scholarly journals Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol

Leukemia ◽  
2009 ◽  
Vol 23 (6) ◽  
pp. 1073-1079 ◽  
Author(s):  
V H J Van der Velden ◽  
L Corral ◽  
M G Valsecchi ◽  
M W J C Jansen ◽  
P De Lorenzo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Minimal Residual

scholarly journals PROGNOSTIC SIGNIFICANCE AND TREATMENT IMPLICATIONS OF MINIMAL RESIDUAL DISEASE STUDIES IN PHILADELPHIA-NEGATIVE ADULT ACUTE LYMPHOBLASTIC LEUKEMIA

2014 ◽  
Vol 6 (1) ◽  
pp. e2014062 ◽  
Author(s):  
Orietta Spinelli ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
Marie Lorena Guinea Montalvo ◽  
Elena Maino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Cure Rates ◽  
Sensitive Individual ◽  
Minimal Residual ◽  
Risk Of Relapse

Acute lymphoblastic leukemia (ALL) is curable in about 40-50% of adult patients, however this is subject to ample variations owing to several host- and disease-related prognostic characteristics. Currently, the study of minimal residual disease (MRD) following induction and early consolidation therapy stands out as the most sensitive individual prognostic marker to define the risk of relapse following the achievement of remission, and ultimately that of treatment failure or success. Because substantial therapeutic advancement is now being achieved using intensified pediatric-type regimens, MRD analysis is especially useful to orientate stem cell transplantation choices. These strategic innovations are progressively leading to greater than 50% cure rates. 

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.

Minimal Residual Disease Status Is the Most Important Preditive Factor in Adults with Acute Lymphoblastic Leukemia. Prospective, Multicenter PALG 4-2002 MRD Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2821-2821 ◽  
Author(s):  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Sebastian Giebel ◽  
Krystyna Jagoda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Disease Status ◽  
High Dose ◽  
Risk Criteria ◽  
Minimal Residual

Abstract Current therapeutic protocols for adult acute lymphoblastic leukemia (ALL) take into account the risk of relapse, in order adjust the treatment intensity to individual patient needs. It is postulated that in addition to “classical” risk criteria the status of minimal residual disease (MRD) should be considered for treatment decisions. The aim of this study was to prospectively evaluate the feasibility and prognostic significance of MRD detected with the use of immunophenotyping for outcome of ALL patients treated according to 4-2002 protocol of the Polish Adult Leukemia Group (PALG). Induction therapy included PDN, Asp and 4x epirubicin+VCR. Consolidation consisted of 2x high-dose AraC+Cy, 2x Mtx+Vep, 6MP, and CNS prophylaxis. Patients stratified to high risk (HR) group according to “classical” criteria based on those formerly developed by GMALL (bcr/abl(+), WBC>30 G/L, prepreB, early or mature T phenotype, age>35y, or prolonged time to achieve CR) were further referred for hematopoietic cell transplantation (HCT), whereas those assigned to standard risk (SR) group were treated with maintenance for 2 years. MRD was tested at the level of 0.1% after completion of induction and consolidation therapy in patients achieving CR, employing multicolor flow-cytometry, including a new “empty spaces” method taking into account an individual pattern of antigen expression on blast cells. 165 ALL pts (B-lineage 79%, T-lineage 21%), aged 29 y (17–60) were included. CR rate equaled 85,5%. 23% of CR pts were assigned to SR, 77%- to HR according to classical criteria. MRD evaluation was possible in all but 8 pts. After induction 37% of CR pts were found MRD(+). Among those who remained in CR, MRD after consolidation was detected in 26% of cases. 64% of patients were MRD(−) at both time-points, whereas in the remaining 36% of cases MRD was detected at least once. MRD status affected both relapse incidence (RI) and leukemia-free survival (LFS). After 3 years the RI was higher for pts with MRD(+) vs. MRD(−) if assessed after induction (82%vs.29%,p=0.00007) and after consolidation (62%vs.41%,p=0.05). For pts with MRD(−) at both study end-points the probability of LFS was 65% whereas for those with MRD(+) after either induction and/or consolidation − 26% (p=0.008). In the respective subgroups RI equaled 28% and 73% (p=0.004). The difference was observed for patients assigned to SR group (20%vs.92%,p=0.01) as well as to HR group (33%vs.70%,p=0.05). In a multivariate analysis including classical risk criteria the MRD status remained the only significant factor predictive for RI (HR: 2.5(1.3–4.8),p=0.006) and LFS (HR: 2.1(1.2–3.9),p=0.01). We conclude that immunophenotyping employing “empty spaces” method is feasible for MRD evaluation in adults with ALL. MRD stzatus after induction and consolidation is the most important predictive factor for RI and LFS. Based on our findings patients with MRD detected after induction and/or consolidation should be offered intensified treatment with the use of HCT irrespective of the absence of other risk factors.

Prognostic Significance of Minimal Residual Disease in Adult Patients with B-Lineage Acute Lymphoblastic Leukemia by 8-Color Flow Cytometry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4789-4789
Author(s):  
Xiang-Qin Weng ◽  
Yang Shen ◽  
Yan Sheng ◽  
Bing Chen ◽  
Jing-han Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Treatment Response ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Color Flow ◽  
B Lineage ◽  
Minimal Residual

Abstract Abstract 4789 Monitoring of minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) by immunophenotyping and/or molecular techniques provides a way to precisely evaluate early treatment response and predict relapse. In this study, we have investigated the prognostic significance of MRD in adult patients with B-lineage acute lymphoblastic leukemia (B-ALL) by 8-color flow cytometry. A cohort of 106 patients with B-ALL who had achieved a complete remission (CR) and at least 1 LAIP characteristics were enrolled to perform MRD assessment at the end of induction and 1 cycle of consolidation. LAIPs were identifiable in 96% of the patients by 8-color flow cytometric assay, in which, most cases (90.6%) containing 2 or more LAIPs had a sensitivity as high as identifying 1 leukemic blast among 1×105 BM nucleated cells. MRD negative status could clearly predict a favorable 1 year relapse free survival (RFS) and 2 year overall survival (OS) when a cut-off level of 0.01% was used to define MRD positivity at the point of achieving CR (P=0.000 and 0.000, respectively) and after 1 cycle of consolidation (P=0.000 and 0.000, respectively), respectively. In multivariate analysis including cytogenetic abnormalities, clinical factors and MRD status, late CR (P=0.046), MRD status at the points of obtaining CR (P=0.016) and 1 consolidation (P=0.007) were associated with RFS independently, while only MRD status after 1 course of consolidation was independent prognostic factor for OS (P=0.000). Of note, in exploring the fewer patients with MRD negative status experienced recent relapse, we have identified that most of such patients had a MRD level of 10−4−10−5 comparing to undetectable MRD level. Furthermore, our evidences showed that MRD assessed by flow cytometry and by RQ-PCR assay targeting to BCR-ABL fusion gene yielded concordant results in the vast majority of cases (90%). In conclusion, immunophenotypic evaluation of MRD by 8-color flow cytometry could work as an important tool to assess the treatment response and prognosis precisely in adult B-ALL. Disclosures: No relevant conflicts of interest to declare.

Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report From Children's Oncology Group (COG) Study AALL0232

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1440-1440 ◽  
Author(s):  
Michael J. Borowitz ◽  
Brent L. Wood ◽  
Meenakshi Devidas ◽  
Mignon L Loh ◽  
Elizabeth A. Raetz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Oncology Group ◽  
Children And Young Adults ◽  
Minimal Residual

Abstract Abstract 1440 Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report from Children's Oncology Group (COG) Study AALL0232. Minimal residual disease is one of the strongest prognostic factors in pediatric ALL. COG AALL0232 was a phase 3 randomized trial for patients 1–30 years old with newly diagnosed NCI HR B precursor ALL that used a 2×2 factorial study design comparing dexamethasone (DEX) versus(vs.) prednisone(PRED) during induction, and high dose methotrexate (HD-MTX) vs. Capizzi methotrexate (C-MTX) during interim maintenance 1(IM-1). We previously reported improved event-free survival (EFS) for patients receiving HD-MTX vs. C-MTX (J Clin Oncol 29: 6s, 2011) and for DEX vs. PRED among patients <10 years old randomized to HD-MTX(J Clin Oncol 29: 586s,2011). MRD was measured by 6 color flow cytometry in two central labs (MJB and BLW) to a level of sensitivity of 0.01% at end induction. Patients with >=0.1% MRD at end induction, as well as patients with morphologic slow early response or specific adverse genetic features received intensified therapy including IM-2 and a second delayed intensification, and then had MRD determined at end consolidation, (about 13 weeks post diagnosis). End induction MRD > =0.01% was highly predictive of inferior outcome, though patients with 0.1–1% MRD who received intensive therapy had very low rates of early relapse and a much higher rate of late relapse. 5 year EFS for end-induction MRD positive (>=0.01%) patients was 63±5% vs. 86±2% for MRD negative patients. However, patients who were MRD positive at end induction who became negative by end consolidation had improved 5y EFS of 79±9%(n=136) compared to 52±14% for those who remained MRD positive(n=52) (p=.0012). Both end induction MRD positive and negative patients benefitted from HD-MTX vs. C-MTX, though the effect was small and did not reach statistical significance for MRD positive patients. By contrast, end-induction MRD was highly predictive of outcome for patients receiving either HD-MTX or C-MTX. 5 y EFS as a function of MRD status and IM regimen.End induction MRDCapizziHDMTXP value<.01%84 ± 3%88 ± 2%.04>.01%59 ± 6%67 ± 7%.12P value<.0001<.0001 End induction MRD negative patients <10y receiving DEX had better outcome than those getting PRED (5 y EFS 92±3% vs. 87±4% P=.027) while MRD positive patients or those>10y showed no difference. However, DEX patients <10y if anything had a slightly higher rate of end induction MRD positivity than those given PRED (22% vs. 17%, p=.073). In multivariate analysis, end consolidation MRD was the most powerful prognostic factor for the small subset of patients in whom this was assessed. Excluding this, end induction MRD was the most significant variable; age, white blood cell count, day 15 marrow morphology and HD-MTX vs. C-MTX were also significant. We conclude that MRD remains the most powerful prognostic factor even in the context of improved therapy. Additionally, for those patients who were MRD positive at end induction, achieving MRD negative status by end consolidation improved outcome significantly. The higher frequency of MRD in younger patients receiving DEX calls into question the validity of using end induction MRD as a surrogate for outcome when testing novel interventions during induction therapy. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding.

scholarly journals The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia

2013 ◽  
Vol 25 (3) ◽  
pp. 135-142 ◽  
Author(s):  
Mohamed A. Samra ◽  
Hossam K. Mahmoud ◽  
Thoraya M. Abdelhamid ◽  
Nahla M. El Sharkawy ◽  
Yasser H. Elnahass ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Egyptian Patients ◽  
Minimal Residual

Minimal Residual Disease Monitoring by Quantification of Fusion Gene Transcripts In Infant with MLL-rearranged Acute Lymphoblastic Leukemia Treated by MLL-Baby Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2731-2731
Author(s):  
Grigory Tsaur ◽  
Alexander Popov ◽  
Tatyana Nasedkina ◽  
Olga Kalennik ◽  
Anatoly Kustanovich ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Remission Induction ◽  
Long Distance ◽  
Gene Transcripts ◽  
Minimal Residual

Abstract Abstract 2731 Background. Despite many attempts worldwide treatment results for infants with MLL rearrangements and especially MLL-AF4 remain unsatisfied. MLL-Baby protocol was developed for infant acute lymphoblastic leukemia (ALL). In this treatment approach conventional chemotherapy is augmented by administration of all-trans retinoic acid (ATRA). This treatment program is successfully applied for infant ALL within Russian Federation and Republic of Belarus (L. Fechina et al, ASH 2007 #2828). Minimal residual disease (MRD) is a strong tool for risk-adapted treatment. Majority of infants carry MLL rearrangements, so in this group MRD monitoring by quantification of fusion gene transcripts (FGt) is fast, easy and cost-effective approach. Objective. To evaluate the prognostic significance of MRD monitoring by FGt measurements in MLL-rearranged infant ALL, enrolled into MLL-Baby study. Methods. Twenty three infants with defined MLL translocation partner genes who received at least two ATRA courses were included in the current study. Median of follow-up period in the observed group was 41 months. Presence of MLL rearrangements was detected by FISH and confirmed by long-distance inverse PCR (C. Meyer et al, 2005). MRD detection in bone marrow (BM) was performed by real-time quantitative PCR and qualitative nested reverse-transcriptase PCR as previously described (A. Borkhardt et al.,1994, J. van Dongen et al., 1999, N. Palisgaard et al., 1998, J. Gabert et al, 2003) with sensitivity 1E–05. MRD-negativity was defined as absence of FGt in both assays. Among 23 infants there were 13 MLL-AF4-positive patients (pts), 4 MLL-MLLT10-positive pts, 3 MLL-EPS15-positive pts, 2 MLL-MLLT1-positive pts and one MLL-MLLT3-positive patient. BM samples were obtained at the time of diagnosis, on day 15 of remission induction (time point (TP) 1), at the end of remission induction (TP2) and after each course of ATRA administration (TP3-TP9). Informed consent was obtained in all cases. Results. All patients were MRD-positive at TP1. At TP2 two MLL-MLLT10-positive patients became MRD-negative. At TP3 other 4 pts (3 MLL-AF4-positive and 1 MLL-MLLT1-positive) converted to MRD-negativity. By TP4 18 pts were MRD-negative, while FGt were detected in 5 pts. 2 pts became MRD-negative before protocol II (at TP9), while 3 pts never achieved MRD-negativity. Retrospectively, we compared prognostic significance of MRD at each TP. TP4 was the earliest TP when discriminative data was obtained. According to the qualitative MRD results at this TP pts were divided into MRD-positive and MRD-negative groups. The first group consisted of 18 pts with different MLL translocation partner genes, while the second group included 5 MLL-AF4-positive pts, who remained MRD-positive at TP4. Groups did not differ in age at diagnosis, sex distribution, initial WBC count, immunophenotype, type of MLL partner gene, number of blast cells at day 8 of dexamethasone prophase, BM status on day 15, CNS disease, and achievement of hematological remission at day 36. Number of relapses was significantly higher in the second group (p=0.017). Odds ratio was 20.00 with 95% CI 1.61–247.99. In the first group there were 3 relapses (in one MLL-AF4-positive case and two MLL-EPS15-positive cases) while in the second group 4 relapses occurred. Cumulative incidence of relapse for pts who achieved MRD-negativity by TP4 was 0.17, for MRD-positive pts 0.80 (p=0.005). 7-years event-free survival in the first group was 0.82±0,09, in the second group 0.20±0.17 (p=0.008) (fig 1). Conclusions. MRD monitoring by FGt measurements has significant prognostic value in infants with MLL-rearranged ALL treated by MLL-Baby protocol. In our series achievement of MRD-negativity by TP4 corresponds to favorable outcome in infant ALL with MLL rearrangements treated by MLL-Baby protocol. Persistence of MRD-positivity at TP4 allows to define group with high incidence of relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group Study

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3512-3522 ◽  
Author(s):  
I-Ming Chen ◽  
Richard C. Harvey ◽  
Charles G. Mullighan ◽  
Julie Gastier-Foster ◽  
Walker Wharton ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Relapse Free Survival ◽  
Full Cohort ◽  
Free Survival ◽  
Minimal Residual

As controversy exists regarding the prognostic significance of genomic rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia (ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal residual disease (MRD) in 1061 pediatric ALL patients (499 HR and 562 SR) on COG Trials P9905/P9906. Whereas very high CRLF2 expression was found in 17.5% of cases, only 51.4% of high CRLF2 expressors had CRLF2 genomic lesions. The mechanism underlying elevated CRLF2 expression in cases lacking known genomic lesions remains to be determined. All CRLF2 genomic lesions and virtually all JAK mutations were found in high CRLF2 expressors, whereas IKZF1 deletions/mutations were distributed across the full cohort. In multivariate analyses, NCI risk group, MRD, high CRLF2 expression, and IKZF1 lesions were associated with relapse-free survival. Within HR ALL, only MRD and CRLF2 expression predicted a poorer relapse-free survival; no difference was seen between cases with or without CRLF2 genomic lesions. Thus, high CRLF2 expression is associated with a very poor outcome in high-risk, but not standard-risk, ALL. This study is registered at www.clinicaltrials.gov as NCT00005596 and NCT00005603.

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