Assessment of Minimal Residual Disease (MRD) In Relapsed CLL Patients Treated with Fludarabine and Cyclophosphamide with or without Rituximab (REACH)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1390-1390
Author(s):  
Annika Dufour ◽  
S. K Bohlander ◽  
Karsten Spiekermann ◽  
Stephanie Schneider ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Small Sample ◽  
Patient Specific ◽  
Molecular Response ◽  
Igh Rearrangement ◽  
Minimal Residual

Abstract Abstract 1390 Introduction: Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher et al. Leukemia, 2009). Patients who remain MRD positive after treatment have a higher risk of relapse. Eradication of MRD is therefore a desirable clinical endpoint of treatment. We were interested to assess this correlation in REACH, a randomized international clinical study in previously treated CLL patients, randomized 1:1 for treatment with rituximab, fludarabine and cyclophosphamide© R-FC (276 patients) or FC alone (276 patients); (Robak et al. JCO 2010). Methods: While MRD quantification by flow cytometry requires an identifiable stable phenotype and fresh blood samples, PCR based methods can be performed centrally on frozen samples. We have therefore developed a Realtime Quantitative (RQ) PCR method, using patient-specific IgVH (immunoglobulin variable heavy chain) gene rearrangements as targets. Briefly, genomic DNA was isolated from CD19 sorted B-cells. ASO (allele-specific oligonucleotide) primers were designed matching the hypervariable N-D-N region of the patient-specific leukemic clone and used with reverse consensus primers and hydrolysis probes annealing to the family-specific joining region of the IGH rearrangement (Brüggemann et al., Leukemia, 2004). Maximum sensitivity and quantitative range were defined for every RQ-PCR. Patients were categorized as molecular responders (MRD negative) if there was no detectable clonal IgH rearrangement, using a sensitivity cut-off of 1×10-4. Molecular response was assessed at the time of CR confirmation and 6 months later (if CR was maintained). Results: Among the 103 patients who achieved CR during the study, 86 patients had at least one MRD assessment in peripheral blood, 92 patients in bone marrow. Since many patients had a CR confirmation at different time points during the follow-up period, we initially analyzed the MRD levels only in patients who had achieved confirmed complete response at end of treatment +/−3 month (“EOT - period”). The rate of MRD negativity in blood (22 pts: 5(15) FC, 6(7)R-FC) at EOT was 33% for patients treated with FC, and 86% for patients treated with R-FC (p=0.06); In bone marrow at the EOT (61 patients: 5(27) FC, 20(34) R-FC) the rates were 19% and 59%, respectively (p= 0,02), indicating higher efficacy of the Rituximab containing regimen in eradication of residual disease; This is in line with the previously reported results using FACS analysis of MRD in the CLL8 trial; the differences in the detection rate in blood versus bone-marrow, suggest a higher sensitivity for detection of MRD in bone marrow. We therefore compared the levels of MRD negativity in samples from blood and bone marrow in patients where both samples were taken at the same time point. Results were concordant in 8/9 patients, one patient had a positive result in bone marrow with no detectable signal in blood. This supports the notion that assessment of MRD in bone marrow of CLL patients may be more sensitive than assessment in blood only. However, for a definitive statement larger sample size would be needed. We then correlated MRD status at EOT, regardless of treatment arm, with PFS: In line with previous reports, there was a clear trend to longer PFS in patients who had reached MRD negativity (median PFS not reached), while patients with residual disease had shorter PFS; however, due to small sample numbers, statistical significance could not be reached. We also analyzed the correlation of MRD negativity reached at any time during and after treatment with PFS, bearing in mind that this sample set is inherently biased, since patients with early progression will be lost from the analysis; the results are consistent with the EOT findings. Summary: ASO IgVH RQ-PCR is a powerful method to detect residual levels of disease in CLL patients with clinical complete response and undetectable MRD correlates with longer PFS. Among patients in REACH achieving clinical CR on either study arm, a higher percentage achieved MRD negativity on the R-FC arm, consistent with the increased efficacy shown for the Rituximab treatment arm by the REACH clinical data. Disclosures: Mundt: Roche: Employment. Smith:Roche: Employment. Lin:Genentech: Employment. Barrett:Roche: Employment. Hurst:Genentech: Employment. Geisler:Roche: Research Funding, Speakers Bureau. Hiddemann:Roche: Research Funding.

Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 694-694 ◽  
Author(s):  
Timothy P. Hughes ◽  
Jeffrey H. Lipton ◽  
Nelson Spector ◽  
Brian Leber ◽  
Ricardo Pasquini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

High Incidence of Bcl-2/IgH Rearrangement in Mexican Patients With Follicular Lymphoma and Its Relevance as a Marker for Minimal Residual Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4493-4493 ◽  
Author(s):  
Rosa M. Arana ◽  
Pedro Sobrevilla-Calvo ◽  
Silvia Rivas-Vera ◽  
Enrique Baez ◽  
Severiano Baltazar ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Chimeric Protein ◽  
Tissue Type ◽  
Molecular Response ◽  
Chi Square ◽  
Igh Rearrangement ◽  
Minimal Residual ◽  
Mexican Patients

Abstract Follicular lymphoma is frequently associated with the chromosomal rearrangement t(14;18)(q32;q21), which joints one of the JH segments of the heavy chains of immunoglobulins (IgH) gene in 14q32 with the Bcl-2 gene in 18q2, originating a chimeric protein. The frequency of this marker is unknown in the Mexican population. OBJECTIVE: To determine the incidence of the Bcl2-IgH rearrangement in Mexican patients with follicular lymphoma and its frequency as a marker of minimal residual disease after therapy. PATIENTS AND METHODS: 200 patients (102 male and 98 female) were evaluated; the analysis was made in peripheral blood samples (PB) in 64 cases (32%) or bone marrow (BM) in 136 (68%). Genomic DNA was obtained and the Bcl-2/IgH rearrangement was amplified by both PCR and nested PCR using primers for JH and exon-intron 3 region of Bcl-2 (MBR and MCR regions). The Bcl-2/IgH rearrangement was used as a marker to determine minimal residual disease (MDR) in 90 out of 200 patients in clinical remission, with a follow up ranging from 12 to 60 months; The incidence and tissue type analysis were compared using chi-square statistics. RESULTS AND DISCUSSION: We found a positive Bcl-2/IgH rearrangement in 80% of the Follicular NHL cases, with a breakage in the MBR region in 160 cases and in MCR in 10 cases, in the remaining 30 patients the Bcl-2/IgH was negative. We detected the Bcl-2/IgH rearrangement more frequently in the BM samples (86%) than in the PB (42%) (p<0.0001). Fifty of 90 initially Bcl-2/IgH positive patients converted to negative PCR, after treatment. It is also of interest that in this population the molecular response rates in BM were lower (18/50=36%) than in the PB (32/50=64%) (p<0.0001). In conclusion we found a high frequency of Bcl-2/IgH rearrangement in cases of follicular lymphoma in Mexican patients, highlighting the relevance of the molecular analysis at diagnosis and its use as a marker for molecular minimal residual disease.

Sustained High Rates of Complete Response and Minimal Residual Disease Negativity after 8 Cycles of Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R) in Patients with High-Risk Smoldering Multiple Myeloma: Updated Results of Clinical and Correlative Phase 2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3339-3339 ◽  
Author(s):  
Dickran Kazandjian ◽  
Neha S Korde ◽  
Mark Roschewski ◽  
Sham Mailankody ◽  
Candis Morrison ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Combination Therapy ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Risk Of Progression ◽  
Minimal Residual

Abstract Background: High-risk smoldering multiple myeloma (HR-SMM) is a plasma cell dyscrasia which has a 5-year risk of progression to symptomatic multiple myeloma (MM) of approximately 75% based on current risk models. With the availability of novel therapies, early treatment may decrease the risk of progression and prolong survival as evidenced by the recent QuiRedex study results. More recently, studies have demonstrated that triplet regimens are superior to doublet in MM and whole exome sequencing in HR-SMM is indicative of treatment susceptible biology in early disease; supporting the use of effective combination therapy as early intervention. Expanding on our initial results using modern CRd-R therapy in HR-SMM patients (Korde et al. JAMA Onc 2015) we show unprecedented high rates of obtained and sustained complete response (CR) and minimal residual disease negativity (MRDneg CR) in an expanded cohort of patients with a median follow-up of ~3 years. Methods: Treatment-na•ve patients with HR-SMM (IMWG 2010 criteria; Mayo or PETHEMA models) were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective was best response (ORR), followed by secondary objectives of progression free survival (PFS) and response duration (DoR) which were assessed after every cycle of induction and every 90 days during maintenance. Correlative studies including assessment of minimal residual disease (MRD) by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) as defined by updated 2016 IMWG response criteria were performed after 8 cycles of induction and 1 and 2 years of maintenance LEN. Results: Eighteen patients meeting eligibility criteria were enrolled (data-lock 7/20/2016). Demographics and disease characteristics are shown in Table 1. Best ORR and >= VGPR rate (n=18) with CRd-R was 100% (Table 2). The proportion of patients who obtained stringent CR/CR after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 61%, 89%, and 89%, respectively. Of evaluable patients who achieved at least a CR, the proportion of patients who obtained MRD negativity (MRDneg CR) at the same time-points was 91%, 71%, and 75%, respectively. DoR and PFS at 36 months was 94% and overall survival with a median follow-up duration of 31 months was 100%. Toxicities Grade 3-4 occurring in >1 patient included lymphopenia (39%), neutropenia (28%), anemia (22%), diarrhea (17%), lung infection (17%), hypophosphatemia (11%), and thromboembolic event (11%). Significant serious adverse events included CHF which occurred in one patient. Conclusions: Early treatment of HR-SMM with modern CRd-R combination therapy with by-default-delayed HDM-ASCT resulted in unprecedented high rates of CR and MRDneg CR after 8 cycles of CRd. Following 2 years of additional LEN maintenance therapy, the CR and sustained MRDneg CR rates were 89% and 69%, respectively. Given the significant risk of progression to symptomatic MM and associated life limiting end-organ damage, early intervention for patients with HR-SMM with effective triplet-based therapies may be warranted. This first proof-of-principle study has thus far demonstrated exceptional clinical benefit. Therefore, this study will be re-opened to enrollment and long-term follow up results collected to expand on these promising results. Updated results will be presented at the Annual Meeting. Disclosures Korde: Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:BMS: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria.

scholarly journals The Use of Next Generation Gene Sequencing to Measure Minimal Residual Disease in Patients with AL Amyloidosis and Low Plasma Cell Burden: A Feasibility Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4353-4353 ◽  
Author(s):  
Shayna Sarosiek ◽  
Vaishali Sanchorawala ◽  
Mariateresa Fulcinti ◽  
Allison P. Jacob ◽  
Nikhil C. Munshi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Plasma Cells ◽  
Residual Disease ◽  
Al Amyloidosis ◽  
Next Generation ◽  
Minimal Residual

Background: AL amyloidosis is a bone marrow disorder in which clonal plasma cells produce light chains that misfold and deposit in vital organs, such as the kidneys and heart, leading to organ failure and eventual death. Treatment is directed towards the clonal plasma cell population in an effort to halt the production of toxic light chains and recuperate organ function. Pallidini et al. demonstrated that almost 50% of patients with AL amyloidosis who achieved a complete hematologic response to prior therapy had minimal residual disease (MRD) detectable in their bone marrow by multiparametric flow cytometry (MPF).1. Next generation gene sequencing (NGS) has been a successful tool in measuring MRD among patients with multiple myeloma2 though the data regarding its use in AL amyloidosis are limited. AL amyloidosis is a disease with a much smaller plasma cell burden at baseline (typically 5-10%), making the task of isolating an initial clonal sequence even more challenging. We sought to evaluate NGS as a method of isolating a clonal population of plasma cells among patients with systemic AL amyloidosis in a first-ever feasibility study. Methods: Patients were eligible if they had systemic AL amyloidosis and no clinical evidence of concurrent active multiple myeloma. In this study, feasibility was deemed successful if discovery of a clone could be achieved in 3 out of 10 of patients. Approximately five cc's of peripheral blood and bone marrow aspirate were collected from each patient and processed for CD138 selection and DNA isolation/purification. De-identified samples were sent to Adaptive Biotech Inc. (Seattle, WA) for initial clonal identification using the ClonoSEQ immunoglobulin heavy chain (IGH) assay. Genomic DNA was amplified by implementing consensus primers targeting the IGH complete (IGH-VDJH) locus, IGH incomplete (IGH-DJH) locus, immunoglobulin κ locus (IGK) and immunoglobulin l locus (IGL). The amplified product was sequenced and a clone identified based on frequency. After proof of feasibility in the first 10 patients an additional 27 patients had initial clonal identification via the same process mentioned above. Results: In total, 37 patient samples underwent NGS via the ClonoSEQ IGH assay method. The median patient age was 66 years old (range: 44 to 83), 24% of which were female. All 37 patients had measurable disease based on serum electrophoresis and immunofixation and/or serum free light chain assay (Table 1). Four patients had no monoclonal protein detected on SIFE or UIFE and 13 patients had a normal sFLC ratio. Of the 33 patients with monoclonal disease on immunofixation, 12 patients had only a free lambda monoclonal protein and the remaining 21 patients had a clonal heavy chain with an associated light chain. Bone marrow biopsies demonstrated clonal plasmacytosis of 40% or lower. ClonoSEQ IGH assay identified trackable clones in 31 of 37 patients (84%) (see Table 1). Four patients had at least one trackable sequence (range: 1 to 5 sequences) in the peripheral blood and 29 patients had at least one trackable sequence in the bone marrow aspirate (range: 1 to 7 sequences). No correlation was seen between the detection of a clone and standard measures of plasma cell tumor burden (SIFE, SPEP, UIFE, UPEP, and sFLCs). Conclusion: NGS was successful in identifying an initial clone in 29 of 37 patients with systemic AL amyloidosis, four of which were detectable in the peripheral blood. Due to the low clonal burden in patients with AL amyloidosis, it is often difficult to assess disease status, especially post-treatment. These encouraging results may enhance disease monitoring and improve patient care in this rare disease. We are currently tracking MRD in the patients with identifiable clones as they receive systemic treatment, the results of which will be available for presentation in December 2019. REFERENCES 1. Palladini G, Massa M, Basset M, Russo F, Milani P, Foli A, et al. Persistence of Minimal Residual Disease By Multiparameter Flow Cytometry Can Hinder Recovery of Organ Damage in Patients with AL Amyloidosis Otherwise in Complete Response. Abstr 3261. 2016; 2. Ladetto M, Brüggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28:1299-307. Table 1 Disclosures Sarosiek: Acrotech: Research Funding. Sanchorawala:Proclara: Consultancy, Honoraria; Takeda: Research Funding; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Munshi:Amgen: Consultancy; Adaptive: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy.

scholarly journals Value of Immunohistochemistry-Based Direct Visualization for Localization, Lineage Determination and Monitoring of IDH1 p.R132H Mutant Clones in AML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1726-1726
Author(s):  
Habibe Kurt ◽  
Carlos E. Bueso-Ramos ◽  
Joseph D Khoury ◽  
Mark Routbort ◽  
Rashmi Kanagal-Shamanna ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Advisory Board ◽  
Post Treatment ◽  
Immature Cells ◽  
Minimal Residual

Abstract Background Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are important prognostic biomarkers in acute myeloid leukemia (AML). Although the clinicopathologic correlates of IDH mutations have been extensively studied, the distribution of abnormal myeloid cells carrying these mutations has not been studied. Specific localization of cells carrying IDH mutations will be useful in further understanding the pathophysiology and post-treatment biology of IDH mutant cases of AML. This characterization is becoming particularly relevant for identification of minimal residual disease, especially for patients treated with novel IDHinhibitors. In this study, we characterized IDH1 p.R132H clones in bone marrow specimens involved by AML using a mutation specific antibody. Materials and Methods Bone marrow tissue sections (biopsy or clot specimens) from 32 AML cases with IDH1 p.R132H mutation were stained with IDH1 p.R132H-mutation specific antibody. These cases include 20 de novoAML and 12 cases of AML with myelodysplasia-related changes (AML-MRC). We also included 10 AML cases with wild-type IDH1 as a control. After confirmation of the positive IDH1 immunohistochemical (IHC) signal in the primary specimens, follow up bone marrow specimens (n=67) including (a) persistent disease, (b) minimal residual disease by flow cytometry, (3) complete remission by morphology and flow cytometry, but, positive for mutation by PCR, as well as (4) relapsed cases after complete remission were included in the study (in progress). We also included pre- and post-treatment (unresponsive with increasing blast counts, stable disease, persistent disease with decreasing blast counts, complete remission, and relapse) bone marrow specimens (n=72) from 16 patients treated with IDH inhibitors (in progress). Results All the IDH1 wild type AML cases were negative for IDH1 IHC stain showing 100% specificity. Positive signal was detected in all de novo AML and AML-MRC (allelic frequency ranges from 1.8% to 47% by PCR) except one AML case with 8.9% allele burden which was a limited sample; overall sensitivity was 96%. The IHC signal was detected in the cytoplasm of myelomonocytic cells, their precursors, and megakaryocytes. Erythroid precursors, lymphoid cells, endothelial cells, and osteoblasts were consistently negative. The signal intensity ranged from weak (n=10) to moderate (n=9), to strong (n=13). The positive cells predominantly showed an interstitial distribution in the bone marrow. In the de novo AML group, only the immature cells were positive in 100% of pre-treatment AML cases. However, both mature and immature cells were positive in 7/13 (54%) post-treatment AML cases (6 cases treated with hypomethylating agents). One case was transformed from MPN which also showed positivity in mature and immature cells. In two cases with complete morphologic remission and one case with minimal residual disease detected by flow cytometry, IHC signal was detected in both mature and immature cells; both patients relapsed in 8 and 11 months. In the AML-MRC group, both immature and mature cells were positive in 11/12 (92%) cases of which 2 were not previously treated indicating the possibility that IDH1 mutation is an early event. Since the remaining 9 patients were treated with hypomethylating agents, the positivity of both mature and immature cells as a result of maturation effect versus an early event cannot be assessed. Additional studies for follow-up AML cases, including cases on an IDH inhibitor clinical trial are in progress. Conclusions Our preliminary data indicate that IDH1 IHC is a highly specific and sensitive tool to detect IDH1 R132H mutated cases and can be used as a primary method to localize the population of mutation-bearing cells in the bone marrow. IHC also allows determination of whether the IDH1 mutation in the post-treatment setting is arising from immature or mature cells. IHC provides an opportunity to understand the difference between these two populations and, based on characterization of cell type and distribution, may be helpful to predict whether the risk of relapse is high. Disclosures DiNardo: Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

Minimal Residual Disease Detection Identifies Differences between the Risk Groups Defined by the ALL IC-BFM 2002 and the ALL-BFM 2000 Protocols.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1085-1085
Author(s):  
Eva Fronkova ◽  
Leona Reznickova ◽  
Katerina Muzikova ◽  
Ester Mejstrikova ◽  
Ondrej Hrusak ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Treatment Response ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Risk Groups ◽  
Fast Response ◽  
Complete Analysis ◽  
Patient Specific ◽  
Significant Difference ◽  
Minimal Residual

Abstract Minimal residual disease (MRD) testing based on a unique Ig/TCR gene rearrangement pattern of each patient’s leukaemia turned out to be an independent tool to determine treatment response and the risk of relapse in paediatric acute lymphoblastic leukaemia (ALL). Since 07/2000, MRD information at week 5 and 12 of therapy has been used for stratification in ALL-BFM 2000 trial. In parallel, ALL IC-BFM 2002 has been designed by the International-BFM Group to test the morphological assessment of the early treatment response. Patients are stratified according to the blast proportion in peripheral blood (PB) at day 8 and in bone marrow (BM) at day 15 and 33 of therapy, age, initial WBC and the presence of BCR/ABL and MLL/AF4 fusion. One of the goals of the study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. In the Czech Republic, 73 patients were treated according to ALL IC-BFM 2002 protocol from 11/2002 to 12/2003, 29 in the standard-risk (SR), 35 in the intermediate-risk (IR) and 9 in the high-risk (HR) group. The SR, HR and all T-cell ALL patients were examined for clonal Ig/TCR rearrangements. RQ-PCR patient-specific systems were designed for each of these patients according to the ESG-MRD-ALL criteria. For 39 of the 40 patients tested (97.5%) at least one target with minimal sensitivity of 10(−4) was identified. MRD was evaluated in BM samples from 34 patients at several time points inclusive of the mandatory 5 and 12 week ones. Simultaneously the PB specimens of the T-ALL patients were tested. In total, 205 BM and 64 PB specimens were included. In 7 patients of 24 in the SR group, MRD positivity at week 5 and/or at week 12 was observed (ranging between 9.7x10(−4) and 1.5x10(−2)), thus identifying patients who would not qualify to the MRD-based SR group in ALL-BFM 2000 despite the identical induction regimen. In T-ALL patients, PB-MRD levels paralleled those in BM. MRD results showed no separation of MRD levels between IR- and HR-stratified T-ALL patients. These preliminary findings reveal a significant difference between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast response as measured by the morphology criterion (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. The complete analysis of MRD is planned for the international consortium participating in the ALL IC-BFM 2002 protocol.

FLT3-ITD Positive AMLs Harbouring A Second MRD Molecular Marker May Benefit From a Minimal Residual Disease (MRD) Guided Transplant Decision

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2621-2621
Author(s):  
Joanna Schiller ◽  
Michael Hallek ◽  
Karl-Anton Kreuzer
Keyword(s):  
Complete Remission ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
Patient Specific ◽  
Consolidation Therapy ◽  
Qrt Pcr ◽  
Highly Sensitive ◽  
Minimal Residual

Abstract Introduction The FLT3 internal tandem duplication (FLT3-ITD) occurs in 15%-35% of all AMLs. FLT3-ITD-positive AMLs are associated with high relapse rates after reaching complete remission. Therefore these patients are considered for allogeneic stem cell transplantation (allo-SCT). Data shows that allo-SCT does not influence the overall survival (OS) of these patients. Minimal residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) can predict relapse clearly in advance and therefore allows early therapeutic intervention. Studies on MRD monitoring have shown a positive influence on OS in AML patients. Due to the high sequence variability of individual FLT3-ITD a universal PCR approach has a low sensitivity (approx. 1: 5x102) and therefore cannot be used for MRD monitoring. Methods We developed a novel cDNA-based, highly sensitive, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay for the detection of the FLT3-ITD mutation level. On the basis of individual FLT3-ITD, mutation- specific forward or reverse primers were designed. The expression of FLT3-ITD was determined using complementary DNA samples at different points in time during diagnosis and subsequent treatment. Results Retrospectively we studied 53FLT3-ITD-positive AML patients. 10 patients received palliative treatment, seven died during induction therapy; three patients are still in induction course of treatment. 32 patients achieved complete remission and 12 of them had undergone allo-SCT. For 47 patients we designed patient-specific qRT-PCR with mutation-specific forward and reverse primers. 41 (87%) assays were highly specific (1:104 - 1:106) and yielded similar results when compared to other high sensitive assays for molecular markers like NPM1 or PML-RARA.The median of follow-up time was 754 days (68-2546 days). MRD status was available for 23 patients after consolidation therapy. In 16 (81%) of these patients, FLT3-ITD negativity was demonstrated. MRD negativity predicted lasting remission independent of allo-SCT (N = 4) or non-allo-SCT (N=12). 3 patients relapsed after reaching MRD negativity. Only one patient relapsed without molecular relapse. 7 out of 32 patients stayed MRD positive after consolidation therapy. 5 of them underwent allo-SCT, nevertheless 3 of them stayed MRD positive (molecular non-responders) and finally relapsed. Furthermore we compared paired PB and BM samples at diagnosis and after induction therapy in 5 cases. The differences in FLT3-ITD expression were not statistically significant (p=0.8) which is in line with recent studies. Conclusion We conclude that highly sensitive detection of individual FLT3-ITD possesses equal prognostic power in AML like established molecular MRD markers. Using this approach MRD guided treatment decisions appear to be justified and should be incorporated in future studies. Disclosures: Hallek: Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria.

Leopard: A Phase II Study of Maintenance Lenalidomide and Prednisolone Post Autologous Stem Cell Transplantation (ASCT) for Myeloma, Incorporating Minimal Residual Disease Assessments

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2103-2103
Author(s):  
Anna Kalff ◽  
Nola Kennedy ◽  
Patricia A. Walker ◽  
Tiffany T. Khong ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Phase Ii ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Multi Centre Study ◽  
Poor Risk ◽  
Depth Of Response ◽  
Grade 3 ◽  
Minimal Residual

Abstract Background Despite improved outcomes achieved with high dose melphalan conditioned ASCT for Myeloma (MM) patients, relapse is inevitable. Maintenance therapy following ASCT improves the depth of response achieved by induction therapy and prolongs both progression free (PFS) and overall survival (OS). Achievement of stringent (s) complete response (CR) is predictive of improved outcome, as is minimal residual disease (MRD) negativity (-neg) assessed by sensitive techniques such as multiparameter flow cytometry (MFC) of bone marrow (BM). Aim To document disease response changes, PFS/OS in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after ASCT. To sequentially quantify MRD in patients achieving a complete response (CR) utilising freeLite chain (FLC) and MFC. To assess safety and tolerability. Methods Phase II, open label, single arm, multi-centre study. Newly diagnosed patients with MM commenced RAP maintenance (lenalidomide 10mg/continuous daily increasing to 15mg after 8/52 and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP continued until toxicity or relapse/progression. Serum for FLC was collected every 2/12, patients achieving CR had serial BM MFC. Statistical analysis: Prism v5.0a. Results 60 patients (M=37, F=23), with a median age of 61 years (range 41-71) commenced RAP maintenance. ISS stage at diagnosis: I: 20, II/III: 37 (3 unknown). 51/60 patients had diagnostic cytogenetics ± FISH performed – 15 had poor risk features (t(4;14), t(14;16), del17p, del13, +1q21), 11/15 had +1q21. After a median 23 months (range 12-36) following initiation of RAP, 33 patients remain on therapy. One patient has been lost to follow-up. Discontinuation was due to relapse/progressive disease (10), AEs (13), physician choice (2), poor compliance (1) and death (1). 15 patients have relapsed/progressed, 11 patients have died; 7 due to MM, 2 due to therapy related AML (tAML) and 2 other. Both the median PFS and OS have not been reached. When looking at the association between survival and poor risk cytogenetics ± FISH, those with +1q21 had both inferior PFS and OS: median PFS was 646 days vs not reached (NR) for those without +1q21 (P=0.04), median OS was 701 days vs NR for those without +1q21(P=0.013). 34 patients improved their post ASCT response on RAP. Best response was CR in 36 (60% - 25 sCR), 21 VGPR (35%) and 2 PR (3%), achieved in a median of 77 days (range, 0-447). 30 of 36 patients in CR went on to have sequential MRD studies: 21/30 were multiply MRD-neg and 9/30 were multiply MRD-pos. There was no difference in PFS between MRD-pos and MRD-neg patients (p=0.3). Of the MRD-neg patients, 16/21 had predominantly normal FLC ratios (sCR), 4/21 MRD-neg patients relapsed, 3 had normal FLC ratios. Of the MRD-pos patients, 6/9 had normal FLC ratios (sCR), 3/9 MRD-pos relapsed. Correlation between MRD neg and sCR was poor (r2=0.05) and there was no difference in relapse rate between patients achieving MRD-neg versus those who achieved sCR. All grade haematologic AEs comprised thrombocytopenia 15/60 (25%)(grade 3/4: 6 [10%]), neutropenia 10/60 (grade 3: 5), and anaemia 5/60 (%)(grade 3: 1). All grade non-haematologic AEs regardless of relatedness to study treatment (>10%) were: infections (URTI: 35%, LRTI: 25%, VZV reactivation: 13%), diarrhoea (38%), insomnia (32%), fatigue (26%), peripheral neuropathy (20%), cramps (18%), hyperglycemia (12%). There have been six second primary malignancies (SPMs) – 2 tAML (onset post C1D1: 15m, 21m), 1 adenocarcinoma of bowel (onset post C1D1: 30m) and 3 skin cancers (SCCs). AEs leading to discontinuation were myelosuppression (9), SPM (2), retinal vein thrombosis (1) and fatigue (1). 24 patients (40%) tolerated lenalidomide dosing as per protocol, 13 were not increased from 10mg/d to 15mg day, and 23 required dose modifications for AEs. Conclusion RAP maintenance improved depth of response post-ASCT (including conversion to deeper response categories > 14months), with high rates of CR/sCR (60%). Neither MFC or FLC demonstrated superiority over the other for prediction of outcome and correlation between the two was poor. Recapitulating earlier findings of an interim analysis, patients with +1q21 had inferior PFS/OS, suggesting that this group may benefit less from RAP maintenance. Only 21% of patients discontinued RAP due to toxicity, comparable to IFM 2005-02 and CALGB 100104 studies. Disclosures Off Label Use: Lenalidomide used as maintenance post-ASCT. Spencer:Takeda: Consultancy, Honoraria; janssen-Cilag: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Minimal Residual Disease in the Maintenance Setting in Myeloma: Prognostic Significance and Impact of Lenalidomide

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 904-904
Author(s):  
Ruth M de Tute ◽  
David Cairns ◽  
Andy Rawstron ◽  
Charlotte Pawlyn ◽  
Faith E. Davies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Powerful Predictor ◽  
Advisory Committees ◽  
End Of Treatment ◽  
Minimal Residual ◽  
Support Research

Abstract Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). A recent meta-analysis has confirmed this and demonstrated a hazard ratio for PFS of 0.41; 95% CI, 0.36-0.48; P &lt; .001 (Munshi et al, JAMA Oncol, Jan 2017). We have previously demonstrated the prognostic impact of MRD both following ASCT in transplant-eligible (TE) patients and following induction in transplant non-eligible (TNE) patients. There is more limited data on the applicability and significance of MRD assessment in the maintenance setting, largely as a consequence of high rates of drop-off historically within myeloma trials but improved outcomes have seen larger numbers of participants with samples at later timepoints. Patients and Methods. This analysis aims to assess the impact of MRD on PFS amongst patients receiving maintenance or no further therapy in the NCRI Myeloma XI trial. In this study patients were randomised between thalidomide (CTD) and lenalidomide (RCD) based induction therapies. For patients with a sub-optimal response to initial therapy, induction was supplemented with sequenced bortezomib-based induction (CVD). Intensively treated patients then proceeded to an autologous transplant and then responding patients from both intensive and non-intensive arms were subsequently randomised to maintenance with lenalidomide monotherapy, lenalidomide and vorinostat or no further therapy. Bone marrow aspirates were obtained prior to maintenance randomisation (100 days post ASCT for TE and at the end of (sequenced-) induction treatment for TNE) and 6 months post maintenance randomisation. This analysis represents a subset of 389 patients (median age 63.5 years) with an informative post maintenance randomisation bone marrow aspirate. MRD was assessed using flow cytometry (sensitivity 0.004%) with a minimum of 500,000 cells evaluated with six- or eight-colour antibody combinations including CD138/CD38/CD45/CD19/CD56/CD27 in all cases and CD81/CD117 added latterly. Results. Taking the group as a whole, MRD-negativity was demonstrated in 206/389 (55.8%) and this was associated with a significant outcome advantage as the median PFS was &gt;50 months versus 20 months for MRD-positive patients (Fig.1(a), p&lt;0.0001, HR 0.2, 95% CI 0.11-0.37). When the pre-maintenance MRD result was also taken into account, outcome was best for patients achieving negativity post ASCT/end of treatment and remaining MRD-negative and worst for those patients who were MRD-positive post ASCT/end of treatment and remained so (Fig 1(b), p&lt;0.0001). Conversions to MRD-negativity were seen in 32% of MRD-positive patients on maintenance compared to 4% of patients randomised to no further therapy (p=0.0045). This conversion is associated with some improvement in outcome, but this group still have inferior outcome relative to those patients achieving MRD-negativity earlier in protocol treatment. Conversions to MRD-positivity were also seen in 24 (9.5%) of 252 patients and the outcome for this patient group was similar to that of the patients who remain MRD-positive throughout (Fig. 1(b)). For those patients that remained MRD-positive, a benefit from maintenance could be demonstrated by a lower level of residual disease relative to those patients on observation (median level of neoplastic plasma cells 0.15% on maintenance vs 0.39%, p=0.04). Conclusions. We would conclude that MRD is a particularly powerful predictor of outcome in the maintenance setting and is clearly a desirable therapeutic goal in this patient group. The hazard ratio of 0.2 demonstrated here appears superior to those demonstrated in previous studies examining post induction or ASCT time-points. Approximately one third of MRD-positive patients receiving maintenance became MRD-negative and maintenance therapy also results in a decrease in disease levels in those patients remaining positive. These results support the role of MRD monitoring in assessment of the efficacy of different maintenance/consolidation strategies within clinical trials. In the longer term, a stratified approach to treatment based on sequential MRD assessments is feasible. The predictive ability of MRD during maintenance will be assessed with respect to overall survival when the primary endpoint matures in September 2017 and presented at the meeting. Disclosures Rawstron: BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Pawlyn: Celgene: Honoraria, Other: Travel support; Janssen: Other: Travel support; Takeda: Honoraria, Other: Travel support. Davies: Bristol-Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Jones: Celgene: Honoraria, Other: Travel Support, Research Funding. Kaiser: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; BMS: Consultancy, Other: Travel expenses; Chugai: Consultancy. Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jenner: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support , Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees. Gregory: Janssen: Honoraria; Celgene: Consultancy, Honoraria. Jackson: Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Chugai: Honoraria. Morgan: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria. Owen: Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding.

Minimal Residual Disease (MRD) Analysis in Non-MRD Based ALL IC-BFM 2002 Protocol for Childhood ALL: Is It Possible To Omit Minimal Residual Disease in Risk Stratification?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2271-2271
Author(s):  
Eva Fronkova ◽  
Smadar Avigad ◽  
Ki Wai Chik ◽  
Luis Castillo ◽  
Manor Sigal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hong Kong ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Risk Group ◽  
Univariate Analysis ◽  
Response To Treatment ◽  
Molecular Response ◽  
Childhood All ◽  
Minimal Residual

Abstract More than 800 children with acute lymphoblastic leukaemia (ALL) are treated every year according to ALL IC-BFM 2002 protocol, which was designed by the International-BFM Group as a parallel to MRD-based ALL/AIEOP BFM 2000 study. The ALL-IC BFM 2002 risk group stratification comprises blast proportion in peripheral blood (PB) after 7 days of prednisone and one IT-MTX (prednisone response) and bone marrow (BM) morphology evaluation at days 15 and 33 of therapy together with age, initial WBC and presence of BCR/ABL and MLL/AF4 fusion. One of the aims of the ALL IC-BFM 2002 study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. We analyzed a total of 203 patients treated according to the ALL IC-BFM 2002 in the Czech Republic, Israel, Hong Kong and Uruguay for the presence of clonal antigen receptor rearrangements. MRD was evaluated in 175 patients at several time-points of therapy including mandatory points at week 5 and 12, which are used in the ALL/AIEOP BFM 2000 stratification. In total, 654 follow-up BM specimens and 80 PB samples were tested. In the univariate analysis, a good molecular response defined as MRD negativity at both week 5 and 12 was associated with the age of 1–6 years (p=0.0001), WBC<20,000/mm3 (p=0.0002), non-T immunophenotype (p<0.0001), good prednisone response (p=0.0006), presence of TEL/AML1 fusion (p=0.003) and non-M3 morphology (≤25% blasts in BM) at day 15 (p=0.02). There was no significant association of MRD negativity with sex and hyperdiploidy; non-M3 BM morphology at day 8 was significant only when analyzing non-T ALL (p=0.02). Patients with BCP ALL had significantly lower MRD levels at day 15 (p=0.03) and at day 33 (p=0.001) than T-ALL patients; the difference was no more significant at week 12. Patients stratified to standard risk group (SRG) according to the ALL IC-BFM 2002 criteria had a significantly better molecular response defined as MRD negativity at week 5 and 12 than intermediate risk group (IRG) patients (p=0.009). However, in 24 of 69 SRG patients (34.7%), MRD positivity at week 5 and/or at week 12 was observed (ranging from borderline positivity to 1.5x10(-2)), thus identifying patients who would not qualify to MRD-based SRG in ALL/AIEOP BFM 2000. Within ALL IC SRG, patients with slow molecular response did not differ significantly from those with good MRD response in age, sex, WBC, BM morphology at day 15 and presence of hyperdiploidy or TEL/AML1 fusion. The only difference was in a higher proportion of M3 BM at day 8 in MRD slow-responders (p=0.04). Our findings revealed a significant divergence between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast morphological response to treatment (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. Supported by MSM0021620813, Israel Cancer Association and Children’s Cancer Foundation Hong Kong.

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