Cord Colitis: An Antibiotic-Responsive Colitis Syndrome Following Cord Blood Stem Cell Transplantation

Abstract Abstract 1270 After umbilical cord blood transplantation (CB-SCT), we have observed a new syndrome of culture-negative antibiotic-responsive diarrhea, with pathologic findings on biopsy suggestive of an infectious/inflammatory colitis, but distinct from graft-versus-host disease (GVHD). The clinical characteristics and epidemiology of this gastrointestinal syndrome have not been previously described. We studied the entire CB-SCT cohort at our center from 3/2003 through 3/2010. Charts were reviewed in detail for all episodes of diarrheal illness after engraftment. Demographic, CB-SCT, and diarrheal illness characteristics, and gastrointestinal pathology were analyzed. Cord colitis syndrome (CCS) was defined as a persistent diarrheal illness in a CB-SCT recipient not due to GVHD, cytomegalovirus, Clostridium difficile or other identifiable etiology on extensive microbiologic and pathologic examination, with histopathological evidence of colitis, and who responded to empirical antibacterial treatment. 104 patients underwent CB-SCT during the study period; 101 were double cord recipients. 72 underwent reduced-intensity conditioning, most commonly with fludarabine, melphalan, and thymoglobulin; 32 underwent myeloablative conditioning with cyclophosphamide, fludarabine, total-body irradiation or other agents. GVHD prophylaxis with sirolimus and tacrolimus was used in 69 patients, cyclosporine and mycophenolate mofetil in 17, and other combinations in the rest of the cohort. Median follow up was 452 days (range, 1–2409). Eleven (10.6%) patients met criteria for CCS; an additional patient had relapsing antibiotic-responsive diarrhea compatible with CCS, but was not biopsied and not included in the analysis. The 1-year cumulative probability of CCS was 0.159. Median time to onset of CCS was 131 days after CB-SCT (range, 88–314). Patients reported watery, non-bloody diarrhea, commonly associated with weight loss. 8 patients required hospital admission. 7 patients underwent abdominal imaging during their evaluation, 6 had colonic involvement (3 with pancolitis). All patients underwent colonoscopy a median of 18 days (range, 5–59) after the onset of CCS. On gross inspection, 9 had mucosal erythema and 7 had mucosal ulcerations. Pathologic review of the colorectal biopsy specimens revealed diffuse active colitis (6 cases) or chronic active colitis (5 cases); 7 of them demonstrated loose granuloma formation. No biopsies had evidence of active GVHD, pseudomembranous colitis, viral cytopathic changes, nor evidence of CMV or adenovirus on immunostains. 9 patients were treated with a fluoroquinolone and metronidazole, 2 others were treated with metronidazole alone. All patients responded to antibiotic treatment initially, but 4 relapsed, requiring further treatment courses. Patients were initially treated for a median of 14 days (range, 10–90 days) and relapsed patients were treated for a median of 120 days (range, 30–330). There was no association between the occurrence of CCS and age, underlying disease, conditioning or GVHD prophylaxis agents used. There was no clustering of cases over time. CCS patients (5/11) were more likely to have a prior diagnosis of grade II or higher acute GVHD compared to the cohort (16/93; p=0.04), without organ-specific predominance. The median time from acute GVHD to CCS diagnosis was 184 days (range, 105–328). The crude mortality at the end of follow-up was lower among patients who developed CCS (27.3%) compared to the rest of the cohort (58.1%; Log-rank 0.04). Conclusions: CCS is a distinct diarrheal illness that affects CB-SCT recipients that is antibiotic-responsive and differs from other common causes of diarrhea following SCT. Histologic findings mimic idiopathic inflammatory bowel disease and often include granulomatous colitis. This entity should be considered in CB-SCT patients with diarrhea in which other common causes of diarrhea have been ruled out. Further investigation is underway to determine whether there is an infectious etiology responsible for this syndrome or if it is an inflammatory colitis of alloimmune or autoimmune origin. Disclosures: No relevant conflicts of interest to declare.

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Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽

10.1182/blood.v116.21.223.223 ◽

2010 ◽

Vol 116 (21) ◽

pp. 223-223 ◽

Cited By ~ 4

Author(s):

Vanderson Rocha ◽

Myriam Labopin ◽

Annalisa Ruggeri ◽

Marina Podestà ◽

Dolores Caballero ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

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Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood for Leukemia and Thalassemia

Blood ◽

10.1182/blood.v128.22.1235.1235 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1235-1235

Author(s):

Chunfu Li ◽

Yuelin He ◽

Xuedong Wu ◽

Xiaoqin Feng ◽

Jianyun Liao ◽

...

Keyword(s):

Stem Cells ◽

Cord Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Mixed Chimerism ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Unrelated Cord Blood ◽

Kinetics Of

Abstract Background Unrelated Cord Blood (UCB) Transplantation is a potentially curative therapy for leukemia and thalassemia; however, engraftment failure and slow immune reconstitution remain key clinical issues. We hypothesized that complementary transplantation (CT) of UCB with haploidentical stem cell graft (hap-SC) tolerized with post-transplant cyclophosphamide would result in rapid engraftment and low relapse rate without additional risk of graft-versus-host disease (GVHD). Therefore, we developed a novel complementary transplant approach. Patients and Method Sixty-six patients received CT between December 2012 and June 2016. Of them, 30 patients had malignance diseases (MD), including 11 lymphoid and 19 myeloid diseases, and 36 had thalassemia major (TM). Median age was 12 (range; 2-13) and 8 (3-17) years in the MD and TM group, respectively. Median follow-up time was 13 (7-32) and 19 (2-25) months, respectively. Conditioning (Regimen CT-13) included Cyclophosphamide on day-8 to -7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. Hap-SC was infused on day 0. GVHD prophylaxis consisted of Cyclophosphamide on day+3 to +4. UCB was infused on Day+6. Mycophenolate mofetil and Tacrolimuswas started on day+6 for GVHD prophylaxis. For 26 TM patients transplanted since 2014, they received identical regimen except with the additional Thymoglobulin on day -11 to -9 (Regimen CT-14). Results The chimerism status at last follow-up was Hap-SC, UCB, mixed stem cells (MSC) and rejection in 20, 9, 1 and 0 patient in the MD group; and 16, 14, 3 and 3 patients in the TM group. Interesting, the initial chimerism on day+28 in the TM group was Hap-SC, UCB and MSC engrafted in 15, 7 and 12 patients, respectively. Thus, the MSC was not stable in TM patients; UCB typically became dominant overtime instead of the initial majority from hap-SC (Fig. 1). In the MD group, the time to neutrophil >= 0.5x109/L, platelet >=20 x109/L and hemoglobin >=80 g/L was day+18 (14-36), +10.0 (6-51) and +7 (1-20) in the final hap-SC engrafted group; and+30 (22-35), +25 (1-64) and +7 (3-28) in the final UCB engrafted group. Overall survive (OS), disease-free survive (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were 75.6%, 64.3%, 24.7£¥ and 13.7%, respectively, in all 30 MD patients; and 79.3%,73.8%,15.5% and 12.3% (Fig.2), respectively, in the 25 cases with complete remission (CR) at the time of transplantation. The corresponding data were 89% vs. 88.9%£¬65.0% vs. 77.8%£¬31.1 % vs.12.5% and 10.3% vs.11.1%£¨p>0.05 in all pairs), respectively, in hap-SC and UCB engrafted groups. Donor carrying KIR centromeric B motif was associated with reduced RI (10 % vs. 33.9%). In TM group, OS, thalassemia free survive (TFS), rejection and transplant-related mortality were 91.2%, 85.7%, 5.6% and 8.8%, respectively in all 36 patients. Impressively, all of the 26 patients who received the newer CT-14 protocol were alive without TM (Fig. 2). 7/10 UCB carrying KIR centromeric B motif engrafted. In the MD group, 23.3% had grade II-IV and10.0% had III-IV acute GVHD. Grade II, III and IV acute GVHD occurred in 3 patients, respectively, in TM group. One MD patient had severe chronic GVHD (lung) after DLI for relapse. No moderate chronic GVHD occurred in TM groups. Summary The CT-13 regimen resulted in high OS and DFS, especially in CR patients in the MD group. The CT-14 leaded to 100% TFS in thalassemia patients. Acute and chronic GVHD were acceptable. Donor carrying centromeric B motif promoted engraftment and reduced RI. A multicenter study should be developed in the future based on our favorable results. Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 3. Thalassemia-free survive resulted from regimen CT-14 Figure 3. Thalassemia-free survive resulted from regimen CT-14 Disclosures No relevant conflicts of interest to declare.

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Infusion of a Non HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitor Cell Product Following Myeloablative Cord Blood Transplantation Is Safe, Decreases the Time to Hematopoietic Recovery, and Results in Excellent Overall Survival

Blood ◽

10.1182/blood.v124.21.46.46 ◽

2014 ◽

Vol 124 (21) ◽

pp. 46-46 ◽

Cited By ~ 11

Author(s):

Filippo Milano ◽

Shelly Heimfeld ◽

Ivy B. Riffkin ◽

Ian Nicoud ◽

Frederick R. Appelbaum ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Acute Gvhd ◽

Ex Vivo ◽

Control Group ◽

Platelet Recovery ◽

Concurrent Control ◽

Hematopoietic Recovery ◽

Concurrent Control Group

Abstract Background: Myeloablative cord blood transplant (CBT) recipients experience delayed hematopoietic recovery and an increased risk of transplant related mortality (TRM). With the primary goal of generating increased numbers of hematopoietic stem and progenitor cells (HSPC) to supplement a conventional cord blood (CB) graft and thereby enhance engraftment and reduce early TRM, we have developed methods to ex vivo expand CB-derived HSPC in the presence of Notch ligand for 14 days. The product is then harvested and cryopreserved for future clinical use. We have previously reported that infusion of non-HLA matched, off-the-shelf ex vivo expanded CB progenitor cells in patients undergoing myeloablative CBT is safe and associated with faster neutrophil (ANC) recovery. We now present updated outcomes data with a median follow-up of 3.2 years (range 1.9-3.7). Methods: Between September 2010 and August 2012, 15 patients with hematologic malignancies were enrolled in this single center Phase I trial to assess the safety of infusing a non-HLA matched expanded CB HSPC product to augment conventional CBT. Conditioning consisted of Fludarabine (75mg/m2), Cytoxan (120mg/kg) and TBI (13.2 Gy). On the day of transplant, 1 or 2 unmanipulated CB units were infused first followed 4 hours later by infusion of the expanded CB product. Donor(s)/host chimerism studies were performed weekly from day 7 to 28, then at days 80, 180 and 1 year on peripheral blood flow sorted into myeloid and lymphoid fractions. Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine and MMF beginning on day -3. ANC and platelet engraftment were calculated using cumulative incidence rates to accommodate competing risks. Disease-free survival (DFS) was analyzed using Kaplan-Meier estimates. Results: The median age was 21 years (range, 5-45) and weight 59 kg (range, 23-89). Other patient characteristics and median infused cell doses are shown in Table 1. Four patients (26%) received only 1 unmanipulated CB unit along with the expanded graft. All patients engrafted at a median of 19 days (range, 9-31 days), significantly faster than the 25 days (range, 14-45) observed in 41 recipients of two unmanipulated units otherwise treated identically (p=0.01) (Figure 1A).Similar to our initial expansion trial using partially HLA-matched expanded CB cells, early (day 7) myelomonocytic (CD33 and CD14) recovery was almost entirely (98–100%) due to cells arising from the expansion product. Cells derived from the expansion product were no longer detected at day 14 in all but 2 patients. The median time to platelet recovery (>20 x 10^9/L) was 35 days (range 21–45).The cumulative incidence of platelet recovery by day 100 was significantly higher than that observed in our concurrent control group 92% (CI 95%: 59-99) vs. 69% (95%: 51-81), respectively (p=0.005) (Figure 1B). The probability of 3-year DFS was 86% (95% CI, 57-97). No TRM was observed throughout the study period (Figure 1C), although 2 patients relapsed at days 53 and 219 posttransplant and subsequently died after further therapy. All patients presented with grade II acute GVHD at a median time of 32 days (14-86), with no grade III-IV aGVHD observed (Figure 1D). The skin was the most commonly affected organ (n=12). Eight (53%) patients were treated for pre-engraftment syndrome at a median time of 6 days (range 4-9) and five (33%) patients had GVHD after day 100. At 2 years only 2 patients are still on immunosuppressive therapy for mild chronic GVHD. Conclusions: The results of this Phase I safety study demonstrated that infusion of an off-the-shelf non-HLA matched expanded CB HSPC product to augment a CB graft in the myeloablative setting was safe and led to more rapid neutrophil and platelet recovery compared to our concurrent control group. Importantly, no TRM was observed among the 15 patients on this study, with only 2 deaths due to relapsed disease, leading to an excellent OS of 86% at a median follow-up of 3.2 years. Quite interesting is the observation of no grade 3-4 acute GVHD, even with infusion of a non-HLA matched expanded cell product that may induce increased alloreactivity of the unmanipulated CB unit(s). However, in this preliminary pilot study, it appeared that infusion of the non HLA-matched product was associated with less severe acute GVHD. Based on these very promising results, a prospective multicenter randomized trial utilizing this product is underway. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽

10.1182/blood-2019-122762 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3320-3320

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Javier Bolanos-Meade ◽

Richard J. Jones

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Prospective Trial ◽

Stopping Rules ◽

High Dose ◽

Gvhd Prophylaxis ◽

Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

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Low-Dose Methotrexate Could Reduce Severe Early Immune Reactions but Probably Increase Garft Failure in Umbilical Cord Blood Transplantation

Blood ◽

10.1182/blood-2019-131524 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5679-5679

Author(s):

Liu Huilan ◽

Xiaoyu Zhu ◽

Kaidi Song ◽

Xiang Wan ◽

Guangyu Sun ◽

...

Keyword(s):

Cord Blood ◽

Graft Versus Host Disease ◽

Low Dose ◽

Cord Blood Transplantation ◽

Immune Reactions ◽

Graft Versus Host ◽

Blood Transplantation ◽

Dose Methotrexate ◽

Gvhd Prophylaxis

Early immune disorders, including preengraftment syndrome (PES)and acute graft-versus-host disease(aGvHD)are problematic in cord blood transplantation (CBT), and optimal prophylaxis has not been established. Here, we prospectively investigated whether intensive GvHD prophylaxis by adding low-dose methotrexate (MTX)at day 3 after CBThas a prognostic impact on CBT. 16 consecutive single-unit CBT recipients treated for high-risk hematologic malignancies (10 cases) and non-malignancies (6 cases) between February 2019 and March 2019. The patients, 6 female and 10 males, had a median age of 9 years (range 4-40) and a median weight of 26 kg (range 14-68). Myeloablative preparative regimen comprised fludarabine, busulfan and cyclophosphamide for malignancies and reduced-intensity-conditioning comprised fludarabine, cyclophosphamide and total-body irradiation (4 Gy) for non-malignancies. Graft-versus-host disease (GvHD) prophylaxis was cyclosporine and mycophenolate mofetil plus MTX 3 mg/m2 on day+3. 14 patients achieved engraftment at a median of day 19 and had more than 95% (complete) donor chimerism on day+14.Two patients without hematopoietic reconstitution were engrafted after a second CBT. PES was characterized by high-grade fever, rash, pulmonary edema, weight gain, liver and renal dysfunction developed on a median of day 8 in 11 of the 16 evaluable patients, including 2 who did not achieve engraftment. The PES patients received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 2 patients were requiredBasiliximab to improve clinical symptoms. Grade I to IV and aGvHD developed in 4 and only 1 patient developed severe aGvHD with Grade Ⅲ. Follow-up so far, one death occurred at day 103 because of pneumonia. 15 patients are alive well at a median follow-up of 135 days (131-163). Adding low-dose MTX at day +3 may be offer one optimal regimen to reduce severe early immune reactions and improve outcomes in CBT. Disclosures No relevant conflicts of interest to declare.

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Sirolimus and Tacrolimus as Graft-vs.-Host Disease Prophylaxis in Allogeneic Stem Cell Transplantation: The Dana-Farber Cancer Institute Experience.

Blood ◽

10.1182/blood.v104.11.1227.1227 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1227-1227

Author(s):

Corey Cutler ◽

Shuli Li ◽

Haesook T. Kim ◽

Edwin Alyea ◽

Vincent Ho ◽

...

Keyword(s):

Stem Cells ◽

Overall Survival ◽

Stem Cell ◽

Serum Level ◽

Acute Gvhd ◽

Cell Function ◽

Peripheral Blood Stem Cells ◽

Gvhd Prophylaxis ◽

Blood Stem Cells

Abstract Sirolimus is a novel immunosuppressant similar to tacrolimus, however, sirolimus inhibits T cell function uniquely via FKBP12/mTOR and can impair dendritic cell function. Sirolimus acts synergistically with tacrolimus and has a non-overlapping toxicity profile, making their use in combination attractive. We began employing sirolimus as GVHD prophylaxis in 2000, and herein describe our experience with this compound in the myeloablative transplant setting. Methods: Two clinical trials were performed using sirolimus (target serum level 3–12 ng/ml) and tacrolimus (target serum level 5–10 ng/ml) as primary GVHD prophylaxis. Cytoxan (1800 mg/m2/d x 2) and TBI (14 Gy, 7 fractions) was the conditioning regimen used in all patients. Trial 1 enrolled 76 patients who received HLA-matched, unrelated or 1-Ag mismatched related or unrelated bone marrow or peripheral blood stem cells. Abbreviated methotrexate (20 mg/m2 total) was routinely given post-transplant. Trial 2 enrolled 53 patients who received HLA-matched, related peripheral blood stem cells. No methotrexate was given post-transplant. Results: The median times to neutrophil engraftment (>500/ml) after transplantation were 17 (range 11–32) and 14 (range 9–17) days for trials 1 and 2 respectively. The median times to platelet engraftment (>20,000/ml) after transplantation were 29 (range 11–98) and 12 (range 10–47) days for trials 1 and 2. Grade II–IV acute GVHD occurred in 35% and 19% of patients in the two trials. Grade III–IV acute GVHD occurred in 21% and 4% of patients in the two trials. The median time to first hospital discharge was 33 and 19 days from transplantation for trials 1 and 2. Seven patients in trial 1 (9%) and 3 patients in trial 2 (6%) did not survive to first hospital discharge. The non-actuarial incidence of chronic GVHD in the two trials was 49 and 44%, respectively. Treatment-related mortality at 100 days was 13% and 6% in the trials. At two years, the relapse-free and overall survival estimates for trial 1 are 46 and 48% (Median follow-up of survivors: 27 months). One year relapse-free and overall survival estimates for trial 2 are 71% and 75% (Median follow-up of survivors: 15 months). Overall survival at 2 years is 72%. Toxicity related to the addition of sirolimus was modest. Among all patients (n=129), VOD occurred in 16 patients (12%), idiopathic pneumonia syndrome occurred in 9 patients (7%) and thrombotic microangiopathy occurred in 13 patients (10%). Conclusions: Sirolimus, when added to tacrolimus after allogeneic stem cell transplantation is effective for GVHD prophylaxis. Engraftment is prompt, the incidence and severity of acute GVHD are reduced and transplant-related morbidity and mortality is reduced, regardless of stem cell source and methotrexate use. Early survival estimates are excellent due to reduced GVHD and transplant-related toxicity. Sirolimus is worthy of broader study in allogeneic transplantation.

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Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽

10.1182/blood.v104.11.730.730 ◽

2004 ◽

Vol 104 (11) ◽

pp. 730-730 ◽

Cited By ~ 3

Author(s):

Edwin P. Alyea ◽

Shuli Li ◽

Haesook Kim ◽

Corey Cutler ◽

Vincent Ho ◽

...

Keyword(s):

Serum Level ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Dose Methotrexate ◽

Gvhd Prophylaxis ◽

Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

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Platelets Recovery and Transfusion Needs after Reduced Intensity Conditioning (RIC) Allogeneic Peripheral Blood Stem Cell (PBSC) Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v108.11.2989.2989 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2989-2989

Author(s):

Thomas Prebet ◽

Mohamad Mohty ◽

Patrick Ladaique ◽

Christian Chabannon ◽

Catherine Faucher ◽

...

Keyword(s):

Platelet Count ◽

Acute Gvhd ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Platelet Recovery ◽

Gvhd Prophylaxis ◽

Study Population ◽

Grade 3 ◽

Few Data

Abstract Few data are currently available regarding platelets trasfusion needs and the kinetics and predicitive factors for platelets recovery after RIC allo-SCT. In this study, we analyzed the profile of platelets recovery and transfusion needs in the first 100 days after sibling PBSC RIC in a single institution series of 166 consecutive transplantations. Patients and graft characteristics were: age 49 y. (range: 18–70), diagnoses: 66 myeloid malignancies (40%), 64 lymphoid malignancies (39%), and 36 metastatic solid tumors (21%). 112 pts (67%) received an ATG-based RIC, while 54 pts (33%) received a low dose irradiation-based RIC. 75 pts (45%) developed grade 2–4 acute GVHD. Platelets recovery (>20 G/L) was observed at a median of 9 days (range: 0–99). The kinetics profile of platelets recovery is shown in the figure below. In the whole study population, the nadir was observed around day +7 after allo-SCT, and a plateau was reached about day +35. Filtered and irradiated donor apheresis platelets were used and patients needed a median of 1 unit (range: 0–53). In this series, 83 pts (50%) did not require any platelets transfusion during the follow-up period (median follow-up: 442 days) and 83 patients (50%) received at least one transfusion of platelets (54 were not transfused beyond day +100 after allo-SCT). Platelets count prior to RIC allo-SCT (median count 144 G/L; HR 0.44 (0.28–0.7) p=0.002), conditioning regimen (use of ATG; HR 1.86 (1.08–3.2) p=0.025) and the occurrence of acute (HR 1.54 (1.17–2.01); p=0.001) and severe GVHD (HR 2.36 (1.38–3.05) p=0.0006; 82% of patients with grade 3–4 acute GVHD were transfused) were the parameters significantly associated with platelets transfusion needs in multivariate analysis. In this cohort, 145 pts could be assessed for platelets recovery at day +100: among them, 99 (68%) had a platelet count >99 G/L. Univariate analysis found a significant impact of acute GVHD (p=0.0001) and platelet count prior to conditioning (p=0.012) but only acute GVHD (HR 5.52 (2.48–12.25); p=0.001) was associated with a delayed platelet recovery in a multivariate model. No impacts of pathology, GVHD prophylaxis regimen or CD34+ cell dose were demonstrated. Overall, these observations show a significantly lower rate of platelets transfusions and a quicker kinetic of platelets recovery after RIC allo-SCT and point out the effect of acute GVHD. In addition, considering the low level of myeloablation observed, RIC could be an appropriated field of investigation for the testing of megakaryocytic stimulating agents, towards further improving the safety and outcome of RIC allo-SCT. Platelets recovery after PBSC RIC allo-SCT Platelets recovery after PBSC RIC allo-SCT

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Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽

10.1182/blood.v108.11.605.605 ◽

2006 ◽

Vol 108 (11) ◽

pp. 605-605

Author(s):

Karen K. Ballen ◽

Corey Cutler ◽

Thomas R. Spitzer ◽

Beow Yeap ◽

Steve McAfee ◽

...

Keyword(s):

Cord Blood ◽

Total Dose ◽

Aplastic Anemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cord Blood Unit ◽

Reduced Intensity ◽

Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count >500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count >20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

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Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.

Blood ◽

10.1182/blood.v110.11.2023.2023 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2023-2023

Author(s):

Koji Kato ◽

Ayami Yoshimi ◽

Etsuro Ito ◽

Kentaro Oki ◽

Jun Hara ◽

...

Keyword(s):

Cord Blood ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

Disease Status ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

Cd34 Cells ◽

Advanced Stages ◽

Grade Ii

Abstract Cord blood transplantation (CBT) became one of the important alternatives in allogeneic stem cell transplantation for children with hematological malignancies. We have analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified risk factors of transplant outcome, when they had no prior transplant. From 1997 to 2006, total 332 children with ALL have undergone CBT from unrelated donor and 270 of them had no prior transplant. They are 0–15 yrs (median 5) and 4 to 60kg of body weight (median 18). Serological disparities of HLA for graft-versus-host disease (GVHD) direction were 0(n=54), 1(n=168) and 2(n=47), and disease status at transplant were 1st complete remission (CR) (n=120), 2nd CR (n=71), and more advanced stages (n=75). The median number of nucleated cells in cord blood unit was 4.93×107/kg (1.35–24.9), and that of CD34+ cells was 1.53×105/kg (0.17–15.0). As preconditioning, total body irradiation (TBI) was given in 194 patients and methotrexate (MTX) was given as GVHD prophylaxis in 159 patients. The neutrophil engraftment was achieved in 88.5% (95%CI: 84.1–91.8%) of patients and platelet engraftment (>50k) was obtained in 72.6% (95%CI: 66.8–77.7). The incidence of grade II–IV and III–IV acute GVHD was 45.6% (95%CI: 39.5–51.4) and 20.4% (95%CI: 15.8–25.4) respectively. Non-relapse mortality was observed in 22.6% (95%CI: 17.7–27.8) and 35.2% (95%CI: 29.2–41.3) of patients relapsed after CBT. The five year event free survival (EFS) of all patients was 38.1% (95%CI: 34.9–41.3); 47.4%(95%CI: 42.4–52.4) in 1st CR, 45.5%(95%CI: 38.9–52.1) in 2nd CR and 15.2%(95%CI: 10.8–38.9) in more advanced stages, respectively. The multivariate analysis revealed that the larger number of CD34+ cells (p<0.01) and administration of granulocyte colony stimulating factor after CBT (p<0.01) were associated with earlier neutrophil engraftment. Preconditioning with TBI (p<0.01) and absence of MTX (p=0.037) significantly affected the development of grade II-IV acute GVHD. Advanced disease at transplant was the most predominant factor for leukemic relapse (p<0.01). GVHD prophylaxis with MTX (p=0.042), less allele mismatches (p=0.013) and disease status of 1st and 2nd CR at transplant (p<0.01) were significantly associated with better EFS. Our results showed the favorable effect of MTX for the development of acute GVHD and EFS. In conclusion, GVHD prophylaxis including MTX is important in CBT for children with ALL.

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