scholarly journals Impact of Minimal Residual Disease in Transplant Ineligible Myeloma Patients: Results from the UK NCRI Myeloma XI Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 245-245 ◽  
Author(s):  
Ruth Mary de Tute ◽  
Andy C Rawstron ◽  
David A Cairns ◽  
Charlotte Pawlyn ◽  
Faith E Davies ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Continuous Variable ◽  
Powerful Predictor ◽  
Qualitative Variable ◽  
The Impact ◽  
Minimal Residual ◽  
Support Research

Abstract Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). We have previously demonstrated, in transplant eligible patients, that the level of MRD as a continuous variable independently predicts both PFS and OS, with approximately a one year median OS benefit per log depletion (J Clin Oncol 2013; 31:2540-7 and Blood 2015; 125:1932-5). The impact of MRD also appears to be independent of therapy received. There is more limited data on the applicability of MRD assessment in transplant ineligible patients, largely as a consequence of low rates of CR historically within this patient cohort. Patients and Methods. In this analysis we have assessed the impact of MRD on PFS amongst patients treated within the non-intensive arm of the NCRI Myeloma XI trial. Patients were randomised between thalidomide (CTDa) and lenalidomide (RCDa) based induction therapies with responding patients being subsequently randomised to maintenance with lenalidomide monotherapy, or no further therapy. Bone marrow aspirates were obtained at the end of induction and this analysis represents a subset of 297 patients (median age 74 years). MRD was assessed using flow cytometry (sensitivity 10-4) with a minimum of 500,000 cells evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. Results. Overall MRD-negativity was demonstrated in 41/297 (13.8%). When considered according to induction therapy received 25/154 (16.0%) of patients randomized to RCDa were MRD-negative compared to 16/143 (10.8%) of those randomized to CTDa (p=0.24; Fisher's exact test). MRD-negativity was associated with a significant outcome advantage as the median PFS was 34 months versus 18 months for MRD-positive patients (p<0.0001, HR 0.44 [95% confidence interval (CI 0.29-0.67)]). This effect was noted in both RCDa (median PFS 17m v 32m; p=0.001, HR 0.41 [95%CI 0.23-0.69]) and CTDa (median PFS 19m v 34m; p=0.03, HR 0.49 [95%CI 0.26-0.95]). When the impact of MRD was assessed according to induction regimen the outcome of MRD-negative and MRD-positive patients was similar with both regimens (see figure). The impact of MRD was also assessed as a continuous variable across 5 logs of residual disease. Sequential improvements in outcome with each log reduction were demonstrable. Median PFS for the following disease levels; <0.01%, 0.01 - <0.1%, 0.1% - <1%, 1% - <10% and >/=10% were 34, 26, 16, 14 and 9 months respectively (p<0.0001). This pattern was demonstrable in both RCDa and CTDa treated patients (p<0.0001 for both). Multivariate analysis confirmed the independent predictive value of MRD both as a qualitative and continuous quantitative variable (p<0.0001 for both). In both instances achieving an immunofixation-negative CR was not a significant prognostic variable when included in the model with MRD. Conclusions. We would conclude that MRD is a powerful predictor of outcome in transplant ineligible patients and is a meaningful therapeutic goal in this patient group. In contrast to conventional CR it retains independent prognostic significance both as a quantitative and qualitative variable. This data further supports the role of MRD as a primary endpoint and surrogate marker for survival in future clinical trials. Figure. Figure. Disclosures Rawstron: Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jackson:MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel support; Janssen: Consultancy, Other: Travel support.

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.

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

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

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

scholarly journals The Alpha Emitter Astatine-211 Targeted to CD38 Can Eradicate Multiple Myeloma in Minimal Residual Disease Models

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1941-1941 ◽  
Author(s):  
Shyril O'Steen ◽  
Melissa C. Comstock ◽  
Johnnie J. Orozco ◽  
Donald K. Hamlin ◽  
D. Scott Wilbur ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Cell Lines ◽  
Research Funding ◽  
Residual Disease ◽  
Therapy Studies ◽  
The Impact ◽  
Gamma Counter ◽  
Minimal Residual

Abstract Introduction Multiple myeloma (MM) is considered incurable but patients achieving minimal-residual disease (MRD) negative status following treatment have significantly better overall and progression-free survival. MM is highly heterogeneous both between and within patients, limiting the curative potential of novel agents targeting specific pathways. However all MM is highly sensitive to radiation. The α-emitter astatine-211 (211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks, making 211At, targeted to MM cells, particularly suited to eliminating MRD. CD38 is expressed on malignant plasma cells regardless of mutational status, and CD38 monoclonal antibodies (mAbs) constitute a proven targeted therapy for MM but do not alone eradicate disease. We proposed that 211At conjugated to an anti-CD38 mAb could effectively eliminate MM MRD, and tested this hypothesis in cellular and murine models. Methods We conjugated the anti-CD38 mAb OKT10 and an isotype matched control mAb, BHV1, to the amine-reactive labeling agent B10-NCS and labeled the final constructs with 211At. To assess in vitro cell binding we incubated each labeled construct with CD38+ cell lines, washed, and then measured cell pellet radioactivity in a gamma counter. To assess cytotoxicity we incubated CD38+ and CD38- cell lines with unlabeled or 211At-labeled OKT10-B10 for 60 hrs, then assayed viability. NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ (NRG) mice bearing H929luc or OPM-2luc MM xenografts were generated by subcutaneous (SQ) flank injection of 107 cells 7 days prior to treatment. MRD was modeled by intravenous (IV) injection of 2.5 - 5 x 105 cells 5 days prior to treatment. Radioimmunotherapy (RIT) was administered by IV injection of 7.5 - 45 µCi of 211At-OKT10-B10 or 211At-BHV1-B10. For biodistribution studies (n = 5/group) mouse tissues were harvested 24 hrs post RIT and measured in a gamma counter. For therapy studies (n = 8-10/group), all mice received syngeneic bone marrow transplant 3 days post RIT. Disease progression was assessed by tumor dimensions, luminescence imaging and survival. Results 211At-CD38 mAb selectively bound and killed CD38+ but not CD38- MM cells in vitro. In vivo, biodistribution experiments demonstrated that 211At-CD38 RIT delivered 2.4 times more radiation to MM xenografts than did control 211At-BHV1 RIT (p = 0.007), and delivered significantly higher dose to tumor than to healthy tissues including lung (p = 0.04) and kidney (p = 0.015). In murine therapy studies, 211At-CD38 RIT at 15 - 45 µCi at least doubled median survival relative to untreated controls in each of two MM SQ xenograft models (p < 0.003). However, no mice in these models achieved complete remission and all eventually died of disease. In contrast, therapy studies using MRD models showed that 30 µCi 211At-CD38 RIT eliminated detectable disease in 80% of mice at day 21, compared to 20% of mice receiving nontargeted 211At RIT and 0% of untreated mice. At day 130, 50% of the 30 µCi 211At-CD38-RIT mice remained alive and disease-free, while all nontargeted and untreated mice died before day 85 (Fig. 1, survival of 30 µCi > 15 µCi 211At-CD38-RIT [p = 0.016] and all other groups [p < 0.0007]). The impact of therapy on body weight as well as hematopoietic, liver and kidney function was mild and returned to normal within 32 days of treatment. Conclusions The efficacy of CD38 targeted 211At appears to be a function of disease distribution and malignant plasma cell access, as compellingly demonstrated by our models. Bulky tumor geometry reduces mAb penetration. In contrast, the isolated cells and small tumor clusters that define MRD are readily accessible to mAbs, creating optimal conditions for α-emitter cell kill. In an era of highly potent MM therapy, preventing relapse remains frustratingly rare. Our approach is both agnostic to high-risk cytogenetic features and offers the potential to eliminate all residual MM cell clones. These encouraging findings will be explored in a clinical trial of 211At-CD38 RIT. Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Jones:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Gopal:Teva: Research Funding; Spectrum: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Pfizer: Research Funding; Aptevo: Consultancy; Takeda: Research Funding; Merck: Research Funding; Asana: Consultancy. Green:Juno Therapeutics: Patents & Royalties, Research Funding.

TMOD-15. CHARACTERIZATION OF THE MINIMAL RESIDUAL DISEASE STATE REVEALS DISTINCT EVOLUTIONARY TRAJECTORIES OF HUMAN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi218-vi218
Author(s):  
Maleeha Qazi ◽  
Sabra Salim ◽  
Kevin R Brown ◽  
Neil Savage ◽  
Nicholas Mickolajewicz ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
A Priori ◽  
Prognostic Significance ◽  
Disease State ◽  
Cell Populations ◽  
Human Glioblastoma ◽  
Transcriptomic Level ◽  
Minimal Residual

Abstract Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either a priori, pre-existing fitness, or equipotent fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human glioblastoma, and the prognostic value of the interrogating of the MRD state in solid cancers.

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

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

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

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

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

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

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