Post Induction Minimal Residual Disease Levels Identifies a Group of High Risk Relapsed Childhood Acute Lymphoblastic Leukemia (rALL) with a Favorable Outcome Independent of Induction Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1294-1294
Author(s):  
Catriona Anne Parker ◽  
Marie Reeves ◽  
Sharon Love ◽  
Jeremy Hancock ◽  
Peter M Hoogerbrugge ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Favorable Outcome ◽  
Childhood All ◽  
Post Induction

Abstract BACKGROUND: The determinants of outcome in children with rALL are the duration of first remission (CR1), site of relapse and immunophenotype. High risk (HR) relapses are defined as those occurring with a CR1 of <18 months; B-cell precursor (BCP) with bone marrow (BM) relapse within 6 months of stopping therapy and T-cell BM or combined relapses at any time. All other relapses are defined as standard risk (SR). In the UKALLR3 clinical trial for rALL, HR patients had a lower CR2 rate, higher post induction MRD and inferior survival when compared to SR patients treated in identical fashion. We investigated the effect of further intensifying induction therapy with clofarabine in HR patients. METHODS: Clofarabine was added to the UKALLR3 consolidation block of cyclophosphamide, etoposide (CCE) and used as induction therapy, with dexamethasone and PEG-Asparaginase for HR patients. The previous induction block with mitoxantrone (M) was given as consolidation and all patients were eligible for stem cell transplantation (SCT) with any donor after a third intensification block. The outcomes assessed were improvements in CR2, MRD and progression-free survival (PFS) when compared to historical controls of patients receiving idarubicin (I) or M induction in UKALLR3. A Fleming-style design, based on observed response and toxicity, was incorporated to allow an increase in the dose of cyclophosphamide from 300 mg/m2 to 440 mg/m2. RESULTS: 61, 39 at lower and 22 at the higher dose of cyclophosphamide, CCE patients were compared to 30 I and 69 M patients with HR rALL. Patients in the CCE group had a lower median age at presentation, but other prognostic variables were comparable. CR2 rates of 73%, 83%, 71% and low MRD (≤10-4) was seen in 32%, 0%, 25% of CCE, I and M groups. The higher cyclophosphamide dose was associated with improved CR rates, lower MRD but also increased toxicity levels in CCE compared to M group patients. The proportions of patients reaching transplantation were 43%, 60% and 55% of CCE, I and M patients respectively. 73/82 eligible patients received a SCT, 48 (66%) with matched and 25 (34%) with mismatched donors. The 2-year PFS with CCE, M and I regimens were 17% (11,23), 27% (19,34) and 30% (25,36) respectively (p=0.08). Outcomes of matched sibling, matched unrelated and mismatched SCT were comparable (p=0.9). Seventeen patients with a post induction MRD<10-4, had a 2-year PFS of 63% (50,75), compared to 21% (15,27) for 53 patients with MRD≥10-4 and 21% (17, 25) for the 90 patients with unknown MRD (p=0.005). All 4 patients with MRD≥10-3 prior to SCT and 8/9 not transplanted suffered a second relapse. Overall outcomes of BCP (2-year PFS 21% (15,28)) and T-cell ALL (2-year PFS 26% (16,35)) were comparable (p=0.9). PFS in BCP-ALL was 31% (24,38) and 13% (6,20) (p=0.1) for those receiving M and CCE respectively. CONCLUSIONS: We define two groups of HR rALL patients based on MRD levels attained post induction, independent of the induction regimen. Approximately a quarter of HR patients continue to have chemosensitive disease as evidenced by rapid MRD clearance (<10-4 at week 5). This group includes high-risk cytogenetics and T-cell rALL with MRD as the single discriminatory factor for outcome. These patients have a favorable outcome after SCT with any donor. In the other group (MRD≥10-4) over half of HR patients do not reach SCT primarily due to refractory disease (27%) or disease recurrence (14%). One third of patients relapse post SCT. For this group novel agents and newer treatment strategies are urgently required. Disclosures Off Label Use: Clofarabine 1st relapse childhood ALL.

Improved Outcome in Adult T-ALL by Risk Adapted Treatment Strategies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 682-682 ◽  
Author(s):  
Nicola Goekbuget ◽  
Eckhard Thiel ◽  
Joachim Beck ◽  
Frank Griesinger ◽  
Frank Hartmann ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
New Drugs ◽  
Childhood All ◽  
Improve Outcome ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Standard Risk ◽  
Multicenter Study Group

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 25% of adult ALL and is characterised by specific clinical and biologic features such as phenotype with early (cyCD3+,CD7+) (E-T), thymic (CD1a+) ) (Thy-T) and mature T-ALL (M-T) (sCD3+). The formerly poor prognosis of T-ALL was more recently improved in some studies albeit not in all, even not in childhood ALL. Patients: To improve outcome of T-ALL the German Multicenter Study Group for Adult ALL initiated two consecutive studies with subtype adapted therapies. 503 T-ALL pts were recruited between 4/93 and 10/03. The median age was 30 (15–55)yrs, 75% were male, 66% had mediastinal tumor (MedTu), 24% WBC > 100.000 and 7% CNS involvement with subtypes as follows: 53% Thy-T, 26% E-T and 21% M-T. Study Design: In Study 05/93 all T-ALL pts were treated uniformly with 8drug induction incl. prophylactic CNS (24 Gy) (CNSRAD) and proph. mediastinal (24 Gy) irradiation (MEDRAD) followed by 7x consolidation (HDAC/MITOX, HDMTX/ASP, reinduction, 2xVM26/AC, 2xCYCLO/AC) and maintenance (6MP/MTX). In Study 06/99 treatment of T-ALL was risk adapted with a shortened, intensified 8drug induction (CNSRAD in all but MEDRAD only in pts with residual MedTu after induction) followed by consolidation I (HDAC/HDMTX/VP16). Thy-T was then treated as standard risk with 6x consolidation (3xHDMTX/ASP,reinduction,VM26/AC,CYCLO/AC). E-T and M-T were considered as high risk and scheduled for stem cell transplantation (SCT) in CR1. Results: In Study 05/93 the CR rate in 291 pts was 89% (94%, 73% and 90% for Thy-T, E-T and M-T; p=.0006) and even 97% for Thy-T in adolescents (15–25 yrs) . Overall 4% failed to achieve CR and 7% died in induction. The probability of continuous CR (CCR) at 5 yrs was overall 53% and 64% for Thy-T, but only 30% (p<.0001) for E-T and M-T. The survival of CR pts (S) was overall 44% and 61%, 19% and 28% (p<.0001) for Thy-T, E-T and M-T. 10% died in CR mainly due to infections - particularly pts with prolonged cytopenias after prior MEDRAD. Immunophenotype was the only prognostic factor confirmed in multivariate analysis. This led to a risk adapted strategy in the subsequent study 06/99. The CR rate in 212 pts was again high (85% overall and 90%, 80% and 76% for subtypes; p=.04). 10% failed to achieve CR and 5% died in induction. 68% of pts with early/mature T-ALL received SCT in CR1 (13 allo sibling, 25 MUD, 11 auto). In these high-risk pts survival after SCT was surprisingly good with 64% at 3 yrs. Survival of all CR pts at 3 yrs was 57% (69% for Thy-T and 50%/34% for E-T/M-T; p=.007). Death in CR did not increase despite SCT (9% overall; 7% after SCT). Conclusion: In a very large cohort of prospectively treated pts excellent results for adult T-ALL could be achieved with subtype adapted strategies. For early/mature T-ALL a doubling of survival of CR pts from 23% to 43% in studis 05/93 versus 06/99 was achieved by SCT. Thus this is the first study showing a substantial benefit of SCT in these subtypes of T-ALL. To improve outcome further, new drugs for T-ALL (e.g. Campath, Cladribine, Nelarabine) are evaluated in relapse pts and in the ongoing GMALL study additional pts for SCT are identified by prospective analysis of minimal residual disease (supported by Deutsche Krebshilfe and partly BMBF, Grant No 01GI 9971)

Improved Prognosis of Children and Adolescents with Acute Lymphoblastic Leukemia (ALL) and Very-High Minimal Residual Disease (MRD) and the End of Induction therapy (EOI)? Preliminary Results of the FRALLE 2000 Protocol

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2541-2541
Author(s):  
Jean-Michel Cayuela ◽  
Kheira Beldjord ◽  
Sylvie Fasola ◽  
Marie-Françoise Auclerc ◽  
Benoît Brethon ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Children And Adolescents ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Treatment Intensification ◽  
Childhood All ◽  
Dismal Prognosis ◽  
Very High

Abstract MRD at EOI is a powerful prognostic indicator in childhood ALL. Cave et al (N Engl J Med 1998) and van Dongen et al (Lancet 1998) have shown that a very high EOI-MRD (≥ 10−2) is associated to a dismal prognosis (5y EFS: 15–20%). From December 2000 to July 2007 1496 children and adolescents (1–20 years, no Ph+) have been included in the ongoing FRALLE 2000 protocol. EOI-MRD at D35–42 was measured by competitive PCR of Ig/TCR markers and Gene Scan analysis and was decisional for further treatment intensification if ≥ 10−2. 1017 pts are fully evaluable (monitored data, no induction failure, evaluable EOI-MRD, outcome). MFU is 36 months. Three risk-groups have been defined. A (n=620): NCI standard risk BCP-ALL, B (n=265): NCI high risk-ALL, T (n=132): T-cell ALL. Fifty-eight pts (5.7%) have a very high EOI-MRD, 2.6% in group A, 9% in group B, 14% in group T. These pts were more likely than pts with lower MRD (&lt; 10−2) to have a D8 poor prednisone response (PPR) (31% vs 10%, p &lt;.001), a slow marrow response (D21M2 or M3, 24% vs 5%, p &lt;.001) or both (22% vs 1.5%, p &lt;.001). A very high MRD only (no high-risk cytogenetic features, no D8 PPR, no D21 M2/M3 marrow) was found in 33 out the 58 pts (57%), i.e. 3% of all pts. A group pts (n=16) with very high EOI-MRD received a 3 block-consolidation plus a double delayed intensification (DDI) while B or T group pts received a 3 block-consolidation plus DDI (24 pts) or HSCT (18 pts). 5y EFS and OS where 50±10% and 74±7% respectively for the 58 pts. A similar 5 y EFS was found for pts with BCP-ALL or T-cell ALL with very high MRD (50±12% and 48±12%, respectively). There is a trend for a better EFS for pts with very high EOI-MRD only compared to those with other associated high-risk features (60±11% vs 39±11%, p=.10). Conclusion: these results compare favourably with published results suggesting that intensification of therapy may improve the outcome of pts with bad early response to initial chemotherapy.

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.

Outcome of Patients with T-Cell Lymphoblastic Leukemia or Lymphoma: The GRAALL Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2818-2818
Author(s):  
Stéphane Leprètre ◽  
Martine Escoffre-Barbe ◽  
Patrice Chevallier ◽  
Thibaut Leguay ◽  
Laurence Legros ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Cell Phenotype ◽  
High Dose ◽  
Cns Involvement ◽  
Childhood All ◽  
High Risk Disease ◽  
Mediastinal Disease

Abstract In 2003, the GRAALL intergroup initiated two twin protocols for adult patients with acute lymphoblastic leukemia (ALL; ≥ 20% marrow blasts) or lymphoblastic lymphoma (LL; < 20% marrow blasts), namely the GRAALL-2003 and LL-2003 trials. Treatment strategy was inspired by childhood ALL trials, including corticosteroid prephase, 5-drug induction, high dose-intensity consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and 2-year maintenance. An original induction reinforcement with sequential cyclophosphamide (HyperC) was offered to ALL patients with poor early response (cortico- and/or chemo-resistance) and to all LL patients. A total of 108 patients with T-cell phenotype have been treated (76 ALL and 32 LL; median age, 30 years; M/F sex ratio, 86/22; CNS+, 9; median follow-up, 2 years). Baseline characteristics were not different among ALL and LL subgroups, except for marrow blast percentage and mediastinal enlargement (47% vs 78% for ALL vs LL; P=.005), which correlated negatively, as well as for blood counts (WBC, 27 vs 8.7 × 109/L; platelets, 60 vs 328 × 109/L; Hb, 116 vs 134 g/L for ALL vs LL; P<.001). Bulky mediastinal disease was present in 57% LL vs 22% ALL patients (P=.002). Two patients (1 ALL, 1 LL) died early while the 106 remaining (98%) reached CR. With respect to mediastinal involvement, need for a salvage course with idarubicine and high-dose cytarabine to reach CR was more frequent in LL than in ALL patients (10 LL vs 2 ALL, P<.001). Allogeneic stem cell transplantation (SCT) was offered to patients with high-risk disease, defined here as CNS involvement, poor early response, or need for salvage. Among the 55 CR patients with high-risk disease (41 ALL, 14 LL), 26 received allogeneic SCT in first CR (20 ALL, 6 LL). Overall, 23/106 CR patients relapsed (18 ALL, 5 LL) while 8 died in first CR (7 ALL, 1 LL; 4 after SCT). At 2 years, estimated DFS and overall survival were 66% (64% vs 75% for ALL vs LL, P=.59) and 75% (74% vs 78% for ALL vs LL, P=.75), respectively. The only factors which influenced outcome in this risk-adapted strategy were need for salvage (higher relapse incidence) and CNS involvement (shorter survival). As compared to historical experiences, we report here a notable gain in outcome when treating patients with T-cell lymphoblastic disease, including lymphoma, with a pediatric-inspired ALL strategy. The efficacy of this approach leads to comparable outcome for both diseases. The systematic use of HyperC induction in LL patients was well tolerated, but the need for salvage therapy was more frequent in these patients possibly due to difficulty in early mediastinal response evaluation. The presence of CNS disease at diagnosis remains an unfavorable feature. The role of HyperC during induction and the place of allogeneic SCT in first CR deserve further evaluation in this new context.

scholarly journals Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 409-415 ◽  
Author(s):  
SB Murphy ◽  
SC Raimondi ◽  
GK Rivera ◽  
M Crone ◽  
RK Dodge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Term Survival ◽  
Childhood All ◽  
Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Minimal residual disease at end of induction and consolidation remain important prognostic indicators for newly diagnosed children and young adults with very high-risk (VHR) B-lymphoblastic leukemia (B-ALL): Children’s Oncology Group AALL1131.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10004-10004
Author(s):  
Wanda L. Salzer ◽  
Michael James Burke ◽  
Meenakshi Devidas ◽  
Yunfeng Dai ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Young Adults ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Post Induction ◽  
Children And Young Adults ◽  
Very High ◽  
Minimal Residual

10004 Background: Children and young adults with very high risk (VHR) B-acute lymphoblastic leukemia (B-ALL) [13-30 years of age with any features or 1-30 years of age with adverse prognostic features including KMT2A rearrangements, iAMP21, hypodiploidy (<44 chromosomes/DNA index < 0.81), central nervous system disease, end of induction (EOI) minimal residual disease (MRD) >0.01%, or induction failure] collectively have a predicted 4-year disease free survival (DFS) of approximately 70%. Whether patients with VHR B-ALL who are MRD positive at EOI and become MRD negative at the end of consolidation (EOC) will have improved survival versus patients remaining MRD positive at EOC is unknown. Methods: Patients with newly diagnosed NCI high risk B-ALL enrolled on AALL1131 or NCI standard risk B-ALL enrolled on AALL0932 and classified as VHR at EOI were treated on the VHR stratum of AALL1131 which sought to improve DFS with intensive post-Induction therapy using fractionated cyclophosphamide (CPM), etoposide (ETOP) and clofarabine (CLOF).Patients were randomly assigned post-Induction to Control Arm (CA) with modified augmented BFM CPM + fractionated cytarabine + mercaptopurine, Experimental Arm 1 (Exp1) with CPM + ETOP, or Experimental Arm 2 (Exp2) with CLOF + CPM + ETOP during Part 2 of Consolidation and Delayed Intensification. Doses of vincristine and pegaspargase were identical on all arms. Exp2 was permanently closed September 2014 due to excessive toxicities, and these patients are excluded from this report. MRD was measured by 6-color flow cytometry at EOI and for those who consented at the EOC. Results: 4-yr DFS for all patients (n=823) with VHR B-ALL was 76.8 ± 2.0%. As we reported previously, 4-year DFS was not significantly different between CA and Exp 1 (85.5 ± 6.8% versus 72.3 ± 6.3%; p=0.76; Burke, Haematologica 2019). 4-yr DFS for patients who were EOI MRD <0.01%, (n=325) versus >0.01 (n=498) was 83.3% ± 2.6% vs 72.0% ± 2.8%, p=0.0013. 4-Year DFS of Patients EOI MRD > 0.01%. Conclusions: MRD is a powerful prognostic indicator in VHR B-ALL with inferior outcomes in patients who are EOI MRD positive. Among patients who were EOI MRD positive treated on Exp1, outcomes were similar for EOC MRD negative and EOC MRD positive, though numbers were small. In contrast, patients who were EOI MRD positive treated on CA that were EOC MRD negative had significantly improved DFS compared to those that were EOC MRD positive. The CA remains the standard of care for COG ALL trials. With this therapy, patients with VHR B-ALL that are EOI MRD positive and EOC MRD negative have significantly improved DFS compared to those that remain MRD positive at EOC. Clinical trial information: NCT02883049. [Table: see text]

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)

scholarly journals Prospects for evaluation of the minimal residual disease in the post-induction period in pediatric B-precursor acute lymphoblastic leukemia

2020 ◽  
Vol 7 (2) ◽  
pp. 15-22 ◽  
Author(s):  
M. A. Shervashidze ◽  
T. T. Valiev ◽  
N. N. Tupitsyn
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Prognostic Value ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Research Centre ◽  
Post Induction ◽  
Minimal Residual

Relevance. Currently, the assessment of the level of minimal residual disease (MRD) is the standard in evaluating the effectiveness of therapy in acute lymphoblastic leukemia (ALL) in adults and children. Although, the necessity to study MRD at the induction therapy is not in doubt, the prognostic value of MRD in the period after induction is the subject for scientific discussion. Several studies suggest that MRD-positive status after induction chemotherapy associated with poor prognosis, and the reappearance of significant level MRD during follow-up allows impending relapse to be identified and to begin appropriate therapy in low leukemic cells level.Aim – to determine the prognostic value of post-induction MRD on overall (OS), relapse-free (RFS), and event-free (EFS) survival in children with B-precursor ALL who received program treatment at the N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia.Materials and methods. The study included 73 pediatric patients with initial B-precursor ALL. The median age of the patients was 5.2 years (from 1 to 16 years). The treatment was according to the ALL IC-BFM 2009 protocol. MRD detected on day 15 and 33 of induction therapy, and day 78 of consolidation beginning. MRD level was determined by flow cytometry method.Results. EFS and RFS were the same for patients with MRD-positive status on 78 day of treatment 76.8 ± 12.3 % and 96.2 ± 2.6 % for MRDnegative (p = 0.06). Detailed assessment of MRD revealed a cohort of high-risk patients with MRD-negative status on 78 day of therapy with 100 % OS (observation time – 6 years).Conclusion. In all risk groups, patients with negative MRD status showed a better survival result, which indicates the possibility of additional stratification by risk groups not only at the induction, but also during a consolidating treatment protocol.

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