Graft Failure In Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4559-4559
Author(s):  
Richard Olsson ◽  
Daniel Moreno Berggren ◽  
Olle Ringden ◽  
Jonas Mattsson ◽  
Mats Remberger
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Solid Tumors ◽  
Graft Failure ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Unrelated Donors ◽  
Reduced Intensity

A decade ago reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was successfully introduced to facilitate transplantation in patients with co-morbidities. In contrast to myeloablative conditioning regimens RIC transplants are associated with less toxicity and thus preferred in the elderly population. However, there are also disadvantages with RIC such as the increased risk of graft failure caused by rejection by remnant recipient T-cells at transplant, which often results in mixed chimerism during the first months post-transplant. Here, we present risk factors for graft failure in all first RIC allo-HSCTs performed at our center from 1995 to mid-2010 (n=357). Graft failure was defined as >95% recipient T-cells any time after engraftment or reinfusion of donor cells due to >50% recipient cells with no clinical or laboratory signs of relapse. Thirty-six patients (10%) experienced graft failure. The median age of the patients was 51 and 57% were males. In univariate analysis, graft failure was 3-fold increased in male compared to female patients (15% versus 4%; P<0.01). Furthermore, patients with non-malignant disorders (26% versus 2%; P<0.01) and solid tumors (20% vs. 2%; P<0.01) had an increased risk of graft failure when compared to acute leukemia. Graft versus host disease (GVHD) prophylaxis using cyclosporine A (CSA) in combination with mycophenolate mofetil (MMF) resulted in increased numbers of graft failure when compared to our standard regimen with CSA and methotrexate (18% vs. 5%; P<0.01). The graft failure rate was the lowest among HLA-identical sibling donors (6%), slightly higher in 8/8 matched unrelated donors (10%), and the highest in 6/6 matched unrelated donors (18%; P<0.01). Total nucleated cell (TNC) dose was also important with less graft failures when the TNC dose was >10 x 108/kg, whereas CD34+ cell dose had no impact on graft failure (P=0.15). Moreover, in univariate analyses year of transplant, donor sex, cell source, CMV mismatch, ABO mismatch, or pre-planned G-CSF did not influence graft failure rates (P>0.05). In multivariate analysis (Table 1), solid tumors were associated with markedly increased risk of graft failure (RR=10.95; P=0.03), whereas there was a tendency towards increased graft failure risk in non-malignant disorders (RR=8.01; P=0.05). Graft failures were also increased in male recipients (RR=3.27; P<0.01), in grafts with a TNC dose less than 10 x 108/kg (RR=2.17; P=0.03), when using MMF containing GVHD prophylaxis (RR=3.61; P<0.01), and in transplants with HLA match less than 8/8 (RR=4.94; P<0.01). In conclusion, graft failure is augmented in male recipients, and associated with diseases which usually do not receive high-dose chemotherapy pre-transplant such as solid tumors. HLA mismatch as well as TNC dose and GVHD prophylaxis were also important risk factors for graft failure in the present study.Table 1Multivariate analysis of risk factors for graft failure in reduced intensity conditioning allo-HSCT.CharacteristicsNRR95% CIP-valueNo of patients357Recipient sexFemale1531Male2043.271.35-7.93<0.01DiseaseAcute leukemiaa661CML276.810.70-66.310.10CLL225.380.55-52.630.15Lymphoma361.540.10-24.830.76MDS324.260.38-47.190.24MPD187.400.67-82.360.10Multiple myeloma2300-82.361Aplastic anemia382.540.25-26.210.43Non-malignant disorders348.010.96-66.800.05Solid tumors6110.951.34-89.170.03HLA matchHLA-identical sibling1561Unrelated donor 6/6454.941.84-13.24<0.01Unrelated donor 8/81232.160.90-5.180.09Other matched300-13.241Other mismatched303.301.18-9.240.02Total nucleated cell dose (x108/kg)0-58615-10920.540.24-1.220.1410-14870.370.15-0.940.04>14870.240.08-0.750.01GVHD profylaxisCSA+MTX2401CSA+Pred142.160.63-7.400.22CSA+MMF403.611.38-9.44<0.01Fk 506 +Rapamune451.320.43-4.080.63Other176.242.27-17.16<0.01aAML (n=60) and ALL (n=6). Disclosures: No relevant conflicts of interest to declare.

scholarly journals MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (7) ◽  
pp. 1183-1191 ◽  
Author(s):  
Damiano Rondelli ◽  
Judith D. Goldberg ◽  
Luis Isola ◽  
Leah S. Price ◽  
Tsiporah B. Shore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Survival Rate ◽  
Graft Failure ◽  
High Survival ◽  
High Survival Rate ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Key Points ◽  
Unrelated Donors ◽  
Reduced Intensity

Key Points A high survival rate was seen in primary or secondary MF patients transplanted from matched related donors using the FluMel regimen. FluMel plus ATG in HSCT from unrelated donors for MF patients is associated with an increased risk of graft failure.

Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1599-1606 ◽  
Author(s):  
Christoph Schmid ◽  
Myriam Labopin ◽  
Arnon Nagler ◽  
Dietger Niederwieser ◽  
Luca Castagna ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Prognostic Score ◽  
Working Party ◽  
Reduced Intensity Conditioning ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.

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

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2006-2006
Author(s):  
Jessica Guarino ◽  
Morris Kletzel ◽  
Reggie Duerst ◽  
David Jacobsohn ◽  
Jennifer Schneiderman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Median Time ◽  
Primary Immunodeficiency ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Cd34 Cells ◽  
Unrelated Donors ◽  
Reduced Intensity

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

Age Does Not Predict Outcomes For Elderly Patients With Myelodysplastic Syndromes Undergoing Hematopoietic Stem Cell Transplantation With Reduced-Intensity Conditioning

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2147-2147
Author(s):  
Gregory A. Abel ◽  
Haesook T. Kim ◽  
Philippe Armand ◽  
Corey S. Cutler ◽  
Joseph H. Antin ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Older Patients ◽  
Prognostic Score ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Very High ◽  
Reduced Intensity

Background The National Care Determination for allogeneic hematopoietic stem cell transplantation (allo HSCT) for the treatment of myelodysplastic syndromes (MDS) stated that there is an absence of convincing evidence that allo HSCT improves health outcomes. A prospective data-gathering trial sponsored by the CIBMTR is ongoing; however, until such results are available, retrospective methods specifically comparing older populations are illustrative. Methods We analyzed outcomes for older patients with MDS undergoing HSCT with reduced intensity conditioning (RIC) at the Dana-Farber/BWH with uniform conditioning and graft versus host disease (GVHD) prophylaxis regimens from 2001 to 2011. Patients with CMML were excluded. Those aged 60-65, and those ≥ 66 were compared to assess overall survival (OS), progression free survival (PFS), and other HSCT-related outcomes. Aiming to build a better prognostic score using its significant components, we also assessed the association of the IPSS-R at transplantation as well as each of its components with OS, and fit multivariable Cox regression models with the new prognostic score as well as age. Results We identified 67 patients aged 60 or older who underwent RIC HSCT for MDS. All patients received fludarabine and intravenous busulfan as conditioning, and peripheral blood stem cells. GVHD prophylaxis included tacrolimus/rapamycin +/- MTX. The median age was 64 (60-74) years, and the majority (64%) had unrelated donors. 60% had advanced MDS (IPSS-R high risk or very high risk), 46% had poor risk cytogenetics, and 67% had high or very high disease risk index (DRI). The median age for the 60-65 group was 63; the median age for the ≥ 66 group was 69. We found no significant differences in PFS or OS by age category, as shown below (also see figure): In addition, rates of 6-month grade III-IV GVHD (p=.45) and 2-year incidence of cGVHD (p=0.78) did not significantly differ. The IPSS-R performed only modestly in predicting 4-year OS for this older cohort (p=.20); however, a new 3-level score (including collapsed cytogenetic categories, dichotomous platelet count [ ≥ 50 or < 50], percent blasts in marrow and dichotomous ANC) performed better (p=.008; see figure). In two multivariable models, one that included the IPSS-R and another that included the new score, age was not a significant predictor of OS (p=.78 and .77 respectively). Conclusions Our data suggest that age alone should not limit availability of RIC HSCT for patients with MDS, as older patients in our elderly cohort faired similarly to younger ones with respect to important HSCT-related outcomes. Our new prognostic score, if validated, may be able to help risk-stratify patients. Finally, continued efforts are needed to reduce relapse in high-risk elderly MDS patients. Disclosures: No relevant conflicts of interest to declare.

Thrombotic Microangiopathy with Tacrolimus/Sirolimus-Based GVHD Prophylaxis Regimen in Patients Undergoing Hematopoietic Stem Cell Transplant from a Matched Unrelated Donor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 797-797 ◽  
Author(s):  
Tam Khuu ◽  
Sepideh Shayani ◽  
Joycelynne Palmer ◽  
Roberto Rodriguez ◽  
Pablo Miguel Parker ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Increased Risk

Abstract Thrombotic microangiopathy (TMA) is a multifactorial complication of related and unrelated allogeneic hematopoietic stem cell transplant (allo-HSCT). The true incidence of TMA is difficult to estimate due to lack of agreement on a single definition. Diagnosis is often complicated by multiple potential etiologies for the clinical findings. Sirolimus (SIR), an inhibitor of mammalian target of Rapamycin (mTOR), is a novel immunosuppressive agent that works synergistically with calcineurin inhibitors (CNI) to prevent graft-versus-host disease (GVHD) in allo-HSCT. Recently, the addition of SIR to CNIs was reported to result in a higher than expected incidence (10.8%) of TMA (Cutler et al. BBMT2005; 11:551–7). We evaluated the incidence and risk factors for TMA in a cohort of patients undergoing matched unrelated (MUD) HSCT using SIR combined with tacrolimus (TAC) and mini-methotrexate for GVHD prophylaxis at City of Hope. TMA was defined as SCr increase of ≥ 50% above baseline, LDH twice the institutional upper normal limit, presence of schistocytes or persistent presence of nucleated red blood cells, and prolonged or progressive thrombocytopenia (platelets <50 × 109/L or ≥ 50% decrease from previous count). A case series of 47 MUD-HSCT patients were included in this retrospective chart review study. The median age was 50 years (range: 19–67); (male/female: 28/19). Conditioning regimens consisted of fludarabine/melphalan (65%) and FTBI combined with cyclophosphamide or etoposide (35%). Diagnoses included ALL (32%), AML (25%), NHL (15%), MDS (15%), MPD (9%), CML (2%), CLL (2%). Twenty-six patients (55%) had a 10/10 matched (HLA-A, B, C, DRB1, and DQB1) donor by high-resolution on typing. The median follow up for the 30 surviving patients is 14.5 months (2.8–26). The one-year probabilities of overall survival and non-relapse mortality (NRM) were 61% and 19%, respectively. Grade II-IV acute GVHD (aGVHD) was reported in 60% of all patients (grade III-IV: 25%). Thirteen (28%) patients met the above diagnostic criteria for TMA. In addition, we included two patients who did not meet the criteria due to missing tests but were clinically diagnosed with TMA by independent attending physicians, resulting in the total incidence of 32% (15/47). Four of the 15 patients met the criteria for TMA as a result of ongoing multi-organ failure secondary to other causes. The median time to TMA onset was five weeks (2–20 weeks). Most cases (93%) occurred within the first 100 days post-HSCT. Thirteen patients developed both TMA and aGVHD, in which the majority of patients (70%) developed TMA after a diagnosis of aGVHD had been made. Initial treatments for TMA included holding TAC (33%), holding SIR (20%), holding or adjusting doses (27% and 20%, respectively) for both drugs. One patient underwent plasma exchange. Sixty percent of patients subsequently recovered from TMA as defined by normalization of laboratory values. Of the 17 expired patients, ten were diagnosed with TMA. Causes of death were as follows: for TMA cases, relapse mortality=3, NRM=7; for Non-TMA patients, relapse mortality=6, NRM=1. At the time of TMA diagnosis, the median TAC and SIR levels were 11.3 (0–18.8) and 7 (0–23.9) ng/ml, respectively, in contrast to the median TAC and SIR levels for non-TMA patients at 6.1 (p= 0.02) and 5.5 (p=0.13) ng/ml, respectively. To identify other possible risk factors for TMA, the following patient and treatment-related characteristics were examined: age, conditioning regimen, disease type, degree of HLA match, and exposure to triazole antifungals. Only higher tacrolimus levels (HR: 6.9, p<0.01) and aGVHD grades III-IV (HR: 3.5, p=0.02) were associated with an increased risk for TMA. In conclusion, TMA is common after MUD allo-HSCT using SIR-containing GVHD prophylaxis. The risk factors for TMA suggest that careful monitoring and adjustment of TAC/SIR dosages to avoid super-therapeutic levels is critical, particularly during ongoing GVHD.

Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Multicenter Open French Study In High-Risk pediatrics

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 534-534
Author(s):  
Catherine Paillard ◽  
Patrick Lutz ◽  
Guy Leverger ◽  
Gerard Michel ◽  
Pierre Bordigoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Solid Tumors ◽  
Median Time ◽  
Graft Failure ◽  
Hematological Malignancies ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Abstract 534 Introduction: There is increasing information about reduced intensity conditioning regimen AlloHSCT (Allogeneic Hematopoietic Stem Cell Transplantation) in children. The safety of this approach is now well established but data regarding efficacy are limited and the role in pediatric cancer has yet to be defined. Materiels and methods: We report results of a French pediatric AlloHSCT protocol with ATG-fludarabine (180 mg/m2) - Busilvex (3.2 at 4.8 mg/kg/d for 2 days) conditioning regimen. Related, unrelated bone marrow (BM) and Peripheral blood stem cell (PBSC) donors and Cord blood units (CB) were allowed. In case of CB a TBI 2 grays, Cyclophosphamide 50 mg/kg, Fludarabine 100 mg/m2 conditioning regimen was recommended. GVH prophylaxis consists in cyclosporine alone. A rapid discontinuation of systemic immunosuppression and re-injecting donor lymphocytes to initiate graft-versus-tumor effect are based on tumor assessment and blood chimerism. Inclusion criteria are children with malignancies that can be potentially cure by allograft but a conventional conditioning regimen being impossible due to toxicity and children with solid tumor or hematological malignancy remaining unresponsive to the reference strategies according to French best practices in pediatrics. Results: From April 2007 to April 2010, 40 RIC AlloHSCT were performed in 10 different French pediatric graft centers: 13 Hodgkin Lymphoma, 7 acute myeloblastic leukaemia, 2 acute lymphoblastic leukaemia, 6 neuroblastoma, 8 rhabdomyosarcoma, 3 desmoplastic tumor and 1 Ewing sarcoma. Median age at transplantation was 15 years and median time from diagnosis to transplant was 18 months. Before transplant, 15 patients are in complete response and 25 patients (14/18 solid tumors) have active disease (11 progressive, 14 partial response). 21 had already received a myeloablative therapy (18 autograft and 3 allograft). Graft source was PBSC in 17 cases (7 related and 10 unrelated), BM in 18 (10 related and 8 unrelated), and 5 CB. The RIC Bu-flu conditioning regimen permits rapid engraftment without major toxicity contrary to the Cy-TBI in CB. 1 patient had primary graft failure: 1 CB and 5 patients experienced secondary graft failure: 3 CB, 1 PBSC and 1 BM. Median time to reach an ANC of 0.5 109/l was 16 days. Median time to reach a platelet count of 20 × 109/l was 2 days. Platelet count did not decrease below 20 109/l in 10 allografts. At day 30 post-transplant, chimerism is mainly donor for 30 and partial for 6 children. At day 100 post transplant, 4 out of 6 with initial mixed chimerism were converted into full donor chimerism. 8 patients received DLI and 17 patients experienced acute graft versus host disease (GvH) (2 grade IV and 15 grade ≤ II). A low day 365 TRM of 5% is reported in these heavily pre-treated patients. With a median follow-up of 15 months, the estimated 2 yr overall survival (OS) was respectively 57 % (71% for hematological malignancies and 42% solid tumors) (fig 1) and event free survival (EFS) 36% (50% for hematological malignancies and 19% solid tumors). Univariate analysis of EFS and OS showed no effect of related versus unrelated stem cell sources and BM versus PBSC. Our analysis identified a group of patients, who had no measurable disease at transplant, with a 2 yr OS and EFS of 86%. In term of efficacy, we observe a graft versus lymphoma effect in patients with advanced active Hodgkin lymphoma. Concerning solid tumors, all children included had a very bad prognosis and detectable disease before transplant. Our results may suggest that an immune-mediated effect cannot be excluded in some refractory solid pediatric tumors particularly in neuroblastoma. The main cause of failure of this approach is disease progression. Immunologic approaches after transplantation may help cure more of these very-high-risk patients. Conclusion: Even if further follow up is needed, this prospective study suggest that RIC regimen provides promising outcome in children previously not eligible for myeloablative AlloHSCT. This study “RICE” was registered at www.clinicaltrials.gov as NCT 007 50 126 Disclosures: No relevant conflicts of interest to declare.

Robust Immune Reconstitution in Children with Severe Primary Immunodeficiency after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3923-3923
Author(s):  
William T. Tse ◽  
Jessica Ward ◽  
Jennifer Schneiderman ◽  
Sonali Chaudhury ◽  
Ramsay Fuleihan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Failure ◽  
Immune Reconstitution ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Once Daily ◽  
Post Transplant ◽  
Cell Counts ◽  
Primary Graft Failure ◽  
Reduced Intensity

Abstract Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe primary immunodeficiency diseases (PID), but it is still unclear what is the optimal transplant approach. To help answer this question, the stem cell transplant team at Ann & Robert H. Lurie Children's Hospital of Chicago (formerly Children's Memorial Hospital) evaluated the risks and benefits of a reduced-intensity conditioning (RIC) transplant approach for treatment of severe PID. Between 2000 and 2013, 42 children with severe PID were treated with allogeneic HSCT following a RIC regimen consisting of fludarabine (30mg/m2/day x 6), rabbit anti-thymocyte globulin (once daily x 4), and intravenous busulfan (once daily x 2). Total busulfan exposure, as measured by the plasma concentration-time area-under-the-curve (AUC), was targeted individually for each patient at 4000 µM*min/day in an earlier cohort (n=14), and 5000 in a later cohort (n=28). Patients were treated in an ambulatory setting and were hospitalized only for specific medical or social reasons. There were 31 male and 11 female patients. The median age at the time of transplant was 8.2 months (range 1 month-17.4 years). The median weight was 7.6 kg (range 2.5-81.5 kg). Patients were diagnosed with severe combined immunodeficiency (n=17), Wiscott-Aldrich syndrome (n=7), hyper-IgM syndrome (n=5), major histocompatibility complex II deficiency (n=3), X-linked lymphoproliferative disease (n=3), NEMO syndrome (n=2), Omenn syndrome, reticular dysgenesis, Chediak-Higashi syndrome, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, and IPEX-like syndrome (n=1 each). Fourteen patients had related donors and 28 had unrelated donors. Twenty-eight patients received peripheral blood HSC, 12 received cord blood, and 2 received bone marrow as the source of HSC. All patients tolerated the conditioning regimen with minimal nausea, vomiting, or pain. No severe mucositis, sinusoidal occlusion syndrome, seizure, grade III/IV acute GVHD or extensive chronic GVHD were seen. In most patients, the engraftment was rapid, with ANC ≥ 500 at a median of +15 days post-transplant, following a nadir at day +10 with a median ANC nadir of 60. In the AUC 4000 cohort, 2 patients (14%) developed primary graft failure and 2 patients (14%) developed immune-mediated secondary graft failure; in the AUC 5000 cohort, 2 patient (7%) developed primary graft failure and 1 patient developed secondary graft failure after primary EBV infection. Two patients died from complications associated with primary graft failure, 2 from complications caused by EBV infections, and 2 from complications related to their underlying diseases in the early post-transplant period. Kaplan–Meier analysis shows overall and event-free survival rates of 81.9% and 73.6%, respectively, at a median follow-up of 4.3 years. Most engrafted patients have stable donor chimerism over time. At a mean of 3.5 years post-transplant, the median donor chimerism in total white blood cells was 97% and the first and third quartiles were 77% and 99%, respectively. Engrafted patients demonstrated robust immune reconstitution with B and T cell counts normalized by 3 months and 9 months post-transplant, and CD45RA+ naive T cells by 1 year. Between 1 to 4 years post-transplant, the median absolute CD4+, CD8+ and CD19+ cell counts were 1388, 976 and 720 per mm3, respectively, percentage of CD45RA+ naive CD4 and CD8 cells were 68% and 81%, and endogenous IgG and IgM levels were 840 and 97 mg/dL. T cells showed regular responses to antigen and mitogen stimulation and exhibited normal TCRVβ repertoires. Endogenous IgG levels returned to normal by day +100, and no intravenous immunoglobulin infusion was required after day +100 in all but 1 patients. Positive vaccine-specific antibody responses were seen in patients after reimmunization at 12-24 months post-transplant. Clinically, patients have normal growth and development and do not exhibit increased susceptibility to infection. Our data showed that HSCT after RIC offers an optimal treatment for severe PID by providing robust post-transplant immune reconstitution while minimizing side effects. To reduce the risk of graft failure, we recommend a targeted busulfan AUC of 5000 µM*min/day for 2 days. Disclosures No relevant conflicts of interest to declare.

Cyclosporine a and Mycophenolate Mofetil Vs Cyclosporine a and Methotrexate as Gvhd Prophylaxis in Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation from HLA-Identical Sibling Donor.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2229-2229
Author(s):  
Jose Luis Piñana ◽  
David Valcarcel ◽  
Rodrigo Martino ◽  
Francesc Fernandez ◽  
Pere Barba ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
Cyclosporine A ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Sibling Donor ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract J.L.Piñana is supported by grants from the Instituto de Salud Carlos III (expedient CM06/00139, Ministerio de Sanidad) Background: Cyclosporine A (Csa) with methotrexate (MTX) is the most common prophylactic regimen against acute graft versus host disease (aGVHD). Although some studies show that Mycophenolate Mofetil (MMF) in combination with Csa for patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is associated with early hematologic recovery, less toxicity as mucositis and no diferencies in terms of aGVHD. Limited data is available comparing these two combinations in reduced intensity conditioning Allo-HSCT (Allo-RIC). In this case-control study from two Spanish BMT centers, we retrospectively analyzed the introduction of MMF as GVHD prophylaxis in comparison with a short course of MTX in a large series of patients who underwent HLA identical sibling donor Allo-RIC. Patients and methods: We include 145 consecutive Allo-RIC patients, who received peripheral blood (PB) as source of stem cells, between April 2000 and August 2007. The median follow-up for the whole group was 514 days (8 to 3170 days). The study group included 91 males and 54 females. Median age was 55 years (range 18 to 71 years). Diagnoses were acute leukemia/myelodisplastic syndrome/myeoloproliferative disorders) (n=37/15/13), multiple myeloma (n= 32), Hodgkin lymphoma (n= 6), chronic lymphocytic leukemia (n=15) and non-Hodgkin lymphoma (NHL) (n= 27). GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with busulfan (59 recipients) or melphalan (86 cases). Results: The occurrence of mucositis grade 2–4 was higher in the CsA/MTX group than in the CsA/MMF group (57% vs 23% p= 0.001). No significant differences were found between CsA/MMF and CsA/MTX groups in time to neutrophil recovery (15 +/−3 days vs 15 +/− 2days) (p= 0.5). Cumulate incidence of acute GVHD were 50% (95% C.I., 38–65) for CsA/MMF group and 48% (95% C.I. 39–60%) for CsA/MTX group (p= 0.9). Although chronic GVHD was also similar [71% (95% C.I. 58–86%) in CsA/MMF group vs 68% (95% C.I. 57–80%) in Csa/MTX group (p= 0.7)], we observed that the development of chronic GVHD was delayed in the CsA/MMF group [174 days (range 100–365) vs 134 days (range 84–302) p= 0.008)]. Non relapse mortality (NRM) at 100 days was higher in MTX group (6% vs 18%, p=0.04). However, relapse and overall survival at median follow-up were still similar between groups (25% vs 18%, p= 0.4 and 52% vs 51%, p=0.7, respectively). Conclusion: We conclude that the combination Csa/MMF appears to be at least equivalent to the standard Csa/MTX GVHD prophylaxis in HLA identical sibling donor Allo-RIC. The toxicity profile of Csa/MMF was better, reflected by a significantly less incidence of mucositis.

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