scholarly journals Development of a Nomogram for Predicting the Cumulative Incidence of Disease Recurrence of AML After Allo-HSCT

2021 ◽  
Vol 11 ◽  
Author(s):  
Tongtong Zhang ◽  
Xiebing Bao ◽  
Huiying Qiu ◽  
Xiaowen Tang ◽  
Yue Han ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Residual Disease ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Disease Status ◽  
Disease Recurrence ◽  
High Ratio ◽  
Cutoff Score ◽  
Internal Validation ◽  
Actual Observation

Using targeted exome sequencing, we studied correlations between mutations at diagnosis and transplant outcomes in 332 subjects with acute myeloid leukemia (AML) receiving allotransplantation. A total of 299 patients (299/332, 90.1%) had at least one oncogenic point mutation. In multivariable analyses, pretransplant disease status, minimal residual disease (MRD) before transplantation (pre-MRD), cytogenetic risk classification, and TP53 and FLT3-ITDhigh ratio mutations were independent risk factors for AML recurrence after allotransplantation (p < 0.05). A nomogram for the cumulative incidence of relapse (CIR) that integrated all the predictors in the multivariable model was then constructed, and the concordance index (C-index) values at 6, 12, 18, and 24 months for CIR prediction were 0.754, 0.730, 0.715, and 0.690, respectively. Moreover, calibration plots showed good agreements between the actual observation and the nomogram prediction for the 6, 12, 18, and 24 months posttransplantation CIR in the internal validation. The integrated calibration index (ICI) values were 0.008, 0.055, 0.094, and 0.136 at 6, 12, 18, and 24 months posttransplantation, respectively. With a median cutoff score of 9.73 from the nomogram, all patients could be divided into two groups, and the differences in 2-year CIR, disease-free survival (DFS), and overall survival (OS) between these two groups were significant (p < 0.05). Taken together, the results of our study indicate that gene mutations could help to predict the outcomes of patients with AML receiving allotransplantation.

scholarly journals Impact of NCCN Risk Stratification and Minimal Residual Disease on Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2296-2296
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Yan-Li Zhao ◽  
Xing-Yu Cao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Donor Type ◽  
Minimal Residual

Abstract Introduction: Cytogenetic abnormality is considered to be an independent prognostic factor in newly diagnosed acute myeloid leukemia (AML). However, recent studies have demonstrated that acquired gene mutations also play an important role in the pathogenesis and prognosis of AML. It has been well known that minimal residual disease (MRD) pre-conditioning has remarkable impact on disease-free survival (DFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia, but the effect of MRD pre-transplant on allo-HSCT in AML is still unclear. Objective: In present study, the effect of NCCN risk stratification which has integrated gene mutations into cytogenetics as well as MRD pre-transplant on DFS after allo-HSCT in AML was studied in order to learn whether risk-directed conditioning and prevention of relapse are needed. Methods: Between April 2012 and March 2015, consecutive 258 patients with AML in complete remission (CR) (186 cases in CR1 and 72 cases in CR2) who underwent allo-HSCT in our hospital were analyzed retrospectively. The median age was 25 (1.8-64) years. Male (M) to female (F) was 147:111. The median disease course was 6 (1-51) months. According to 2015-NCCN risk stratification, 63 (24.4%) cases were in low risk, 112 (43.4%) cases in intermediated risk, and 83 (32.2%) cases in high risk. MRD in bone marrow pre-conditioning was detected by eight-color flow cytometry. Results: With the median follow up 18 (5-41) months, overall 2-year DFS was78.0%. No significant difference in DFS was found among low-risk (78.6%), intermediated-risk (76.0%) and high-risk (80.3%) patients (P=0.886). 205 (79.5%) cases were MRD- and 53 (20.5%) cases were MRD+ before conditioning. DFS after transplant in MRD+ patients was significant lower than that in MRD- patients(65.0% vs. 81.4%, P=0.003). Univariate analysis showed that DFS was not associated with patient age (≤14years vs.>14years, P=0.292), disease course before HSCT (≤6 months vs.>6months, P=0.532), WBC counts at diagnosis (≤50×109/L vs.>50×109/L, P=0.120), CBC recovery pre-HSCT (yes vs. no, P=0.664), disease status (CR1 vs. CR2, P=0.201), extramedullary leukemia before transplant (yes vs. no, P=0.532), conditioning regimen (BUCy/Flu-based vs. TBICy/Flu-based, P=0.753), donor type (identical sibling vs. unrelated vs. haploidentical, P=0.743), donor-recipient gender (M-M vs. M-F vs. F-M vs. F-F, P=0.245), donor-recipient blood type (compatibility vs. major incompatibility vs. minor incompatibility vs. major and minor incompatibility, P=0.402), mononuclear cells infused (≤8×108/kg vs.>8×108/kg, P=0.583), CD34+ cells infused (≤4×106/kg vs.>4×106/kg, P=0.946), and CD3+ cells infused (≤1.6×108/kg vs.>1.6×108/kg, P=0.143). DFS was significant lower in the patients with secondary AML (79.4% in primary AML vs. 53.5% in secondary AML, P=0.006) and MRD+ cases before transplant (81.4% in MRD- vs. 65.0% in MRD+, P=0.003). Accumulative non-relapse mortality (NRM) was significant higher in secondary AML (11.7% in primary AML vs. 33.3% in secondary AML, P=0.004) and MRD+ patients (10.5% in MRD- vs. 21.9% in MRD+, P=0.010). Accumulative relapse rate was significant higher in CR2 cases (8.0% in CR1 vs. 17.5% in CR2, P=0.046). Multivariate analysis showed that MRD pre-HSCT was the only impact factor on DFS and NRM with higher DFS (P=0.020) and lower NRM (P=0.045) in MRD- cases. Conclusions: Allo-HSCT has attenuated the influence of cytogenetics and gene mutations on DFS in AML. Secondary AML has lower DFS and higher NRM. Although disease status (CR1 vs. CR2) has no significant influence on DFS, relapse rate in CR2 is higher than that in CR1. MRD pre-conditioning was a key impact factor on DFS after allo-HSCT in AML but not conditioning regimen and donor type. Disclosures No relevant conflicts of interest to declare.

scholarly journals Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000)

2018 ◽  
Vol 36 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Martin Schrappe ◽  
Kirsten Bleckmann ◽  
Martin Zimmermann ◽  
Andrea Biondi ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Cumulative Incidence ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Young Patients ◽  
Disease Free Survival ◽  
Standard Risk ◽  
Minimal Residual ◽  
Reduced Intensity

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

scholarly journals Impact of Cytogenetic and Molecular Markers on Disease-Free Survival of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3217-3217
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Xing-Yu Cao ◽  
Yan-Li Zhao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Leukocyte Count ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Donor Source

Abstract Introduction: Cytogenetics is an independent prognostic factor in acute myeloid leukemia (AML). Molecular genetics including leukemia fusion gene, gene mutation and gene over expression are recognized to have significant impact on survival in patients with AML as well. In present study, the impact of cytogenetic and molecular markers on disease-free survival (DFS) of allogeneic hematopoietic stem cell transplantation (HSCT) for AML was investigated. Methods: Between April 2012 and December 2014, consecutive 345 patients with AML who underwent allogeneic HSCT in our center were analyzed retrospectively. All patients were either in poor-risk or in good-risk/intermediate-risk but with persistent minimal residual disease. The median age was 19 (1.8 to 64) years old. Children (≤14 years) were 96 (27.8%) cases and adults (>14 years) were 249 (72.2%) cases. Male to female was 200:145. The median disease course was 6 (1-64) months. Leukocyte count at diagnosis was < 30 x 109/L in 230 (66.7%) patients (low leukocyte) and ≥30 x 109/L in 115 (33.3%) cases (high leukocyte). Transplants at CR1, ≥CR2, and advanced disease were 168 (48.7%), 53 (15.4%) and 124 (35.9%), respectively. Donor sources were identical sibling (IS) in 45 (13.0%) cases, unrelated (UR) in 71 (20.6%) cases and haploidentical (HI) in 229 (66.4%) cases. Myeloablative conditioning regimens were administered with either Busulfan (Bu) plus Cyclophosphamide (Cy)/Fludarabine (Flu)-based in 285 (82.6%) patients or total body irradiation (TBI) plus Cy/Flu-based in 60 (17.4%) patients. Antithymocyte globulin was used in unrelated and haploidentical HSCT. Unmanipulated bone marrow and peripheral blood stem cells (PBSC) for IS and HI HSCT and PBSC for UR transplant were applied as the grafts. Cyclosporine, short-term Methotrexate, and Mycophenolate mofetil were employed for GVHD prophylaxis. Results: Univariate analysis showed that DFS after allogeneic HSCT in AML was not associated with patient age (children vs. adults, 70.3% vs. 69.4%, p=0.6), leukocyte count at diagnosis (low leukocyte vs. high leukocyte, 68.8% vs. 71.3%, p=0.8), donor source (IS vs. UD vs. HI, 77.3% vs. 76.8% vs. 65.8%, p=0.21), and conditioning regimen (Bu-based vs. TBI-based, 70.1% vs. 67.3%, p=0.45). Multivariate analysis indicated that disease status before HSCT was the only impact factor on DFS (CR1 vs. ≥CR2 vs. advanced disease, 81.6% vs. 70.0% vs. 53.1%, p<0.0001). Therefore, total 221 of 345 patients with AML in complete remission pre-conditioning were analyzed for impact of cytogenetic and molecular markers on survival after HSCT. DFS rates were 79.1%, 80.4%, 74.1% in good-risk, intermediate-risk, poor-risk cytogenetics groups (p=0.81), respectively. According to gene mutations, the DFS rates were 100% in CEBPA+, 91.6% in IDH1+/NPM1+, 85.7% in Flt3-ITD+, 81.5% in c-KIT+, 75.0% in no mutation, 70.2% in MLL-PTD+/ASXL1+/TET2+, 54.3% in Flt3-ITD+ with other mutations (p=0.42). According to gene expression, the DFS rates were 100% in DEK-CAN+, 100% in HOX11+/EVI1+, 84.8% in no abnormal gene expression, 83.3% in CBFb-MYH11+, 78.5% in WT1+, 76.5% in MLL+, 74.9% in AML1-ETO+, 0% in TLS-ERG+ (p=0.004). Conclusions: Under our HSCT protocol, disease status before transplant for the patients with AML has significant impact on DFS but not patient age, leukocyte count at diagnosis, donor source and conditioning regimen. Allogeneic HSCT has attenuated the influence of cytogenetics on DFS in patients with AML. Our preliminary data have shown that patients with CEBPA+, IDH1+/NPM1+, DEK-CAN+, HOX11+/NPM1+ have favorable survival, but patients with both Flt3-ITD+ and other gene mutations or with TLS-ERG+ have poor survival after allogeneic HSCT in AML. Disclosures No relevant conflicts of interest to declare.

Post-Remission Therapy with Imatinib and HAM Improve MRD before Tansplant for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL): Results of the GRAALL AFR03 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1877-1877
Author(s):  
Thibaut Leguay ◽  
Francis Witz ◽  
Stéphane De Botton ◽  
Jean Gabert ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Molecular Remission ◽  
Before And After

Abstract Combination of Imatinib with chemotherapy has been reported as very promising for patients with Ph+ ALL. In this study, we attempted to minimize the MRD (Minimal Residual Disease) level before transplant for Ph+ ALL by combining Imatinib with HAM (HAMI). This regimen consisted to Cytarabine 2g/m2/12 hours between day1 and day4, Mitoxantrone 10mg/m2/day between day1 and day3 combinated with Imatinib (3 different doses) between day1 and day45. MRD was studied by RT-PCR at day1 (before treatment) and day45 (after treatment) and was exprimed by BCR-ABL/ABL levels. Between April 2002 and September 2005, 36 patients in complete remission (CR) after induction chemotherapy have been analysed. This group consisted of 13 females and 23 males with a median age of 42 years (19–60). Three doses of Imatinib (400 mg, 600 mg and 800 mg/day) have been tested for six patients in each cohort (the first eighteen patients). After an intermediate analysis, the dose of 800 mg per day has been shown to be toxic (one grade IV hypokaliemia), and a last cohort of 18 patients were treated with 600 mg/day. No toxic-death related to HAMI regimen was reported. Thirthy-one patients could be studied for MRD before and after HAMI consolidation. Four patients were in molecular remission (level of BCR-ABL/ABL<10−5) before treatment and 12 after. No difference between 3 cohorts of dose was observed. The median level of MRD was 10−3 (0–0.7) and 3 × 10−5 (0–0.004) before and after treatment respectively (p=0.0015). After a median follow-up of two years and for all patients, the estimated overall survival (OS) and disease free survival were respectively of 71% (51%–84%) and 52% (32%–69%). The cumulative incidence of relapse and the cumulative incidence of death in CR were respectively of 15% (6%–32%) and 31% (17%–52%). Twenty patients had allogenic matched transplantation (thirteen related, seven unrelated) and composed the group with donor. In this first group, seven patients obtained MRD negativity after HAMI treatment. The others sixteen patients composed the second group of patients without donor or older than 55 years. In this second group, eleven patients received autologous stem-cell transplant followed by imatinib for nine of them, and five received imatinib in maintenance with or without chemotherapy. In this group, six patients had obtained MRD negativity after HAMI. The two-years OS was identical for patients with or without donor (71%). In conclusion, imatinib combined with high dose chemotherapy improved molecular remission before transplantation and lead to an improve outcome.

Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) Not in First Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4388-4388 ◽  
Author(s):  
Kendra L Sweet ◽  
Jeffrey E Lancet ◽  
Ryan Hillgruber ◽  
Megan Melody ◽  
Amina Llishi ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Mutational Status ◽  
The Impact

Abstract Background: Approximately 60 - 80% of AML patients achieve a complete remission [CR] with one or two cycles of induction chemotherapy, leaving many patients with refractory AML [PIF]. Unfortunately, the majority of patients in CR1 ultimately relapse. With salvage therapy, only 30-50% achieve CR2. Those with PIF or relapsed AML have shortened survival and few therapeutic options. Risk stratification is primarily based on karyotype, however other factors including age, initial white blood cell count, secondary AML and mutational status are also utilized to determine prognosis. HCT is an effective option for treatment of AML with intermediate/high risk features in CR1. It has also been utilized in refractory or relapsed disease. Advances in HCT over the last decade have improved overall survival (OS) and extended this option to older patients. Our aim is to characterize outcomes after HCT for AML patients who are not in CR1. Methods: We analyzed 136 AML patients who were not in CR1 at the time of HCT from 2004 - 2013. The conditioning regimen was fludarabine and myeloablative doses of PK targeted busulfan. IWG AML response criteria were used to define disease status at the time of transplant. Cytogenetic risk was based on the NCCN AML guidelines. OS is defined as the time from HCT until the time of death from any cause. Disease free survival (DFS) is defined as the time from HCT to the time of relapse or death from any cause. Results: Disease status consisted of 74 (54.4%) in CR2, 6 (4.4%) in CR3 or beyond, 27 (18.9%) were PIF, 21 (15.4%) with relapsed AML (REL) that was treated but still present at time of transplant, and 8 (5.7%) who received either no treatment or a hypomethylating agent (HMA). Median age was 52.0 (21.8 - 72.5) years, and 80 (59%) were male. Time from most recent treatment to HCT was < 1 month in 8 (5.8%), 1-3 months in 75 (55.8%), >3 months in 50 (36.8%) and not applicable in 3. Ninety-six (70.6%) had de novo AML, while 40 (29.4%) had secondary AML. Cytogenetic risk was favorable in 32 (23.5%), intermediate in 57 (42%), poor in 40 (29.4%) and unknown in 7 (5.1%). Graft-versus-host disease prophylaxis was tacrolimus with methotrexate or sirolimus, or mycophenolate mofetil. Donors included 41 (30.2%) matched related, 2 (1.4%) mismatched related, 65 (47.8%) matched unrelated and 28 (20.6%) mismatched unrelated donors. Peripheral blood stem cells were used in 97.2% of cases. Two year OS, DFS, cumulative incidence (CI) of relapse and CI-NRM for all patients was 45.3%, 35.2%, 47.1% and 18.2%, respectively. Two-year DFS stratified by disease status at time of HCT was 41.9%, 33.3%, 25.9%, 33.3% and 12.5% in CR2, CR3 or beyond, PIF, REL and HMA, respectively(p=0.011 for CR2 vs HMA) (Figure 1). Two-year DFS stratified by cytogenetic risk was 43.8%, 31.6%, 37.1% and 14.3% in favorable, intermediate, poor and unknown, respectively (p>0.05) (Figure2). CI-Rel stratified by disease status was 43.2%, 16.7%, 66.7%, 42.9% and 50% in CR2, CR3 or greater, PIF, REL and HMA, respectively (Figure 3). Conclusions: We analyzed 136 AML patients after undergoing HST outside of CR1 and the cumulative incidence of relapse at two years was 47%. Relapse was highest in those with primary induction failure or residual disease after either no or low intensity therapy. These data suggest that patients with active disease at the time of transplant fare worse than those who are transplanted in remission, highlighting the importance of effective upfront therapies in order to obtain the maximum potential benefit from HCT. Cytogenetic risk stratification did not significantly impact outcomes, although those with favorable risk cytogenetics trend towards higher 2-year DFS vs those with intermediate or poor-risk disease. Trials looking at the impact of maintenance therapy post-transplant may be valuable in this patient population. Table 1. Disease Status @ HSCT CR2 CR3 or beyond PIF RES HMA/untreated 2 years 41.9% (30.6 - 52.8) 33.3% (4.6 - 67.6) 25.9% (11.5 - 43.1) 33.3% (14.9 - 53.1) 12.5% (0.7 - 42.3) Table 2. Cytogenetic Risk Group Favorable Intermediate Unfavorable Unknown 2 years 43.8% (26.5 - 59.8) 31.6% (20.1 - 43.7) 37.1% (22.5 - 51.8) 14.3% (0.7 - 46.5) Table 3. Cumulative Incidence of Relapse CR2 (1) CR3 or beyond (2) PIF (3) REL (4) HMA/untreated (5) 2 years 43.2% (32.2 - 54.6) 16.7% (0.0 - 53.5) 66.7% (48.1 - 82.9) 42.9% (23.0 - 64.0) 50.0% (18.1 - 81.9) Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sweet: Novartis Pharmaceuticals: Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Karyopharm Therapeutics Inc: Research Funding; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy; Pfizer: Research Funding; Kalo-Bios: Consultancy; Amgen: Consultancy. Perkins:PDL Biopharma: Research Funding. Field:PDL Biopharma: Research Funding.

Haploidentical Unmanipulated G-CSF-Primed Peripheral Blood Stem Cell Transplantation for Patients with High-Risk Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4365-4365
Author(s):  
Dai-Hong Liu ◽  
Li Yu ◽  
Wenrong Huang ◽  
Liping Dou ◽  
Honghua Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Continuous Line ◽  
Free Survival ◽  
Grade 3

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective, even curative, treatment for patients with high-risk hematologic malignancies. Transplantation from haploidentical donors (haplo-HCT) has been applied for the treatment of hematologic malignancies within the past 2 decades. Bone marrow (BM), G-CSF-primed peripheral blood stem cells (PBSCs), G-CSF-primed BM (G-BM) or the combination of PBSCs and G-BM can serve as stem cell sources for allo-HCT. The optimal source of stem cells in cases of haplo-HCT without ex vivo TCD under myeloablative conditioning is not yet clear. Therefore, we initiated a study of unmanipulated haplo-HCT from PBSCs (haplo-PBSCT) for the treatment of high-risk hematologic malignancies. In this report, we analyzed 89 adult patients who received consecutive haplo-PBSCT to evaluate the efficacy and safety of this transplantation procedure. PATIENTS AND METHODS Eighty-nine patients received consecutive haploidentical allo-PBSCT between July, 2007 ¨C June, 2014 at the Chinese PLA General Hospital, Beijing, China (Table 1). PBSCs were freshly isolated and infused into the recipients. The conditioning regimen consisted of Bu (3.2 mg.kg-1.d-1 intravenously, days -10 to -8), Carmustine, 250 mg.m-2, day -5), cytarabine (4 g.m-2.d-1, days -7 to -6), cyclophosphamide (60mg kg-1.d-1, days -4 to -3), and ATG (Thymoglobuline, rabbit; 2.5 mg.kg-1.d-1, days -5 to -2). All transplant recipients received CsA, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. "High-risk'' hematologic malignancies were defined as: 1) AL with the [t(9;22)(q34;q11)], Flt3-ITD mutation, mixed lineage leukemia genes and complex cytogenetics regardless of disease stage; 2) AML-CR1 after 3 or more cycles of induction, ALL-CR1 after 4 weeks of induction or AL-CR1 with positive MRD after 2 cycles of consolidation; 3) AL beyond CR2 or in non-remission (NR) regardless of cytogenetics, or CML beyond CP1; and 4) T cell lymphoblastic lymphoma in CR and T cell lymphoma resistant to chemotherapy or autologous transplantation. The endpoint of the last follow-up for all surviving patients was January 31, 2015. RESULTS Sustained myeloid engraftment with full donor chimerism was achieved in 89 patients (100%) at a median of 16 (10 - 26) days. Eighty patients (89.9%) achieved platelet recovery in a median of 28 (10 - 207) days. The occurrence of GVHD was showed in Fig 1. The 3-year of cumulative incidence of transplant-related mortality was 23.4% ± 5.4%. Non-remission status prior to transplant was found to be significantly correlated with relapse (P = 0.006, odds ratio [OR] = 3.17), leukemia-free survival (P = 0.013, OR = 2.48) (Fig. 2) and overall survival (P = 0.03, OR = 2.27). CONCLUSION The results described rapid and complete neutrophil engraftment, a low incidence of grade 3-4 GVHD and promising survival in patients with high-risk hematologic malignancies. It demonstrated the reliability of G-CSF-primed PBSCs as a graft source in unmanipulated haplo-HCT under myeloablative conditioning. Table 1. Patient and donor characteristics Cases % Gender, n (%) Male 69 77.5 Age, y, median(range) Patient <46 y, n (%) 28(6-59) Donor >40 y, n (%) 38(9-61) Hematologic malignancy, n (%) AML 51 57.3 CR1 CR2* 23 3 NR*/beyond CR2 23/1 ALL 20 22.5 CR1 CR2 10 7 NR 3 CML 5 5.6 CP1* 2 AP/CP2 1/2 Lymphoma 13 14.6 CR 5 Resistant 8 Donor/recipient relationship, n (%) Parent 47 52.8 Sibling 26 29.2 Child 12 13.5 Lateral relative 4 4.5 No. of HLA antigens (A/B/DR) mismatched, n(%) 1 18 20.2 2 25 28.1 3 46 51.7 Second HCT 9 10.1 Graft: MNC (108/kg) 11.04 (5.64-36.46) CD34+ (106/kg) 5.83 (2-23.73) Figure 1. Acute and chronic GVHD. (A) CI (Cumulative Incidence) of grade 2-4 (continuous line) and grade 3-4 (dotted line) acute GVHD. (B) CI of total (continuous line) and moderate to severe (dotted line) chronic GVHD. Figure 1. Acute and chronic GVHD. (A) CI (Cumulative Incidence) of grade 2-4 (continuous line) and grade 3-4 (dotted line) acute GVHD. (B) CI of total (continuous line) and moderate to severe (dotted line) chronic GVHD. Figure 2. Disease-free survival according to disease status. Figure 2. Disease-free survival according to disease status. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic Value of Minimal Residual Disease Assessed By WT1 Expression Level and Flow Cytometry in Acute Myeloid Leukemia Patients Undergoing Allogeneic Marrow Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1027-1027
Author(s):  
Livia Giannoni ◽  
Fabio Guolo ◽  
Paola Minetto ◽  
Federica Galaverna ◽  
Chiara Ghiggi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Disease Status ◽  
Leukemic Cells ◽  
Free Survival ◽  
Relapse Risk ◽  
Disease Free

Abstract Background: Allogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for most patients affected by acute myeloid leukemia (AML). Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict disease relapse after BMT. WT1 expression levels and multicolor flow cytometry (MFC) are widely used as markers of MRD. We recently reported that combined evaluation of MRD by WT1 and MFC after induction therapy can predict relapse risk in AML patients. Aims: The aim of the present study was to apply the same MRD assessment in pre BMT setting to evaluate its reliability in predicting relapse. Methods: We retrospectively analyzed BMT outcome of 66 AML patients with both WT1-based and MFC-based MRD evaluation on bone marrow samples before transplant. Median age at transplant was 44 years. Forty-one were transplanted in first and twenty-five in second or subsequent complete remission. Induction therapies included fludarabine-containing regimens or standard ara-C and daunorubicin schedule (3+7). Median follow-up was 44 months (range 0-119 months); pre-transplantation evaluations were performed at a median of one month before transplant (range 1-3). Disease-free survival (DFS) was calculated from the time of transplantation until last follow-up or documented leukemic relapse. Overall survival was calculated from the time of transplantation to the last follow-up or death for any cause. All causes of death not directly due to relapse or progression of leukemia were considered as non-relapse mortality. A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells /105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. Real-time PCR for WT1 was performed on DNA Engine 2 (Opticon®, MJResearch®). WT1 copy number/Abl copy number 500x104 was used as cut-off value for high WT1 expression. Results: Twenty-five relapses (37.9%) were observed. Median DFS was 31 months. Our analysis shows that the probability of relapse was significantly influenced only by disease status (first or subsequent CR) and MRD status at transplantation. Specifically, MFC-MRD was the strongest predictor of longer disease free survival (p <0.001) since no relapses occurred in the eleven MFC-MRD negative patients. Among MFC-MRD positive patients a further stratification of relapse risk is obtained by the evaluation of WT1. Patients with double positive MRD had a significantly worse DFS compared with patients who were MRD positive by MFC but MRD negative by WT1 (p <0.01). The predictive value of MRD was independent from different induction schedules; furthermore the favorable prognostic value of achieving a negative MRD status was not affected by undergoing BMT in second or subsequent remission. Median OS was 26 months and was significantly influenced by disease status and MRD status at transplantation and by relapse after BMT. Cumulative non relapse mortality was 23% at 36 months and was not associated with pre-BMT status. Conclusion: pre BMT MRD evaluation by WT1 and MFC on bone marrow samples is a reliable tool to predict relapse risk. Patients with negative pre-BMT MRD have a significantly longer DFS and OS, while MRD positive patients by both methods display a higher risk of relapse. Patients at higher risk of poor outcome should undergo a more stringent program of post BMT evaluations, in order to detect disease relapse earlier and might be candidate for pre-emptive therapeutic interventions aimed at delaying or avoiding AML reoccurrence. Disclosures No relevant conflicts of interest to declare.

Phase II Trial of WT1 Analog Peptide Vaccine in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3624-3624
Author(s):  
Todd L. Rosenblat ◽  
Mark G. Frattini ◽  
Suzanne M. Chanel ◽  
Tao Dao ◽  
Yvette Bernal ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Phase Ii ◽  
Residual Disease ◽  
Peptide Vaccine ◽  
Disease Free Survival ◽  
Disease Recurrence ◽  
Gm Csf ◽  
Analog Peptide ◽  
Immunologic Activity

Abstract Abstract 3624 WT1 is a transcription factor which has been implicated in leukemogenesis and has been used as a marker of minimal residual disease (MRD). We previously demonstrated the feasibility of vaccinating AML patients in CR with a multivalent WT1 peptide vaccine and inducing immune responses. In an effort to further explore the safety and efficacy of this approach, we are conducting a Phase II study in which the vaccine is administered to AML patients in first CR and who completed all planned postremission chemotherapy. Eligible patients had WT1 transcript detectable by RT-PCR. The vaccine consisted of 4 native and derived WT1 peptides administered with the immune adjuvants Montanide and GM-CSF. Patients received 6 vaccinations over 10 weeks. Early toxicity was assessed at weeks 2 and 4. Immune responses were evaluated at week 12 by CD4+ T cell proliferation, CD3+ T cell interferon-g interferon release (ELISPOT) and WT1 peptide tetramer staining. Patients who were clinically stable and without disease recurrence could continue with up to 6 more vaccinations administered approximately every month. To date, 12 patients have been accrued to the study (6-M, 6-F; median age – 66 years, range 26–73 years). Cytogenetic subtypes varied among the study patients (Favorable-3, Intermediate-5, Unfavorable-4). The median time to vaccination after achieving CR was 7.5 months (range: 3–22 months). One patient was removed early because of relapse prior to receiving the first vaccination. Four patients have received at least 6 vaccines and 2 others have completed 12 vaccinations. Eight patients are alive without evidence of disease. One of these patients has an HLA-A02 subtype and was found to have developed T cells reactive with WT1-A (native peptide) HLA tetramers following 6 vaccinations which persisted (at a lower level) until after the 12th vaccination. Three patients relapsed during vaccination (after 1, 5 and 11 vaccines) and 2 of the 3 have died. Two of the relapsed patients who had sample available for immunologic evaluation, did not develop a CD4+ response to any of the peptides tested. Two other patients discontinued vaccination because of toxicity (hypersensitivity/pain with GM-CSF administration). Both remain in CR. No episodes of anaphylaxis or generalized urticaria were observed. Neither median disease free survival nor overall survival has been reached in this small cohort of patients. These preliminary findings demonstrate that the WT1 peptide vaccine is relatively well tolerated and has immunologic activity. Trial accrual is ongoing and further follow-up is required before any beneficial effect on outcome can be determined. Disclosures: Scheinberg: Formula Pharma: WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma, WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma Patents & Royalties.

scholarly journals Myeloablative Cord Blood Transplantation Yields Excellent Disease Free Survival in Patients with Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4693-4693
Author(s):  
David Charles Keahi Oliver ◽  
Ryan D Cassaday ◽  
Ralph P Ermoian ◽  
Ann Dahlberg ◽  
Colleen Delaney ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Disease Free Survival ◽  
Free Survival ◽  
Blood Transplantation ◽  
Disease Free

Abstract Background: Allogeneic hematopoietic cell transplantation (HCT) is a potential curative treatment for children and adults with acute lymphoblastic leukemia (ALL). However, relapse occurs in approximately 30% of patients with ALL after HCT, with even worse outcomes in patients with minimal residual disease (MRD) pre-transplant [1]. Lower relapse rates have been reported for patients undergoing cord blood transplantation (CBT) compared to unrelated donor transplant. In the present study we sought not only to evaluate outcomes for ALL patients undergoing a myeloablative CBT, but also to see if the outcomes varied according to MRD status. Methods: Using prospectively collected data, we reviewed 67 consecutive patients with ALL who received a CBT between 2006 and 2016. The conditioning regimens consisted of either TBI (1320 cGy), Cytoxan and Fludarabine (FLU), (n=49) or Treosulfan (Treo), FLU and 200 cGY TBI (n=18). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil (MMF). Donor units were selected to be at least a 4 out of 6 match to recipient at HLA-A and HLA-B antigens and HLA-DRB allele. Ten-color multiparameter flow cytometry studies on bone marrow aspirates were performed before HCT to determine the presence of MRD. Disease free-survival (DFS) was evaluated using the method of Kaplan and Meier. Probabilities of non-relapse mortality (NRM) and relapse were summarized using cumulative incidence estimates using the appropriate competing risks. Results: Patient characteristics are shown in Table 1. The median age and weight was 22 years (range, 0.6-58 years) and 57 kg (range 8-99 kg), respectively. Thirty-nine patients (58%) were non-Caucasian. At the time of transplant 32 patients (47%) were in first complete remission (CR1), 28 (42%) in CR2 and 7 (11%) in CR≥3. Any level of residual disease was considered MRD-positive (n=22). Fifteen patients (22%) had Ph+ ALL. Nine patients (13%) had a prior allogeneic transplant. The majority of patients (n=48; 72%) received a double-CB graft; the rest received a single-CB graft. In addition, 14 patients (21%) received an ex-vivo-expanded CB unit as part of their graft, combined with an unmanipulated CB unit. Median time to engraftment was 31 days (range, 21-80 days). The overall DFS at 5 years was 74% (CI 95%: 60-83) with no difference between MRD-negative 78% (CI 95%: 61-88) and MRD-positive patients 67% (CI 95%:43-81) (p=0.40) [Figure 1A and 1B]. The overall cumulative incidence of relapse and NRM at 5 years post-transplant was 14% (CI 95%: 5-31) and 12% (95%: 3-26), respectively. The risk of relapse was not significantly higher in MRD-positive compared to MRD-negative (HR 1.80 (95 CI: 0.50-6.51) p=0.36), when adjusting for year of transplant, CMV serostatus, age, and disease risk. The cumulative incidence of acute GVHD grade II-IV and III-IV at day 100 was 86% (CI 95%: 75-92) and 16% (CI 95%: 8-26), respectively. Conclusions: Our data suggest that outcomes in patients with ALL following myeloablative CBT are remarkable with 74% DFS at 5 years and very low rate of relapse. The implication of these results is particularly important for patients from racial and ethnic minorities. Indeed, because mismatches in CB units can be tolerated, it is possible to find suitable donors for nearly all patients, regardless of their race/ethnicity. Furthermore, the risk of relapse was similar between MRD-negative and positive patients, although this requires further study in larger populations given the relatively low number of MRD-positive patients. References: 1. Bar M, Wood BL, Radich JP et al. Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. Leuk Res Treatment. 2014;2014:421723 Disclosures Delaney: Nohla Therapeutics: Employment.

Identical-Twin Transplants for B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3330-3330
Author(s):  
Steven Pavletic ◽  
Guimei Zhou ◽  
Kathleen Sobocinski ◽  
Kristine Doney ◽  
John DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Identical Twin ◽  
High Rate ◽  
Post Transplant ◽  
Disease Free

Abstract Studies of genetically identical-twin transplants are a novel opportunity to study how transplants work because: (1) there is no allogeneic effect; (2) no leukemia cells in the graft; and (3) no graft exposure to therapy. We conducted an international study that identified 19 subjects who received syngeneic bone marrow (N=11) or blood cell (N=8) transplants after myeloablative conditioning. 11 were males; age 51 y (range, 37–68 y). 18 received total body radiation. None had Richter transformation. Interval from diagnosis to transplant was 27 mo (5–171 mo). At transplant 8 had Rai stage 3/4, 5 had >50x10e9/L lymphocytes, 10 received ≥3 prior therapies, 8 had prior fludarabine, and 5 had a prior complete remission (CR). 18 engrafted and 13 achieved posttransplant CR; median time to CR was 3 mo (1–5 mo). Probability of 100 d survival was 89% (95% CI, 72–99%).10 subjects are alive (8 disease-free) at median follow-up of 63 mo (9–116 mo). Ten subjects either never achieved CR (N=6) or relapsed posttransplant (N=4). 5-y cumulative incidence of relapse was 52% (27–77%). Estimated 5-y survival and disease-free survival were 59% (34–81%) and 43% (20–67%), respectively. Causes of death included interstitial pneumonitis (N=1) and leukemia (N=8). 5-y cumulative incidence of treatment-related mortality (TRM) is 5% (0–20%). We used a highly sensitive (10e-4 to 10e-5) PCR method to examine post transplant blood (2 pts) or bone marrow (2 pts) samples for the tumor specific IgH gene (CDR)III to assess minimal residual disease (MRD). IgH CDR III was PCR amplified in pre transplant B-CLL samples from 4 pts to obtain the sequence to design tumor-specific primer probes for MRD. No evidence of MRD was detected in two pts at 12 and 21 mo posttransplant. A very weak clonal signal was identified in one pt at 64 mo. All three of these pts were in continuous clinical CR at 12, 60, and 66 mo, respectively. In one pt, who relapsed with B-CLL 6 y after transplant, molecular studies at 10 y follow-up demonstrated a very strong molecular signal but of a different clone. Additional investigation identified familial CLL where the donor was also diagnosed with B-CLL soon after marrow donation. Molecular analysis of the donor B-CLL showed a clone identical to the recipient’s post-transplant relapse, strongly indicating B-CLL transmission at the time of transplant. This study demonstrates that identical twin transplants can be performed in advanced B-CLL with little TRM and with a high-rate of durable clinical and molecular remissions. The 5-y leukemia relapse rate of 52% is higher than that in studies of similar subjects receiving allotransplants but lower than after autotransplants. We also report B-CLL transfer from a twin donor demonstrating the need for careful evaluation of allogeneic donors prior to graft collection.

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