Increased Incidence of Chronic Graft-Versus-Host Disease (GVHD) and No Survival Advantage with Filgrastim-Mobilized Peripheral Blood Stem Cells (PBSC) Compared to Bone Marrow (BM) Transplants From Unrelated Donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a Phase III, Prospective, Randomized Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1-1 ◽  
Author(s):  
Claudio Anasetti ◽  
Brent R. Logan ◽  
Stephanie J. Lee ◽  
Edmund K Waller ◽  
Daniel J. Weisdorf ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Disease Risk ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Phase Iii ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Abstract 1 Background: Randomized trials demonstrated that filgrastim-mobilized PBSC compared to BM from HLA-identical siblings improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Retrospective analyses of unrelated donor transplants did not appreciate the same PBSC protective effect. Patients and Methods: The BMT CTN, sponsored by the NHLBI and NCI, conducted a Phase III, randomized, multicenter, trial of unrelated donor PBSC versus BM. The primary objective was to compare two-year survival probabilities in the two study arms using an intent-to-treat analysis. Both patients and donors provided informed consent. Fifty centers in the U.S. and Canada enrolled patients between January, 2004 and September 2009. Median follow up is 36 months (interquartile range 25 – 37 months). Randomization was performed in a 1:1 ratio to either PBSC or BM and stratified by transplant center and disease risk. Of the 278 subjects randomized to BM, 5% had no transplant, and 4.3% crossed over to PBSC; of the 273 randomized to PBSC, 4% had no transplant, and 0.4% crossed over to BM, so subjects on both arms had greater than 90% compliance with the assigned therapy. Patient primary disease (AML, ALL, CML, MDS, CMML, and MF), disease risk, gender, age, race, ethnicity, CMV serology, performance status, comorbidity, organ function, conditioning regimen, GVHD prophylaxis, use of growth factors, and donor characteristics were all well balanced between the two groups. Overall, 90% were adults over age 20, 47% had AML, 28% had high risk disease, 48% were conditioned with cyclophosphamide plus total body irradiation, and 71% received tacrolimus plus methotrexate for GVHD prophylaxis. Results: There were no observed differences in outcomes between the two groups except for a higher incidence of overall chronic GVHD (see Table) and more common chronic extensive GVHD with PBSC (46% vs. 31%). There were no survival differences according to graft sources in planned subset analyses of low and high risk malignancy or in those received HLA-matched or mismatched grafts. Primary causes of death were relapse in 54% vs. 49%, graft failure in 7% vs. 0%, acute or chronic GVHD in 22% vs. 34%, others in 16% vs. 16% of the BM and PBSC arms, respectively. Conclusion: This large randomized trial shows that PBSC from unrelated donors is associated with higher rates of chronic GVHD compared to BM, although rates of acute GVHD, relapse, non-relapse mortality and overall survival are similar. Disclosures: Off Label Use: Cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, irradiation were used to eradicate malignancy. Tacrolimus, cyclosporine, methotrexate were used for GVHD prophylaxis. Westervelt:Novartis: Speakers Bureau.

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4545-4545
Author(s):  
Jorge Gayoso ◽  
Mi Kwon ◽  
David Serrano ◽  
Pascual Balsalobre ◽  
Javier Anguita ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Haploidentical Transplantation ◽  
Gvhd Prophylaxis

Abstract Abstract 4545 Introduction: Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor. Patients and Methods: We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5. Results: From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated. Conclusions: HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution. Disclosures: No relevant conflicts of interest to declare.

A Randomized Trial of Rabbit Anti-Thymocyte Globulin, Given on Day+7 after Alternative Donor Transplants.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 754-754 ◽  
Author(s):  
Andrea Bacigalupo ◽  
Teresa Lamparelli ◽  
Fabio Ciceri ◽  
Fedro Peccatori ◽  
Anna Locasciulli ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Risk Score ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hemopoietic Stem Cell ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Cox Analysis ◽  
To Receive

Abstract Background. We have shown that the risk of transplant mortality (TRM) can be predicted by using laboratory values, on day+7 after an allogeneic hemopoietic stem cell transplant (HSCT) (Sormani et al, Bone Marrow Transpl.2003). TRM in patients with low, intermediate and high risk on day+7, is 15%, 40% and 69%: increased mortality is mainly, but not exclusively, due to increased acute graft versus host disease (GvHD). In a pilot study we have shown that a small dose of rabbit anti-thymocyte globulin (rATG) (Thymoglobulin, Genzyme), was feasible and reduced GvHD and TRM. Aim of the study. We have therefore opened a randomized trial testing this hypothesis in patient undergoing an unrelated donor HSCT, with rATG (7.5 mg/kg) in the conditioning regimen. Patients. 170 were eligible: all patients received rATG 3.75 mg/kg x2 pre-transplant, and on day+7 they were scored and randomized to receive an additional dose of rATG (1,25 mg/kg day +7 and day+9) (n=84) or to receive no further treatment (n=86) (control arm). The two groups were balanced for age, disease phase and day+7 score. Results. The predictive value of day+7 score on TRM was confirmed in the control arm (18% vs 42% for intermediate and high risk patients, p=0.03), whereas in the day+7 ATG arm, there was no difference (29% vs 29%, p=1.0). TRM was overall reduced from 35% in the control arm to 29% in the ATG day+7 arm (p=0.37) : the difference was more pronounced in patients with early disease and high risk on day 7 (35% vs 15% p=0.08). Acute GvHD grade III–IV was reduced overall from 16% to 6% (p=0.04), and chronic GvHD was reduced 32% to 14% (p=0.02). In multivariate COX analysis TRM and overall survival was predicted by risk score day7 and disease phase. Conclusions. We confirm that patients with different risk of TRM can be identified on day+7 after HSCT. Administration of rATG on day+7 can influence the risk of TRM, by reducing acute and chronic GvHD. Additional intensified supportive care (including anti-infectious therapy) may further reduce TRM in patients with a high risk score on day+7.

Unrelated Cord Blood Transplants in Children with Acute Leukemia: Experience of a Single Center

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4424-4424
Author(s):  
Rosa Branca Ferreira ◽  
Carlos Pinho Vaz ◽  
Isabel Barbosa ◽  
Susana Roncon ◽  
Fernando Campilho ◽  
...  
Keyword(s):  
Cord Blood ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Successful Transplantation ◽  
Unrelated Donors ◽  
Alternative Sources ◽  
Unrelated Cord Blood

Abstract Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant diseases. However, the ability to identify suitable related or unrelated donors can be difficult in some patients (pts). Alternative sources of stem cells such as cord blood (UCB) provide a readily available graft mainly for pediatric patients. Between October 1996 and May 2008, 23 consecutive patients (pts), with a median age of 6 years old (range:1 – 11), 13 male and 10 female, underwent UCB transplant for the treatment of acute lymphoblastic leukemia (n= 15), acute myeloid leukemia (n=7) and acute byphenotypic leukemia (n= 1). Conditioning regimen consisted of intravenous busulfan (3.2 mg/kg/day x 4 days), cyclophosphamide (120 mg/Kg) and rabbit antithymocyte globuline (15 mg/Kg) ±melphalan (140 mg/m2) and GVHD prophylaxis consisted of a calcineurin inhibitor and MMF or MTX. All grafts were HLA mismatched. The median infused cell doses were, respectively 3.2× 107/kg (range: 1.2–21) and 1.27×105/kg (range:0.2–4.3) for nucleated cells (NC) and CD34 + cells. Engraftment occurred in 18 pts (75%). Five pts failed engraftment, of wich 4 underwent a second transplant (3 autologous and 1 haploidentical) and 1 died of infection at day +59. Grade II–IV acute GVHD occurred in 12 pt and chronic GVHD in 2 of 14 pt at risk. With a median follow up of 1,5 years (range: 3 months-9.5 years), overall survival (OS) at 3 years is 40% (± 13%) and event free survival (EFS) at 3 years is 32% (± 11%). Non relapse mortality (NRM) was 13.6 % (± 7.3%). UCB transplants represents a valuable alternative to bone marrow or peripheral blood especially for pts requiring urgent transplant or lacking an HLA matched unrelated donor and having the potential advantage of an immune tolerance allowing successful transplantation despite HLA disparity

No Improvement of Overall-Survival in Children with High-Risk Acute Myeloid Leukemia by Stem Cell Transplantation in 1st Complete Remission.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 320-320 ◽  
Author(s):  
Dirk Reinhardt ◽  
Bernhard Kremens ◽  
Martin Zimmermann ◽  
Josef Vormoor ◽  
Michael Dworzak ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Children And Adolescents ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hla Typing ◽  
Unrelated Donor ◽  
The Impact

Abstract One aim of the AML-BFM 98 study was to evaluate prospectively the impact of matched sibling donor (MSD)-SCT in 1st complete remission (CR) in children with high-risk (HR)-AML. Patients: Between 7/1998 and 3/2004 494 children and adolescents were enrolled in the studies AML-BFM 98 and the AML-BFM 98 Interim 2003. Patients with favorable cytogenetics [t(8;21), inv(16), t(15;17)], corresponding morphology (AML FAB M1/2 with Auer rods, M4eo, M3) and < 5% blasts on day 15 were defined as standard risk (SR)-group (n=177). All others were stratified to HR-group (n=317) and eligible for SCT in 1st CR. Out of 275 patients achieving 1st CR (87%) 63 patients had a MSD and 188 had no MSD (intent-to-treat group, ITT) while 24 patients had to be excluded due to missing HLA typing or initial refusal to SCT. Thirty-six patients received MSD-SCT (=as-treated group), another two children were transplanted from a matched unrelated donor (MUD) although an MSD was available. The reasons not performing SCT in 1st CR in the remaining 25 children with a donor available were early relapse (n=7), death in CR (n=2), clinical reasons (n=8), or refusal of SCT (n=8). Chemotherapy (CHT) only was given in 192 patients (n=167 without MSD, n=25 with a MSD). Another 21 children were transplanted from an unrelated donor (n=18), family donor (n=1), haploidentical donor (n=2). The reasons were slow response, very poor cytogenetics or other clinical reasons. Treatment: All patients received double induction and consolidation. MSD-SCT in 1st was scheduled after 4 blocs of treatment. Children who were not transplanted in 1st CR received intensification and a 1-year maintenance therapy. The recommended conditioning regimen consisted in busulfan and cyclophosphamide. Results ITT analysis revealed no significant differences in of 5 year disease-free survival (DFS) and overall survival (OS) between children with or without a donor (no donor vs. donor: DFS 43±4% vs. 47±7% plog rank 0.52; OS 56±4% vs. 58±9%, plog rank 0.16). The as-treated analysis gave similar results: CHT only vs. MSD-SCT: DFS 35±11% vs. 59±9% p Mantel-byar 0.13; OS 59±13% vs. 62±12%, p Mantel-byar 0.51). The major reasons of treatment failures were relapses in all groups [CHT only n=100 (52%), MSD-SCT n=13 (34%), MUD-SCT n=9 (50%)]. A 2nd CR was achieved in 71% of the CHT only group (n=74). After SCT in 2nd CR, OS was 40±6%. By contrast, only two children (9%) of 22 children after relapse following SCT in 1st CR could be salvaged. Severe late adverse events (e.g. severe chronic GvHD CTC grade IV, destruction of big joints, intracerebral bleedings) were more frequent in children transplanted in 1st CR (15%) than in those with CHT only (including SCT in 2nd CR; 5%, p×2< 0.05). Conclusion: In the population-based, prospective multi-center study AML-BFM 98 allogeneic MSD-SCT in 1st CR showed no advantage in children and adolescents with HR-AML. Considering the higher toxicity of allogeneic SCT, in the ongoing trial AML-BFM 2004, this SCT (MSD or MUD) is restricted to patients in 2nd CR and refractory AML.

A Randomized Prospective Multicenter Phase III Trial Comparing Standard GvHD Prophylaxis with Cyclosporine and Methotrexate with Additional Pretransplant ATG Fresenius (ATG-F) in Allogeneic Stem Cell Transplantation from Matched Unrelated Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 57-57 ◽  
Author(s):  
Jürgen Finke ◽  
Wolfgang Andreas Bethge ◽  
Claudia Schmoor ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Group Versus ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Trial ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Treatment Comparisons ◽  
Grade Iii

Abstract Graft versus host disease is a major cause of morbidity and mortality after allogeneic stem cell transplantation from unrelated donors. Strategies using intensified GvHD prophylaxis including T cell depletion did not result in better outcome due to increased risks of infection and relapse. The use of ATG in the conditioning regimen for in vivo-Tcell depletion for GVHD prophylaxis has been reported by several groups but not been tested in a large prospective randomized trial. Here we report on results from the first large prospective, randomized, multicenter, open-label, phase III trial comparing standard GvHD prophylaxis with cyclosporine A (CyA) and short course methotrexate (Mtx) days +1, +3, +6, +11 (15/10/10/10 mg/m2) with or without 3×20mg/kg ATG-Fresenius (ATG-F) after a median follow-up time of two years. Between 2003 and 2007, 201 patients, median age 40 (range 18–60) years with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94), were transplanted from HLA-A and -B (2 digit), DRB1, DQB1 (4 digit) identical unrelated donors after highdose myeloablative conditioning with marrow (n=37) or PBSC (n=164) grafts. Median follow up time was 732.5 (25%-quartile 604, 75%-quartile 1097) days. For treatment comparisons with regard to the occurrence of aGvHD grade III-IV or death within 100 days post Tx, logistic regression adjusted for status of disease, source of stem cells, and center was used. For treatment comparisons with regard to time-to-event variables, cumulative incidence rates considering relapse and death as competing events were estimated, and Cox regression modelling the event-specific hazard rates and adjusting for status of disease and source of stem cells was used. Engraftment with WBC &gt; 1000/μl was achieved in 97% in the ATG-F group after median 26 days, and in 95% in the control group after median 19 days (p&lt;0.0001). At day +100, the rate of patients experiencing the primary efficacy endpoint-severe aGvHD (grade III–IV) or death - was 21.4% in the CyA/Mtx/ATG-F arm versus 33.7% in the CyA/Mtx only arm (p=0.1286). Incidence of grade III–IV acute GvHD was 11.7% in the ATG-F arm and 24.5% in the control group (p=0.054), grade II–IV aGvHD was 33.0% vs. 51.0% (p=0.0108), and grade I–IV aGvHD was 56.3% vs. 74.5% (p=0.0073). Incidence of chronic GvHD (limited and extensive) after two years was 30.8% in the ATG-F group versus 58.8% in the control group (p&lt;0.0001). Incidence of extensive chronic GvHD after two years was 12.2% in the ATG-F group versus 42.6% in the control group (p&lt;0.0001). Disease-free survival (DFS) after two years was 51.6% in the ATG-F and 47.5% in the control group (p=0.65). Incidence of relapse/progression after two years was 28.9% in the ATG-F and 23.6% in the control group (p=0.55). Incidence of death without former relapse/progression (TRM) after two years was 19.6% in the ATG-F and 28.9% in the control group (p=0.198). Overall survival (OS) after two years was 59.2% in the ATG-F and 51.9% in the control group (p=0.47). Number of infections per follow up year was 4.54 in the ATG-F and 4.76 and in the control group. The addition of ATG-F to standard CyA/Mtx prophylaxis results in decreased incidence of acute and chronic GvHD without increase of relapse or TRM rates. This is the first randomized trial answering the long-standing question regarding the beneficial effect of additional ATG-F to a standard GvHD prophylaxis. A reduction of GvHD without compromising survival could be demonstrated.

Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2002-2008 ◽  
Author(s):  
Ann E. Woolfrey ◽  
Claudio Anasetti ◽  
Barry Storer ◽  
Kristine Doney ◽  
Laurie A. Milner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Marrow Transplant ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Conditioning Treatment ◽  
Unrelated Donors ◽  
Total Body

Abstract Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P &lt; .0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P = .10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P = .23). LFS rates were lower in patients with advanced disease (P &lt; .0001), age 10 years or older (P = .002), or short duration of CR1 (P = .007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.

scholarly journals Busulfan, Cyclophosphamide and Melphalan As Conditioning Regimen for Pediatric Patients with AML in 1st or 2nd CR: A Retrospective Analysis from the AIEOP HSCT Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2106-2106
Author(s):  
Annalisa Ruggeri ◽  
Marco Zecca ◽  
Franca Fagioli ◽  
Adriana Balduzzi ◽  
Mattia Algeri ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Pediatric Patients ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Donor Type

Abstract Allogeneic stem cell transplantation (HSCT) is largely adopted as post-remissional therapy in children with acute myeloid leukemia (AML) in first complete remission (CR1) but with high-risk characteristics (including high-risk cytogenetics or high levels of minimal residual disease at the end of induction therapy) or to rescue patients reaching CR2 after a previous relapse. Busulfan-based regimens represent the standard of care for these patients in association with alkylating agents. One of the most frequent drugs combination used in Europe in pediatric patients is Busulfan, Cyclophosphamide and Melphan (BuCyMel), which provide a potent anti-leukemic effect, despite remarkable extramedullary toxicities, especially in adolescents. We aimed at analyzing the results of children with AML receiving BuCyMel and reported to the AIEOP registry from 2008 to 2015. A total of 182 patients were reported by 15 transplant centers. Median age at HSCT was 9 years (range 0.3-18); 100 patients (55%) were male. Disease status at HSCT was CR1 in 159 (88%) patients and CR2 in the remaining 23 (12%). All patients received the same myeloablative conditioning regimen with BuCyMel and GVHD prophylaxis was mainly based on calcineurin inhibitors, with the addition of methotrexate in unrelated donors recipients. In vivo T-cell depletion/modulation with ATG was used in 90 cases (49.5%). In almost all cases, pharmacokinetics monitoring of Busulfan was performed, with the drug dosage adjusted according to the systemic exposure evaluated after the first dose. Donor type was an HLA-matched family donor (MFD) in 82 (45%) patients and an unrelated donor (UD) in 100 (55%); 154 (85%) patients received bone marrow (BM) as stem cell source, while the remaining patients (15%) were transplanted with peripheral blood stem cells (PBSCs). Median follow up for surviving patients was 39 months (range 1-111). All patients achieved neutrophil engraftment. The cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD was 35% (95%CI 28-42) and 11% (95% CI 7-16), respectively. The CI of aGVHD was not different according to the type of donor, being 37% (95%CI 28-50) and 32% (95%CI 24-46) in MFD and UD, respectively (p=0.38). The CI of chronic GVHD at 3 years was 17% (95%CI 12-24), while that of extensive cGVHD was 6% (95%CI 3-10). No difference was found in the CI of CGVHD according to the donor employed (MFD 15% and UD 19%, p=0.49). Overall, the CI of relapse and non-relapse mortality (NRM) at 3 years was 18% (95%CI 12-26) and 15% (95%CI 10-22), respectively. The CI of relapse and NRM was significantly different according to age at HSCT (using 12 years as cut-off): (Relapse age<12y: 21% (95%CI 15-32) and age>12y: 11% (95%CI 3-32), (p=0.003); NRM age<12y: 10% (95%CI 5-20) and age>12y: 24% (95%CI 15-37), (p=0.005). According to disease status at HSCT the CI of relapse and NRM were as follows: Relapse: CR1: 18% (95%CI 18-26), CR2 15% (95%CI 5-41) p=0.90) and NRM CR1: 14% (95%CI 9-21), CR2 19% (95%CI 8-46) p=0.38). Also, there was no difference in relapse and NRM by donor type, relapse: MFD 16% (95%CI 9-28), UD 19% (95%CI 11-32) p=0.38) NRM: MFD 19% (95%CI 11-34), UD 11% (95%CI 7-20) p=0.62). Causes of deaths were disease recurrence (39%), infections (27%), and GVHD (12%). Three- years overall survival (OS) and disease-free survival (DFS) were 74% (95%CI 67-81) and 68% (95%CI 60-70). DFS was 70% (95%CI 60-77) and 67% (95%CI 47-87) for patients transplanted in CR1 and CR2 respectively, (p=0.39); and was 70% (95%CI 59-81) and 65% (95%CI 53-78), p=0.77, for UD and MFD HSCT recipients, respectively. In conclusion, our results confirm the efficacy of BuCyMel in preventing relapse in a large series of pediatric patients affected by AML in CR1 and CR2. Adolescents represent a population of more fragile patients at risk of developing transplant-related fatalities. Optimization of toxicity profile and supportive care could further improve outcomes. Prospective randomized clinical trials are warranted to assess the best conditioning regimen for children and adolescents with AML. Disclosures Zecca: Chimerix: Honoraria. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Immunotransplantation for multiple myeloma using allogeneic peripheral blood stem cell transplantation

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17516-17516
Author(s):  
E. S. Santos ◽  
S. Shah ◽  
J. Rink ◽  
R. S. Weiner ◽  
A. M. Miller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Gvhd Prophylaxis ◽  
Methylprednisolone Treatment

17516 Background: Despite the improvement seen in patients with multiple myeloma (MM) treated with autologous hematopoietic cell transplantation (auto-HCT), most of the patients relapse or die of their disease. The objective of the study was to decrease toxicity of allogeneic HCT for MM patients while allowing the benefit of graft-versus-myeloma effect by using a non-myeloablative HCT (NM- HCT) approach. Methods: Newly diagnosed or previously treated myeloma patients of any stage were enrolled. All patients but one received VAD regimen prior to conditioning regimen which consisted of Fludarabine at 30 mg/m2/day on days -5, -4, -3 and Melphalan at 80 mg/m2 x 2 on days -2 and -1. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine 3 mg/kg intravenously on day -2 and methotrexate at 10 mg/m2 intravenously on days 3, 6, and 11. Results: A total of 8 MM patients (4 IgG, 1 IgA, 1 light chain restriction, 2 non-secretory MM) with a median age of 46 years old (range, 35 to 57 years) have been enrolled. Only one patient received 3 regimens prior to NM-HCT. The initial responses to therapy prior to NM-HCT were: 2 CR, 1 nCR, and 5 PR. All patients received identical 6/6 HLA sibling donor stem cells. All patients but one attained CR (88%) after NM-HCT. The median time for ANC engraftment (≥ 500/mm3) was 12.5 days (range, 10–22 days). Four patients developed acute GVHD grade I-II (3 skin, 1 gastrointestinal); all of them responded well to methylprednisolone treatment. Four patients developed chronic GVHD (grade I-II). The 100-day mortality rate was 12% (1 patient died at day + 96 without evidence of MM). Post-transplant, all patients have reported a Karnofsky’s scale performance status between 80%-100%. Two patients relapsed after 31 months post-transplantation. After a median follow-up of 46 months, median survival has not been reached. Only 1 patient who relapsed has received treatment including auto-HCT. Conclusions: NM-HCT is a feasible treatment option in MM patients with a manageable toxicity profile and acceptable treatment-related mortality. Longer follow-up is needed to evaluate for graft-vs- myeloma effect using this approach. No significant financial relationships to disclose.

Influence of Allele Level HLA Typing on Unrelated Donor (UD) Transplantation for High Risk Myeloid Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2916-2916
Author(s):  
S. Parmar ◽  
M. Fernandez-Vina ◽  
P. Liu ◽  
P. Cano ◽  
B. S. Andersson ◽  
...  
Keyword(s):  
High Risk ◽  
High Resolution ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Myeloid Leukemias ◽  
Reduced Intensity

Abstract Donor-recipient histocompatibility is a major determinant of outcome after UD HSCT, and matching pairs by high-resolution (Hi-res) HLA typing is likely to improve results. Methods: We studied 66 pts with myeloid leukemias in complete remission (CR) transplanted with UD bone marrow (n=58) or peripheral blood (n=8) from 01/02 to 12/04. Preparative regimens were ablative [Busulfan (Bu)/Cyclophosphamide (Cy)(n=13), Cy/TBI (n=2), Fludarabine (Flu)/Bu 130 mg/m2x4 doses (n=33)] and reduced intensity [Flu/Bu 130 mg/m2x2 doses+Gleevec (n=7), Flu/Melphalan 140mg/m2 (n=11)]. ATG was given in 61 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate, with additional pentostatin in 24 pts. Hi-res typing of HLA-A, B, DRB1 and DQB1 loci was done prospectively; HLA-DPB1 and C loci were typed prospectively in 50% of cases and retrospectively in 50%. Hi-res typing was sequencing-based for HLA-A, B, DRB1, SSP-based for DRB3/4/5, DQB1 and DPB1; and SBT/SSOP-based for HLA-C. A Cox’s proportional hazards regression model was used to study overall (S), event-free (EFS) and aGVHD-free survival. Variables with a p-value &lt;0.25 by univariate analysis were included in the multivariate model (MV). Variables were age, conditioning regimen, use of pentostatin, diagnosis, cytogenetics, SC source, ABO typing, infused total nucleated cell (TNC) dose, HLA matching and GVHD. Results: Median age was 45yrs (21–72). Diagnoses were MDS (n=5), AML (n=39), and CML (n=22). 21 pts were in 1st CR, 23 pts in 2nd or 3rd CR, 22 pts in 2nd or greater chronic phase (CP) CML. 45 pts were 10/10 HLA match (HLA-A, B, C, DRB1, DQB1), and 21 had one or more mismatches. All pts engrafted neutrophils at a median of 13 days; 32 pts (48%) had gd. II–IV aGVHD and 33 pts (57%) had cGVHD. With a median follow-up of 9 mo, 44 pts are alive; 11 pts have relapsed. There were no regimen-related deaths; 100-day mortality was 13% due to aGVHD (n=7), relapse (n=1) and infection (n=1). Median S and aGVHD-free survival in 10/10 pts have not been reached. Median EFS for 10/10 pts vs others is 34 vs.9.66 mos. MV for S: age ≥60yrs (P=0.02; HR 4.17 (95%CI 1.24–14), Flu-based regimen (P=0.0004; HR 0.14 (95%CI 0.05–0.41), use of pentostatin (P=0.02; HR 0.27 (95%CI 0.09–0.78) and grade II–IV aGVHD (P=0.02; HR 3.25 (95%CI 1.19–8.88). MV for EFS: age ≥60yrs (P=0.046; HR 3.06 (95%CI 1.02–9.18), Flu-based regimen (P=0.001; HR 0.21 (95%CI 0.08–0.54) and use of pentostatin (P=0.02; HR 0.34 (95%CI 0.13–0.85). MV for aGVHD-free survival: age ≥60yrs (P=0.039; HR 3.43 (95%CI 1.06–11.1), Flu-based regimen (P=0.0027; HR 0.09 (95%CI 0.02–0.43), use of pentostatin (P=0.003; HR 0.22 (95%CI 0.08–0.6) and CP CML (P=0.004; HR 0.06 (95%CI 0.01–0.41). S and EFS for 10/10 matched pts were improved with Flu-based regimen (p=0.01), and higher infused TNC dose (p=0.02). aGVHD-free survival was improved by using reduced intensity regimens (p=0.004) and worsened by presence of 2 DPB1 mismatches (1.18 mo vs not reached; HR=3.43; p=0.08). Conclusion: A combination of donor selection by high-resolution typing, less toxic preparative regimens and improved GVHD prophylaxis can optimize outcomes in this high-risk disease context. Figure Figure

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