transplants (HSCTs). Primary endpoints of Grade II or >Grade III aGvHD (1994 Consensus Conference on Acute GVHD Grading) were compared with 178 similar HSCT historical controls over the preceding 3 yrs at our institution: 26% >Grade III, 74% Grade II. Safety endpoints included engraftment, relapse/progression by day (d) 180, non-relapse mortality by d 180, and serious drug-related adverse reactions. Experimental data were collected on blood endotoxin levels and stool microbiome composition. The study was powered to detect 20% or 50% reduced rates of, respectively, Grade II or >Grade III. We report results from a planned interim analysis triggered when the first 22 evaluable patients (pts) reached d 100. Of 27 evaluable pts, 24 were beyond d 180 by completion of this interim analysis. The study was designed to treat pts for two days prior to, and day of HSCT, and for an additional 98 days post-transplant, but pts were considered evaluable if they completed >14 days of post- transplant TMS, including pre-determined dose reductions. One enrollee received TMS for 13 days post-HSCT and was excluded from analysis. Five pts received 14-24 days of drug (4 by choice, 1 died of sepsis). More than half the evaluable patients (17/27) completed >94 days of post-HSCT therapy, including 6 who experienced an episode of hypotension. Almost half (13/27) received >80% of the full 101 day dose (16,160 mg), including 5 who experienced hypotension. Of the 6 enrollees receiving <24 days of drug, two had documented hypotension. No other serious drug-attributed adverse reactions were reported. Reasons cited for pts choosing to discontinue TMS were inconvenience of taking pills, and home stool sampling. Safety Endpoints: All pts engrafted promptly (ANC >500/uL, platelet >20,000/uL). Peripheral donor CD3+ T cell median and range of chimerism on days 28 and 84 were 99.5% (37-100) and 100.0% (36-100); bone marrow donor CD34+ cell chimerism was 97.0% (62-100). There was a single NRM during the 180 d study, and no graft rejection or increase in relapse or progression. Four relapses occurred within 180 days, and 2 more after d 180, resulting in two relapse deaths (d 370, and d 600). Primary Endpoints:A single individual developed hyperacute Grade III skin GvHD on day 7 p-HSCT. Another 12 of 27 patients developed Grade 2 aGvHD, one after the conventional 100 d window (d 141). Compared with historical controls, the incidence of aGvHD was significantly reduced for Grade II (p < 0.005) and Grade >III (p = 0.01), using the two-tailed Z-test of proportions. Experimental Endpoints: Acute GvHD is associated with increased gut permeability, bacterial translocation, and loss of gut microbiome diversity. Endotoxemia, an indicator of intestinal integrity, as measured by the endotoxin activity assay (EAA, Spectral Medical) reached septic levels in 40% of patients during pre-transplant conditioning (d -3 - d 0), and subsequently returned to, or maintained, non-septic levels from week 5 onward in 90% of patients, with an overall downward group trend of EAA scores during 180 days of follow up. Genotyping and analysis of bacterial V4 16S ribosomal DNA from weekly stool samples of the first 10 evaluable patients revealed no decrease in OTU richness or Shannon diversity at any time point pre- vs. post- treatment. Among the 5 most abundant phyla, Bacteroidetes was significantly less abundant post-treatment compared to pre-treatment. Among the 8 most abundant families, Bacteroidaceae significantly decreased post- vs. pre- treatment. While historic microbiome controls from our institution are not available, our finding of increased Bacteroidetes is in contrast to reported decreased Bacteroidetes in allogeneic HSCTs not receiving TMS, but may resemble changes after autologous HSCT. This trial, funded by the Gateway Foundation, is ongoing. Preliminary results indicate TMS is well tolerated, with a beneficial impact on aGvHD and no increased relapse or NRM, with excellent engraftment, and preservation of anti-tumor effect, intestinal barrier integrity, and gut microbial diversity. Disclosures Iyengar: Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent.. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Schwartz:Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent. OffLabel Disclosure: Telmisartan. Indicated for treatment of hypertension.

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Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽

10.1182/blood.v110.11.2167.2167 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2167-2167

Author(s):

Sebastian Giebel ◽

Aleksandra Holowecka-Goral ◽

Izabela Nowak ◽

Tomasz Czerw ◽

Jerzy Wojnar ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Kir Genes ◽

Increased Risk ◽

Grade Ii ◽

Card15 Gene ◽

Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

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Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (DCBT) Is Associated with Unique Clinical Features Including a Higher Incidence of Grade III-IV Acute GVHD in Children

Blood ◽

10.1182/blood.v118.21.3044.3044 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3044-3044

Author(s):

Doris M Ponce ◽

Anne Marie Gonzales ◽

Marissa N Lubin ◽

Hugo Castro-Malaspina ◽

Sergio A Giralt ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Treatment Response ◽

Acute Gvhd ◽

High Rate ◽

Hematopoietic Stem ◽

Systemic Corticosteroids ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Unit Unit ◽

Grade Iii

Abstract Abstract 3044 While the GVHD incidence after unrelated donor CBT is lower than expected for the degree of human leukocyte antigen (HLA)-mismatch, GVHD can be a serious complication and at our center has been the second most common cause of transplant-related mortality after DCBT. However, relatively little is known about DCBT GVHD manifestations, treatment response, and risk factors. Therefore, we evaluated 108 DCBT recipients (median 37 years, range 0.9–69) transplanted for hematologic malignancies. The majority had acute leukemia and high-risk disease. Patients received either myeloablative (n = 81) or non-myeloablative (n = 27) conditioning and 4–6/6 HLA-matched grafts. GVHD prophylaxis consisted of a calcineurin-inhibitor with mycophenolate mofetil, and no patient received anti-thymocyte globulin (ATG). With a median follow-up of 28 months (range 9–64), the cumulative incidences of day 180 grade II-IV and III-IV acute GVHD (aGVHD) were 52% (95%CI :42–62) and 24% (95%CI :15–32), respectively. The median onset was 40 days (range 14–161); the gut was most commonly affected (43/54, 80%) followed by skin (35/54, 65%). Twenty-five patients with mainly grade II gut aGVHD were treated with budesonide alone, 26 patients with predominantly grade III-IV aGVHD received systemic corticosteroids, and complete or partial treatment response was achieved in over 80% by day 56 of therapy. However, 41 patients had active GVHD after day 100 with the majority (25/41, 61%) having aGVHD (persistent, recurrent or late onset), particularly of the gut. Overlap syndrome and classical chronic GVHD were uncommon. Only 1 patient had oral ulceration, and no patient had moderate or severe ocular or sclerotic skin involvement, joint, or pulmonary GVHD manifestations. Univariate analysis of the association between patient/ graft characteristics and grade III-IV aGVHD showed the only significant factor associated with a higher severe aGVHD incidence was age 0–15 years (Figure). Diagnosis, patient ancestry, cytomegalovirus seropositivity, conditioning intensity, and infused cell doses/kg (total graft and engrafting-unit nucleated cell, CD34+ and CD3+) were not significant. A higher engrafting unit-recipient HLA-match of 8–9/10 was associated with a lower incidence of severe aGVHD, and a better unit-unit HLA-match of 6–10/10 was associated with a higher incidence of severe aGVHD, although these differences were not significant (p = 0.128 and 0.266, respectively). To further investigate these findings multivariate Cox regression analysis was performed (Table). Younger age was independently associated with a higher incidence of severe aGVHD (p = 0.042) whereas better engrafting unit-recipient match at 8–9/10 HLA-alleles was protective (p = 0.053). There was a trend toward better unit-unit HLA-match being associated with a higher incidence of grade III-IV aGVHD, but, surprisingly, total infused TNC/kg had no relationship. The 2-year PFS of 72% (95%CI :51–94) in children was higher than the 56% (95%CI :45–66) in adults despite their greater incidence of severe aGVHD. Nine patients (all adult) have died of GVHD including 5 patients initially treated with systemic corticosteroids and 4 with budesonide. We conclude that aGVHD after DCBT is common in the absence of ATG, predominantly affects the gut, and has a high rate of treatment response. Furthermore, GVHD after day 100 frequently has acute features. While the GVHD incidence does not preclude a high rate of survival, improved prophylaxis and treatment are needed. Notably, in contrast to single-unit CBT and adult hematopoietic stem cell transplantation, children receiving DCBT are at a higher risk for severe disease. A possible approach to reduce aGVHD in pediatric DCBT recipients with adequate CB units doses would be to prioritize high resolution HLA-match. Moreover, our data does not currently support an upper limit of infused TNC/kg in DCBT recipients. Further investigation of the biology underlying these unique observations (including the role of specific cellular subsets) should be a major priority. Disclosures: Off Label Use: Mycophenolate Mofetil as GvHD prophylaxis.

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Donor Lymphocyte Infusion Management and Impact on Transplant Outcome after Reduced Intensity Conditioning Allogeneic Transplantation.

Blood ◽

10.1182/blood.v104.11.2305.2305 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2305-2305

Author(s):

Mauricette Michallet ◽

Quoc-Hung Le ◽

Anne-Sophie Michallet ◽

Anne Thiebaut ◽

Emannuelle Tavernier ◽

...

Keyword(s):

Retrospective Analysis ◽

Prospective Studies ◽

Acute Gvhd ◽

Mixed Chimerism ◽

Reduced Intensity Conditioning ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Grade Ii ◽

Reduced Intensity ◽

Grade Iii

Abstract Management of donor lymphocyte infusions (DLI) after reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation (RICT) remains not clear and needs prospective studies. We performed a retrospective analysis on 47 patients (29 males and 18 females) who received 94 DLI among 96 patients who underwent RICT in our institution. Twenty-four patients received 1 DLI (D) [mean dose: 0.3x108 CD3 /Kg (0.01–1)] and 70 escalating doses (ED) [2 DLI (n=10), 3 DLI (n=9), 4 DLI (n=1), 5 DLI (n=1), 6 DLI (n=1) and 8 DLI (n=1)] from 0.1 to 5.6x108 CD3/Kg. The diagnosis pretransplant was acute leukemias (n=10) and myelodysplasia (n=3), chronic myeloid leukemia (n=2), Hodgkin (n=7) and non Hodgkin lymphomas (n=6), multiple myeloma (n=14) and solid tumours (n=5). Twenty patients have already been transplanted before RICT and 9 patients were in complete remission (CR), 19 in partial response (PR), 18 in evolutive disease (EDis). As hematopoietic stem cells, 22 patients received peripheral blood and 25 bone marrow and as conditioning 26 patients received busulfan, fludarabine and anti-thymocytes globulines (ATG), 13 patients TBI 2 grays associated to fludarabine (n=8) and 6 grays associated with cyclophosphamide (n=5), 5 patients received cyclophosphamide and ATG and 3 patients aracytine, idarubicine and fludarabine. After transplant and before any DLI, 21 developped acute GVHD (11 grade I, 8 grade II and 2 grade III). The indications and results after DLI are given in the Table 1. Only 4 patients received DLI for two different indications within time: 2 for relapse firstly and partial chimerism secondly and 2 according to protocol requirement firstly and for relapse secondly. After DLI, we noted 18 acute GVHD (7 grade I, 4 grade II, 6 grade III and 1 grade IV), 9 were resolutive after specific therapy and 18 patients developed chronic GVHD (13 limited and 5 extensive). Probability of overall survival at 2 years of patients who underwent RICT including DLI (n=47) was significantly better than for patients undergoing RICT without DLI (n=57) [43% (95%CI 30.5–60.4) vs 31.5 (95%CI 18.8–52.8) (p=0.01)] but there was no difference when we consider EFS [20.7% (95%CI 11.6–36.8) vs 21.6% (11–42.5) (p=0.49)]. We performed for patients receiving DLI a multivariate analysis stratified on diagnosis studying sex, age, status at transplant and mean dose of infused lymphocytes and we demonstrated that lymphocyte dose had a significant negative impact on EFS (HR= 1.06 95% CI 1.01–1.10) (p=0.01). To better understand the real place of DLI within allogeneic immunotherapy against malignancies, we need more details about the results of DLI in retrospective analysis but principally prospective studies in the future. TABLE 1 Indication of DLI Nb of patients Nb of DLI DLI (D) DLI (ED) Dose x 10 exp8 CD3/Kg Response to DLI Evolutive Disease N = 34 23 2.26 10 13 1.46 EDis 5 1.6 2 3 0.66 CR 6 1.5 2 4 0.45 PR Mixed Chimerism N = 7 6 1.5 5 1 0.7 Total Donor 1 1 1 0 0.7 Mixed Chimerism Protocol N = 6 1 1 1 0 0.1 CR 3 1.6 2 1 0.34 PR 2 2 1 2 0.52 EDis

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Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults.

Blood ◽

10.1182/blood.v106.11.1134.1134 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1134-1134 ◽

Cited By ~ 1

Author(s):

Masamitsu Yanada ◽

Tomoki Naoe ◽

Hiroatsu Iida ◽

Yoshiko Atsuta ◽

Kazuhito Yamamoto ◽

...

Keyword(s):

Survival Rate ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Philadelphia Chromosome ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Younger Age ◽

Grade Ii ◽

Risk Of Relapse ◽

Grade Iii

Abstract The prognosis for Philadelphia chromosome-positive ALL (Ph+ALL) is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently considered the only established procedure with curative potential. It is therefore quite important to clarify what are essential elements of the success of allogeneic HSCT. Thus, we performed a retrospective study covering 197 Ph+ALL cases aged 16 years or older who underwent allogeneic myeloablative HSCT to identify factors affecting the transplant outcome. The subjects comprised 120 males and 77 females, and their median age was 37 years (range, 16 to 59 years). Transplantation during complete remission (CR) accounted for 57% (112 cases), and only 19 patients received transplantation during their second or subsequent CR. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (p<0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation (TBI), and human leukocyte antigen (HLA)-identical sibling donor (p<0.0001, p<0.0001, p=0.0301, p=0.0412, respectively). Next, we investigated whether development of graft-versus-host disease (GVHD) had a significant influence on survival. The presence or absence of each type of GVHD (grade II-IV acute GVHD, grade III-IV acute GVHD, any form of chronic GVHD, and extensive chronic GVHD) was included separately in the Cox model containing the four significant pre-transplant risk factors. Although the survival rate was almost identical for patients with and without grade II-IV acute GVHD, grade III-IV acute GVHD had a significant impact on survival (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.34 to 0.98; p=0.0430). For patients developing any form of chronic GVHD, there was a non-significant increase in survival rate compared with those who did not (HR, 1.40; 95% CI, 0.85 to 2.32; p=0.1877). As for extensive chronic GVHD, the survival advantage was statistically significant (HR, 2.10; 95% CI, 1.13 to 3.88; p=0.0179). The 5-year survival rate was estimated to be 51% for those with extensive chronic GVHD, and 29% for those without. Chronic GVHD was associated with a lower risk of relapse without increasing the risk of treatment-related mortality (TRM), whereas acute GVHD was associated with a higher risk of TRM without diminishing the risk of relapse. From the analysis of the data for 197 Ph+ALL patients who had undergone allogeneic myeloablative HSCT, we identified four prognostic pre-transplant factors. Younger age, CR at the time of transplantation, TBI conditioning, and HLA-identical sibling donor were found to be associated with significantly better survival. Chronic GVHD reduces the risk of relapse without increasing the risk of TRM, and development of extensive chronic GVHD even prolongs survival. These findings should be helpful for achieving the success of allogeneic HSCT for Ph+ALL.

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Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402

Blood ◽

10.1182/blood.v120.21.739.739 ◽

2012 ◽

Vol 120 (21) ◽

pp. 739-739 ◽

Cited By ~ 12

Author(s):

Corey Cutler ◽

Brent R. Logan ◽

Ryotaro Nakamura ◽

Laura Johnston ◽

Sung W. Choi ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Graft Vs Host Disease ◽

Grade Ii ◽

Related Donor

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.

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Post-Transplantation High Dose Cyclophosphamide As Gvhd Prophylaxis in 9/10 HLA-Matched Unrelated Donors Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3135.3135 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3135-3135 ◽

Cited By ~ 1

Author(s):

Rohtesh S. Mehta ◽

Rima M Saliba ◽

Julianne Chen ◽

Gabriela Rondon ◽

Aimee E Hammerstrom ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Hla Class I ◽

Conventional Group ◽

Unrelated Donor ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p <0.001). Correspondingly, incidence of grade III-IV GVHD at day 30 was 0% in the PTCy group and 8% in the conventional group (p=0.08). Cumulative incidence of chronic GVHD was similar between the two groups at 6 months (20% vs 15%), 1-year (30% vs 31%) or 2-years (30% vs 42%). Risk factors analysis showed that use of PTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=0.01). None of the risk factors evaluated, including PTCy use, were shown to predict the rate of grade II-IV acute GVHD within day 100. Two-year cumulative incidences of NRM (35% vs 25%), disease progression (20% vs 31%), DFS (42% vs 38%) and OS (52% vs 40%) were similar in the PTCy and the conventional groups, respectively. [Figure 1] Median times to neutrophil (18 vs. 12 days, p<0.001) and platelet (25.5 vs. 18 days, p=0.05) engraftment were prolonged in PTCy group. Disease recurrence/persistence was the leading cause of death in both groups, accounting for about 46% of all deaths. Subgroup analysis restricting to patients with BM grafts produced similar findings. In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

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Comparison of Two Doses of Antithymocyte Globulin (ATG) in Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT)

Blood ◽

10.1182/blood.v126.23.4328.4328 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4328-4328

Author(s):

Hassan Issa ◽

Amy S. Ruppert ◽

Patrick Elder ◽

Craig Hofmeister ◽

Don M Benson ◽

...

Keyword(s):

Stem Cell ◽

Competing Risks ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Grade Ii ◽

Cmv Reactivation ◽

Grade Iii

Abstract Introduction: The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. In our previous retrospective analysis we compared two dosing schedules of ATG (7.5 mg/kg vs 6 mg/kg) in 136 patients who had undergone RIC allo-HSCT, and found no significant differences in the incidence of acute or chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse, progression-free survival (PFS) or overall survival (OS). As of October 2013, our ATG dosing was lowered from 6.5 to 4.5 mg/kg. We now compare the outcomes of patients who received ATG at a dose of 4.5 mg/kg (r-ATG) to 6 mg/kg (R-ATG) Methods: We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo HSCT for hematologic malignancies and received r-ATG (40 patients) vs R-ATG (216 patients) at The Ohio State University Comprehensive Cancer Center between October 2007 and September 2014. Cumulative incidences of GVHD, infection, NRM, and relapse were analyzed using Gray's test, accounting for competing risks. PFS and OS were analyzed using the log-rank test. Results: Patients with hematologic malignancies included AML/MDS (53%), NHL/Hodgkin's (19%), CLL (12%), and other hematologic malignancies including ALL (16%). There was a significant association between disease group and ATG dose (p<0.001), with none of the patients diagnosed with CLL receiving r-ATG and a higher percentage of those with other malignancies receiving r-ATG vs R-ATG than expected. Secondary to the imbalance in disease groups, those receiving r-ATG were younger (median 50 vs 59 yrs, p=0.01) and more likely to have bone marrow stem cell source (18% vs 5%, p=0.008). There were no significant differences in recipient or donor sex, degree of HLA match, prior autografts, comorbidity index, donor/recipient CMV status and CD34 cell dose between the two groups. The cumulative incidences of acute GVHD grade II-IV at day 180 in the r-ATG and R-ATG groups were 63% and 44% (p=0.009), and of grade III-IV 18% and 11% (p=0.25) respectively (Figure 1A and B). When controlling for differences in underlying disease, the estimated risk of acute GVHD grade II-IV was 1.6 times higher with r-ATG (p=0.04). The respective cumulative incidences at 6 months of chronic GVHD were 14% and 16% (p=0.65), and of extensive chronic GVHD 14% and 13% (p= 0.29). With limited follow-up in patients receiving r-ATG (median 10 months), significant differences were not observed in longer-term outcomes between the two groups including relapse rate (p=0.83), NRM (p=0.91), PFS (p=0.92), and OS (p=0.996). The incidence of CMV reactivation at day 180 was lower in the r-ATG group (5% vs 26%, p=0.005), though the incidence of competing risks including GVHD, relapse and death prior to documented reactivation was higher in the r-ATG group (p<0.0001). No statistically significant differences were seen in Epstein-Barr virus reactivation (p=0.74), BK-virus associated hemorrhagic cystitis (p=0.79), bacterial infections (p=0.11), or Clostridium Difficile infections (p=0.22). Conclusions While there was an increase in grade II-IV acute GVHD with r-ATG, there was no significant difference in acute GVHD grade III-IV, relapse, NRM, PFS and OS between the two cohorts. r-ATG resulted in a lower proportion of CMV reactivation, but in a higher proportion of other competing risks. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽

10.1182/blood.v112.11.1170.1170 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1170-1170 ◽

Cited By ~ 1

Author(s):

Sung-Won Kim ◽

Takahiro Fukuda ◽

Shotaro Hagiwara ◽

Tsunehiko Komatsu ◽

Tetsuya Goto ◽

...

Keyword(s):

Whole Blood ◽

Acute Gvhd ◽

Trough Level ◽

Chronic Gvhd ◽

Gvhd Prophylaxis ◽

Starting Dose ◽

Grade Ii ◽

Reduced Intensity ◽

Grade Iii ◽

Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

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GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Blood ◽

10.1182/blood.v112.11.825.825 ◽

2008 ◽

Vol 112 (11) ◽

pp. 825-825 ◽

Cited By ~ 1

Author(s):

Vincent Ho ◽

Glenn Dranoff ◽

Haesook Kim ◽

Matthew Vanneman ◽

Mildred Pasek ◽

...

Keyword(s):

Immune Suppression ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Leukemia Cell ◽

Sustained Remission ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Gm Csf ◽

Grade Ii ◽

Reduced Intensity

Abstract Studies have shown that leukemia specific donor immune responses can be elicited by cancer vaccination after allogeneic SCT. Given the likelihood of disease progression in patients with active leukemia at the time of transplant, potential anti-tumor vaccines must be administered early post-transplant if they are to exert a meaningful effect. Early vaccination after SCT could capitalize upon the rapid homeostatic lymphoid expansion associated with post conditioning lymphopenia. However, there is concern about the efficacy of vaccinations early after allogeneic transplant when patients remain on immune suppression to prevent GVHD. GVAX, a cancer vaccine composed of leukemia cells genetically modified to secrete GM-CSF, has demonstrated activity in MDS and AML. We completed a trial investigating the feasibility and safety of administering GVAX early after allogeneic HLA matched reduced intensity conditioning (RIC) SCT for patients with MDS-RAEB or active AML. Prior to SCT, autologous myeloblasts were harvested and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Conditioning consisted of fludarabine 30mg/m2/d IV × 4, and busulfan 0.8mg/kg IV q12H × 8 doses prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. Vaccination started between day +30 to +45 post SCT if there was adequate count recovery and no grade II–IV acute GVHD. GVAX was administered SC/ID weekly × 3 doses, then q2 wks × 3 doses. Taper of tacrolimus began after vaccine completion (» d+120). Twenty four patients (13 URD, 11 MRD) were transplanted: 16 AML, 6 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 62 (range, 41–71 years). Median marrow blast content at transplant was 22% (range, 6–91%). GVAX was successfully generated for all patients. Of the 24 patients transplanted, 9 could not start vaccine due to rapid leukemia progression (4); acute GVHD requiring systemic steroids (3); sepsis (1) and IPS (1); Among the 15 patients who started vaccination per protocol, 10 completed all 6 vaccines. Mild injection site reaction with induration, erythema, and pruritus was the only common side effect. After vaccination, 3/15 patients developed grade II acute GVHD and 7/15 had cGVHD. Relapse free (RFS) and overall survival (OS) at 2 years for patients who started GVAX were 46% and 56%, respectively. This is superior to the 2-yr DFS and OS of 12% and 16% (p=0.02), respectively, in a matched cohort of 34 patients with the same disease receiving RIC SCT during the same time period. Among the patients who completed all 6 vaccines, 9/10 remain in complete remission (6 AML, 3 MDS-RAEB) with median follow-up of 22.5 months post SCT (range, 7–38 mos). Three patients with disease relapse/progression early post SCT entered CR after vaccination and taper of tacrolimus. Pathologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils in all patients who responded. Concordant with prior studies showing that anti-cancer activity after GM-CSF secreting tumor cell vaccines is associated with NKG2D-target-cell interactions mediated by NK and NK-T cells, our immunologic studies revealed progressively decreasing levels of soluble NKG2D ligands in patients with sustained remission after GVAX. Our results demonstrate that GVAX vaccination early after RIC SCT elicits important biologic activity despite administration during full immune suppression with tacrolimus. Given that all of the patients had active disease at transplant and received a reduced intensity conditioning regimen, we would have expected few to enter complete and sustained remission. Our encouraging results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after allogeneic SCT.

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Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) In Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Interim-Analysis From the AZARELA-Trial (NCT-00795548).

Blood ◽

10.1182/blood.v116.21.1294.1294 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1294-1294

Author(s):

Thomas Schroeder ◽

Akos Gabor Czibere ◽

Nicolaus Kröger ◽

Uwe Platzbecker ◽

Gesine Bug ◽

...

Keyword(s):

Overall Survival ◽

Missing Data ◽

Salvage Therapy ◽

Interim Analysis ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Significant Activity ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Abstract 1294 Background: Patients with AML or MDS who relapse after allogeneic HSCT have a poor prognosis and therapeutic options are limited. The DNA hypomethylating agent Aza has significant activity in patients (pts) with AML and MDS and retrospective analyses have recently shown encouraging results with the use of Aza +/− DLI in patients with AML and MDS, who relapsed after allogeneic HSCT (Czibere et al., 2010; Luebbert et al., 2010). In line with these clinical observations preclinical data suggest that Aza enhances a Graft-versus-Leukemia (GvL) effect while mitigating Graft-versus-Host Disease (GvHD). Design/Methods: To evaluate the activity and safety of Aza in combination with DLI as first salvage therapy in pts with AML or MDS relapsing after HSCT, we conducted a prospective, multicenter, single-arm phase-II trial. Pts were allowed to receive up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 days) and 3 DLI with increasing dosages (1-5×106 – 1–5×108 cells/kg) after every 2nd Aza treatment cycle. Additional DLI were permitted. Results: Between January 2009 and May 2010, 30 pts from 6 German transplant centres were included into this trial. So far, 25 pts (15 female/10 male) were evaluable and are presented in this analysis: Of these, 23 (92%) suffered from AML (15 de novo/8 secondary following MDS), 1(4%) from a MDS (RAEB-1) and 1 (4%) from a myelodysplastic/myeloproliferative syndrome (MDS/MPS, CMML-1). Median age was 54 years (range 29–71). Conditioning was myeloablative in 24 pts (96%) and non-myeloablative in 1 patient (4%). Eight pts (35%) received a graft from a matched sibling donor, while 15 (65%) were transplanted with a matched unrelated donor (2 pts missing data). Peripheral blood stem cells (PBSC) were used in 24 pts (96%; 1 pt missing data). At the time of transplant 6 pts (24%) had primary induction failure, another 6 (24%) suffered from first or secondary relapse, 10 pts (40%) were in first or second complete remission (CR), while 3 pts (12%) were untreated. With regard to their molecular and genetic characteristics at diagnosis, 21 pts belonged to an adverse (9 pts) or intermediate (12 pts) group, whereas 2 pts were diagnosed with a favourable genetic phenotype (2 pts not performed). Prior to relapse 9 (36%) and 3 (12%) pts had episodes of acute GvHD and/or chronic GvHD, respectively. Relapse occurred in all pts after a median of 160 days (range 19–1199) following HSCT (median BM blasts: 34%, range 5–100%, median chimerism: 63% range-1-100%). At the time of relapse, karyotype was evaluable in 13 of 25 pts (52%). Of these 13 pts, 4 pts had a normal karyotype, while 9 had chromosomal aberrations including 6 pts with a complex karyotype. Patients received a median of 3 courses Aza (range 1–8) and 18 of 25 pts (72%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–207×106). Following treatment, overall response rate was 64% with 5 pts (20%) achieving a CR or CRi, 3 (12%) a partial remission (PR) and 8 (32%) a stable disease (SD). Median response duration was 266 days. Acute GvHD occurred in 6 pts (24%) (2 skin/6 liver/ 2 gut) after a median of 65 days (range 19–179) following the first DLI, while chronic GvHD was observed in 3 pts (12 %, all limited). Hematotoxicity (grade III-IV) was observed in 64% of all evaluated patients. Common adverse events were gastrointestinal side effects as well as infections. After a median follow-up of 100 days (range 25–485) 15 of 25 pts (60%) are currently alive. Median overall survival of all pts is 184 days (range 87–281). All pts, who achieved a CR/CRi, remained in ongoing remission for a median time of 229 days. Achieving a CR (CR: not reached vs. no CR: 117 days, p .008) or any type of response (CR/CRi, PR or SD) to the combination of Aza and DLI (any response: not reached vs. no response: 79 days, p .0001) were associated with a significantly longer overall survival. Conclusion: The combination of Aza and DLI as salvage treatment for patients with AML or MDS who relapse after allogeneic HSCT seems to be safe and shows significant anti-leukemic activity. Response, including CR rates, so far match those from retrospective analyses. Data presented in this interim-analysis suggest that salvage therapy with Aza and DLI is of substantial therapeutic benefit in these challenging patients. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Celgene: Honoraria. Luft:Celgene: Research Funding. Fenk:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

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