Impact of Minimal Residual Disease (MRD) on Prognosis in Children with Philadelphia Positive Acute Lymphoblastic Leukemia (ALL) Treated in the AIEOP-BFM ALL 2000 Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1511-1511
Author(s):  
Andrea Biondi ◽  
André Schrauder ◽  
Maria Grazia Valsecchi ◽  
Claus R Bartram ◽  
Georg Mann ◽  
...  
Keyword(s):  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Patient Specific ◽  
Poor Responders ◽  
Induction Phase ◽  
Hematopoietic Stem ◽  
Group I ◽  
Minimal Residual

Abstract Introduction: The International “Berlin-Frankfurt-Münster” Study Group (I-BFM-SG) pioneered the evaluation of minimal residual disease (MRD) based on Immunoglobulin and T-cell Receptor gene rearrangements as PCR targets. The prospective AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica)-BFM ALL 2000 study is the largest in which standardized quantitative assessment of PCR-MRD at two time points (TP) was used for stratification in 127 centers. Objective: To assess whether PCR-MRD levels discriminate outcome in patients with childhood Philadelphia positive (Ph+) ALL treated with intensive chemotherapy. Material and Methods: Between 07–2000 and 07–2006, 79 Ph+ patients were enrolled in the AIEOP-BFM ALL 2000 study. They were eligible for the high risk (HR) treatment arm and treated with Induction (protocol IA + IB), poly-chemotherapy blocks, reinduction (by one or more Protocols II or III), followed by maintenance therapy. BM samples obtained at day 33 (Time Point 1, TP1) and 78 (TP2) of induction therapy were used for MRD analysis by patient specific PCR targets. At least one or two sensitive markers (≥ 1 × 10−4) could be determined in 62 (78.5%) and 54 (68.4%) patients, respectively. MRD-Standard Risk (SR) was defined by MRD-negative at both TP1 and TP2; MRD-HR by MRD ≥1×10−3 at TP2; MRD-Intermediate Risk (IR): all others. Median follow-up was 3 years; 5-year survival and event-free survival (EFS) (SE) estimates are given. Results: Out of 79 registered patients, 3 (3.7%) died during Induction phase, 15 (19.2%) were Prednisone-poor responders (PPR), 12 (19.2%) were resistant to phase IA and 75 (94.9%) achieved CR. Forty-six patients (58.2%) underwent hematopoietic stem cell transplantation (HSCT). Overall, EFS and Survival (SE) were 44.3%(6.5) and 61.5%(6.2), respectively. Sixty-two patients were stratified by MRD (i.e. they were alive and valuable at day 78 and had at least one sensitive PCR marker). Eleven patients (17.7%) were at MRD-SR: 8 remained in CCR (4 after BMT), 1 died in CCR and 2 relapsed at 2.7 and 5.7 years from diagnosis; 28 (45.2%) were at MRD-IR: 18 remained in CCR (14 after BMT), 1 died in CCR and two for TRM after HSCT; 7 relapsed after 0.6 to 5.1 years; 23 (37.1%) were at MRD-HR and only 4 remained in CCR (all after BMT). The relapse rate was 18% in MRD-SR, 25% in MRD-IR and 61% in MRD-HR. Of note, within the Prednisone good-response subgroup (n=61), the evaluation of MRD identified those patients (MRD-HR, n=12 out of 51 PGR, MRD stratifiable) at very high risk of relapse (6/12: 50%). Conclusions: PCR-MRD is a strong predictor for outcome in Ph+ ALL patients treated with BFM therapy. MRD response detected by PCR can tailor the selection of the best treatment (Imatinib or other tyrosine kinase inhibitors and chemotherapy with or without transplant). The prognosis in the subgroup of Ph+ALL as defined HR according to PCR-MRD detection is still very poor even after HSCT and accordingly new therapeutic strategies are needed.

Treatment of High-Risk Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia in Adolescents and Adults According to Early Cytologic Response and Minimal Residual Disease After Consolidation Assessed by Flow Cytometry: Final Results of the PETHEMA ALL-AR-03 Trial

2014 ◽  
Vol 32 (15) ◽  
pp. 1595-1604 ◽  
Author(s):  
Josep-Maria Ribera ◽  
Albert Oriol ◽  
Mireia Morgades ◽  
Pau Montesinos ◽  
Josep Sarrà ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Prognostic Factor ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Low Flow ◽  
Hematopoietic Stem ◽  
Adolescents And Adults ◽  
Minimal Residual

Purpose Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation. Patients and Methods Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10−4 at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10−4. Results Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10−3 after induction and ≥ 5 × 10−4 after early consolidation) as the only prognostic factor for DFS and OS. Conclusion Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy

2016 ◽  
pp. 210-221 ◽  
Author(s):  
Amrita Krishnan ◽  
Ravi Vij ◽  
Jesse Keller ◽  
Binod Dhakal ◽  
Parameswaran Hari
Keyword(s):  
Multiple Myeloma ◽  
Disease Control ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
The Other ◽  
Novel Agents ◽  
Patient Specific ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Minimal Residual

For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, significant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also increasing rates of minimal residual disease–negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance—a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease–driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma–specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment.

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.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2321-2321
Author(s):  
Sebastian Giebel ◽  
Beata Stella-Holowiecka ◽  
Malgorzata Krawczyk-Kulis ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 2321 Poster Board II-298 The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT. Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases. With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009). CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease At 3 Months, Combined to the Presence of IKZF1 Deletion in B-Lineage or Absence of NOTCH1 pathway Mutation in T-Lineage, Recapitulates the Disease Risk Assessment in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia - A GRAALL Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 572-572 ◽  
Author(s):  
Kheira Beldjord ◽  
Elizabeth Macintyre ◽  
Véronique Lhéritier ◽  
Marie-Laure Boulland ◽  
Thibaut Leguay ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Disease Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cns Involvement ◽  
Risk Patients ◽  
Minimal Residual

Abstract Abstract 572 Aim. In recent series of adults with acute lymphoblastic leukemia (ALL), the GRAALL (ASH 2009, abstract 577) and other cooperative groups have confirmed the strong prognostic value of Ig/TCR minimal residual disease (MRD) on patient outcome. Despite this, age, WBC, CNS involvement, recurrent chromosomal translocations, and early response to steroids and chemotherapy remain frequently used to tailor post-remission therapy and envision allogeneic stem cell transplantation (SCT) in most adult ALL trials. We updated our MRD study, now with 262 patients who all achieved complete remission (CR) after the first induction and were assessed for MRD after induction (MRD1, at 6 weeks) and consolidation (MRD2, at 12 weeks). One hundred and fifty-eight patients had Philadelphia chromosome (Ph)-negative B-cell precursor ALL (BCP-ALL), while 104 had T-cell ALL (T-ALL). Since 107 of the BCP-ALL (68%) were studied for IKZF1 deletion and 90 of the T-ALL patients (87%) for NOTCH1/FBXW7 mutations, we were able to reassess the MRD significance according to these newly described oncogenic markers. These two covariates (i.e. MRD and IKZF1/NOTCH1/FBXW7 genetics) allowed us to redefine a much simpler yet more powerful stratification of disease risk in both BCP- ALL and T-ALL subsets. Methods. All 262 patients studied (median age, 31.5 years) were treated in the GRAALL-2003 and GRAALL-2005 trials. Although they were younger and had more frequently circulating blasts, other characteristics and outcome did not differ from patients treated in the same trials but not assessed for MRD. Ig/TCR MRD levels were determined according to Euro-MRD guidelines (Leukemia 2007;21:604). IKZF1 deletions were assessed by multiplex multi-fluorescent PCR. NOTCH1/FBXW7 mutations were assessed as previously described (Blood 2009;113:3918). Multivariate backward stepwise selection Cox models were used for the cumulative incidence of relapse (CIR), disease-free (DFS) and overall survival (OS) endpoints, after censoring transplanted patients at SCT. Models were always adjusted on age (35-year cutoff), WBC (30 and 100 G/L cutoff for BCP- and T-ALL, respectively), CNS involvement, and trial. Additional BCP-specific covariates included CD20 expression, t(4;11) and t(1;19) translocations, and IKZF1 deletion. Additional T-specific covariates included cortical immunophenotype according to the EGIL classification, TLX1 overexpression, and NOTCH1/FBXW7 mutation. Finally, allogeneic SCT was re-evaluated in the newly defined risk subsets, as a time-dependent covariate. Results. An initial multivariate analysis revealed that among blood response after 1 week of steroid, bone marrow response after 2 weeks of therapy, and molecular response at both MRD1 and MRD2 time-points, the MRD2 level was the main and sole independent predictor of relapse (P=0.003). In BCP-ALL patients, persistent MRD2 and IKZF1 deletion were the only two independent factors identified, the presence of at least one factor defining 51% high-risk patients with 52% versus 15% CIR (HR, 3.8; P= 0.008), 41% versus 81% DFS (HR, 3.6; P= 0.005), and 54% versus 80% OS (HR, 3.9; P= 0.015) at 4 years. Allogeneic SCT in first CR significantly decreased relapse incidence and prolonged DFS in these new high-risk BCP-ALL patients (HR, 0.23 and 0.40; P= 0.016 and 0.05, respectively). In T-ALL patients, persistent MRD2 and lack of NOTCH1/FBXW7 mutation were the only two independent factors identified, the presence of at least one factor defining 49% high-risk patients with 64% versus 12% CIR (HR, 6.4; P= 0.002), 36% versus 88% DFS (HR, 6.4; P= 0.002), and 41% versus 95% OS (HR, 7.3; P= 0.015) at 4 years. SCT had no significant effect on relapse incidence and DFS in these new high-risk T-ALL patients. Conclusion. In adult patients with Ph-negative ALL treated with the pediatric-inspired GRAALL regimen, IKZF1 deletion in BCP-ALL, NOTCH1/FBXW7 mutation in T-ALL, and MRD at 3 months in both subsets replace all classical risk factors, leading to a new simplified prognostic scoring system based only on IKZF1 and NOTCH1/FBXW7 genetics and MRD clearance. This new risk score identifies approximately half of the patients as good-risk, with a relapse incidence as low as 10–15%. It will be validated and used prospectively in the next generation of GRAALL trials, to stratify both new drug evaluation and SCT in first CR. Disclosures: No relevant conflicts of interest to declare.

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]

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.

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.

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