Use Of Minimal Residual Disease Research Articles

The use of minimal residual disease in patients with high-risk breast cancer.

e12521 Background: Breast cancer is the most frequently diagnosed cancer worldwide and the second leading cause of cancer death in women in the United States. Despite being disease-free after primary treatment, studies have shown that up to 30% of patients present with disease recurrence. Circulating tumor DNA (ctDNA) in blood is a minimally invasive technique to characterize individual cancer biology and monitor disease. Previous studies have demonstrated that ctDNA can be a sensitive and specific approach to breast cancer follow up and surveillance of disease recurrence for all subtypes. Methods: We evaluated 38 high risk breast cancer patients utilizing a personalized and tumor-informed ctDNA assay at 3-6 month intervals. We defined high risk as: any stage III disease, triple negative breast cancer (TNBC) or HR-/HER2+ breast cancer who received neoadjuvant chemotherapy treatment (NACT), pregnancy associated breast cancer, metastatic breast cancer without any evidence of disease, history of bilateral breast cancer, high risk genetics (i.e. BRCA1 or BRCA2 mutations), young age at diagnosis (<40 years old) and/or breast cancer recurrence of any subtype. Results: Patient ages ranged from 34 to 83 (average: 53.3 years old) and included a diverse race/ethnicity population: White (n=12, 31%), Japanese (n=9, 23.7%), Native Hawaiian (n=6, 15.8%), Chinese (n=4, 10.5%), Filipino (n=4, 10.5%), Black (n=1, 2.6%), Hispanic (n=1, 2.6%), and Korean (n=1, 2.6%). Of the 38 cases, there was one ctDNA positive finding seen in a high risk case (young age at diagnosis and BRCA2 mutation) of clinical stage IIA HR+/HER2- breast cancer. After NACT, bilateral mastectomies, and radiation, patient remained on tamoxifen (declined ovarian function suppression) and was initially ctDNA negative until a second test identified detectable ctDNA. Restaging scans however did not show any evidence of disease. A third ctDNA test three months later, continued to be positive without any evidence of disease. All other cases showed negative ctDNA testing with an average of 1.55 ctDNA tests done per patient over two years. However, one case of clinical stage IIB TNBC had contralateral recurrence despite negative testing. After receiving NACT, bilateral mastectomies, post-operative paclitaxel and radiation, two ctDNA tests done three months apart were negative. Conclusions: There is potential use for this ctDNA platform in high risk breast cancer patients but larger studies need to be done. [Table: see text]

The use of minimal residual disease in thoracic oncology: Gaps between promises and the on-the-ground reality of daily practice.

The assessment of minimal residual disease (MRD) from blood samples of patients with resected non-small cell lung carcinoma (NSCLC) is promising and opens up many opportunities for the optimisation of patient care in daily practice. Notably, this includes the potential for escalation or de-escalation of adjuvant therapies. Thus, the evaluation of MRD status can directly contribute to an increase in the overall survival of early stage NSCLC patients and/or limit therapeutic but also "financial" toxicity. Therefore, several clinical trials recently evaluated MRD in early stage NSCLC by integrating and retrospectively comparing the results of MRD assessments. In this context, there is an urgent need to close the gap between clinical research and the use of the evaluation of MRD in routine daily practice. Further action needs to be taken, particularly in evaluating the pertinence of the detection of MRD in prospective interventional clinical studies. This may be done in part by comparing different parameters, such as the techniques used, the different time points and the cutoffs of MRD assessments. This article investigates the assessment of MRD in non-small cell lung cancers, with a special focus on the issues associated with the various assays and the limitations of using circulating free DNA analyses for MRD assessment in early stage lung cancer. Recommendations and tips for the optimisation of MRD evaluation in non-small cell lung cancers are provided.

Optimal approach to T-cell ALL.

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.

Genome-Based Medicine for Acute Myeloid Leukemia: Study and Targeting of Molecular Alterations and Use of Minimal Residual Disease as a Biomarker

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy characterized by the clonal proliferation of hematopoietic stem and progenitor cells (HSPCs) and blockade of differentiation and proliferation of immature myeloid cells that accumulate in bone marrow at the expense of normal hematopoiesis. AMLs originate from the expansion of HSPCs progressively acquiring somatic mutations. The development of high-throughput sequencing techniques has helped to discover the genetic heterogeneity and complexity of AMLs, revise diagnostic and prognostic criteria, and to identify new therapeutic targets. These studies have allowed the identification of several recurrent driver mutations and the definition of a rational molecular classification of these tumors. In parallel, the development of techniques for the determination of single-cell mutational profiling has considerably contributed to understanding the clonal heterogeneity and evolution of AMLs. The acquisition of these genetic data coupled with the identification of molecular therapeutic targets has determined a considerable expansion of the therapeutic armamentarium, with the development of several new drugs highly active against specific AML subtypes. These developments have increased the interest and the need for sensitive techniques for the identification of minimal residual disease, the population of leukemia cells that survives despite morphological remission and causes disease relapse.

Straight to the Point-The Novel Strategies to Cure Pediatric AML.

Although the outcome has improved over the past decades, due to improved supportive care, a better understanding of risk factors, and intensified chemotherapy, pediatric acute myeloid leukemia remains a life-threatening disease, and overall survival (OS) remains near 70%. According to French-American-British (FAB) classification, AML is divided into eight subtypes (M0–M7), and each is characterized by a different pathogenesis and response to treatment. However, the curability of AML is due to the intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy. The treatment of childhood AML continues to be based primarily on intensive, conventional chemotherapy. Therefore, it is essential to identify new, more precise molecules that are targeted to the specific abnormalities of each leukemia subtype. Here, we review abnormalities that are potential therapeutic targets for the treatment of AML in the pediatric population.

ES20.02 Charting a New Path: Defining Better Endpoints in Immune Therapy Trials in Lung Cancer

The use of immune checkpoint inhibitor therapy has transformed the face of lung cancer management. Trials of such agents for metastatic and locally advanced disease have used the traditional endpoint of overall survival (OS) by time-to-event analysis. However, obtaining this endpoint in a randomized trial takes some time and other endpoints are being considered, particularly for the radical or operable setting. To consider the most appropriate endpoint to use for immunotherapy, we must consider the aims of our treatment of lung cancer. For radically treatable disease through surgery is the aim always to improve the cure rate, or is another aim such as delaying recurrence (e.g., disease-free survival) just as clinically meaningful, if it doesn’t correlate with OS? We must also consider the magnitude of the effect size we wish to observe, particularly when using a surrogate endpoint of OS. Here, hazard ratios of 0.85 may not be clinically meaningful anymore, and we need to consider if we are prepared to accept uncertainty in effect by using a surrogate (earlier) endpoint for more rapid regulatory approval. If using a surrogate endpoint, will this give enough information to be able to pass HTA reimbursement value thresholds? We have clear guidance from the regulatory agencies on endpoints to be used for clinical trials. EMA give different definitions of endpoints for phase 1 and 2 trials from confirmatory phase 3 trials, giving a different stance for trials of cytotoxics to those non-cytotoxic based1. They recognize that immunomodulatory treatments may work most effectively where tumour bulk is low, and may take time to generate an defect, indeed with effect occurring post progression, and for phase 3 trials, progression-free survival remains acceptable. In the curative setting, EMA is clear that if event-free survival (EFS) is being used then this is justified under certain conditions and they give clear direction on using surrogates for the (neo)adjuvant setting1. The FDA also gives clear guidance on endpoints, with OS as the gold standard, but may allow other endpoints, recognizing that non-small cell lung cancer (NSCLC) is a heterogeneous disease, and the effects of different subsets should be explored2. When immunotherapy is being considered as the investigational medical product, endpoints such as progression-free survival (PFS), objective response rate (ORR) and even OS can have several benefits and risks. Measuring the benefit from immunotherapy can be difficult due to different patterns of benefit, and altered kinetics of benefit from cytotoxic therapy, alongside the heterogenous nature of NSCLC. Several surrogate endpoints e.g., ORR, duration of response, relapse-free survival, major pathological response or complete pathological response can be considered, but each give several benefits, but are prone to biases that need accounting for. The latter pathology-based endpoints have unclear definitions and the IASLC have proposed a structure for their definition3. When considering such surrogate endpoints, we should consider if such surrogates really to result in earlier approval or whether OS-based randomized trials are the main strategy- giving the example of extensive-stage small cell lung cancer4. Finally, if considering disease-free survival (DFS), multiple considerations need to be given. There are multiple emerging endpoints such as minimal residual disease in myeloma and the field of surrogate endpoints continues to evolve5. 1. EMA. Guideline on the clinical evaluation of anticancer medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-evaluation-anticancer-medicinal-products-man-revision-6_en.pdf 2. FDA. Clinical Trial Endpoints for the Approval of Non- Small Cell Lung Cancer Drugs and Biologics. Published 2015. https://www.fda.gov/media/116860/download 3. Travis WD, Dacic S, Wistuba I, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. Journal of Thoracic Oncology. 2020;15(5):709-740. doi:10.1016/j.jtho.2020.01.005 4. Gill J, Cetnar JP, Prasad V. A Timeline of Immune Checkpoint Inhibitor Approvals in Small Cell Lung Cancer. Trends in Cancer. 2020;6(9):736-738. doi:10.1016/j.trecan.2020.05.014 5. EMA. Guideline on the use of minimal residual disease as a clinical endpoint in multiple myeloma studies. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-use-minimal-residual-disease-clinical-endpoint-multiple-myeloma-studies_en.pdf endpoint, Clinical trials, immunotherapy

Cross-Sectional Physician Survey on the Use of Minimal Residual Disease (MRD) Testing in the Management of Pediatric and Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Introduction:Acute lymphoblastic leukemia (ALL) is a rare disease that progresses quickly and may be fatal within a few months if untreated. Although the majority of adults and pediatric patients with ALL achieve complete remission (CR) with current chemotherapy regimens, a significant proportion will ultimately have a relapse, particularly in the adult population. Minimal residual disease (MRD) has been demonstrated as a prognostic factor; higher levels of MRD indicate a higher likelihood of relapse. New techniques have been developed to quantitatively detect the presence of MRD in patients who achieve CR. The objective of this study was to explore use of MRD testing in the adult B-cell ALL patient population compared to its use in pediatric B-cell ALL patients, as well as to compare its use in academic versus community settings.Methods:This cross-sectional, non-interventional study used a quantitative survey to explore use of MRD testing among US physicians who treat ALL. Prior to implementation, 2 rounds of qualitative interviews were conducted to develop the content of the quantitative survey (4 in-person interviews and 2 online/phone interviews). Following the qualitative phase, a 20-minute quantitative online survey was conducted with US-based academic hematologists who actively monitor or treat ≥5 B-cell ALL patients and use MRD testing in practice. Physicians self-reported their primary hospital affiliation as being academic- or community-based and were classified as adult or pediatric treaters based on their reported proportion of adult versus pediatric B-cell ALL patients. Descriptive analyses (frequencies and percentages) of survey responses were conducted and Pearson's chi square test was used to assess differences by physician practice setting (academic versus community-based) and by primary patient population (adult versus pediatric).Results:One hundred fifty adult treaters (100 community adult treaters and 50 academic adult treaters) and 30 pediatric treaters (10 community pediatric treaters and 20 academic pediatric treaters) participated in the survey, for a total of 180 physician participants. Physicians used a variety of MRD tests, with flow cytometry being the most frequent choice among both adult and pediatric treaters, followed by polymerase chain reaction and next generation sequencing testing.The use of MRD testing was found to be higher among physicians who primarily treat pediatric patients (93%) than those who treat adult patients (73%) (p<0.05). Among the physicians who primarily treat adults (n=150), the number of patients receiving MRD testing was higher among those receiving treatment from an academic center compared to those from a community setting (84% and 67%, respectively; p<0.01). Academic adult treaters were also more likely to give patients ≥5 tests through the course of disease compared to community adult treaters (16% and 5%, respectively; p<0.05) (Table 1).Pediatric patients commonly received an MRD test during/after induction or upon relapse, while there was no consensus on the timing of MRD tests for adult patients. MRD testing was most common following maintenance treatment phase rather than during treatment (Figure 1). Collectively, physicians often conduct MRD testing after induction or consolidation of treatment.When asked to identify barriers that affected their decisions to conduct MRD tests, a greater proportion of academic adult treaters (32%) reported no barriers to conducting MRD testing compared to community adult treaters (13%) (p<0.01). Community adult treaters were more likely to indicate cost (50%) and lack of insurance coverage (42%) as barriers to MRD testing compared to academic adult treaters (24% each) (p<0.05) (Table 2; Figure 2).Conclusion:In this survey of physicians who treat patients with B-cell ALL and have used any MRD tests, physicians who primarily treat pediatric patients were more likely to conduct MRD testing than physicians who primarily treat adults. Physicians who treat patients with ALL in academic settings were also more likely to perform MRD testing compared with physicians who treat patients in community settings; some of the reasons for differences in MRD testing rates were cost and insurance barriers. Resolving these issues would be critical to improving detection of a molecular relapse in patients with ALL, most importantly among adults and in community settings. [Display omitted] DisclosuresChia:Amgen, Inc.: Employment, Equity Ownership. Delaney:Amgen, Inc.: Consultancy. McNamara:Amgen, Inc.: Consultancy. Kim:Amgen, Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership.

Use of Minimal Residual Disease and Advances in Clinical Trials

Use of Minimal Residual Disease and Advances in Clinical Trials

Use of Minimal Residual Disease in Acute Myeloid Leukemia Therapy.

The expanding availability of minimal or more precisely measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) with its possible implications for therapeutic decisions is of high interest to clinicians treating AML patients. A variety of mostly retrospective studies have shown that AML patients with a positive MRD test, assessed by different techniques at defined cutoffs and time-points, are at significantly higher risk of relapse and experience shorter overall survival compared to MRD-negative patients. How this valuable information may be adapted in the daily routine of patients' treatment to distinguish individuals who need more aggressive therapy from the ones who can be spared additional therapy to avoid treatment-related toxicities is still being investigated. With the exception of MRD analyses in acute promyelocitic leukemia (APL), the clinical implications of MRD tests for the individual AML patient are still mostly unknown. We currently lack hard evidence that MRD-based therapy modulation during treatment or pre-emptive intervention in MRD-positive patients after therapy would improve outcomes in non-APL AML patients. These questions will be evaluated in prospective randomized clinical trials. Today, however, some conclusions with regard to MRD assessment in AML can be drawn from the published data and are reviewed in this article.

Daratumumab (DARA) Plus Lenalidomide Versus Lenalidomide Alone As Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma (NDMM) after Frontline Autologous Stem Cell Transplant (ASCT): Use of Minimal Residual Disease (MRD) As a Novel Primary Endpoint in the Phase 3 Auriga Study

Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM), in combination with standard-of-care (SoC) regimens in RRMM and upfront in transplant ineligible NDMM. DARA is also under investigation as part of induction, consolidation, and maintenance treatment in patients with NDMM who are transplant eligible. However, no studies have specifically compared DARA maintenance to current SoC maintenance regimens. Although deep response as measured by MRD negativity has been associated with positive long-term clinical outcomes, and previous studies have demonstrated that DARA increases MRD negativity rates when combined with SoC therapy, MRD as a primary end point has not been examined in the context of frontline DARA treatment in NDMM. The ongoing phase 3 AURIGA (MMY3021) study will evaluate whether the addition of DARA to lenalidomide maintenance therapy increases the conversion rate to MRD negativity after 1 year of maintenance treatment, compared to lenalidomide alone, in patients with NDMM who are MRD positive after ASCT. Study Design and Methods: This ongoing multicenter, open-label, randomized phase 3 study will enroll approximately 214 patients from up to 60 sites in the United States. Patients 18-79 years of age are eligible if they have NDMM, have not been previously treated with an anti-CD38 antibody, have completed 4-8 total cycles of induction therapy (and/or consolidation therapy), have undergone ASCT, have achieved a very good partial response or better by International Myeloma Working Group (IMWG) criteria after ASCT and/or consolidation therapy, are MRD-positive by next-generation flow (NGF) or next-generation sequencing (NGS), at 60-100 days post-ASCT (or ≤60 days post consolidation therapy). Patients will be stratified by cytogenetic risk status (high risk vs standard risk/unknown status) and randomized 1:1 to DARA plus lenalidomide versus lenalidomide alone. Patients in both arms will receive 10 mg lenalidomide orally continuously during each 28-day cycle. After Cycle 3, if lenalidomide is well tolerated, the dose may be increased to 15 mg at the discretion of the investigator. Patients in the DARA plus lenalidomide arm will receive DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. Treatment will continue until disease progression, unacceptable toxicity, withdrawal, or for a maximum of 36 cycles. The primary endpoint is the MRD-negativity conversion rate (assessed at a 10-5 sensitivity threshold) at 12 months of treatment, assessed via NGS. MRD will also be assessed at 6, 18, 24, and 36 months. Importantly, use of the novel primary endpoint of MRD-negativity will allow for earlier assessment of outcomes and evaluation of deeper response than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD-negativity rate at any time, duration of MRD negativity, rate of complete response or better (≥CR), duration of ≥CR, PFS, OS, health-related quality of life, and safety. The ClinicalTrials.gov identifier is NCT03901963. Disclosures Shah: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Krevvata:Janssen: Employment. Kane:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Hampras:Janssen: Employment. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

Progress in adult ALL: incorporation of new agents to frontline treatment.

Treatment of acute lymphoblastic leukemia (ALL) in adults remains a challenge, as the delivery of intensive chemotherapeutic regimens in this population is less feasible than it is in the pediatric population. This has led to higher rates of treatment-related toxicity as well as lower overall survival in the adult population. Over the past several years, a host of novel therapies (eg, immunotherapy and targeted therapies) with better tolerability than traditional chemotherapy are now being introduced into the relapsed/refractory population with very encouraging results. Additionally, insights into how to choose effective therapies for patients while minimizing drug toxicity through pharmacogenomics and the use of minimal residual disease (MRD) monitoring to escalate/de-escalate therapy have enhanced our ability to reduce treatment-related toxicity. This has led to the design of a number of clinical trials which incorporate both novel therapeutics as well as MRD-directed treatment pathways into the frontline setting. The use of increasingly personalized treatment strategies for specific disease subsets combined with standardized and rapid molecular diagnostic testing in the initial diagnosis and frontline treatment of ALL will hopefully lead to further improvements in survival for our adult patients.

FDA analysis of MRD data in hematologic malignancy applications.

2541 Background: There is considerable interest in the use of minimal residual disease (MRD) in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval. Although surrogacy has not yet been established in most hematologic malignancies (except CML), MRD data has been submitted in applications to the agency to allow for further characterization of the product’s activity. Here we describe the new drug applications (NDA) or biologics licensing applications (BLA) that included MRD data and provide an analysis of the MRD data and the Agency’s decisions. Methods: The authors reviewed internal databases for all original and supplemental NDA and BLA applications submitted to the Division of Hematology Products (DHP) between 2014 and 2016 that pertained to malignant hematologic conditions. The applications were reviewed for inclusion of MRD data. The clinical reviews and prescribing information (PI) of the identified applications were reviewed for assessment of MRD data and FDA’s findings. Results: There were 34 NDAs or BLAs submitted between 2014-2016. Of these, 13 (38%) included MRD data, in the following diseases: CML, CLL, ALL, and MM. MRD data was added to the PI in 6 cases (46%), not included in 4 (31%), and was not proposed for inclusion in 3 (23%). Among the 6 cases in which MRD data was included in the PI, 5 used PCR testing and 1 used flow cytometry. Among the 4 in which MRD data was not included in the PI, the identified issues included: missing data among those in CR, incomplete test performance characteristics data (e.g.-limit of detection), disparate sample sources (blood, bone marrow), high amount of test failure rates (i.e.-inability to identify a clonal rearrangement), lack of test validation in the proposed disease setting, and inappropriate planned statistical analyses. Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.

Current Management of Childhood Acute Myeloid Leukemia.

The outcome for children with acute myeloid leukemia (AML) has improved significantly over the past 30years, with complete remission and overall survival rates exceeding 90 and 60%, respectively, in recent clinical trials. However, these improvements have not been achieved by the introduction of new agents. Instead, intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy have all contributed to this success. Nevertheless, novel therapies are needed, as the cure rates for many subtypes of childhood AML remain unacceptably low. Here, we briefly review advances in our understanding of the biology and genetics of AML, the results of recent clinical trials, and current recommendations for the treatment of children with AML.

Modern strategies in AML treatment

Acute myeloid leukemia (AML) is a complex disease that is characterized by diverse genetic and epigenetic abnormalities. The heterogeneity of AML subtypes implies that improvements in clinical outcome will require the development of therapies that are specific for each subtype of the disease and the design of novel clinical trials to test these strategies. In this review, we briefly summarize recent clinical trials, the genetic diversity of AML, and the use of minimal residual disease in the treatment of AML.

Different Aspects of Stem Cell Procedures in Children with Poor Responding Aml: When is HSCT the Best Answer?

Acute myeloid leukemia in children is a heterogeneous disease with different morphological and cytogenetic features. New diagnostic tools and treatments, improved supportive care and the use of genomic tissue typing in selecting donors for hematopoietic stem cell transplantation (HSCT) adds to increased survival rates. Candidates to HSCT in first complete remission are patients with cytogenetic or molecular unfavorable prognostic markers, or blasts &gt;15% after first induction. The use of minimal residual disease can also identify children benefiting from HSCT in first complete remission and the patients post HSCT with signs of relapse. The outcome and cure rate of acute myeloid leukemia, still remains poor and new diagnostic tools and treatments strategies need to be evaluated. In this management perspective, future management of novel minimal residual disease tools are discussed, conditioning therapies, as well as different transplantation procedures including haplo-transplantation and haplo-identical natural killer cell transplantation, but also altered graft-versus-host-disease treatments.

Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study.

The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status ≥2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

Is it time to change conventional consolidation chemotherapy for acute myeloid leukemia in CR1?

Choosing the most appropriate postremission therapy (PRT) for a patient with acute myeloid leukemia (AML) in first complete remission remains a challenging task. Factors such as risk for disease relapse, nonrelapse mortality associated with different PRT approaches, donor availability, prospects for salvage should disease relapse, and patient preference all affect PRT choice. New genetic markers refine AML risk stratification and identify patients within the 'classical' risk groups who may benefit from transplant-based or chemotherapy-based PRT. The use of minimal residual disease in first remission to guide PRT choice and the application of novel, targeted therapies have the potential to alter PRT approaches across AML risk groups. The advent of alternative donor sources, use of reduced intensity regimens, and improved supportive care all affect the availability and safety of transplant-based PRT and challenge the relevance of the older legacy 'donor/no-donor' genetically randomized trials. Genetic risk assessment, monitoring of minimal residual disease in first remission, use of targeted agents, and the newer transplant strategies all have the potential to 'personalize' PRT choice in the AML patient. The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials.

Minimal Residual Disease Monitoring By 8-Color Flow Cytometry in Mantle Cell Lymphoma Is Complementary to Q-PCR Monitoring and Will Facilitate Pre-Emptive Treatment: An EU-MCL and Lysa Study

Introduction: Mantle Cell Lymphoma (MCL) is characterized by frequent blood and bone marrow involvement. It has been demonstrated that use of Minimal Residual Disease (MRD) quantification in blood and/or bone marrow might be helpful in patient management. Gold standard MRD is based on Q-PCR clone specific amplification of IgH VDJ or IgH-BCL1 rearrangements, but these are relatively complex and time consuming and over half of the positive results are in a grey zone of borderline positivity. Flow cytometry (FCM) is more rapid and better adapted to individual patient management if quantitatively reproducible, but insufficiently sensitive when only 4 colors are used. We therefore developed a universal, 8-color, EuroFlow inspired, FCM strategy, which we compared with classical Q-PCR MRD in 61/97 patients included in (and 1 treated according to) the EU-MCL Younger and Elderly prospective trials who underwent Q-PCR MRD monitoring at Necker Hospital.Method: Q-PCR MRD from IgH VDJ (n=92) or BCL1-IgH (n=5) was performed prospectively from ficolled blood (PB) or bone marrow, from which residual material was cryopreserved in DMSO for FCM quantitation, using 10 antibodies labelled with 8 fluorochromes for positive and negative (CD45, CD19, CD5, LAIR1, CD11a, IGK, IGL, CD3, CD14 and CD56) gating, after diagnostic phenotyping of fresh material, using the same panel and a EuroFlow B lymphoid screening tube. Sensitivity of both techniques was at least 0.01% (1E-04). FCM was only considered positive if above 0.01%, whereas Q-PCR results were considered positive below quantifiable range (BQR) if borderline, above sensitivity, within Euro-MRD criteria for MRD positivity. BQR samples were separated based on the number of positive, triplicate samples. The objectives were to compare the two techniques and to determine their suitability for regular screening, with a view to pre-emptive treatment on molecular or phenotypic (MRD) relapse. Two patients were treated with Rituximab at MRD relapse, prior to clinical relapse, as proof of principle.Results: A total of 302 blood or bone marrow samples from 62 patients were quantified. Overall, 79% (42/53) of samples positive at or above 0.01% by PCR were also positive by FCM, compared to 29% (19/65) of those below 0.01%, but with at least 2 positive triplicates and virtually none of those with only 1 or no results above sensitivity (1%, 2/184). Quantification of the paired MRD results positive with PCR and/or FCM were significantly correlated (r2=0.74, P<0.0001).Amongst the 62 patients, 30 have relapsed and 19 have died. Nine relapsing patients (including one off protocol patient treated and monitored at initial and second MRD relapses) had sufficient MRD points to assess the capacity of PB Q-PCR or FCM to predict future clinical relapse sufficiently to justify pre-emptive treatment at MRD relapse. Clinical relapse was preceded by MRD relapse in 9/10 relapses by Q-PCR and 7/9 by FCM. Six of the 9 relapsing patients had achieved Q-PCR negativity in at least one PB sample. The mean latency for prediction by Q-PCR, when considering any increase in positivity to at least 2 positive triplicates as positive, was 11.3 months (range 1-24mths) and 5.4 months (0.5-11) when only results above 0.01% were considered positive. The equivalent latency by FCM was slightly shorter, at 6.5 months (0.5-21) Pre-emptive treatment of 2 patients at MRD relapse, prior to clinical relapse allowed re-establishment of molecular complete remission and a durable second remission in at least one with sufficient follow-up (Cf Fig.). [Display omitted] Conclusion: Eight color flow cytometry is a promising alternative to classical clone-specific Q-PCR strategies in monitoring therapy in MCL, with an excellent correlation (29/31, 94%) for MRD levels of at least 0.1% and acceptable correlation at 0.01-0.1% (13/22, 59%). While less sensitive at very low levels on cryopreserved material, FCM may clarify the clinical relevance of low-level borderline positivity; however it remains to be determined prospectively which technique will have greater prognostic value in patient management. FCM sensitivity will be improved by prognostic testing of fresh whole blood or bone marrow, and this pilot data clearly justifies such studies. Finally, MRD relapse precedes clinical relapse by several months, justifying pre-emptive treatment, monitored by prospective FCM and IgH Q-PCR within clinical trials. DisclosuresDreyling:Roche: Honoraria, Research Funding.

Role of allogeneic hematopoietic stem cell transplantation in adult patients with acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease, due to the expression of different biological and clinical risk factors, for which allogeneic stem cell transplantation (alloHSCT) is an effective consolidation therapy. The non-relapse mortality of alloHSCT remains significantly higher compared with that of conventional chemotherapy. Therefore, one of the main challenges in the care of ALL is to establish a more precise prognostic definition to select patients who could take advantage from an alloHSCT. Currently, the use of minimal residual disease following induction and early consolidation therapy has improved the prognostic accuracy in defining ALL risk class. In Philadelphia-positive ALL, the introduction of tyrosine kinase inhibitors pre and post alloHSCT appears to improve outcomes significantly and, in the absence of specially designed clinical trials, alloHSCT remains the most effective post-remission therapy. Nowadays, alloHSCT can be performed according to various modalities encompassing the use of different conditioning regimens, as well as distinct donors and stem cell source, with a significant accessibility to transplant.

Outcome of childhood acute Lymphoblastic leukemia in Egyptian children: A challenge for limited health resource countries

In childhood acute lymphoblastic leukemia (ALL) the reported 5-year event-free survival (EFS) rates are as high as 80%. Since 2004, multiple Egyptian centers shifted protocol of therapy of ALL to the CCG 1991 (the single delayed intensification arm) and CCG 1961 protocol for standard risk and high-risk ALL therapy, respectively, being cost effective. We aimed to evaluate the efficacy and safety of the CCG protocol in treatment of childhood ALL in Ain Shams and Menoufeya University hospitals.MethodsFifty-two ALL patients, aged 1–17 years, treated according to the modified CCG protocol in both centers and registered from November 2004 to December 2005 were included. They were classified into three risk groups, standard risk (SR), high-risk standard arm (HR-SA), and high-risk augmented arm (HR-AA).ResultsThe mean age at diagnosis was 5.9 + 3.3 years, male/female ratio of 1.6:1, and central nervous system leukemia represented 6%. The 5-year overall survival (OS) and EFS were 84.6% and 67%, respectively. The 5-year OS and EFS were 92.6% and 70% in SR, 68.8% and 55% in HR-SA, 88.9% and 80% in HR-AA patients, respectively. Six patients had grade 3–4 adverse events.ConclusionThe outcome of HR-SA protocol was inferior to the other two groups, necessitating shift to a more intensified arm with double delayed intensification. The use of minimal residual disease for better risk classification of childhood ALL is recommended in our centers