Impact of Pretransplant Cytogenetics and Marrow Remission Status on Outcome of Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation Conditioned with Busulfan and Fludarabine

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 341-341
Author(s):  
Ebru Koca ◽  
Rima M Saliba ◽  
Marcos De Lima ◽  
Uday Popat ◽  
Partow Kebriaei ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Prognostic Factors ◽  
Stem Cell Transplantation ◽  
Scoring System ◽  
Myeloid Leukemia ◽  
Remission Status ◽  
The Impact ◽  
Acute Myeloid

Abstract BACKGROUND: The purpose of this study was to determine the impact of cytogenetics and remission status on outcome of allogeneic stem cell transplantation (alloSCT) conditioned with busulfan and fludarabine based regimens for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: We retrospectively collected data on all consecutive patients (pts) who received busulfan and fludarabine with alloSCT at MD Anderson Cancer Center for AML and MDS between January 2001 and December 2007. All pts received busulfan and fludarabine in myeloablative (busulfan 130 mg/m2 for 4 days and fludarabine 40 mg/m2 for 4 days) or reduced intensity doses. ATG was added to the regimen for unrelated and mismatched related donor transplants. Pts in first complete remission (CR) or advanced CR (2nd or 3rd CR) and also pts with morphologic remission but platelet count <100,000/mcl (termed “marrow remission”) were included. Pts were divided into subgroups according to cytogenetic abnormalities based on the MRC, SWOG, CALGB, and the recently described Dana-Farber (DF) categorization systems. Cox’s regression analysis was used to evaluate the impact of the prognostic factors on overall survival (OS), progression free survival (PFS) and non-relapse mortality (NRM). The cumulative incidence of NRM was estimated considering progression of disease as a competing risk. RESULTS: 215 pts were included in the analysis with a median age 47 (range 13–69). Four pts were less than 18 years old and 117 (54%) were older than 45 years. Diagnoses were AML (n=176), MDS (n=14) and AML evolving from MDS (n=25). Disease status at alloSCT was; first CR (n=111), advanced CR (n=65) and marrow remission (n=39). Donors were matched related (n= 114), matched unrelated (n=86), 1 antigen mismatched related (n=7), or 1 antigen mismatched unrelated (n=6). Stem cell source was bone marrow (n=84) or peripheral blood (n=131). Median follow-up time of surviving pts was 36 months (range 1.6–85). The 3 years actuarial probabilities of OS and PFS were 59% and 51%, respectively. The 3 years cumulative incidence of NRM was 22%. On univariate analysis, adverse cytogenetics according to the DF scoring system (but not the MRC, SWOG and CALGB classifications) was associated with a significantly lower OS (HR=1.8, P=0.03) and PFS (HR=1.7, P=0.02). Three year PFSs for pts in CR with favorable, intermediate or adverse cytogenetics were 58%, 56% and 49%, respectively (Figure 1). In addition, pts in marrow remission compared to those who were in first or advanced CR with full platelet recovery prior to transplant had a significantly poorer OS (41 vs 63 % at 3 yrs, HR=2.1, P=0.01), and PFS (33 vs 55% at 3 yrs, HR=1.9, P=0.01). Outcomes were comparable for pts in first and advanced CR (Figure 2). AML evolving from MDS was a significant adverse risk factor for OS (HR=1.9, P=0.04) but not for PFS (HR=1.6, P=0.08). On multivariate analysis, pts had the highest mortality rate if they had both a marrow remission and adverse cytogenetics, classified according to the DF system (HR (OS)=3.4, P<0.001; and HR (PFS)=3.2, P<0.001). A diagnosis of AML evolving from MDS remained as a significant adverse factor for OS on multivariate analysis (HR=2.1; P=0.01). Significant adverse prognostic factors for NRM on univariate and multivariate analysis included alloSCT later than one year after diagnosis (HR=2; P= 0.02) and AML evolving from MDS (HR=2.6; P=0.01). There was no impact of cytogenetics on the rate of NRM. CONCLUSION: Cytogenetic characteristics and remission status before alloSCT correlate with transplantation outcome in MDS or AML pts conditioned with busulfan and fludarabine. This regimen with alloSCT produced improved outcomes compared to published results with standard chemotherapy for pts in the intermediate and high risk cytogenetic groups. Figure 1. PFS by DF cytogenetic scoring system for patients in first and advanced CR. Figure 1. PFS by DF cytogenetic scoring system for patients in first and advanced CR. Figure 2. PFS by remission status prior to transplant. Figure 2. PFS by remission status prior to transplant.

Allogeneic Hematopoietic Stem-Cell Transplantation In Early Phase Might Overcome the Adverse Prognosis of Acute Myeloid Leukemia with Translocation t(6;9)(p23;q34)/DEK-NP214(CAN) Rearrangement. A Retrospective Analysis From the Acute Leukemia Working Party of EBMT

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3501-3501 ◽  
Author(s):  
Jordi Esteve ◽  
Myriam Labopin ◽  
Gerard Socie ◽  
Per T. Ljungman ◽  
Johan Maertens ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Early Phase ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 3501 Acute myeloid leukemia (AML) with translocation t(6;9)(p23;q34)/DEK-NUP214(CAN) rearrangement (t(6;9) AML) is a rare but well-characterized entity, associated to a poor prognosis. In this regard, a possible benefit of allogeneic hematopoietic stem-cell transplantation (alloHSCT) has been suggested, based on small series of patients. To investigate the potential role of alloHSCT for the management of t(6;9) AML we analyzed the outcome of patients with this AML subtype submitted to alloHSCT and reported to the ALWP, and compared it to other well-defined cytogenetic categories. Overall, we identified 74 patients (median age: 38, 18–65; 51% male) diagnosed with t(6;9) AML allografted since 1988 (median year of transplant: 2004). Most transplants were performed in complete response (CR1=56, 76%; CR2=8, 11%), whereas only a minority were performed in advanced phase (primary refractory, n=5; relapse, n=5). Donor was an HLA-identical sibling in 43 transplants (58%), and a matched unrelated donor in 24 (32%). Conditioning regimen consisted of a myeloablative regimen in most patients (n=61, 82%), and source of stem-cells was peripheral blood in 41 (55%) and bone marrow in 32 (43%). After a median follow-up of 51 months, 3-year leukemia-free survival (LFS), relapse incidence (RI), and non-relapse mortality (NRM) for patients allografted in CR1 was 51±7%, 19±6%, and 30±7%, respectively, whereas LFS for patients transplanted in other disease status was only 16±10% (p<0.0001). A multivariate analysis performed among patients who received alloHSCT in CR1 identified a short interval CR-alloHSCT (<90 days) as the only favorable outcome for LFS (3-yr LFS: 57±10% vs. 51±7%; hazard ratio, HR=0.36, 95% CI:0.15-0.89; p=0.03) and NRM (47±11% vs. 17±8%; HR:3.84, 1.18–12.5; p=0.03), whereas reduced-intensity conditioning was followed by a higher RI (3-yr RI: 32±20% vs.17±6%; HR:4.86, 1.06–22.36; p=0.04). Moreover, the outcome of t(6;9) AML patients submitted to alloHSCT in CR1 was compared to that of patients with normal cytogenetics AML (NC-AML, n=2767) and poor cytogenetics AML (PR-AML, n=714) also allografted in CR1 in a multivariate analysis which included main prognostic variables. Interestingly, LFS and RI after alloHSCT of t(6;9) AML patients was similar to that observed in patients with NC-AML (51±7% and 58±1% for LFS, 19±7% and 23±1% for RI, respectively). On the contrary, the outcome of PR-AML was significantly poorer to NC-AML, with a 3-yr LFS and RI of 38±2% (p<0.0001; HR=1.58, 1.39–1.82) and 41±2%, respectively (p<0.0001; HR=2.09, 1.76–2.49; figure). In conclusion, alloHSCT in early phase resulted in a favourable outcome in patients with AML associated to translocation t(6;9), comparable to that of patients with NC-AML, suggesting that this procedure might overcome the adverse prognosis associated to this entity. Disclosures: No relevant conflicts of interest to declare.

Expression of CD25 on Acute Myeloid Leukemia (AML) Blasts Is An Independent Risk Factor Associated with Refractory Disease, Which May Be Overcome by Stem Cell Transplantation (SCT),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3560-3560
Author(s):  
Jan Cerny ◽  
Lesley Woods ◽  
Hongbo Yu ◽  
Muthalagu Ramanathan ◽  
Glen D Raffel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Cd25 Expression ◽  
Acute Myeloid

Abstract Abstract 3560 Introduction: Acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). LSCs are chemotherapy resistant and responsible for disease recurrence. AML containing a high percentage of LSCs displays aggressive biology in animal models. Using humanized mice Saito et al (Sci Transl Med 2010; 2: 1–11) have recently shown that xenografted CD25+ LSCs initiate AML and are chemotherapy resistant. Confirmation with clinical data from human AML is needed. Methods: In order to determine the prognostic impact of CD25 expression on AML outcome we have retrospectively investigated CD25 expression in 56 patients (pts) diagnosed and treated for AML at our institution between 02/2008 to 05/2011. 46 pts who had non-APL morphology, were treated with induction chemotherapy and had an adequate specimen for CD25 assessment were included in further analysis. CD25 expression was assessed in each specimen by flow cytometry and immunohistochemistry and correlated with clinical outcome. Patients: Median age was 61 years (22–84), 18 (39%) pts were older than 65; F:M ratio was 19:27, 3 (7%) patients had good risk (core binding factor leukemias), 26 intermediate (diploid karyotype and no good or high risk; 57%) and 17 (37%) high risk cytogenetics (complex, anbormality of 3q26, monosomy 7 and 5). 6 (13%) pts had NPM1mut/FLT3-ITDwt, 6 (13%) pts had NPM1wt/FLT3-ITDmut and 9 (13%) pts had NPM1mut/FLT3-ITDmut. As induction high dose cytarabine/anthracycline based regimen was used in 36 (78%) pts, 7 pts received 7+3 (15%) and 3 (7%) pts received hypomethylating agent. 24 (53%) pts received stem cell transplantation (SCT; 16 [35%] allogeneic and 8 [17%] autologous). The median follow up of the surviving pts was 11.2 months (1.1–38.7). Results: CD25 was detected in 17 pts (37%; 16 at diagnosis and 1 at relapse). Six CD25+ pts experienced relapse (3 pts with 3 or more relapses) heralded by increase in the percentage of CD25+ blasts. 65% of pts with CD25+ AML also had FLT3-ITDmut (p=0,0012). When comparing CD25+ and CD25- pts there was no statistical difference in distribution of the following characteristics: sex, age (65+), cytogenetics risk, presence of NPM1mut, type of induction, SCT. Fifteen (88%) of CD25+ pts experienced relapse compared to 8 (28%) of CD25- pts (p= 0.00007), 8 (47%) CD25+ pts died and 9 (31%) CD25- pts died (p=ns). The median relapse free survival (RFS) of all pts was 10.8 months with the median overall survival (OS) 12.2 months. The estimated 6-month RFS was significantly decreased in CD25+ pts compared to CD25- pts (26% vs 79%, p= 0.0003). This did not translate into a difference in OS between both groups (1-year OS: CD25+ 43% vs CD25- 65%, p=ns). In univariate analysis CD25 positivity was a stronger predictor for relapse (HR 5.28 [2.21–12.62], p=0.0002) than FLT3-ITDmut (HR 4.72 [2.04–10.92]; p= 0.0003). In multivariate analysis CD25 positivity was also a stronger predictor for relapse (HR 6.54 [1.34–9.15], p=0.01) than FLT3-ITDmut (HR 4.72 [2.04–10.92], p= 0.03). Pts undergoing SCT had significantly longer 1-year OS (66%) compared to pts without SCT (21%; p=0.0004). In multivariate analysis SCT was a predictor for improved OS (HR 0.2 [0.07–0.57], p=0.0002). CD25+ pts who received SCT had also significantly longer 1-year OS (63%) compared to CD25+ pts who did not receive SCT (0%; p=0.0098). SCT did not impact RFS in either group. Conclusion: CD25 represents a novel prognostic factor in AML. The increase in CD25+ blasts at relapse is associated with increased relapsed rate and refractory AML supporting the LSCs hypothesis. The detection of CD25 serves not only as a prognostic marker, but may be valuable for minimal residual disease assessment in patients who lack a molecular marker. In our experience treatment inclusive of stem cell transplantation abrogated the negative impact of CD25 expression on OS. Exploration of CD25 as a therapeutic target in AML is warranted. Disclosures: No relevant conflicts of interest to declare.

Bone Marrow Cellularity, but Not Dysplasia, Is An Additional Prognostic Factor for Patients with Acute Myeloid Leukemia After Allogeneic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4467-4467
Author(s):  
Maximilian Christopeit ◽  
Karolin Miersch ◽  
Evgeny Klyuchnikov ◽  
Mascha Binder ◽  
Francis Ayuk ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Competing Risks ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Survival Outcomes ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 4467 Background: Relapse incidence (RI) and non-relapse mortality (NRM) are competing risks limiting overall survival (OS) after allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Disease and transplant specific factors predicting relapse like measurement of minimal residual disease (MRD) and chimerism analysis are widely used to aid prophylactic and preemptive treatment decisions. Prediction of NRM mostly relies on pretransplant features. Although most transplant centers routinely perform bone marrow (BM) cytomorphology after SCT for AML, the impact of factors beyond blast count is not well studied. Study Design: We analyzed frequencies and prognostic impact of dysplasia and cellularity upon BM cytomorphology of 112 patients (60 m/52 f, median age 53 [range 17–72] years) with AML at 1st manifestation/ relapse at day 30 (d30) and day 100 (d100) after SCT. Using peripheral blood as main graft source (n=106), donors were unrelated in 87 cases, related in 25. Conditioning was reduced (RIC, n=72) or myeloablative (MAC, n=40). All patients received G-CSF from day 5 until stable engraftment was achieved. Dysplasia was assessed following WHO criteria with different thresholds (10%, 20%, 50%) to define a hematopoietic lineage as dysplastic. We performed a correlation of dysplasia and age-adapted cellularity with outcome measures, calculating RI and NRM as competing risks. Only patients who achieved blast clearance on d30 after SCT were included in the study. Patients who developed hematological relapse between d30 and d100 were only evaluated for d30. At d30 (d100), BM aspirates from 75 (65) patients were available for morphologic evaluation. Result: Dysplasia was a frequent event both at d30 and d100, with ≥10% dysplastic features in granulopoiesis in 25.0% of cases at d30 (31% d100), in erythropoiesis in 34.6% of cases at d30 (43.6% d100) and in megakaryopoiesis in 47.7% of cases at d30 (63.5% d100). Overall, cellularity at d30 was increased in 17.3% (d 100: 6.5%), reduced in 37.3% (d100: 38.7), and normal in 45.3% (d100: 54.8%). No significant correlation with CMV reactivation or with the type of immunosuppression (cyclosporine/ methotrexate versus cyclosporine/ mycophenolic acid) was noted. Cumulative incidences of 2-year-RI and 2-year-NRM were 34% (95% CI, 24%-44%) and 17% (95% CI, 9%-25%). Dysplasia both at d30 and d100 did not correlate with OS or RI. Yet, a statistically significant correlation of normal overall cellularity at d30 with less relapses (RI 20.6%) when compared with reduced overall cellularity (RI 32.1%) or increased overall cellularity (RI 76.9%; p=0.001) was observed. Estimated 2-year-OS was 59% in pts with normal overall cellularity versus 31.4% (reduced) and 44.0% (increased), respectively (p=0.009). The same results, favoring normal cellularity, were observed for each lineage (granulopoiesis, erythropoiesis, megakaryopoiesis). Conversely, increased overall cellularity at d30 correlated with lower NRM (8.3%) when compared to normal (NRM 23.7%) and reduced overall cellularity (NRM 39.6%, p=0.031). Thus, whereas reduced overall cellularity at d30 correlated both with higher RI and higher NRM, the impact of increased cellularity on survival was less clear. The analysis of subdistributive hazards in the competing risk factor model revealed a cumulative RI of 62% (95%CI 35%-89%, HR 6.68, p=0.00014) for increased cellularity, making it the most potent hazard in this analysis. Presence of an informative sample was of prognostic value, too (2-year-OS/ NRM 54.7%/ 80.4% for “evaluable” versus 20%/ 36.9% for “not evaluable” due to low cellularity, p<0.001). Cellularity at d100 showed no significant correlation with survival outcomes. We found no correlation of either dysplasia or cellularity with the pretransplant cytogenetic risk group and CMV serostatus. In this study, patients with AML who achieved normal cellularity early in the post-transplant period had improved survival outcomes and a reduced relapsed incidence as compared to patients with abnormal cellularity in bone marrow aspirates. Conclusion: These data suggest that cellularity of BM cytomorphology at d30 after allogeneic SCT aids to assess risk of relapse and NRM in transplant recipients with AML. At this time, it can only be speculated whether underlying persistent leukemia below the microscopic level might be associated with disturbed BM cellularity. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document