scholarly journals Cpit (Check Point Inhibitor Trial) 002: Phase I Study of Single-Agent and Combined Checkpoint Inhibition (CI) after Allogenic Hematopoietic Stem Cell Transplantation (alloHCT) in Patients at High Risk for Post-Transplant Recurrence

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5618-5618
Author(s):  
Jamie Koprivnikar ◽  
James K McCloskey ◽  
Rena Feinman ◽  
Robert Korngold ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Dose Escalation ◽  
Acute Gvhd ◽  
Single Agent ◽  
Myeloablative Conditioning ◽  
Post Transplant ◽  
Tcr Repertoire

Background: AlloHCT is a potentially curative treatment for patients with acute myeloid leukemia (AML) and other myeloid malignancies (MM), however has a 40% relapse rate. The 2-year post-relapse survival rate is less than 20%; sustainable remissions are rare. Multiple strategies to mitigate relapse have been employed with variable degrees of success. An as yet untested approach involves manipulation of the T-cell milieu in the post-alloHCT setting using CI. Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal antibodies(mAbs) can enhance the anti-tumor immune response and result in tumor rejection, suggesting that host mechanisms limit the antitumor response. A murine model of an anti-PD-1 mAb given at the time of transplant showed that PD-1/PD-L1 interactions decrease acute GVHD, but increase chronic GVHD suggesting that PD-1 pathway modulation may provide unique opportunities for stimulating immune regulation post-alloHCT. Use of ipilimumab (I) to treat post-transplant MM resulted in a complete response rate of 42% and decreased the Treg/Tconv cell ratio, consistent with enhancement of the graft-versus-tumor effect. The CPIT-001 Trial demonstrated the feasibility and safety of combined CI with I and nivolumab (N) as consolidation following autologous stem cell transplantation (ASCT) for high-risk hematological malignancies as well as a 67% PFS rate at 18 months post-ASCT, a significant improvement as compared with historical data. Study Design: The study employs a 3x3 design with intrapatient dose escalation. Patients will alternately be assigned to receive either N or I as a single agent. If the safety endpoint is met for each group, enrollment to the combination CI group will open. See table 1 for dosing. For all Groups, intrapatient dose escalation will be utilized. If the patient tolerates 28 days of treatment, he/she will be escalated to the next dose level and the next patient will be enrolled. Enrollment must occur within 60 days prior to HCT conditioning to allow for collection of baseline samples. Patients will start CI therapy 60 to 100 days after stem cell infusion when acute GvHD is adequately controlled on a prednisone dose of 20 mg daily or less, organ function, and peripheral counts are adequate. Key inclusion criteria at study start up included patient age 75 years or less with high risk AML or MDS undergoing alloHCT with a matched-related or 10/10 unrelated donor who were receiving non-myeloablative conditioning. Bone marrow aspiration will be performed for response evaluation approximately every 3 months post CI initiation. The primary objective is to assess the safety of CI in this patient population. Secondary objectives include efficacy, assessment of blood immune reconstitution, phenotype and TCR repertoire by sequencing, assessment of tumor site immune phenotype, TCR repertoire and PD-L1/2 expression both prior to alloHCT conditioning and at relapse. The tertiary objective is to identify specific intestinal microbial strains associated with improved outcomes in alloHCT patients treated with CI. Microbial composition in stool samples of patients will be analyzed at screening, at engraftment, at various time points post-transplant, and at time of relapse, as it occurs. Study Experience Thus Far: The study opened to accrual in May of 2017. Four patients have signed informed consent. Two patients have been treated with CI. One patient withdrew consent prior to treatment and a second patient is currently status post alloHCT, but has not yet reached day 60. One patient received 2 doses of N and the second patient received 1 dose of I. Accrual to trial has been slower than anticipated. A detailed analysis of the patient screening log was completed. It was determined that 139 patients had been screened for trial. Major reasons for being ineligible included a diagnosis of ALL (34 patients; 24%), use of a haploidentical donor (30 patients; 22%), use of a full dose conditioning regimen (14 patients; 10%), diagnosis of CML (12 pateints; 10%), age greater than 75 (12 patients; 9%), diagnosis of CMML (12 patients; 9%). Following this analysis, an amendment was filed to include patients receiving haplo identical transplant and/or myeloablative conditioning, and to expand diagnosis to include all MM including CMML, CML blast crisis, and myelofibrosis. Disclosures Koprivnikar: Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. McCloskey:Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Rowley:Fate Therapeutics: Consultancy; Allergan: Equity Ownership. OffLabel Disclosure: Nivolumab - immunomodulation Ipilimumab - immunomodulation

scholarly journals A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2107-2107
Author(s):  
Christopher R. D'Angelo ◽  
Aric C. Hall ◽  
Kyungmann Kim ◽  
Ryan J. Mattison ◽  
Walter L. Longo ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 299-299
Author(s):  
Michael Schleuning ◽  
Christoph Schmid ◽  
Georg Ledderose ◽  
Johanna Tischer ◽  
Meike Humann ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Chronic Infections ◽  
Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

Is There a Role for Autologous Stem Cell Transplantation (Auto SCT) for Patients with Acute Myelogenous Leukaemia? A Retrospective Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1689-1689
Author(s):  
Nicolas Novitzky ◽  
Valda Thomas ◽  
Cecile du Toit ◽  
Andrew McDonald
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Entire Group ◽  
Myeloablative Conditioning ◽  
Post Transplant ◽  
Significant Difference

Abstract Abstract 1689 Introduction: To better counsel our patients on the role of auto SCT for patients with AML we studied consecutive individuals in CR 1 who had tissue compatible siblings and underwent allogeneic (allo) SCT with subjects who had no HLA donor and actually underwent auto SCT. Methods: Patients were in CR 1 following induction combinations containing 7 days of cyatarabine and etoposide with 3 days daunorubicin followed by similar consolidation therapy. The choice for the type of graft was based on availability of HLA identical siblings. Allogeneic donors underwent PBPC mobilisation with filgrastim and for GvHD prophylaxis grafts were exposed ex vivo to alemtuzumab 1mg/1010 mononuclear cells. Patients were prescribed cyclosporin until day 90 post transplant. Individuals lacking a donor underwent PBPC mobilization with etoposide 2 gr/m2 and harvested PBPC were cryopreserved. Patients received similar myeloablative conditioning followed by infusion of the grafts. Patients were stratified by clinical and laboratory factors as well as cytogenetic risk. The end points were TRM, DFS and OS. Results: The median presentation age for both transplant groups was 35 (14-60) years. Of the 112 consecutive patients achieving remission 37 had HLA identical siblings, but 3 relapsed and donors became unavailable in 2. Thus, autologous or allogeneic grafts were actually transplanted to 43 and 32 patients respectively. There was no significant difference in the presentation clinical features, laboratory parameters, marrow morphology or proportion of low and intermediate cytogenetic risk for both transplant options. Treatment mortality as well as relapse rate was similar (14 and 15%; 39 and 27%, respectively). At a median of 1609 and 1819 post transplant days, 56% and 63% in each group survive. In univariate analysis performance status, cytogenetic risk, morphological features of dysplasia, blast count and LDH were significant factors for survival. While for the entire group there was no difference in survival between both modalities, all patients with unfavourable cytogenetics receiving an autologous graft died of disease recurrence (3 year survival 35% vs 0%; p= 0.05). Conclusions: We conclude that patients with AML who have low or intermediate cytogenetic risk undergoing myeloablative conditioning followed by autologous or allogeneic T-cell depleted stem cell transplantation appeared to have similar outcome. However, those with unfavourable karyotype are unlikely to be cured with autologous grafts and are candidates for experimental modalities. Disclosures: No relevant conflicts of interest to declare.

Familial Haploidentical (FHI) T-Cell Depleted (TCD) with T-Cell Addback Stem Cell Transplantation for Patients with High-Risk Sickle Cell Disease (SCD) (IND 14359)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2582-2582 ◽  
Author(s):  
Cori M. Abikoff ◽  
Julie-An Talano ◽  
Carolyn A. Keever-Taylor ◽  
Mark C. Walters ◽  
Shalini Shenoy ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cord Blood ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Donor Chimerism

Abstract Allogeneic stem cell transplantation (AlloSCT) from HLA-matched unaffected sibling donors (MSD) has been successful for high-risk SCD, and is the only known curative therapy (Freed/Cairo et al, BMT, 2012). We have recently demonstrated 100% event free survival and absence of sickle cell symptoms following reduced toxicity conditioning and HLA matched sibling bone marrow or cord blood AlloSCT (Bhatia/Cairo et al, BMT, 2014). However, 5 out of 6 children who might benefit from this therapy lack an HLA matched family donor. Identifiable matched unrelated adult donors (URD) in this ethnic group are extremely limited and results from unrelated cord blood transplants are poor (Radhakrishnan K/Cairo et al., BBMT 2013, Kamani et al., BBMT, 2012). We previously demonstrated the use of positive CD34 selection followed by T cell add back (2 x 105 CD3/kg) from unrelated donors in pediatric recipients with both malignant and nonmalignant disease lead to 100% engraftment with minimal acute GVHD (aGVHD). In a high-risk FHI TCD thalassemia study, 16/22 cases engrafted without aGVHD and with 90% overall survival (Sodani et al., Blood, 2010). FHI TCD AlloSCT could expand the donor pool and improve outcomes for patients with high risk SCD. This SCD consortium trial is investigating the safety, feasibility, EFS, donor chimerism, graft failure, aGVHD and chronic GVHD (cGVHD), and infectious mortality after FHI TCD AlloSCT in high-risk SCD patients (Figure 1). High risk features included one or more of the following: ≥1 CVA, ≥2 ACS, ≥3 VOC in past 2 years, or 2 abnormal TCDs. Patients (2-20.99 yrs) without an 8/8 HLA MSD or URD and who have ≥1 high-risk SCD features were eligible. Patients received hydroxyurea 60 mg/kg/d and azathioprine 3mg/kg/d, day -59 – day -11, fludarabine (30mg/m2/d x5d), busulfan (3.2 mg/kg/d x4d [<4yrs of age: 4 mg/kg/d x4d]), thiotepa (10 mg/kg/d x1d), cyclophosphamide (50mg/kg/d x4d), R-ATG (2mg/kg/d x4d), and TLI (500cGy) followed by FHI T-cell depleted AlloSCT. AGVHD prophylaxis included tacrolimus single agent. We utilized the CliniMACS (IND 14359) to enrich for peripheral blood hematopoietic progenitor cells (HPC's); target dose of 10 x 106 CD34+ cells/kg with 2 x 105 CD3+ T cells/kg added back as a final CD3/kg concentration. Six patients have received AlloSCT to date (Figure 2). All patients utilized maternal donors who encountered no complications during collection. All had early neutrophil engraftment (median day +9), ≥98% whole blood chimerism and ≥85% RBC donor chimerism, no aGVHD or cGVHD (Figure 2). One patient developed late hepatic SOS and died at day +59; the remainder are alive and free of disease (day +12 to +642). One more patient has been enrolled and has begun conditioning and others are in the early part of their transplant process. Early results indicate FHI TCD AlloSCT is feasible in high-risk SCD patients who lack a MSD or URD. A larger cohort with longer term follow-up is needed to assess long-term safety and outcomes (Supported by FDA 5R01FD004090 and a grant from Otsuka) (IND #14359 and NCT 01461837). http://www.sicklecelltransplantconsortium.org Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Association Between C-Reactive Protein in the First 1-3 Days Post-Transplant and Allogeneic Immune Reactions in Pediatric Haploidentical Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5794-5794
Author(s):  
Yao Chen ◽  
Kai-Yan Liu ◽  
Xiao-Jun Huang ◽  
Chen Huan ◽  
Feng-Rong Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
C Reactive Protein ◽  
Immune Reactions ◽  
Post Transplant ◽  
Reactive Protein ◽  
Haploidentical Stem Cell Transplantation ◽  
Engraftment Syndrome

Abstract Background: C-reactive protein (CRP) has been shown to be a reliable biomarker of innate immunity. The purpose of the current study was to evaluate whether CRP levels in the first 1-3 days could predict allogeneic immune reactions including engraftment syndrome (ES) or acute graft-versus-host disease (GVHD) under haploidentical stem cell transplantation (SCT) in children. Patients and methods: The study population comprised 175 consecutive pediatric patients (age no more than 18 years) who received haploidentical SCT from Oct, 2009 to Dec, 2014. All the children followed Beijing protocol in our institute as previously described. Allogeneic immune reactions include engraftment syndrome and acute GVHD. ROC analysis was performed to identify cutoff CRP value in the first 1-3 days post-transplant that best identified patients with allogeneic immune reactions. Patients were classified into 2 groups as high-CRP group (≥cut-off value) and low-CRP group (<cut off value). Results:Totally, 129 patients (73.7%) were alive and without primary disease.The median age of recipients was 14 years (range: 2-18 years). The primary diseases were as follows: ALL in 95 (54.3%), AML in 62 (35.4%), hybrid acute leukemia in 3 (1.7%), CML in 10 (5.7%), and MDS in 5 (2.9%). Of the 175 patients, 68 (38.9%) developed ES on a median of day 10 (range: 7-16). 51(29.1%) out of 175 children developed 2-4 grade acute GVHD on a median of day 30 (range: 22-89) including 15 (8.6%) patients of severe acute GVHD on a median of day 29 (range: 22-85). Higher incidence of ES, 2-4 grade GVHD and 3-4 grade GVHD were totally observed in high-CRP group, compared to the low-CRP. A multivariate analysis demonstrated that high-level CRP(≥20.1 mg/L)in day 1-3 post-transplant was a risk factor for the development of allogeneic immune reactions. High CRP group was associated with an increased occurrence of ES (HR=2.046; 95%CI=1.204-3.477; P=0.008), II-IV aGVHD (HR=2.203; 95%CI=1.192-4.073; P=0.001) and severe GVHD (HR=6.371; 95%CI=1.798-22.581; P=0.004). Conclusions: Our data suggested higher CRP level during the first 1-3 days post-transplant could be a predictor of allogeneic immune reactions in pediatric haploidentical SCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evaluation of Infectious Complications after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Following Reduced-Intensity and Myeloablative Conditioning: A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5758-5758
Author(s):  
Amandine Fayard ◽  
Fabien Tinquaut ◽  
Didier Blaise ◽  
Patrice Chevallier ◽  
Mauricette Michallet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Infectious Complication ◽  
Ex Vivo ◽  
Infectious Complications ◽  
Bk Virus ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Introduction: Hematopoietic stem cell transplantation (HSCT) is a major treatment for many hematological disorders. However, this treatment comes with significant risks linked to toxicity and infectious complications which may lead to death. Recently haploidentical transplants without ex vivo T-depletion have been developed through the use of post-transplant cyclophosphamide, thus reducing the risk of lethal GVHD. Toxicity data are still limited and few studies have evaluated infectious complications following haploidentical transplants without ex vivo T-cell depletion. In this study, we evaluated the incidence of infectious complications in patients who received haploidentical HSCT with post-transplant cyclophosphamide. Patients and methods: Data from 21 French centers and one Belgian center were retrospectively collected. Between January 2013 and December 2014, 159 patients all older than 18 years, affected with hematological malignancy and having undergone a haploidentical HSCT were included. Informed consent was obtained in accordance with the Declaration of Helsinki. Clinical data were obtained through ProMISe (Project Manager Internet Server), the internet-based system shared by all Francophone transplantation centers. Results: In total, 159 patients were included (Table 1). The median age at transplantation was 51.2 years (20-72 years). All patients were treated with post-transplant cyclophosphamide combined with an anticalcineurin and mycophenolate mofetil as GVHD prophylaxis. The median follow-up of the cohort was 14 months. Meanwhile, 49 patients (13%) developed acute GVHD (grade 2-4). Forty-three patients (27%) developed chronic GVHD. Median overall survival wasn't reached and the median progression-free survival was 571 days. At the end of the study, 69 patients had died, 29 were in relapse and 36 presented treatment related toxicity. TRM was of 14% and 22% at day 100 and 365 respectively. At least one infectious complication occurred in 135 patients. These were mostly clinically or microbiologically documented. Median time from transplant to the first occurrence of infectious complication was 12 days. Twenty five percent of patients presented between 3 and 5 infectious complications. The average number of infectious complications per patient was 2.9 (0-12). Sixty-two percent of early infectious complications occurred throughout conditioning or within 20 days post- transplant. Fifty-two percent of those infections were bacterial, 33% viral (39% of which related to CMV and 28% to BK virus), and 4.5% were parasitic or fungal (50% of which related to aspergillosis). Overall 436 infectious episodes were reported: bloodstream infections (62%) (bacteremia, viremia, fungemia or parasitaemia), respiratory (10%), urinary tract (8%), digestive tract (6%), skin (3%), septic shock and multi organ failure (6%), others (5%). Among those complications, 46% were bacteria related, 36% were virus related (17% of which due to BK virus and 39% to CMV), 7% were parasitic or fungal related (in these cases, 61% aspergillosis related). In total, 26 cases (6%) of BK virus infections were observed. Conclusion: In conclusion, in these preliminary results, except for maybe in the case of BK infections, incidence of infectious disease after haploidentical HSCT seem not to differ to related or unrelated HSCT. Further prospective studies are necessary to confirm these results, especially by evaluating infectious viremia with BK virus after HSCT haploidentical with post-transplant cyclophosphamide following reduced-intensity and myeloablative conditioning for this patient population. Table 1: Patient disease and treatment characteristics Table 1 Table 1. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.

scholarly journals Myeloablative Conditioning Haploidentical Stem Cell Transplantation (MAC-HAPLO) with Post-Transplant Cyclophosphamide (PTCy) As GvHD Prophylaxis in High Risk Leukemias/Myelosdysplastic Syndromes (MDS): Geth Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4690-4690 ◽  
Author(s):  
Jorge Gayoso ◽  
Pascual Balsalobre ◽  
Mi Kwon ◽  
Pilar Herrera ◽  
Arancha Bermúdez ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Control ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Myeloablative Conditioning ◽  
Haploidentical Stem Cell Transplantation ◽  
Gvhd Prophylaxis

Abstract Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results. Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation). Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series. Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. Disclosures No relevant conflicts of interest to declare.

Low-Dose Azacitidine for Relapse of MDS/AML after Unrelated Donor Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5034-5034 ◽  
Author(s):  
James M. Rossetti ◽  
Richard K. Shadduck ◽  
Chandana Thatikonda ◽  
Entezam Sahovic ◽  
John Lister
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Low Dose ◽  
Peripheral Blood Stem Cell ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Blood Stem Cell Transplantation

Abstract Background: Post-transplant relapse in patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) is difficult to manage. Cytogenetic relapse and decreasing donor chimerism often precedes morphological relapse. Weaning of immunosuppressive agents and donor lymphocyte infusion (DLI) may induce graft versus tumor effect (GVT), but is of limited value for patients with existing GVHD. In addition, the degree of GVT in high-risk myeloid disease is suboptimal. We present our experience using low-dose azacitidine (AZA) for cytogenetic relapse post-transplantation. Methods: Six patients with high-risk myeloid malignancy with cytogenetic relapse after matched unrelated donor peripheral blood stem cell transplantation were treated with low-dose AZA at 25 mg/m2 SC or IV for 5 days. An average of 2 cycles of AZA were given (range = 1 to 3). There were 3 females and 3 males with a mean age of 48 years (range = 31 to 59 years). Four had high-grade MDS (including 2 with treatment related disease) and 2 had high-risk AML. Conditioning consisted of fludarabine and ablative doses of busulfan in all patients. Cytogenetic relapse was seen by FISH testing within 187 days post-transplant (range = 30 to 730 days). AZA was given after an initial attempt to wean immunosuppression, which was not possible in 3 patients due to existing GVHD. All patients tolerated AZA well, without major toxicity. DLI was possible in 3 patients following AZA. A reduction in cytogenetic abnormalities (by FISH) and increase in donor chimerism (by FISH or STR) was observed in 5 out of 6 patients (83%) within 21 days post-AZA (range = 7 to 71 days). Three of the 5 responders demonstrated improvement after 1 cycle. The other 2 responders improved after 2 cycles given 28 and 60 days apart, respectively. One of these patients responded to a second AZA cycle after failing DLI. AZA did not appear to induce or worsen GVHD in any patient. One patient remains in CR 4 months after 1 cycle of AZA. Another patient demonstrated ongoing improvement in chimerism until her death from previously existing GVHD 20 days after a third cycle of AZA. The remaining 3 responders relapsed within 30 days from time of first response (range = 17 to 43 days). Conclusions: Low-dose AZA appears to have activity in post-transplant relapse of MDS and AML. This low-dose regimen appears to be well tolerated, however, response to AZA is short-lived in the majority of patients. Further investigation is planned to improve the durability of response by giving AZA at regular intervals from the time of early relapse. The utility of AZA as a preparatory regimen pre-DLI should also be explored.

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