Outcome of Children Who Experience Disease Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies,

Abstract Abstract 4101 Introduction: According to the Center for International Blood and Marrow Transplantation and Research (CIBMTR) data, relapse accounts for 41% of deaths after matched sibling donor hematopoietic stem cell transplantation (HSCT) and 34% of deaths after unrelated donor HSCT. Overall long term survival of 25–30% has been reported in patients who relapse after HSCT. Most of these data are from adult studies. In a recent study, survival following a second allogeneic HSCT ranged from 25–50%. There are limited data on the treatment outcome of children who relapse after an allogeneic HSCT for hematological malignancies. Methods: This multicenter retrospective study was done with the primary objective to examine the incidence and outcome of children who experience relapse after allogeneic HSCT. Patients with a primary diagnosis of acute lymphatic leukemia (ALL), acute or chronic myeloid leukemia (AML or CML), juvenile myelomonocytic leukemia (JMML), biphenotypic leukemia (BL), acute undifferentiated leukemia (AUL), and myelodysplastic syndrome (MDS) were included. After IRB approval, data was collected from review of the medical charts of patients who underwent HSCT at 5 institutions across North America. Results: Data on 532 patients was analyzed; these included 328 males and 204 females. These included ALL (n=254), AML (n=187), MDS (n=35), CML (n=26), JMML (n=3), sAML (n=12), Biphenotypic leukemia (n=10), AUL (n=3) and 1 each with APL and secondary ALL. The median age at HSCT was 9.7 years (range 0.44 to 24.98). Four hundred and fifty (85%) of the 532 patients were in complete remission (CR) at the time of HSCT. Five hundred and fifteen (97%) underwent a myeloablative (MA) HSCT and 16 (3%) had a non-myeloablative (NMA) HSCT. Total body irradiation (TBI) was part of the conditioning therapy in 334 (63%) while 198 (37%) had chemotherapy based regimens. Standard graft versus host disease (GvHD) prophylaxis with calcineurin inhibitors and methotrexate was used in 76% of patients. Grade 1–2 acute GvHD developed in 180 (34%) of patients and 82 (15%) had grade 3–4 acute GvHD. Chronic GvHD was seen in 118 (22%) cases with half having extensive chronic GvHD. After HSCT, 85 (16%) patients died of transplant related complications at 1 year, with infection as the leading (26%) cause of death. The 2, 5 and 10 year overall survival for the entire group was 58.5%, 46% and 44% respectively. Following HSCT, 131 (25%) patients relapsed at a median duration of 7.7 months (range 0.6 to 66.4 months). Of the 131 patients who relapsed 80 (61%) received salvage therapy, 39(30%) did not get any therapy and data were not available for another 12 (9%) patients. Salvage therapy included a combination of withdrawal of immunosuppression, ALL or AML re-induction therapy, or other remission inducing agents, clofarabine, and/or donor lymphocyte infusions (n=22). After salvage therapy 46 (57.5%) patients achieved CR, 26 (32.5%) had no response, 3 (4%) partial response, 2 unknown and 4 (5%) had marrow aplasia and no recovery of counts. Sixty-three (48%) of the relapsed patients underwent a second HSCT: 26 (41%) received a MA, 21 (33%) NMA, 3 (5%) with no conditioning and in 13 (21%) conditioning therapy was unknown. Nearly 22 different conditioning regimens were used for the second HSCT. After the second HSCT 19 (41%) patients died because of transplant related mortality (TRM) and 24 patients died because of relapse. Seventeen (27%) patients are alive and disease free. Conclusions: Relapse remains a major complication following allogeneic HSCT for hematologic malignancies. Our data shows that patients who relapse after HSCT have poor prognosis. In our study 30 different salvage therapies were used for these patients. Currently there is no standard acceptable salvage therapy and most cooperative group or industry sponsored clinical trials exclude patients who underwent HSCT. In addition there are no standard conditioning regimens designed specifically for the second HSCT, which could contribute to the high TRM seen during second HSCT. There is urgent need to develop prospective clinical trials to better understand the optimal therapy for this group of patients. Disclosures: No relevant conflicts of interest to declare.

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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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Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v126.23.4347.4347 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4347-4347 ◽

Cited By ~ 1

Author(s):

Piyanuch Kongtim ◽

Uday R. Popat ◽

Antonio M. Jimenez ◽

Sameh Gabella ◽

Riad O. El Fakih ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Cell Transplant ◽

Hypomethylating Agents ◽

Hematopoietic Stem ◽

Free Survival ◽

Unrelated Donors ◽

Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

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Prospective Validation of a Chronic GvHD-Specific Proteome Pattern (cGvHD-MS14) Post Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v118.21.1970.1970 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1970-1970

Author(s):

Eva M. Weissinger ◽

Daniel Wolff ◽

Jochen Metzger ◽

Christiane E Dobbelstein ◽

Stefanie Buchholz ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Urine Samples ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Abstract 1970 Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many hematologic malignancies and non-malignant hematopoietic disorders, but is associated with significant morbidity and mortality with focus on acute and chronic graft-versus-host disease (GvHD). Chronic GvHD (cGvHD) occurs with increasing frequency, hampering quality of life of patients post-allogeneic HSCT and leading to increased morbidity and mortality even years after allogeneic HSCT. Diagnosis of chronic GvHD is based on clinical features and histology. Here we present the generation of cGvHD-specific proteomic pattern (cGvHD-MS14) using capillary electrophoreses and mass spectrometry to analyze urine sample collected prospectively after allogeneic HSCT. Methods: A proteomic pattern (cGvHD-MS14) was developed in order to diagnose cGvHD, to differentiate acute versus cGvHD, and to predict onset and severity of cGvHD prior to clinical diagnosis of cGVHD as a non-invasive, unbiased laboratory test for diagnosis of cGvHD. This pattern was prospectively evaluated on 329 patients (1034 urine samples) after allogeneic HSCT at MHH and 3 collaborating transplant centers. The majority of the patients had acute leukemias prior to transplantation (n=210) and were transplanted from matched unrelated or related donors (MUD n=134; MRD n=125). Reduced intensity conditioning regimens were used in about 75% of all patients and the majority (80%) received ATG (anti-thymocyte globulin) as GVHD-prophylaxis prior to transplantation and a calcineurin-inhibitor based prophylaxis afterwards. Results: Prospective and blinded evaluation revealed the correct classification of patients developing cGvHD with a sensitivity 78% and specificity of about 71% at time of diagnosis. Differentiation between late onset acute GvHD and chronic GvHD was achieved in 3 patients in this validation set. Acute GvHD prior to day 100 is not recognized by cGvHD-MS14, since aGvHD-specific peptides had been excluded during cGvHD-pattern generation. The pattern consists of 14 differentially excreted peptides, differentiating chronic GvHD from tolerant patients. Four of 14 peptides have been sequenced to date, 2 are fragments from collagen 1, 1 is from inter-alpha trypsin inhibitor heavy chain 4 and 1 is a fragment from the fibrinogen ß-chain. Conclusions: The proteomic pattern of urine proteomics enables diagnosis of cGvHD as well as differentiation of acute versus chronic GvHD. Further prospective evaluation of the cGvHD-specific pattern cGvHD-MS14 for organ specificity as well as severity prediction is currently ongoing. Taken together our results indicate that diagnosis of cGvHD is possible using CE/MS analysis of prospectively collected urine samples with high sensitivity and specificity. Disclosures: Metzger: mosaiques-diagnostics GmbH: Employment. Krons:mosaiques-diagnostics GmbH: Employment.

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Prognostic Value Of Plasma Biomarkers Compared To Urinary Proteome Patterns

Blood ◽

10.1182/blood.v122.21.4593.4593 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4593-4593

Author(s):

Christin Human ◽

Sylvia Borchers ◽

Michael Stadler ◽

Helmut Diedrich ◽

Jürgen Krauter ◽

...

Keyword(s):

Clinical Diagnosis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Phase Iii ◽

Test Set ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Plasma Biomarkers ◽

Time Points ◽

Validation Set

Introduction Graft-versus-host disease (GvHD) is a major complication and cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Prediction of acute GvHD is essential to optimize treatment. An effective method for early investigator independent diagnosis of aGvHD is under investigation in a phase III clinical trial. A urinary proteomic pattern – aGvHD-MS17 – is evaluated in a preemptive treatment trial, administering steroids at the time of pattern positivity. Here we present our data for early diagnosis of GvHD by monitoring easily accessible samples like urine for the presence of a specific proteom pattern and compare the data to published plasma biomarkers. Methods Plasma and urine were collected from patients after HSCT at defined time points (Weissinger et al., Blood 2007). Capillary electrophoresis and mass spectometry (CE-MS) analyses were done according to Weissinger et al., Blood 2007 and Leukemia, 2013. Two peptides found to be highly specific in urine for development of aGvHD were β2-microglobulin (β2m) and CD99. For both, antibodies are available and thus they can be analyzed in plasma samples from the same patients with ready-to-use ELISA-kits (Pasnecey et al., 2010). Plasma biomarkers were first analyzed in a test set based on 34 patients, followed by validation in 31 patients. As a further contribution to harmonization, published plasma biomarkers elafin, soluble IL-2-receptor alpha (IL-2sRα), REG3α, ST2 (IL-1 receptor 4) and sTNFRI were added to the ELISA-panel. Using the angiogenesis panel for bioluminex analyses, IL-8 and hepatocyte growth factor (HGF) were analyzed in addition and the outcomes were compared to the urinary proteomic analyses. Results & Discussion While the urine derived CE-MS pattern was able to predict an upcoming GvHD prior to the development of clinical signs, most of the plasma biomarkers could not predict pending GvHD. The test set for analysis of plasma consisted of 20 patients with aGvHD, from whom samples from the time of clinical diagnosis of aGvHD were used, and 14 controls without aGvHD at any time. Receiver operated characteristic curves were generated, areas under the curve (AUC) were more than 80% for β2m, CD99, sIL2Rα and sTNFRI (p<0.01). The validation set consisted of samples from 31 patients at different time points (7 samples each patient). In the validation set some markers did not reach their established cut-off point for aGvHD-diagnosis prior to or at the day of clinical diagnosis of aGvHD. Especially REG3α and elafin did not turn positive in any samples of patients with acute GvHD. Both markers presumably are organ-specific, but also limiting the analysis to patients with isolated GvHD of the intestine (REG3α) or skin (elafin) did not increase the sensitivity of these markers. CD99 and β2m discriminated patients with aGvHD from controls and CD99 was even specific for chronic GvHD and could distinguish between patients with acute and chronic GvHD with high sensitivity (89%) and specificity (95%); AUC was 86% (p<0.001). Additional problems with the ELISA-technique were the need to dilute samples prior to testing due to highly diverse concentrations of the biomarkers. The concentrations sometimes varied by the factor of 10 or more which required preparation of each sample in different dilutions. This made diagnosis based on ELISA data more time consuming and costly as envisioned. Urine on the other hand has shown to be stable and to provide a reliable proteome pattern. Furthermore, urinary proteom analysis can be normalized within each sample by using internal standards. Conclusion and future perspectives Prediction of pending aGvHD in patients post-allogeneic HSCT is possible with urine monitoring using CE-MS analyses with a sensitivity of 82% and specificity of 77% for aGvHD (Weissinger et al., Leukemia 2013). In contrast, published plasma biomarkers in our hands lack reliable sensitivity and specificity in the validation set. In addition, the markers detected in plasma do not appear to predict development of aGvHD. Biomarkers identified in urine (CD99 and β2m) can be found in plasma as well and are predictive for aGvHD-development. CD99 is also predictive for cGvHD development which can be explained by its function as an activation marker of (donor) T-cells. In conclusion, our results demonstrate that plasma monitoring post-allogeneic HSCT seems less reliable than urinary proteomics for prediction of aGvHD. Disclosures: No relevant conflicts of interest to declare.

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Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

Blood ◽

10.1182/blood-2006-03-005769 ◽

2006 ◽

Vol 109 (1) ◽

pp. 374-382 ◽

Cited By ~ 64

Author(s):

Ralf G. Meyer ◽

Cedrik M. Britten ◽

Daniela Wehler ◽

Klaus Bender ◽

Georg Hess ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Good Manufacturing Practice ◽

Hematopoietic Stem ◽

Log Reduction ◽

Reduced Intensity

Abstract Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with hematologic malignancies, 11 received a total of 21 CD8-depleted DLIs. Five patients developed transient grade I acute GVHD following transfer. Only 2 patients with HLA-C–mismatched donors showed grade II and III acute GVHD and subsequently progressed to limited chronic GVHD. Following DLIs, 4 patients with declining hematopoietic donor chimerism converted to full chimeras. A 2.1-fold median increase of circulating CD4 T cells was observed within 2 weeks after infusion. Non-DLI patients did not show a comparable rise in CD4 counts. Four patients demonstrated enhanced frequencies of cytomegalovirus-specific CD4 and CD8 T cells following transfer. Our results suggest that prophylactic CD8-depleted DLIs accelerate immune reconstitution after lymphodepleted HLA-matched SCT and carry a low risk of inducing severe GVHD.

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A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens

Blood ◽

10.1182/blood-2009-03-207563 ◽

2010 ◽

Vol 115 (5) ◽

pp. 1098-1105 ◽

Cited By ~ 68

Author(s):

Roberto Rodriguez ◽

Ryotaro Nakamura ◽

Joycelynne M. Palmer ◽

Pablo Parker ◽

Sepideh Shayani ◽

...

Keyword(s):

Thrombotic Microangiopathy ◽

Total Body Irradiation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Significant Difference ◽

Conditioning Regimens ◽

Total Body

Abstract Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation–based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation–etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day −4. Sirolimus and tacrolimus were started on day −3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

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Similar Incidence of Severe Acute Gvhd and Less Extensive Chronic Gvhd in PBSCT from Unmanipulated Haploidentical Donor Compared with That from Matched Sibling Donor for Patients with Hematologic Malignancies

Blood ◽

10.1182/blood.v126.23.1964.1964 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1964-1964

Author(s):

Honghua Li ◽

Wenrong Huang ◽

Chunji Gao ◽

Liping Dou ◽

Fei Li ◽

...

Keyword(s):

Cohort Study ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Hematopoietic Stem ◽

Sibling Donor ◽

Matched Sibling ◽

Similar Incidence

Abstract Unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Transplantation with G-CSF mobilized peripheral blood stem cell (PBSCT) has been a stable transplant setting with MSD. Unmanipulated haploidentical donor (haplo-PBSCT) has been applied in patients with hematologic malignancies. However, the characteristics of graft-versus-host disease (GVHD) in unmanipulated haplo-PBSCT are not clear. Here, we report the results of a cohort study on the clinical features of acute and chronic GVHD in haplo-PBSCT compared with PBSCT from MSD in patients with hematologic malignancies. PATIENTS AND METHODS Between July, 2007 and June, 2014, 94 patients with hematologic malignancies received haplo-PBSCT and 100 patients received PBSCT from MSD consecutively at our unit (Table 1). The PBSCs were collected on day 5 and 6 after 4 days of rhG-CSF (5 mg.kg¨C1 °¤day¨C1), then were infused on the day of collection. The conditioning regimen consisted of Bu (9.6 mg.kg-1, iv, days -10~-8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7~-6), CY (120mg kg-1, days -4~-3). Antithymoglobulin (ATG, rabbit; 10 mg.kg-1, days -5~-2) was used for haplo-PBSCT. All recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was July 15, 2015. RESULTS Among the patients with acute GVHD, there was no difference of the rate of the involved organs between these two groups (skin: 67.4% vs 68.0%, p=1.000; liver: 15.2% vs 20.0%, p=0.742; gut: 33.3% vs 32%, p=1.000). Haplo-PBSCT was associated with higher incidence of acute GVHD grade 2-4 (HR: 3.04, 95% CI: 1.55-5.98, p=0.001) and lower incidence of extensive chronic GVHD (HR: 0.49, 95% CI: 0.24-0.99, p=0.047) compared with MSD PBSCT. There was no difference of the incidence of acute GVHD grade 3-4 between these two groups (haplo-PBSCT, 9.6% vs MSD PBSCT 8.9%, p=1.000). According to NIH criteria, the incidence of severe chronic GVHD was lower in haploidentical group (13.6%) compared with MSD group (40.5%, p=0.041). There was no difference of those for mild and moderate chronic GVHD (mild: 27.3% vs 13.5%, p=0.189; moderate: 59.1% vs 45.9%, p=0.422). CONCLUSION In this cohort study, haplo-PBSCT was associated with similar incidence of severe acute GVHD, lower extensive chronic GVHD and lower severe chronic GVHD compared with MSD-PBSCT. It suggested the potential advantage of ATG in improvement of long-term quality of life of the transplant recipients. Table 1. Characteristics of patients and donors Haploidentical donor, n = 94 Matched sibling donor, n = 100 P value Gender, n (%) Receipt, male 73 (77.7) 64 (64.0) 0.041 Donor, male 63 (67.0) 60 (60.0) 0.371 Age Patient, y, median 27 38 0.055 Donor, y, median 38 39 0.364 Hematologic malignances, n (%) Acute leukemia 72 (76.6) 61 (61.0) MDS 3 (3.2) 21 (21.0) 0.000 CML 5 (5.3) 10 (10.0) Lymphoma 14 (14.9) 8 (8.0) Status of disease, n (%) 0.000 CR1 42 (44.7) 76 (76) CR2 14 (14.9) 5 (5) NR/beyond CR2 38 (40.4) 19 (19) Time to transplant (d) 361 299 0.946 Conditioning Regimen, n (%) 0.354 BuCy 60 (63.8) 66 (66.0) TBIcy 28 (29.8) 23 (23.0) FB 6 (6.4) 11 (11.0) CD34+ in graft (106/kg) 5.86 4.77 0.057 ≥4.60 51 (54.3) 41 (41.0) 0.084 Disclosures No relevant conflicts of interest to declare.

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Anaerobic Antibiotics and the Risk of Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1992-1992

Author(s):

John Tanaka ◽

Rebecca Young ◽

Lisa Spees ◽

Kirsten Jenkins ◽

Anthony D. Sung ◽

...

Keyword(s):

Stem Cell ◽

Febrile Neutropenia ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Research Support ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Graft Versus Host ◽

Grade Ii

Background: The gut microbiota interacts extensively with the host immune system and thus may modify the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). During the post-transplant neutropenic period, the majority of allogeneic HSCT recipients receive empirical broad-spectrum antibiotics for febrile neutropenia. We hypothesized that receipt of an antibiotic regimen with an anaerobic spectrum of activity is associated with a higher risk of grade II-IV acute GVHD than receipt of a non-anaerobic antibiotic regimens. Methods: In this single-center retrospective cohort study, we evaluated associations between peri-transplant receipt of antibiotics with an anaerobic spectrum of activity and the risk and severity of GVHD among 877 adults who received an allogeneic HSCT between January 1, 2005 and December 31, 2016. We identified 609 patients who developed febrile neutropenia after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n=333) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, ceftazidime, or cefepime; n=276). Antibiotics received by patients between 7 days before and 28 days after allogeneic HSCT and GVHD diagnoses were verified via manual review of medication orders and provider notes in electronic medical records. Results: Receipt of anaerobic antibiotics was associated with an increased risks of grade II-IV acute GVHD (hazard ratio (HR): 1.41; 95% confidence interval (CI): 1.10-1.79; P=0.01) and acute GVHD mortality (HR: 1.87; 95% CI: 1.13, 3.11; P=0.02). This hazard was primarily associated with acute GVHD of the gut or liver (HR: 1.38; 95% CI: 1.06, 1.79; P=0.02). The association remained with even short (<7 days) courses of anaerobic antibiotics. Anaerobic antibiotic exposure was not associated with acute skin GVHD (HR: 0.97; 95% CI: 0.69, 1.37; P=0.88), chronic GVHD diagnosis (HR: 0.93; 95% CI: 0.70, 1.23; P=0.43), or chronic GVHD mortality (HR: 0.89; 95% CI: 0.44, 1.81; P=0.76). Conclusions: Receipt of anaerobic antibiotics for febrile neutropenia post-HSCT is associated with an increased risks of acute GVHD of the gut or liver and acute GVHD mortality. Limiting use of antibiotics with an anaerobic spectrum of activity after allogeneic HSCT may reduce acute GVHD incidence and mortality. Disclosures Sung: Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Martin:Novartis Pharmaceuticals: Other: research support; Jazz Pharmaceuticals: Other: research support.

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Sirolimus-Containing Graft-Versus-Host Disease Prophylaxis and High- Resolution HLA Typing Improves the Outcome of Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v112.11.2216.2216 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2216-2216

Author(s):

Ronald J. Maggiore ◽

Dennis L. Cooper ◽

Francine M. Foss ◽

Warren D. Shlomchik ◽

Stuart E. Seropian

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Recurrence ◽

Hla Typing ◽

Unrelated Donor ◽

Prophylactic Regimen ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Kaplan Meier ◽

Gvhd Prophylaxis

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors can cure a variety of hematologic diseases; however, decreased survival and graft versus host disease (GVHD) are associated with mismatches at HLA class I and class II loci. Beginning in 2004, we have employed a modified three-drug sirolimus-based GVHD prophylactic regimen (Antin JH et al., Blood2003;102:1601) for all patients undergoing unrelated donor allogeneic HSCT with any antigen or allele mismatch at HLA A, B, C, DR, or DQ in the GVHD direction. Outcomes of 22 patients undergoing mismatched unrelated donor (MMUD) allogeneic HSCT (sirolimus(+) group) were retrospectively reviewed in comparison to 14 patients receiving MMUD allografts between 2000–2004 who received a tacrolimus-based two-drug GVHD prophylactic regimen (sirolimus(−) group). Median age (45 vs. 51), disease status, donor gender, and type of transplant conditioning (reduced-intensity, 9 vs. 8) were similar between the two groups. Seven of 14 patients in the sirolimus (−) group received bone marrow grafts whereas all patients in the sirolimus + group received peripheral blood stem cells. Nine patients in the sirolimus – group had antigen-level typing at HLA A, B, C and DQ loci and allele level typing at HLA DRB1 and 5 patients had allele-level typing at all loci. Patients in the sirolimus+ group had allele-level typing at all loci. One subject was mismatched at HLA DRB1 and DQ at the allele level; the remaining subjects had a single allele or antigen mismatch. GVHD prophylaxis for the sirolimus(−) group included tacrolimus and mycophenolate (n=11) or tacrolimus and low-dose methotrexate x 3 doses (n=3). GVHD prophylaxis for the sirolimus (+) group included sirolimus, tacrolimus and post- transplant methotrexate for 2 or 3 doses, totaling 15mg/m2. Median follow-up for surviving patients was 1921 days (1781–2295) in the sirolimus-group and 447 days (53–1122) in the sirolimus(+) group. The day +100 cumulative incidence of grades II-IV and III-IV acute GVHD were, respectively, 71% and 43% in the sirolimus(−) group, and 14% and 5% in the sirolimus(+) groups (p=0.002; p=0.02). Kaplan-Meier estimates of the probability of chronic GVHD or late onset acute GVHD at two years were 51% in the sirolimus(–) group and 70% in the sirolimus(+) group. Graft failure occurred in 2 patients each in both groups and was successfully treated in two patients by retransplantation or pentostatin plus donor lymphocyte infusion. Adverse effects of sirolimus included 8 patients with renal dysfunction (36%), 4 with thrombotic microangiopathy (TMA) (18%), and 3 with dyslipidemia requiring medical therapy (14%). Deaths in the sirolimus(−) group were due to disease recurrence (n=3), graft failure (n=1), and GVHD (n=7). Deaths in the sirolimus(+) group were due to disease recurrence (n=2), TMA (n=1) and GVHD (n=4). The Kaplan-Meier estimates of disease free (DFS) and overall survival (OS) at 3 years were 21% and 21% for the sirolimus(−) group and 53% and 56% for the sirolimus(+) group. The Kaplan-Meier estimates of non-relapse mortality (NRM) at day +100 and day +365 were 22% and 50% for the sirolimus (−) group and 5% and 13% for the sirolimus(+) group. Summary: High-resolution HLA typing and GVHD prophylaxis with sirolimus, tacrolimus, and low-dose methotrexate in patients undergoing MMUD allogeneic HSCT is associated with low rates of severe acute GVHD and non-relapse mortality. Renal dysfunction and TMA appear more common with sirolimus, and, as in prior studies with this regimen, a lower rate of acute GVHD did not result in less chronic GVHD. Nonetheless, DFS and OS appear to compare favorably to recently reported registry data for MMUD allograft recipients (Lee SJ et al., Blood;110:4576), and a prospective trial has been initiated to further study this regimen in MMUD recipients.

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The Role of Proteinase Inhibitor 9 (PI-9) and Granzyme B in Peripheral Leukocytes for GVL and GVHD After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v118.21.1984.1984 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1984-1984

Author(s):

Osamu Horie ◽

Kaori Minami ◽

Sawako Toji ◽

Kenji Yonezawa ◽

Hiroshi Gomyo ◽

...

Keyword(s):

Nk Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Polymorphonuclear Cells ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Expression Levels ◽

Proteinase Inhibitor 9 ◽

And Gender

Abstract Abstract 1984 The serpin proteinase inhibitor 9 (PI-9) protects cells from serine protease granzyme B (GrB)- and perforin (PFR)-induced cytotoxicity and apoptosis by specifically inhibiting GrB. Graft-versus-leukemia (GVL) effect and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) are the reciprocal aspects of the established immunotherapeutic approach in hematopoietic malignancies, and are thought to be caused at least in part through GrB and PFR produced by donor-derived cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. However, GrB and PFR expressions with respect to a GVL effect, and the role of PI-9 in both GVHD and GVL, are unknown. In this study we analyzed the expression of GrB, PFR and PI-9 in acute leukemia patients to whom allogeneic HSCT was performed during remission. This study was performed under the approval of the ethical committee of Kobe University Graduate Schools of Medicine and Health Sciences, and all human samples were obtained from whom a written informed consent was obtained. We first investigated the age- and gender-related differences of expressions of PI-9 and GrB mRNA by quantitative RT-PCR in mononuclear and polymorphonuclear cells from healthy volunteers. GrB and PFR mRNAs were expressed almost exclusively in mononuclear cells that included CTLs and NK cells, while PI-9 was expressed both in mononuclear and polymorphonuclear cells. GrB and PFR expression levels were comparable among all age and gender groups. Intriguingly, however, the expression of PI-9 mRNA in lymphocytes gradually increased with age, and the PI-9 expression in the volunteer group aged 60 years old or older was significantly higher than the one in the group aged 20 to 39 years old (p=0.002). Meanwhile, the PI-9 expression in polymorphonuclear cells was comparable among all age groups, and there was no gender difference in PI-9 expression levels. Next, we analyzed the expressions of PI-9, GrB and PFR mRNAs in mononuclear and polymorphonuclear cells of 3 patients (male 2, female 1) with acute GVHD and 11 patients without acute GVHD (male 6, female 5). The GrB, PFR and PI-9 expression levels were comparable between patient groups with and without acute GVHD, both before transplantation and a week after engraftment. However, the GrB and PFR expressions prominently augmented when acute GVHD became overt in all 3 patients, while PI-9 expression level increased mildly. As a result, the ratio of GrB (or PFR) and PI-9 expressions was stable in patients with and without acute GVHD. Among them, 4 cohort patients eventually relapsed and 10 cohorts remained in remission. The GrB mRNA expression in lymphocytes one week after engraftment was 3-fold higher in 10 patients without relapse of primary disease than in 4 patients who eventually relapsed (P=0.044). This might suggest that GrB plays a role in eliciting a GVL effect as well as acute GVHD. On the other hand, PFR and PI-9 mRNA expressions were then relatively stable among patients both with and without later relapse (P=0.667; P=0.103), and the ratio of GrB (or PRF) and PI-9 expressions did not change. The expressions of GrB and PFR mRNAs in polymorphonuclear cells of all patients were under the detectable level throughout the course. Finally, we analyzed the expressions of GrB, PFR and PI-9 in leukocytes 6 months after HSCT, to see if these expressions might change in patients with chronic GVHD. Among 14 patients with chronic GVHD, the GrB expression increased (up to 6.2-fold) in 10 patients, but the PFR expression did not change. In contrast, the expression of PI-9 decreased profoundly in all of the cases both with and without chronic GVHD, relative to healthy volunteers (P=0.028). Importantly, the ratio of GrB and PI-9 expressions was significantly higher in patients with chronic GVHD than in those without GVHD (P = 0.035). In conclusion, (1) high PI-9 expression in elderly people might explain a mechanism of escape from tumor immunity in them, where PI-9 might inhibit functions of cytotoxic T cells and NK cells; (2) a high expression of GrB shortly after engraftment may be a novel biomarker for a GVL effect; and (3) a low level of PI-9 expression or an increased ratio of GrB/PI-9 later after allogeneic HSCT might be an important biomarker for cGVHD. Monitoring of both GrB and PI-9 mRNAs in peripheral blood after allogeneic HSCT could be useful for predicting the GVL effect, as well as for monitoring both acute and chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

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