Impact of Minimal Residual Disease (MRD) on Prognosis in Children with Acute Lymphoblastic Leukemia (ALL) According to WBC Count, Age and TEL/AML1 Status at Diagnosis. Results of the AIEOP-BFM ALL 2000 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 544-544 ◽  
Author(s):  
Valentino Conter ◽  
André Schrauder ◽  
Helmut Gadner ◽  
Maria Grazia Valsecchi ◽  
Martin Zimmermann ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Patient Specific ◽  
Specific Gene ◽  
Childhood All ◽  
Historical Factors ◽  
Wbc Count ◽  
Minimal Residual

Abstract Minimal residual disease (MRD), the most sensitive method to evaluate treatment response, has been adopted to stratify patients in study AIEOP-BFM ALL 2000. To assess whether PCR-MRD levels discriminate outcome in patients classified by WBC count, age at diagnosis, NCI criteria (Standard Risk, SR: WBC < 50,000/cmm and age 1–9 years; High Risk, HR: all others) and TEL/AML1 status. Between 07–2000 and 07–2006, 4,730 Ph-negative patients were enrolled in AIEOP-BFM ALL 2000 study. They were treated with BFM Induction (protocol IA) consolidation (protocol IB), extra-compartment/intensified consolidation (HD-MTX in non-HR patients, blocks in HR patients), reinduction therapy (one or more Protocols II or III), followed by maintainance. BM samples obtained at weeks 5 (Time Point 1, TP1) and 12 (TP2) of induction/consolidation therapy were used for PCR-based MRD analysis of patient specific gene targets. At least 2 sensitive markers (≥ 1 x 10−4) could be determined in 3,707 (78.4%) patients. SR was defined by MRD− at both TP1 and TP2; HR by MRD ≥1x10−3 at TP2; Intermediate Risk (IR): all others. Median follow-up was 3 years; 5-year percent EFS (SE) estimates are given.Patients at MRD-SR, IR or HR had, respectively, an EFS of 93.0 (1.0), 80.5 (1.5) and 43.4 (6.0) in patients with WBC <50,000/cmm vs 90.4 (2.6), 72.4 (3.0) and 47.0 (5.1) in patients with WBC ≥50,000/cmm. Patients at MRD SR, IR or HR had, respectively, EFS of 93.6 (1.0), 80.3 (1.5) and 44.1 (5.4) if aged 1–9 years vs 87.2 (3.4), 73.9 (3.0) and 49.3 (5.2) if aged ≥10 years. Patients at SR by NCI criteria [N= 2,355, EFS of 85.3 (1.0)] were stratified by PCR-MRD as SR (N=1046; 44.4%), IR (N=1198; 50.9%), or HR (N=111; 4.7%). EFS in these subgroups was 93.9 (1.0), 81.3 (1.6) and 43.9 (7.2), respectively (p<0.001). In patients at HR by NCI criteria [N=1,352, EFS of 75.6 (1.6)], 403 (29.8%), 774 (57.3%) and 175 (12.9%) respectively were at SR IR and HR by MRD. EFS was 89.4 (2.2) in MRD SR, 74.7 (2.3) in MRD IR and 47.9 (4.2) in MRD HR patients (p<0.001). Of 3,707 study patients, 3,410 were investigated for TEL/AML1 status: 771 (22.6%) were positive and 2,639 were negative. TEL/AML1+ patients were at SR (N=444; 57.6%) or IR (N=317; 41.1%) or HR (N=10; 1.3%) by PCR-MRD; EFS in this subgroup was 94.4% (1.5), 80% (3.7) and 60% (18.4), respectively (p<0.001). TEL/AML1− patients at SR (N=887; 33.6%) or IR (N=1497; 56.7%) or HR (N=255; 9.7%) had an EFS of 91.6% (1.3), 78.5% (1.4) and 45.7% (4.5), respectively (p<0.001). PCR-MRD in patients treated with BFM-oriented therapy overcomes the prognostic value of “historical” factors such as WBC count, age, NCI criteria or TEL/AML1 status, as it markedly discriminates prognosis within each subgroup defined by these variables. Study design for contemporary risk-directed therapy of childhood ALL should incorporate a technique for MRD determination.

Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (4) ◽  
pp. 704-709 ◽  
Author(s):  
Glenn M. Marshall ◽  
Michelle Haber ◽  
Edward Kwan ◽  
Ling Zhu ◽  
Daniella Ferrara ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Maintenance Chemotherapy ◽  
Childhood All ◽  
Second Year ◽  
Minimal Residual

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.

Co-Existence of Various Sub-Clones in TEL-AML1 Positive Acute Lymphoblastic Leukemia in Association with Sub-Microscopic Deletion of AML1.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1096-1096
Author(s):  
Amos Toren ◽  
Rachel Rothman ◽  
Bella Bielorai ◽  
Malka Reichart ◽  
Ninette Amariglio ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Gene Rearrangement ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Submicroscopic Deletion ◽  
Minimal Residual

Abstract The TEL/AML1 fusion gene is the most common gene rearrangement in pediatric acute lymphoblastic leukemia (ALL). Although considered to be a low risk leukemia it has a 20% risk of late relapse. The coexistence of different sub clones at diagnosis, based on polymerase chain reaction (PCR) studies of Ig/TCR gene rearrangement, was recently reported in this subtype of ALL. Their different response to chemotherapy may explain the emergence of certain sub clones at relapse, and may serve as a marker for minimal residual disease follow-up. Several chromosomal rearrangements such as t(9;22), t(8;21), inv(16) and rearrangements of the MLL gene are frequently associated with submicroscopic deletions and some of them have prognostic significance. Such deletions were not reported in t(12;21) positive ALL. Bone marrow cells from 76 pediatric patients with ALL at diagnosis were analyzed for the presence of the TEL/AML1 fusion gene by interphase fluorescence in situ hybridization (FISH). We used a new system of combined analysis enabling a very large-scale study of the cells of interest with regard to morphology, FISH and immunophenotyping. Fourteen patients were positive for the translocation. Four of them had several sub clones associated with various combinations of additional chromosomal abnormalities. The most striking was an atypical and unexpected hybridization pattern consistent with a submicroscopic deletion of the 5′ region of the AML1 breakpoint (intron2) not previously reported. We describe the use of a larger probe for AML1 (AML1/ETO) to exclude the possibility of insertion of TEL into the AML1 region without breakage and to reduce the false positivity due to optical fusion. This may enable a better monitoring of minimal residual disease in cases with submicroscopic deletion. All patients had some sub-clones with TEL deletion. Other abnormalities included trisomy and tetrasomy 21 as well as double TEL-AML1 fusion. The analysis of numerous sub-clones at presentation in these patients suggests clonal evolution at an early stage of the disease. These sub-clones may have different sensitivities to chemotherapy, and some of them may reappear at relapse. The frequency of AML1 deletion in t(12;21) in addition to other chromosomal abnormalities, is unknown. The involvement of these findings in the generation of leukemic sub clones, their prognostic significance and role in minimal residual disease follow-up deserves further studies in a large number of patients and a longer follow-up.

Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4439-4439
Author(s):  
Beata M. Stella-Holowiecka ◽  
Krystyna Jagoda ◽  
Aleksandra M. Holowiecka-Goral ◽  
Tomasz Czerw ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Long Term Results ◽  
Color Flow ◽  
Childhood All ◽  
Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was &lt;0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/&gt; 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

Minimal Residual Disease Monitoring in Childhood Precursor B Lymphoblastic Leukemia with t(12;21)(p13;q22); ETV6-RUNX1: A Comparison Between Quantitative RT-PCR and Flow Cytometry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3774-3774
Author(s):  
Sofie J Alm ◽  
Charlotte Engvall ◽  
Julia Asp ◽  
Lars Palmqvist ◽  
Jonas Abrahamsson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Time Points ◽  
Qrt Pcr ◽  
Minimal Residual

Abstract The translocation t(12;21)(p13;q22) resulting in the fusion gene ETV6-RUNX1, is the most frequent gene fusion in childhood precursor B lymphoblastic leukemia (pre-B ALL), affecting about one in four children with pre-B ALL. In the NOPHO ALL-2008 treatment protocol, treatment assignment in pre-B ALL is based on clinical parameters, genetic aberrations, and results from analysis of minimal residual disease (MRD) at day 29 and 79 during treatment (where MRD >0.1% leads to upgrading of treatment). For pre-B ALL, in this protocol MRD analysis is performed using flow cytometry as the method of choice. In this study, we also analyzed MRD in t(12;21)(p13;q22) cases with quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the fusion transcript ETV6-RUNX1 in parallel with routine MRD analysis with flow cytometry, to determine if qRT-PCR of the ETV6-RUNX1 fusion transcript would be a reliable alternative to FACS. Bone marrow samples were collected at diagnosis and at day 15, 29 and 79 during treatment from 31 children treated according to the NOPHO ALL-2000 (n = 3) and NOPHO ALL-2008 (n = 28) protocols in Gothenburg, Sweden, between 2006 and 2013. Samples were analyzed in parallel with qRT-PCR for ETV6-RUNX1 fusion transcript and with FACS. For qRT-PCR, mRNA was isolated, cDNA synthesized, and qRT-PCR performed with GUSB as reference gene. MRD-qRT-PCR was defined as the ETV6-RUNX1/GUSB ratio at the follow-up time point (day 15/29/79) divided with the ETV6-RUNX1/GUSB ratio at diagnosis (%). MRD analysis with FACS was performed, after lysis of erythrocytes, using antibodies against CD10, CD19, CD20, CD22, CD34, CD38, CD45, CD58, CD66c, CD123, and terminal deoxynucleotidyl transferase, and when applicable also CD13 and CD33. Results of MRD-FACS were expressed as % of all cells. In total, 83 samples were analyzed with both methods in parallel; 31 from day 15 in treatment, 28 from day 29, and 24 from day 79. Overall, MRD-qRT-PCR showed good correlation with MRD-FACS. In total, 31 samples were positive with qRT-PCR and 24 with FACS, with concordant results (positive with both methods or negative with both methods) in 89% of samples, when the limit of decision (positive/negative MRD) was set to 0.1%. The concordance was especially high at the treatment stratifying time points, i.e. day 29 and 79; 89% and 100%, respectively. No samples at these time points were positive with FACS but negative with qRT-PCR. During the follow-up period (6-81 months), one patient relapsed (with negative MRD with both methods at stratifying time points), and two succumbed from therapy-related causes. Our results show that there is a significant relationship between the results of MRD analysis using FACS and MRD analysis using qRT-PCR of ETV6-RUNX1 fusion transcript. The high concordance between the methods indicates that negative MRD using qRT-PCR is as reliable as negative MRD using FACS, and that qRT-PCR could therefore be an alternative to FACS in cases where FACS is not achievable. In comparison to quantitative PCR of TCR/Ig gene rearrangements, which is the current backup MRD method for cases with pre-B ALL in NOPHO ALL-2008, qRT-PCR of ETV6-RUNX1 is much less time and labor consuming, making it appealing in a clinical laboratory setting. Disclosures No relevant conflicts of interest to declare.

Bone Marrow Fibrosis Evaluation in Childhood Acute Lymphoblastic Leukaemia: Correlation to Biological Factors and Treatment Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2280-2280
Author(s):  
Ulrika Norén-Nyström ◽  
Goran Roos ◽  
Anders Bergh ◽  
Ingrid Thörn ◽  
Gudmar Lonnerholm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Myeloproliferative Disorders ◽  
Prognostic Impact ◽  
Childhood All ◽  
Modal Chromosome Number ◽  
Minimal Residual

Abstract Fibrosis may complicate bone marrow (BM) disease and in its advanced stage negatively affect the outcome of the patients due to BM failure, particularly in myeloproliferative disorders. Studies of the potential importance of BM fibrosis are rare in childhood acute lymphoblastic leukemia (ALL). We have previously shown a prognostic impact of BM fibrosis measured as reticulin fibre density (RFD) at diagnosis in childhood ALL. To further investigate the consequence of BM fibrosis in childhood ALL in relation to immunophenotype, cytogenetic findings and minimal residual disease (MRD) we retrospectively evaluated the RFD in 139 diagnostic BM biopsies from patients with a total mean follow up time of five years and eight months from two childhood oncology centers in Sweden. Patients with pre-B-ALL showed a higher mean RFD (19.1%) compared to patients with T-ALL (11.4%, p < 0.001). This was true also when comparing high-risk (HR) pre-B-ALL patients (18.1%) with the T-ALL patients (p = 0.002). RFD correlated inversely with the white blood cell count in the HR group (r = −0.41, p = 0.009), probably reflecting our finding of low degree of fibrosis in T-ALL. The cytogenetic analysis revealed that for patients with a hyperdiploid ALL (modal chromosome number: 51–61, n: 41) in the low-risk (LR) group, mean RFD was higher for relapsed patients (22.6%) compared to patients in continuous complete remission (17.2%, p = 0.019). The probability of disease free survival for the same group using RFD cutoff of 21.1%, representing the upper third of the material, was 85%±8% for patients with hyperdiploid ALL and low RFD compared to 51%±14% for patients with hyperdiploid ALL and high RFD (p = 0.01, Figure 1). Data for 32 of the patients demonstrated an association between high RFD at diagnosis and high minimal residual disease (MRD) on day 29 after start of treatment. Patients with FACS-MRD > 10−3 day 29 displayed higher mean RFD at diagnosis (21.2%) compared to patients with FACS-MRD < 10−3 (16.7%, p = 0.027, Figure 2). When analyzing the PCR-MRD data day 29 the findings were similar. We conclude that RFD is higher in pre-B-ALL compared to T-ALL, that RFD has prognostic impact in LR patients with hyperdiploid ALL and that high RFD at diagnosis is associated to high MRD on treatment day 29. All these findings are to our knowledge novel, suggesting that evaluation of BM fibrosis at diagnosis is a potentially new therapy stratifying factor and support the need of further research on BM fibrosis in childhood ALL and expanded use of BM biopsy at diagnosis. Figure 1 Figure 1. Figure 2 Figure 2.

Thiopurine Methyltransferase Genetics Is Associated with Treatment Outcome and Hepatic Toxicity in Pediatric Patients with Acute Lymphoblastic Leukemia: a Report From the ALL-BFM Study Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2625-2625
Author(s):  
Martin Stanulla ◽  
Elke Schäffeler ◽  
Silke Pohlschmidt ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Thiopurine Methyltransferase ◽  
Wild Type ◽  
Childhood All ◽  
Genotype 2 ◽  
Minimal Residual

Abstract Abstract 2625 Poster Board II-601 The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) play an essential role in treatment protocols for acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurines and underlies phenotypically relevant genetic variation. Heterozygotes or homozygotes for TPMT genotypes conferring lower enzyme activity demonstrate thiopurine drug metabolic patterns distinct from those of TPMT wild-type individuals. Underlining its clinical importance, several studies have demonstrated a relationship between low TPMT enzyme activity and thiopurine-associated toxicity as well as decreased relapse risk. Here we report on a prospective evaluation of the role of TPMT genetics for survival and treatment-related toxicity in a cohort of 814 pediatric ALL patients. These 814 patients were initially selected based on availability of DNA and represent 85.1% of the entire patient population (n=956) enrolled in the German-Austrian-Swiss multi-center trial ALL-BFM 2000 from October 1999 to September 2002. Genotyping for TPMT was performed by a denaturing HPLC method and subsequent sequencing of variant alleles using DNA prepared from either leukemic or remission bone marrows. This analysis revealed 755 (92.8%) patients with TPMT wild-type, 55 (6.8%) with a heterozygous, and 4 (0.5%) with a homozygous variant genotype (*2/*3A, *3A/*3A [n=2], *3A/*11), respectively. Genotype frequencies were in Hardy-Weinberg equilibrium. Allele frequencies were as follows: TPMT*1 = 96.12%, TPMT*2 = 0.25%, TPMT*3A = 2.95%, TPMT*3C = 0.56%, TPMT*9 = 0.06%, and TPMT*11 = 0.06%. Patients (n=55) heterozygous for allelic variants of TPMT conferring lower enzyme activity demonstrated significantly better event-free survival (EFS) and a lower relapse rate compared to homozygous wild-type patients (n=755) (six-years pEFS; heterozygotes vs. wild-type, 95% (SE 3%) vs. 84% (SE 1%), p(log-rank) = 0.04; p(point estimate difference) = <0.001, relapse incidence at six years, 4% (SE 3%) vs. 12% (SE 3%), p = 0.07). In a Cox regression analysis, adjusting for sex, age, presenting leukocyte count, immunophenotype and minimal residual disease the effect of TPMT genotype was still detectable, but lost statistical significance (hazard ratio for TPMT heterozygosity = 0.38, p = 0.10). An analysis stratified by minimal residual disease-defined risk groups will be presented. While TPMT heterozygotes did not demonstrate statistically significant differences when their toxicity data collected according to the National Cancer Institute's Common Toxicity Criteria were compared with wild-type patients for 6-MP-containing treatment phases, they had an increased risk of developing hepatic veno-occlusive disease associated with a two-week exposure towards 6-TG given during re-intensification. In conclusion, TPMT genotyping may contribute important information for clinical decision making in childhood ALL that goes beyond the prevention of toxicity in TPMT deficient patients. Disclosures: No relevant conflicts of interest to declare.

Identification of Post-Induction Minimal Residual Disease by Multidimensional Flow Cytometry Identifies Patients with AML at High Risk of Relapse and Poor Outcome- a Report From the Children's Oncology Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1702-1702
Author(s):  
Soheil Meshinchi ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Phoenix A. Ho ◽  
Alan S. Gamis ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Patient Specific ◽  
Intermediate Risk ◽  
Oncology Group ◽  
Childhood All ◽  
Post Induction ◽  
Minimal Residual

Abstract Abstract 1702 Multidimensional flow cytometry (MDF) is used to identify risk in childhood ALL; however, its utility in AML has been limited. We used 4-color MDF with standard (rather than patient-specific) panels to evaluate diagnostic and postinduction bone marrow specimens from patients treated on Children's Oncology Group (COG) study AAML03P1 for evidence of minimal residual disease (MRD). A total of 254 patients submitted marrow specimens for MRD assessment at the end of induction I, the end of induction II, and the end of therapy. Of the 222 patients with evaluable specimens at the end of induction I, 191 (86%) were in morphologic remission, and 27 (12.2%) had persistence of morphologic disease, 3 had persistent CNS disease and 1 was not evaluable for response. Of those with morphologic disease, 15 were in partial remission (PR, 5%-20% blasts), and 12 had refractory disease (RD, >20% blasts). MDF of specimens showing morphologic disease revealed that 7 (26%) did not have evidence of disease; thus, MDF identified patients with reported morphologic disease who did not have immunophenotypic evidence of disease. Overall, in 222 patients with evaluable marrow at the end of induction I, 69 (31%) had evidence of various levels of MRD by MDF (% blast range, 0.02%-43%, median, 1.5%). For the 208 patients with known cytogenetic data, the presence of MRD was evaluated in the following cytogenetic subgroups: favorable risk, defined as t(8;21) or inv(16) (the Core Binding Factor leukemias); unfavorable risk, defined as –5/del(5q) or –7; and intermediate risk, defined as all other cytogenetic subtypes. MRD prevalence at the end of Induction I in patients with favorable, intermediate-risk, or high-risk cytogenetics was 13%, 36%, and 67%, respectively. Prevalence of MRD at the end of induction I was 50% (10/20) in patients with FLT3/ITD, 40% (4/10) in patients with CEBPA mutations, and 0% (0/5) in patients with NPM1 mutations. Of the 222 patients with evaluable specimens at the end of induction I, 191 had morphologic response to the initial chemotherapy. Of those, 57 (28%) had evidence of disease by MDF. Cumulative relapse risk (RR) and disease-free survival (DFS) was assessed in those with or without MRD. Those with MRD at the end of induction I had a RR at 3 years from the end of induction of 60% vs. 29% for those without MRD (p <0.001). DFS was 32% for those with MRD and 65% for those without MRD (p<0.001). In a multivariate analysis, which included cytogenetic and molecular risk factors, the presence of MRD was highly associated with outcome and was an independent predictor of relapse (p<0.001) and worse survival (p<0.001). We further evaluated the significance of clearance of residual disease. Of the 91 patients evaluated for MRD at the end of therapy, 7 (8%) were MRD-positive (6 of whom relapsed). Of the 84 patients who were MRD-negative, 22 (26%) had previously documented MRD. For those with a history of MRD, RR from the end of therapy was 64%, and for those without previous MRD, it was 25% (p<0.001). Therefore, despite clearance of MRD, patients with previous MRD had a high RR. Given the high correlation of MRD with RR, MDF assessment of post-induction response should be incorporated into AML clinical trials for risk identification and assignment to the appropriate risk-based therapy. Disclosures: No relevant conflicts of interest to declare.

Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4520-4526 ◽  
Author(s):  
Aihong Li ◽  
Jianbiao Zhou ◽  
David Zuckerman ◽  
Montse Rue ◽  
Virginia Dalton ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Minimal Residual Disease ◽  
T Cell Receptor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Gene Rearrangements ◽  
Childhood All ◽  
Minimal Residual

AbstractImmunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide clonal markers useful for diagnosis and measurement of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We analyzed the sequences of Ig and TCR gene rearrangements obtained at presentation and relapse in 41 children with ALL to study clonal stability, which has important implications for monitoring MRD, during the course of the disease. In 42%, all original Ig and/or TCR sequences were conserved. In 24%, one original sequence was preserved but the other lost, and in 14% the original sequences were conserved with new sequences identified at relapse. In 20% only new sequences were found at relapse. Using primers designed from the novel relapse sequences, the relapse clone could be identified as subdominant clones in the diagnostic sample in 8 of 14 patients. Alteration of these clonal gene rearrangements is a common feature in childhood ALL. MRD detection should include multiple gene targets to minimize false-negative samples or include also multicolor flow cytometry. In some cases the leukemic progenitor cell might arise earlier in lineage before DHJH recombination but retain the capacity to further differentiate into cells capable of altering the pattern of Ig and/or TCR rearrangements. (Blood. 2003;102:4520-4526)

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