Adverse Immunologic, Cytogenetic, and Molecular Features of AML in Elderly Patients Could Be Overcome by Allogeneic Hematopoietic Cell Transplantation Following Reduced Intensity Conditioning

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3065-3065
Author(s):  
Haifa Kathrin Al-Ali ◽  
Nadja Jaekel ◽  
Rainer Krahl ◽  
Claudia Nehring ◽  
Cornelia Becker ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Elderly Patients ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Graft Versus Leukemia ◽  
Reduced Intensity ◽  
Graft Versus Leukemia Effect

Abstract Abstract 3065 Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity-conditioning (RIC) is a curative therapeutic option in elderly patients with AML. Yet, hematological relapse (HR) and non-relapse mortality (NRM) remain major issues. The impact of AML characteristics, post-induction consolidation chemotherapy (PCC) in patients with complete remission (CR), type of donor [unrelated (UD) vs. related (RD)], graft cell count, and Donor-cell-chimerism (DCC) on long-term outcome and management of relapse after HCT following 200 cGy TBI + fludarabine 30 mg/m2 for 3 days followed by mycophenolate mofetil and cyclosporine were analysed in 245 consecutive patients with AML [132 male/113 female; median age 62 years] transplanted at the University of Leipzig. De novo and secondary AML were diagnosed in 151 (62%) and 94 (38%) patients respectively. A positive leukemic CD34-phenotype > 15% was present in 60%.Cytogenetics were high and intermediate (IR)-risk in 64 (26.7%) and 166 (69%) patients respectively. FLT3 -mutations (FLT3 mut) were present in 32 (28%) of the 115 patients with known FLT3 status. CR at HCT was present in 85% (CR1, n=155; CR2, n=53). The number of PCC applied was 0 in 88 (42%), 1 in 93 (45%), and 2 in 25 (12%). Donors were UD in 197 (80%) and RD in 48 (20%) patients. DCC in flow-sorted CD34+-marrow cells at days 28, 56, 84, and at 3 months interval thereafter was monitored by PCR of polymorphic micro satellite regions. After a median follow-up of 3.6 years, survival (OS), leukemia-free-survival (DFS), NRM, and Relapse (RI) at 5-years were 39%, 34%, 32% and 51% respectively. Engraftment was 95.5%. Incidence of acute GvHD > grade 3, limited and chronic GvHD was 22.5%, 20%, and 44.6% respectively. In multivariate analysis, type of AML, cytogenetics, CD34+-phenotype, and graft cell counts (CD3+, CD34+- and natural killer-cells) had no impact on outcome. Irrespective of the number of PCC applied, outcome was similar for CR1 and CR2. For the entire cohort and also for patients with IR-cytogenetics in CR, FLT3 mut did not adversely affect OS or RI. The lower RI after UD-HCT (39%) compared to RD-HCT (63%) (p=0.04) was opposed by a higher NRM after UD-HCT (36%) vs. 13% for RD-HCT (p=0.05) so that long-term OS and LFS were similar for both donor types. Chronic GvHD was associated with a superior OS, LFS and lower RI compared to patients without GvHD or with acute GvHD only (p<0.0005). Irrespective of leukemic CD34+-phenotype, CD34+-DCC day28 <90% was highly predictive of inferior OS (12%) and higher RI (95%) vs. OS of 50% and RI of 39% if CD34+-DCC day28 was > 90% (p<0.0001). In multivariate analysis, UD (p=0.007), female donor/male patient (p=0.02), and a higher CD34+- (p=0.01) but not CD3+-cells in the graft correlated with CD34+-DCC day28 was > 90%. HR and CD34+-DCC <90% without HR were managed by immunomodulation + chemotherapy. Overall, CR was achieved in 29% of HR and 36.4% of CD34+-DCC <90%. Relapse beyond day 100, a declining CD34+-DCC rather than a HR, and induction of GvHD correlated with a superior response and OS after relapse. Donor cells rather than the usual AML prognostic features predict long-term survival and relapse after RIC-HCT. In particular, CD34+-DCC is very effective in predicting outcome and identifying patients at risk of relapse thereby allowing early immunomodulation to enhance the graft-versus-leukemia effect. Yet, research is needed to further optimize the graft-versus-leukemia effect without the injurious effects of GvHD. Disclosures: No relevant conflicts of interest to declare.

Factors That Contribute to Long-Term Survival In Patients with Leukemia Not In Remission at Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3551-3551
Author(s):  
Hideo Koh ◽  
Hirohisa Nakamae ◽  
Takahiko Nakane ◽  
Masahiro Manabe ◽  
Yoshiki Hayashi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Term Survival ◽  
Long Term Survival ◽  
Kaplan Meier ◽  
Reduced Intensity

Abstract Abstract 3551 Background: Allogeneic hematopoietic cell transplantation (HCT) may even cure leukemia following relapse or primary induction failure. Several pre-transplant variables including age, duration of remission, poor-risk cytogenetics, tumor burden at HCT, type of donor, and performance status reportedly affected the post-HCT prognosis of leukemia that is not in remission. However, there has been insufficient examination of the factors required to achieve long-term survival or cure of leukemia that is not in remission at HCT. We might consider long-term survival without relapse, particularly for more than 5 years, as ‘likely cure' of leukemia. Therefore, we evaluated the factors that contribute to long-term survival (for more than 5 years) in patients with active leukemia at HCT. Method: We retrospectively performed an analysis of leukemia not in remission at HCT performed at our single institute between January 1999 and July 2009. Forty-two patients aged from 15 to 67 years (median age: 39 years) received intensified myeloablative (n=9), myeloablative (n=11) or reduced-intensity conditioning (n=22) for HCT. Twelve patients received individual chemotherapy for cytoreduction within the three weeks before reduced-intensity conditioning for HCT. Diagnoses included de novo AML (n=17), ALL (n=12), CML-AP (n=2), MDS/AML (n=10) and plasma cell leukemia (n=1). In those with acute leukemia, cytogenetic abnormalities were intermediate (n=17, 44%)or poor (n=22, 56%). Seven patients were primarily refractory to induction chemotherapy. The other patients relapsed after conventional chemotherapy or the first HCT. The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2–100) before the start of chemotherapy for HCT. Six patients had leukemic involvement of the central nerve system. Stem cell sources were related BM (n=3, 7%), related peripheral blood (n=13, 31%) unrelated BM (n=20, 48%) and unrelated cord blood (CB) (n=6, 14%). Thirty-one pairs were matched for HLA-A, B and DRB1 antigens. Three patients were mismatched for one HLA antigen (two at HLA-A, one at HLA-B), and seven were mismatched for two (two at HLA-A and B, five (all CB) at HLA-B and DRB1). The remaining patient was mismatched for all three antigens. Prophylaxis for acute GVHD consisted of calcineurin alone (n=5), calcineurin combined with short-term methotrexate (n=32), calcineurin combined with mycophenolate mofetil (n=2) or none (n=3). In this study, we defined long-term survival as survival without relapse for more than 5 years. Results: Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9–32). Five patients died early after HCT (range 4–20 days). Twenty four (65%) of 37 evaluable patients developed acute GVHD (eight grade I, nine grade II, five grade III, two grade IV), and 12 (50%) of 24 evaluable patients developed chronic GVHD (1 limited, 11 extensive). With a median follow up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariate analyses of impact of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS/AML and CB as stem cell source were significantly associated with worse prognosis (p=.03, p=.01, p=.02 and p<.001, respectively). In addition, the five-year Kaplan-Meier estimates of OS in patients with and without cGVHD were 66.7% and 0% (p<.001) respectively. Conclusion: Graft-versus-leukemia effects mediated by cGVHD may have played a crucial role in long-term survival in, or cure of active leukemia. We speculate that effective cytoreduction by individual chemotherapy and/or conditioning for HCT to control disease until cGVHD subsequently occurred might be also important, particularly in leukemia with rapid proliferation. However, intensive conditioning for HCT did not appear to be indispensable in relatively indolent leukemia, even with non-remission status at HCT. In addition, based on our results, CB might be unsuitable as a source of stem cells for leukemia that is active at the time of HCT. Disclosures: No relevant conflicts of interest to declare.

Matched Unrelated Donor Hematopoietic Cell Transplantation Following Reduced-Intensity Conditioning for Treatment of Myelofibrosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2769-2769
Author(s):  
David S. Snyder ◽  
Anthony S. Stein ◽  
Vinod Pullarkat ◽  
Firoozeh Sahebi ◽  
Sandra Cohen ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Time Interval ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for patients (pts) with myelofibrosis (MF). Outcomes utilizing fully myeloablative conditioning regimens have been disappointing in large part due to transplant related mortality in this generally older pt population. Recently, there have been encouraging results reported with reduced intensity conditioning (RIC) regimens followed by allogeneic HCT. Most of the reports have focused on HLA matched siblings as the stem cell donors. We have treated nine patients with MF (7 idiopathic, 1 secondary to essential thrombocythemia, 1 secondary to polycythemia vera) with RIC HCT utilizing matched unrelated donors (MUD) for 7 of the 9 patients, and sibling donors for 2 patients. The median age was 54 yrs (range 46 to 68); 4 female and 5 male. (See Table) The time interval from diagnosis to HCT ranged from 8 to 156 mos (median 41 mos). By the Lille classification, 4 pts were characterized as high risk, 4 as intermediate, and 1 as low risk. All 9 pts had significant splenomegaly, and 5/9 underwent splenectomy prior to HCT. Eight of the nine pts had ≥ 1% blasts in the PB at the time of HCT; 3 pts had abnormal cytogenetics (although none had +8 or 12p-); and 4 pts had constitutional symptoms. Seven of the 9 pts were RBC transfusion dependent. The RIC regimen consisted of fludarabine (Flu) and a single dose of total body irradiation (TBI) for Pt 1, and Flu/melphalan (Mel) for the subsequent 8 pts. G-CSF primed peripheral blood stem cells (PBSC) were used for all patients, except for Pt 6 who received a total of 3 products because of graft failure. The number of CD34+ cells X 106 /kg ranged from 0.97 to 17.1 (median 2.8). Prophylaxis against graft vs. host disease (GVHD) consisted of cyclosporin/mycophenolate +/− methotrexate. Seven pts successfully engrafted WBC with ANC &gt; 500 by a median of day +15 (range 10 to 21). Pt 6 never engrafted WBC, and the nadir for Pt 1 was &gt;500. Five pts achieved platelet engraftment (&gt;25k) from 15 to 594 days (median 32), 3 pts never engrafted platelets (Pts 2,6,7), and the nadir for Pt 1 was &gt;25k. At the time of the latest FISH and/or STR analysis, 8/9 pts were chimeric with 96 to 100% donor cells and/or DNA. All but 1 pt developed acute GVHD that was ≥ grade III in 4/8 pts. Four of 6 evaluable pts had extensive chronic GVHD. Six of the 9 pts are alive at the time of last contact with follow-up for the living pts ranging from 3.4 to 48.5 mos (median 11.8). The 3 deaths were from: septic shock due to primary graft failure on day +125 (Pt 6), sepsis related to severe acute GVHD on day + 51 (Pt 4), and sepsis with secondary graft failure related to severe acute GVHD on day +45 (Pt 2). The probability of overall and disease free survival was 64.8% (30.8 to 88.4%, 95% CI). These results demonstrate that MUD HCT utilizing PBSC can be an effective treatment for older pts with MF. Treatment Summary Pt Number Age/Gender Dx Donor Cell Material Regimen GVHD Prophylaxis 1 68/M MF MUD PBSC Flu/TBI CSA/MMF 2 58/F MF MUD PBSC Flu/Mel CSA/MMF 3 54/F MF MUD PBSC Flu/Mel CSA/MMF 4 64/F ET to MF Bro PBSC Flu/Mel CSA/MMF 5 46/M MF MUD PBSC Flu/Mel CSA/MMF/MTX 6 53/M MF MUD #1 BM Flu/Mel CSA/MMF/MTX 6 MUD #1 PBSC Flu/ATG 6 MUD #2 BM Flu/Mel 7 63/M PV to MF MUD PBSC Flu/Mel CSA/MMF/MTX 8 54/M MF Bro PBSC Flu/Mel CSA/MMF 9 63/F MF MUD PBSC Flu/Mel CSA/MMF/MTX

Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5544-5544
Author(s):  
El-Cheikh Jean ◽  
Devillier Raynier ◽  
Fürst Sabine ◽  
Crocchiolo Roberto ◽  
Granata Angela ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Objectives The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older. Patients and methods We retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available. Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1. Results No patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years. The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively. Conclusions This retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation. Disclosures: No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning of Allogeneic Transplantation for Nodal Peripheral T-Cell Lymphomas

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2585-2585 ◽  
Author(s):  
Kazunari Aoki ◽  
Ritsuro Suzuki ◽  
Dai Chihara ◽  
Tatsuya Suzuki ◽  
Sung-Won Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
T Cell ◽  
Elderly Patients ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
T Cell Lymphomas ◽  
Reduced Intensity

Abstract Introduction The outcome and the role of allogeneic hematopoietic cell transplantation (Allo-HCT) with reduced-intensity conditioning (RIC) in patients with nodal peripheral T-cell lymphomas (PTCLs) remain unclear. Patients and Methods To address this issue, we retrospectively analyzed the outcome of Allo-HCT for patients with nodal PTCLs using the transplant registry data from the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Patients who fulfilled the following criteria were included in this study: aged 16-69 years, diagnosed with PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), or anaplastic large cell lymphoma (ALCL), and received the first Allo-HCT in Japan between January 1, 2001 and December 31, 2011. In this analysis, conditioning regimen intensity was the main variable of interest. The conditioning regimen was classified as myeloablative conditioning (MAC) if it included total body irradiation (TBI) > 8 Gy, oral busulfan (BU) ≥ 9 mg/kg, intravenous BU ≥ 7.2 mg/kg, or melphalan (MEL) > 140 mg/m2. Otherwise, it was classified as RIC. Results A total of 354 patients (200 PTCL-NOS, 77 AITL, and 77 ALCL) were analyzed. Median follow-up duration of surviving patients was 3.8 years. Donor sources consisted of 122 human-leukocyte-antigen (HLA)-matched bone marrow (BM)/peripheral blood (PB), 122 HLA-mismatched BM/PB, and 110 cord blood. Of the 354 patients, 146 (41.2%) received MAC, which consisted of cyclophosphamide (CY)-TBI-based (n = 84), other TBI-based (n = 24), BU-CY-based (n = 11), fludarabine (FLU)-BU-based (n = 10), FLU-MEL-based (n = 15), and other (n = 2) MAC. The remaining 208 (58.8%) patients received RIC, which consisted of FLU-BU-based (n = 62), FLU-MEL-based (n = 108), and other (n = 38) RIC. Comparison of the patients who received MAC and RIC revealed that the RIC patients were significantly older (median age: 40.5 years vs. 50.3 years; P < 0.001) and more likely to have received autologous-HCT prior to Allo-HCT (15.1% vs. 29.3%; P = 0.002). The unadjusted 3-year cumulative incidence of non-relapse mortality were following: younger patients receiving MAC, 22%; younger patients receiving RIC, 14%; elderly patients receiving MAC, 50%; elderly patients receiving RIC, 30% (P < 0.001; Figure 1). The multivariate analysis showed that patients receiving RIC had a significantly lower non-relapse mortality than patents receiving MAC (HR, 0.51; 95% CI, 0.32-0.80; P = 0.004). Figure 1. Unadjusted non-relapse mortality. Figure 1. Unadjusted non-relapse mortality. The unadjusted 3-year cumulative incidence of relapse mortality were following: younger patients receiving MAC, 35%; younger patients receiving RIC, 30%; elderly patients receiving MAC, 32%; elderly patients receiving RIC, 35% (P = 0.692; Figure 2). The multivariate analysis showed that patients receiving MAC and RIC had a comparable relapse mortality (HR, 1.08; 95% CI, 0.73-1.58; P = 0.711). Figure 2. Unadjusted relapse mortality Figure 2. Unadjusted relapse mortality The unadjusted 3-year overall survival rates were following: MAC for younger patients (aged 16-49 years), 43%; RIC for younger patients, 56%; MAC for elderly patients (aged 50-69 years), 18%; RIC for elderly patients, 35% (P < 0.001; Figure 3). The multivariate analysis showed that patients receiving RIC had a significantly superior overall survival than patients receiving MAC (HR, 0.74; 95% CI, 0.54-1.00; P = 0.047; Table I). Figure 3. Unadjusted overall survival Figure 3. Unadjusted overall survival Table I. Multivariate analysis for overall survival Overall Survival HR (95% CI) P value Conditioning Regimen myeloablative 1.00 - reduced-intensity 0.74 (0.54-1.00) 0.047 Patient Age 16 to 34 1.00 - 35 to 49 1.26 (0.83-1.91) 0.270 50 to 59 2.17 (1.46-3.23) < 0.001 60 to 69 2.24 (1.40-3.59) 0.001 Karnofsly Performance Status 90 to 100 1.00 - 10 to 80 2.02 (1.41-2.91) <0.001 missing 1.50 (1.07-2.10) 0.017 Disease Status complete remission 1.00 - partial remission 1.13 (0.71-1.82) 0.607 resistant relapse 2.02 (1.27-3.21) 0.003 primary induction failure 2.09 (1.33-3.27) 0.001 Conclusion We showed a favorable outcome of Allo-HCT with RIC in patients with nodal PTCLs. The efficacy of RIC Allo-HCT for nodal PTCLs needs to be explored in prospective study. Disclosures No relevant conflicts of interest to declare.

Stärken der Graft-versus-Leukämie-Effekte durch richtig terminierte Photochemotherapie

2018 ◽  
Vol 6 (3) ◽  
pp. 149-150
Author(s):  
Percy Lehmann
Keyword(s):  
Acute Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Graft Versus Host ◽  
Treatment Start ◽  
Graft Versus Leukemia ◽  
Primary Predictor ◽  
Graft Versus Leukemia Effect

Background: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A). Method: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD. Results: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL. Conclusion: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival.

scholarly journals Comparative Effectiveness of Fludarabine and Busulfan Versus Fludarabine and 400 cGy Total Body Irradiation Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Cell Transplantation for AML/MDS

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1920-1920
Author(s):  
Moaath Mustafa Ali ◽  
Donna M Abounader ◽  
Lisa A. Rybicki ◽  
Melissa A Yurch ◽  
Jamie Starn ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Conditioning Regimens ◽  
Total Body ◽  
Reduced Intensity

Abstract Reduced intensity conditioning for allogeneic hematopoietic cell transplantation (alloHCT) has become a standard approach for older patients and for those with co-morbidities that prohibit myeloablative conditioning. The optimal conditioning regimen for patients with AML or MDS undergoing such transplants is not clear. Therefore we performed a single center, retrospective analysis comparing busulfan (100 mg/m2/day on days -5, -4, -3, -2) and fludarabine (40 mg/m2/day on days -5, -4, -3, -2) (BuFlu) versus fludarabine (30 m2/day on days -5, -4, -3) and 400 cGy total body irradiation (200 cGy on days -1 and 0) (FluTBI) conditioning. All of the BuFlu transplants were performed as inpatient hospitalizations while all of those with FluTBI were performed as an outpatient. A total of 71 patients in two cohorts were included. The first study cohort consisted of 38 patients (23 AML, 15 MDS) who received FluTBI from 3/2004-4/2010, and the second included 33 (20 AML, 13 MDS) patients conditioned with FluBu from 6/2010-12/2013. The groups had similar disease risk and HCT comorbidity index scores. The BuFlu patients were older (median age 65 [range, 34-73] vs. 61[range, 44-70] years, P=0.03), but there were no other differences in patient or disease characteristics. All patients received peripheral blood stem cells as the graft source. The donor sources were 53% matched related (MRD) and 47% matched unrelated (MUD) for FluTBI patients and 58% MRD and 42% MUD for BuFlu patients. The BuFlu group received more red blood cell (RBC) transfusions (median 4 vs. 2, P=0.02), but there were no differences in platelet transfusion requirements. Platelet recovery was longer for patients receiving BuFlu than FluTBI (median 16 vs. 12 days, P=0.004), but there was no difference in cumulative incidence of neutrophil recovery. The respective median number of days hospitalized in the first 100 days post-transplant was 22 vs. 10 days (P<0.001) and in the first year was 40 vs. 16 days (P<0.001). Post-transplant outcomes are shown in the Table. The most common causes of death were relapse and infection for both the FluTBI (44% and 13%) and BuFlu (57% and 14%) groups. Quality of life assessments using the FACT-BMT were performed pre-alloHCT, at day 100, 6 months and 1 year. There was no difference in physical, social, emotional, and functional well-beings, additional concerns, trial outcome index or total score between the two groups at baseline or any of the follow-up timepoints. We conclude that alloHCT using FluTBI or BuFlu reduced intensity conditioning regimens results in comparable outcomes in patients with AML/MDS. The greater RBC transfusion requirement and need for inpatient hospitalization with the BuFlu regimen have implications for healthcare resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and cost-effectiveness analyses are warranted. Table 1. Patient outcomes Variable FluTBI N (%) BuFlu N (%) P-value T-cell complete donor chimerism 29 (78) 26 (81) 0.83 Graft failure/rejection 3 (8) 3 (9) 0.87 Grade II-IV acute GvHD 13 (34) 17 (52) 0.24 Grade III-IV acute GvHD 3 (8) 6 (18) 0.21 Any Chronic GvHD 16 (42) 14 (42) 0.91 Extensive chronic GvHD 8 (21) 13 (39) 0.06 CMV reactivation 12 (32) 13 (39) 0.66 Fungal Infection 2 (5) 1 (3) 0.83 Relapse (2-years) 20 (53) 17 (52) 0.96 100 day mortality 13 (95% CI 6-29 ) 9 (95% CI 3-26 ) 0.59 Non-relapse mortality (2-years) 29 (95% CI 15-44) 29 (95% CI 14-45) 0.56 Relapse mortality (2-years) 34 (95% CI 20-49) 36 (95% CI 20-53) 0.86 Overall survival (2-years) 37 (95% CI 22-52) 35 (95% CI 19-51) 0.73 Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

HLA-Haploidentical Familial Donor Hematopoietic Cell Transplantation without Ex Vivo- T Cell Depletion after Reduced-Intensity Conditioning of Busulfan, Fludarabine, and Anti-Thymocyte Globulin: A Preliminary Report.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3077-3077
Author(s):  
Kyoo-Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Ho-Jin Shin ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Animal hematopoietic cell transplantation (HCT) models and several small clinical trials showed that successful engraftment can be achieved across HLA-haplotype difference after reduced-intensity conditioning (RIC). Furthermore, decreased graft-versus-host disease (GVHD) and transplantation-related mortality (TRM) after RIC was shown in a swine leukocyte antigen-haploidentical HCT experiment. Therefore, a protocol investigating the role of RIC in HLA-haploidentical familial donor HCT was initiated in April 2004 and 20 patients [13 male and 7 female; median age 26.5 years (16–65)] without HLA-matched donor enrolled until June 2007. The diagnosis were AML (n=9), ALL (n=4), acute biphenotypic leukemia (n=1), MDS (n=4), and SAA (n=2), and all patients had high-risk features, i.e. first complete remission (CR) but with high-risk chromosomal abnormality (n=1), first CR after salvage (n=1), second CR (n=6), recurrent/refractory state (n=7), immunotherapy failure (n=4), and high-risk MDS (RAEB-1, n=1). The RIC included iv busulfan 3.2 mg/kg × 2, fludarabine 30 mg/m2 × 6, plus anti-thymocyte globulin [Thymoglobuline 3 mg/kg (n=17) or Lymphoglobuline 15 mg/kg (n=3)] × 4. After receiving G-CSF, the donors (13 mothers; 5 offsprings; and 2 HLA-haploidentical siblings) underwent 2 or 3 daily leukapheresis, and the collected cells were given to patients without T cell depletion [medians of; 7.9 (3.7–12.1)×108/kg MNC, 6.9 (3.6–73.5)×106/kg CD34+ cells, and 4.6 (1.8–8.5)×108/kg CD3+ cells]. GVHD prophylaxis was cyclosporine 3 mg/kg/day iv from day -1 and a short course of methotrexate. As a part of separate phase 1 study, the two most-recently enrolled patients received additional donor CD34+ cell-derived NK cells 6 weeks after HCT. Except one patients with SAA who died due to K. pneumoniae sepsis on day 18, all 19 evaluable patients engrafted with ANC> 500/μl median 17 days (12–53) and platelet> 20,000/μl median 23 days (12–100) after HCT. Eight patients experienced acute GVHD (grades I, II, III, and IV; 2, 3, 2, and 1, respectively). Cumulative incidences (CI) of overall and grade II-IV acute GVHD were 40 and 30%, respectively. Eight patients experienced chronic GVHD (limited, 4; extensive, 4; CI, 51%). Fourteen showed positive CMV antigenemia, while 2 suffered CMV colitis, which resolved after treatment. As early as 2 weeks after HCT, 15 of 16 evaluable patients, and, by 4 weeks, all of 17 evaluable patients showed donor chimerism ≥95% on STR-PCR, which was maintained until 24 weeks in all 11 patients tested. Thirteen patients are alive after median follow-up of 13.6 months (1.5–37.9; Kaplan-Meier survival, 55.6%). Of 16 patients with acute leukemia and high-risk MDS, 8 remain alive without recurrence (event-free-survival, 40.9%). Two patients died of K. pneumoniae sepsis and grade IV acute GVHD, respectively (CI of TRM, 11%). Immune recovery in 10 patients without relapse for > 6 months showed robust lymphocyte contents and immunoglobulin levels at 6 months (means of; 1,060/ul CD3+, 222/ul CD4+, 767/ul CD8+ cells, and 1,317 mg/dl IgG) and 12 months. After RIC, consistent engraftment and durable complete donor hematopoietic chimerism can be achieved from HLA-haploidentical familial donor. The frequencies of GVHD and TRM were low.

Sign in / Sign up

Export Citation Format

Share Document