Treatment of Relapsed and Refractory Acute Myeloid Leukemia with a Salvage FLAG-IDA Chemotherapy Regimen Followed by a HLA Matched Related Allogeneic PBSC Infusion without Additional Conditioning.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5050-5050 ◽  
Author(s):  
Mammen Chandy ◽  
Vikram Mathews ◽  
T. Rajasekar ◽  
Auro Viswabandya ◽  
Kavitha M. Lakshmi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chemotherapy Regimen ◽  
Chronic Gvhd ◽  
Median Number ◽  
Salvage Chemotherapy ◽  
Cell Dose ◽  
Refractory Aml

Abstract The clinical outcome of relapsed and refractory AML is dismal. Attempts in this setting to induce a remission, prior to an allogeneic SCT, are frequently frustrated by either failure to respond to chemotherapy or deterioration in the clinical status post chemotherapy. Since December 2005, patients with relapsed and refractory AML were offered salvage chemotherapy with a FLAG-IDA regimen (consisted of G-CSF 10mcg/kg/day starting day −1, Fludarabine 30 mg/m2 x 5 days, Cytosine 2gm/m2 x 5 days and Idarubicin 10mg/m2 x 3 days). On day 10 of chemotherapy a G-CSF mobilized PBSC harvest from a complete HLA matched related donor was infused, targeting a cell dose of 5 x 108 MNC/kg. GVHD prophylaxis consisted of low dose cyclosporine (1.5 mg/kg/day) ± short course low dose methotrexate. Eleven patients were treated with this regimen. The median age was 40 years (range: 2 – 51). There were 7 (64%) males. There were 6 relapsed cases (5 relapse-1 and one relapse-2) and 5 primary refractory cases. Of the relapsed cases, two had relapsed following a prior allogeneic SCT. Among the patients with relapsed AML, the median number of chemotherapy cycles prior to transplant was 3 (range: 2 – 5) and the median time to transplant from relapse was 5 months (range: 5 – 10). Among the 5 refractory patients, the median number of chemotherapy regimens received prior to transplant was 2 (range: 1 – 3) and the median time from diagnosis to transplant was 3 months (range: 1 – 6 months). The median number of bone marrow blasts pre-transplant was 38% (range: 5 – 70). Five cases had an ECOG performance score of 0–1 while 4 had an ECOG score of 2 and 2 had an ECOG score of 3. Salvage FLAG-IDA chemotherapy regimen was well tolerated in all cases. The median cell dose infused on day 10 was 6.59 x 108 MNC/kg (range: 3.5 – 12.73). All but one patient engrafted with a median time to ANC > 500/mm3 of 13 days (range: 9 – 21) post stem cell infusion and Platelet count > 20,000/mm3 of 12 days (range: 9 – 17). One patient failed to engraft and died on day 9 secondary to a fungal pneumonia. Nine patients achieved a complete donor chimerism on day +30 post stem cell infusion. Six (55%) developed grade 2–4 acute GVHD while 2 (18%) developed grade 3–4 acute GVHD. Six of eight who could be evaluated developed chronic GVHD, all had extensive chronic GVHD. Four patients relapsed following transplant at a median of 118 days post transplant (range: 26 – 140). At the time of this analysis 5 (45%) patients are alive and in remission at a mean follow up of 278 days (range: 119 – 551). Of the remaining 6 patients, 4 relapsed and died, 1 died prior to engraftment from a fungal pneumonia and one patient died in remission from an acute cardiac event. FLAG-IDA salvage chemotherapy followed by an allogeneic PBSC graft infusion on day 10 is a reasonable option to consider for patients in this clinical situation.

Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4326-4326
Author(s):  
Leandro de Padua Silva ◽  
Rima M. Saliba ◽  
Sergio Giralt ◽  
Marcos De Lima ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Disease Stage ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
Morbidity Score ◽  
Co Morbidity

Abstract Background: RIC regimens are less myelosuppressive, but remain adequately immunosuppressive, allowing for successful engraftment with acceptable treatment-related mortality (TRM) in older or more frail patients (pts) who otherwise would not be suitable candidates for HSCT. This is particularly relevant in ALL, since pts often sustain toxicity from dose-intense upfront regimens or may be diagnosed in advanced age. The antitumor effect of this approach is not well-established in ALL. Methods: We evaluated outcomes of 30 advanced ALL pts (19 M/11 F) treated from August 1996 to May 2008 with FM140 (fludarabine 120 mg/m2, melphalan 140 mg/m2) and unmanipulated stem cells. Graft vs. host disease (GVHD) prophylaxis consisted of tacrolimus and mini-dose methotrexate in all but 1 pt who received cyclosporine. Anti-thymocyte-globulin was added to matched unrelated pts. Results: The median age was 44 years (range 23–64). ECOG performance status at time of HSCT was 0 (n=16), 1 (n=10) or 2 (n=4) with median co-morbidity score of 3 (range 0–7) by Charlson Comorbidity Index (CCI). Twenty-four pts had B-lineage and 6 had T-lineage disease. Cytogenetic data were available for 26 pts; 19 had high-risk cytogenetics, including 9 with Ph+ disease. Disease stage at time of study entry was CR1 (n=5), ≥CR1 (n=12), or primary or refractory relapse (n=13), with median 2 prior chemotherapy regimens (range 1–4); five pts had a prior allogeneic HSCT. Donor type was matched related (n=13) or matched unrelated (n=17) and stem cell source was bone marrow (n=14) or peripheral blood (n=16). The median total nucleated cell dose and CD34+ cell dose were 3.80 × 108 cells (range 0.68–17.16) and 4.15 × 106 cells (range 1.78–12.03), respectively. Median time to ANC 0.5 × 109/L was 13 days (range 10–24). Median time to platelet count 20 × 109/L was 18 days (range 10–57). Eight pts were alive at a median follow up of 12 months from HSCT (range 3–59). OS and DFS were 32% and 29%, respectively, at 1 year. Of note, only 1 among 5 pts in CR1 had disease progression, compared to 8 among 13 with refractory disease at time of HSCT. The cumulative incidence of acute GVHD, grades II–IV and III–IV were 40% and 13%, respectively, and chronic GVHD was 22% (7% for extensive). The cumulative incidence of TRM at 100 days and 1 year were 17% and 33%, respectively. Among 22 deaths, 14 were related to disease recurrence, 4 related to infection and 4 related to GVHD. Conclusion: RIC HSCT can provide disease control in patients with ALL, and merits further evaluation. Alternative treatment strategies need to be explored in pts with advanced disease. The observed TRM rate is comparable to what has been previously reported for this regimen in heavily pretreated leukemia patients.

Busulfan/Fludarabine/Thymoglobulin as a Reduced Intensity Conditioning Regimen for Lymphoid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3335-3335
Author(s):  
Jeevan Sekhar ◽  
Keith Stockerl-Goldstein ◽  
Qin Zhang ◽  
Amanda F Cashen ◽  
Camille N. Abboud ◽  
...  
Keyword(s):  
Median Time ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Median Number ◽  
Cell Transplant ◽  
Single Institution ◽  
Reduced Intensity Conditioning ◽  
Prior Therapy ◽  
Lymphoid Malignancies ◽  
Reduced Intensity

Abstract Abstract 3335 Poster Board III-223 Introduction Over the last decade there has been an increase in the use of reduced intensity conditioning (RIC) regimens to mitigate transplant related toxicity while maintaining graft viability and maximizing the graft versus disease effect. There is an abundance of data on busulfan (Bu) based RIC for myeloid malignancies; however, there is a paucity of data on Bu based RIC regimen for allografting in lymphoid malignancies. We conducted a retrospective analysis of a large cohort of patients treated at a single institution who were transplanted using a uniform RIC regimen of Bu/Fludarabine (Flu)/Thymoglobulin (Thymo) for a variety of lymphoid neoplasms. Methods We identified 40 patients (pts) who were transplanted for lymphoid malignancies between 2004 and 2008 using the RIC regimen of Bu 0.8 mg/kg q6 hrs x 8 doses on d-4 and d-3, Flu 30 mg/m2 IV daily on days -7 to -3, and Thymo 2 mg/kg x 4 doses on d-4 to d-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.03 mg/kg starting d-2)/methotrexate (5mg/m2 on d+1, 3, 6, 11)/mycophenolate (15mg/kg bid starting d-2) in 34 pts (85%), tacrolimus/methotrexate in 5 patients (12.5%), cyclosporine/mycophenolate/methotrexate in 1 pt (2.5%). Chimerism analysis was done on days +30, 90, 180, and 365. Demographics Median age was 54 (range 35-65) years; males 26 (65%) and females 14 (35%); CLL/SLL 22 (55%), non-Hodgkins lymphoma 15 (37.5%) and transformed lymphomas 3 (7.5%). Median number of lines of therapy prior to transplant was 4 (range 0-12). 12 pts (30%) were refractory to initial therapy (less than a PR). 15 pts (37.5%) had received prior radiation therapy (XRT). 12 pts (30%) had undergone a prior autologous stem cell transplant (ASCT). 22 pts (55%) had chemo-sensitive disease at the time of transplant, and 18 (45%) had disease refractory to their pre-transplant regimen. The donor was related (RD) in 10 pts (25%) and unrelated (URD) in 30 pts (75%). The graft source was peripheral blood for 36 pts (90%) and bone marrow in 4 pts (10%). Median number of CD34+ cells infused was 7.9×10 6 (range, 1.1-17.9) /kg recipient body wt. Results Median time to absolute neutrophil count recovery was 12 (0-21) days. Median time to platelet recovery was 18 days (9-57 days). Median time to 100% donor chimerism was 39 (24-321) days. After a median follow-up of 25.8 (0.87-48.9) months, Kaplan-Meier estimates of median overall survival (OS) and progression-free survival (PFS) were 11.3 months and 9.9 months, respectively. The 2-yr OS and PFS were both 44%. We performed an analysis of the effects of histology, number of lines of prior therapy, prior XRT, prior ASCT, disease status at time of transplant, and graft source (URD vs RD) on OS and PFS (Table 1). Non-relapse mortality (NRM) at 100 days, 1 year, and 2 years was 8% (95% CI, 3-22%), 33% (95% CI, 20-52%), and 41% (95% CI, 26-60%), respectively. Acute GVHD was seen in 19 pts (48%) with Grade III/ IV acute GVHD in 9 pts (23%). Chronic GVHD was seen in 17 pts (43%), limited in 5 pts (13%), extensive in 12 pts (30%). Acute GVHD was more common among pts receiving URD vs RD transplants (35% vs. 13%, p=0.016), but incidence of chronic GVHD did not differ between these two cohorts. Conclusion This analysis represents the largest single institution experience using the RIC regimen of Bu/Flu/Thymo in lymphoid malignancies. Our results demonstrate that this Bu based RIC regimen can successfully be used to allograft heavily pre-treated patients with lymphoid malignancies, with prompt and durable engraftment and relatively low early NRM. In this patient population, OS and PFS were not significantly associated with lymphoma histology, prior therapy, or chemosensitivity. Disclosures DiPersio: Genzyme Corp.: Honoraria. Vij:Otsuka Pharmaceuticals: Research Funding.

Mature Circulating Endothelial Cells and Progenitors in Patients with Chronic Gvhd

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4700-4700
Author(s):  
Rocco Pastano ◽  
Giovanna Andreola ◽  
Patrizia Mancuso ◽  
Federica Gigli ◽  
Angelo Gardellini ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Immunosuppressive Therapy ◽  
Median Time ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Circulating Endothelial Cells

Abstract Abstract 4700 Acute and chronic graft-versus-host disease are a common complication of allogeneic stem cell transplantation. In animal models acute GVHD (aGVHD) is associated with increased neovascularization and number of circulating endothelial cells (CECs), while patients with sclerodermatous chronic GVHD (cGVHD) show a significant decrease in the number of circulating endothelial progenitor cells (EPCs) in peripheral blood as compared to patients with non sclerodermatous cGVHD or controls. In an attempt to evaluate the role of CECs and EPCs in patients with cGVHD, we analysed a total of 15 patients affected by hematological malignancies (3 Non-Hodgkin Lymphoma, 4 Hodgkin Disease, 4 Multiple Myeloma, 2 Myelodisplastic Syndrome, 2 Chronic Lymphocitic Leukemia) having undergone allogeneic stem cell transplantation following reduced intensity conditioning. Donors were HLA identical in 14 patients (12 sibling and 2 matched unrelated donors) and HLA aploidentical in 1. Acute GVHD and cGVHD were defined on the basis of time of manifestation, ≤100 days for aGVHD and >100 days for cGVHD. At the time of the blood sample collection, 8 patients, median age 42 years (28-51), with a median time after transplant of 177 days (21-1373), had no evidence of GVHD; of those 5/8 were evaluable for aGVHD and cGVHD, 2 only for aGVHD; 4/8 were on post-transplant calcineurin inhibitors immunosuppressive therapy; 7 other patients, median age 51 years (38-64), with a median time after transplant of 844 days (314-1779), were all evaluable for acute and cGVHD and had evidence of cGVHD as follows: sclerodermatous in 3 patients requiring systemic immunosuppressive therapy, oral mucosa lichen in 1 patient taking oral corticosteroid and cutaneous erythematous and dischromic cGVHD in the other 3 patients, with only 1 patient on systemic immunosuppressive therapy. Viable and apoptotic CECs and EPCs were evaluated by six color flow cytometry (Mancuso et al, Clin Cancer Res, 2009). Briefly, CECs were defined as DNA+CD45-CD31+ CD146+, EPCs as CD45- CD34+. The combination of Syto16 and 7-AAD was used to discriminate between viable (syto16bright/7-AAD-) and apoptotic (syto16weakly pos/7-AAD+) endothelial cells, and to exclude from analysis, platelets and endothelial macroparticles. The results, expressed as median of cells/mL, are summarized in the following table:Total CECsViable CECsApoptotic CECsEPCsHealthy Subject103 (33–322)21 (3–67)77* (28–303)31 (0–56)Patients with cGVHD46 (29–94)41 (25–68)5* (3–26)30 (0–213)Patients without GVHD138 (30–179)39 (10–153)68* (5–136)49 (0–355)*p<0.017 These preliminary data indicate a significant reduction in apoptotic circulating mature endothelial cells, likely reflecting a poor vascularization of multiple organs and tissues targeted by cGVHD and a trend towards a decreased number of EPCs in patients with cGVHD. A multicentric study is now planned to confirm these hypotheses and investigate a possible predictive/prognostic role of CEC and EPC counts in cGVHD. Disclosures: No relevant conflicts of interest to declare.

The Effect of the Platelet Content of Blood Stem Cell Grafts on GVHD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1077-1077
Author(s):  
Jayesh Mehta ◽  
R. Meagher ◽  
A. Evens ◽  
O. Frankfurt ◽  
S. Singhal ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Ideal Body Weight ◽  
Cell Numbers ◽  
Cell Dose ◽  
Ideal Body ◽  
Platelet Content ◽  
Grade Iii

Abstract Blood-derived stem cell grafts contain large quantities of platelets. Platelets contain cytokines which could contribute to GVHD. However, the role of the number of infused platelets in GVHD has never been explored. Platelet dose data were available for 61 patients (27–66 y, median 52) undergoing submyeloablative HSCT from HLA-matched sib (n=35), 10/10 allele-matched unrelated donors (n=19), or 1-locus/allele mismatched donors (n=7) for hematologic malignancies from 9/01 to 5/04 (minimum follow-up >1 y). The conditioning comprised 100 mg/m2 melphalan with (n=42; no prior autograft) or without (n=19; prior autograft) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate with HLA-matched sibs and tacrolimus-mycophenolate with the rest. G/GM-CSF were not administered post-transplant. Supportive care was uniform. The platelet dose was 21–236 (median 77) x 108/kg ideal body weight. The CD3+ cell dose was 0.9–14.9 (median 3) x 108/kg ideal body weight. The table shows the cumulative incidence and relative risk of acute and chronic GVHD with 95% CI by the number of platelets infused. Cumulative incidence (%) Platelet dose ≤100 (n=39) Platelet dose >100 (n=22) RR P Acute GVHD (any grade) 46 (33–65) 82 (67–100) 2.45 (1.26–4.75) 0.008 Acute GVHD (grade III–IV) 23 (12–42) 70 (47–100) 2.75 (1.04–7.24) 0.041 Chronic GVHD 28 (17–47) 23 (11–49) 0.76 (0.26–2.21) 0.62 There was strong correlation between the platelet dose and the T cell dose (r=0.62; P<0.0001). Only 4 of 30 patients receiving <3 CD3+ cells received >100 platelets compared with 18 of 31 receiving ≥3 CD3+ cells (P=0.001). Since higher CD3+ cell numbers can be associated with more acute GVHD, Cox analysis was undertaken to determine the independent contribution of the platelet dose. When both platelet and CD3+ cell numbers were analyzed as categoric variables (in addition to several other factors potentially likely to affect GVHD), a platelet dose >100 was the only factor independently associated with any grade of acute GVHD (RR 2.5; 95% CI 1.3–4.8; P=0.008), and a CD3+ cell dose ≥3 the only factor associated with grade III–IV acute GVHD (RR 10.0; 95% CI 2.3–43.5; P=0.002). When both were analyzed as continuous variables, the relationship was similar with higher platelet doses being associated with a higher risk of any grade of acute GVHD (P=0.006) and higher CD3+ cell doses being associated with a higher risk of grade III–IV acute GVHD (P<0.0001). The figure shows the effect of the platelet dose on the cumulative incidence of any grade of acute GVHD. Figure Figure The number of platelets infused had no effect on the incidence of chronic GVHD, transplant-related mortality, relapse rates, and disease-free or overall survival. This novel observation needs to be confirmed in a larger series of patients as well as the relative contribution of the T cell dose and the platelet dose to the occurrence of GVHD better defined. If confirmed, reducing the platelet content of blood stem cell grafts may represent a simple way to reduce the risk of acute GVHD partially.

Hematopoietic Stem Cell Transplantation after Reduced Intensity Conditioning in Acute Myeloid Leukemia Patients Older Than 40 Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5074-5074
Author(s):  
Cynthia Huisman ◽  
Ellen Meijer ◽  
Eefke J. Petersen ◽  
Henk M. Lokhorst ◽  
Leo F. Verdonck
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Free

Abstract Reduced intensity conditioning (RIC) protocols are increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients. We retrospectively analyzed the outcome of RIC HSCT in a homogeneous group of acute myeloid leukemia (AML) patients over the age of 40. Forty-three AML or high-risk myelodysplastic syndrome patients were treated with a fludarabine and low dose total body irradiation (TBI) based regimen, followed by a full peripheral stem cell graft. Antithymocyte globulin was given to matched unrelated recipients (34%) before infusion of fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin and mycophenolate mofetil. All but 2 AML patients were in complete remission at the time of transplantation. Seventy-six percent of patients had a poor risk profile. Hematologic recovery was fast and primary graft failure occurred in one patient. Two patients with active disease at the time of HSCT experienced ongoing relapse. Infections were diagnosed in 9 patients (21%) and 6 patients (14%) were treated for CMV reactivation. Sixty percent of patients developed acute GVHD, which was grade 2 in 40% and grade 3 in 12%. Chronic GVHD occurred in 33% of patients. The incidence and severity of both acute and chronic GVHD was similar in patients with related and unrelated donors (P = 0.84 and 0.74, respectively). Treatment-related mortality (TRM) was low (9%), total nonrelapse mortality was 19%. After a median follow-up of 571 days, 16 patients (37%) experienced relapse. One-year progression-free and overall survival were 61% and 67%, respectively. Median disease-free survival has not been reached yet (> 58 months) and median overall survival was 31 months (Fig 1 and 2, respectively). Poor risk AML was significantly associated with disease-free survival in multivariate analysis (P = 0.02). Age > 60 years, gender, donor type, timing of RIC HSCT (upfront or after relapse) and acute GVHD were not identified as prognostic factors. In conclusion, fludarabine plus low-dose TBI-based RIC HSCT is effective in AML patients over the age of 40 without active disease at the time of transplant and is associated with low TRM. Figure Figure Figure Figure

Non-Myeloablative Allogeneic Stem Cell Transplantation in 154 Patients (pts) with Chronic Myeloid Leukaemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4975-4975
Author(s):  
Malek Benakli ◽  
Rose-Marie Hamladji ◽  
Redhouane Ahmed Nacer ◽  
Amina Talbi ◽  
Farih Mehdid ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Transfusion Requirements

Abstract Background: Allogeneic stem cell transplantation using a reduced intensity or nonmyeloablative conditioning (NSCT) represents an attractive treatment modality in CML. The rationale behind such approach is to decrease toxicity while inducing the graft-versus-leukemia (GVL) effect. Because of its significantly lower cost in comparison to Imatinib mesylate, NSCT may be considered an early treatment option in countries where limited resources. Material and Methods: Between April 2001 and December 2006, we treated 154 CML patients (131 in first chronic phase, 23 in accelerated phase) with NSCT from an HLA-identical family donor. The majority of pts has a Gratwohl score <2 prior to NSCT (n=115; 74,6%). The conditioning regimen included Fludarabine 150 mg/m2 and oral Busulfan 8 mg /kg (139 pts). GVHD prophylaxis consisted of association ciclosporine (CSA)-Mycophenolate (MMF). 15 pts received an additional prophylaxis with antithymocyte globulin (ATG). Median age was 35 (range, 18–55) years, and the sex-ratio (M/F) 0,87. The median time from diagnosis to NSCT was 11 (range, 4–50) months. All pts received G-CSF mobilised peripheral blood stem cells, median CD34+ cells count: 7,02.106/kg (range, 1,28–44,9). Results: Leucopenia is found almost at 71 pts (46,1%). The median time to achieve ANC >500. 109/l granulocytes was 14 (range, 7–24) days, and median time of aplasia was 7 (range, 2–19) days. Transfusion requirements were significantly reduced, only 3 pts (1,9%) required red blood cells transfusions. Only 15 pts (9,7%) needed platelets transfusions. Acute GVHD was seen in 65 cases (43,6%) including 26 (17,4%) cases of grade III–IV and 32 cases (21%) of late onset acute GVHD occurring after day 100 post-NSCT. 93 pts (67,3%) had chronic GVHD, of whom 58 with an extensive form. 23 pts (15,4%) had CMV reactivation. 24 pts (16,1%) relapsed (15 in chronic phase, 7 in blast crisis and 2 with a molecular relapse), but 11 pts could be salvaged and are currently in remission (7 after immunosupression discontinuation, one after DLI and 3 after a second conventional allograft). The chimerism of donor origin (STR-PCR method) of patients in remission was at an average of 74% at day 30, 80% at d100, 93% at 6 months, 97% at 1 year, and 99% at 2 years. Fifty pts (33,5%) have died, of whom 39 (22,1%) from GVHD and 10 (6,7%) from disease relapse. Transplant Related Mortality (TRM) at 100 days was 6%, but rose to 31,5% at 3 years. At last follow-up (median, 32 (range 6–68) months), 99 pts (66,4%) are still alive, 97 (65,1%) pts in hematologic remission; of whom 76 (78,3%) in complete molecular remission evaluated by RT-PCR. Overall survival and progression-free survival at 5 years are 61% and 51,6% respectively. Conclusion. The study demonstrates a relatively low rate of short-term toxicities after NSCT. However, long-term TRM is still high because of the GVHD. The GVL effect is well admited. The relapse can be often controled by immunomodulation (stoppage of immunosuppression, DLI) and eventually by second myeloablative allograft.

Tandem Auto-Allo in Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3355-3355
Author(s):  
Luca Castagna ◽  
Sabine Furst ◽  
Thomas Prébet ◽  
Jean El Cheikh ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cause Of Death ◽  
Relapse Rate ◽  
Acute Gvhd ◽  
Prognostic Score ◽  
Chronic Gvhd ◽  
Median Number ◽  
Prognostic Scores ◽  
High Dose

Abstract Abstract 3355 Poster Board III-243 Background. High and intermediate risk AML can benefit by allogeneic stem cell transplantation in first CR. The use of reduced intensity conditioning regimens (ALLO-RIC) decreases the toxicity even if the relapse rate is more pronounced. To contrast the high relapse rate we hypothyzed that if a better quality of remission could be achieved, the relapse incidence could be lowered. Patients and methods. From 2001 to 2008, 31 AML patients in first CR received a tandem auto-allo program. The median number of white blood cell was 3 × 10e9/l (range 0.9-235), 13% of patients have extramedullary localisations. In 13% AML was secondary to previous CT treatment. Cytogenetic was abnormal in 36% of pts. After one or two induction chemotherapies (CT), all but two patients received a consolidation course with high-dose cytarabine (HD-ARAC) CT, followed by autologous stem cell harvest. Then, HD melphalan (HD-PAM 140 mg/m2) followed by autologous stem cells reinfusion was administered, followed by ALLO-RIC. RIC consisted of fludarabine plus (2 Gy) TBI (3 pts) or fludarabine, oral or intravenous busulfan (8 mg/kg) in two days, and anti thymocyte globulin (2.5 or 5 mg/kg). Graft versus host disease (GVHD) prophylaxis was cyclosporine (CyA) plus mycofenolate mofetil (3 pts) or CyA alone (28 pts). Donors were all but one HLA identical sibling. The median number of allogeneic CD34+ and CD3+ cells was 6.1 × 10e6/Kg (range 1.9-11) and 315 (range 166-609). Prognostic scores (HCT-CI, PAM, EBMT) were retrospectively calculated for each patient. All pts have a performance status ≥ 90%. Results. The median follow-up was from diagnosis and ALLO-RIC 40 and 34 months, respectively. The median time between last CT and HD-PAM was 51 days (range 30-77) and HD-PAM and ALLO-RIC was 69 days (55-176). Treatment related mortality after HD-PAM was null. Prognostic scores were: HCT-CI score 0-2= 53% (16 pts), ≥3= 47% (14 pts), 1 pt not evaluable; PAM score 9-16= 30% (10 pts), 17-23= 67% (19 pts), 24-30= 3% (1 pt); EBMT score 1= 9% (3 pts), 2= 78% (24 pts), 3= 13% (4 pts). At last follow-up, 42% of pts (n= 13) died: 5 due to disease relapse and 8 because of toxicity. Grade II-IV acute GVHD and chronic GVHD incidence were respectively 26% and 65% (extensive 84%). GVHD was the cause of death in seven pts. Six pts (19%) reactived CMV, without disease, and 1 pt not survived to an interstitial pneumonitis. The 5-year overall survival (OS), relapse free survival (RFS), and 1-year TRM were 60%, 60%, and 15%, respectively. In multivariate analysis, prognostic scores did not influence TRM and OS. Conclusions. This report showed that i) tandem auto-allo is feasible in AML pts; ii) acute GVHD incidence is not increased iii) prognostic score did not impact on TRM and survival; iv) the TRM is quite low with GVHD as main cause of death. A retrospective comparison with a cohort of pts not receiving HD-PAM is on going. Disclosures: No relevant conflicts of interest to declare.

Patterns of Acute and Chronic Graft-Versus-Host Disease Following ATG-Based Conditioning for Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4479-4479
Author(s):  
Nandita Khera ◽  
Amylou C. Dueck ◽  
Veena Devi Salem Fauble ◽  
Lisa Sproat ◽  
Pierre Noel ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Median Number ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Grade Ii

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.

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