Impact Of Minimal Residual Disease Research Articles

Impact of Minimal Residual Disease (MRD) Assessed before Transplantation on the Outcome of Children with Acute Myeloid Leukemia Given an Allograft: A Retrospective Study By the I-BFM Study Group

Acute myeloid leukemia (AML) is a heterogeneous disease where selected subgroups of patients, linked by the presence of biological and clinical high-risk features, are candidates to receive allogenic hematopoietic stem cell transplantation HSCT) as post-remission consolidation treatment. The achievement of morphological complete remission (CR) before HSCT is an important pre-requisite to optimize the chance of successful post-transplant outcome. Minimal residual disease (MRD) assessment by quantitative polymerase chain reaction (q-PCR) has been shown to increase the ability to monitor therapy response in AML, improving prognostic accuracy and allowing to refine transplant strategies. Although MRD assessment was shown to have potential benefit when measured after induction and consolidation therapy courses, its role before HSCT remains to be fully elucidated. In order to contribute to better clarify this issue, we conducted a q-PCR I-BFM-AML collaborative study to measure MRD in bone marrow samples collected within 5 weeks prior to HSCT of 108 pediatric AML patients harboring one of the main recurrent AML aberrancies t(8;21)(q22;q22); RUNX1-RUNX1T1, inv(16)(p13.1q22)/t(16;16)(p13.1;q22); CBFB-MYH11, t(9;11)(p22;q23); KMT2A-MLLT3 or FLT3-ITD. Sixty patients underwent HSCT in first complete remission (CR1) with an overall survival (OS) of 84% versus 54% for the 48 transplanted in CR2 achieved after an initial relapse. Sixty patients showed q-MRD negativity (defined as a value lower than 2.1x10-4 calculated by ROC curve analysis with respect to diagnosis or relapse), whereas in 48 patients we detected q-MRD levels >2.1x10-4. Five-year OS after HSCT was 83% for patients with q-MRD negativity, while that of patients with q-MRD above the cutoff was 57% (p=0.012). As regards, cumulative incidence of relapse (CIR), q-MRD above the cutoff was associated with a high risk of recurrence (26% versus 10% for patients with q-MRD <2.1x10-4, p=0.036), q-MRD positivity representing an independent prognostic factor. When we interrogated the 3 genetic subgroups (namely CBFr, KMT2Ar and FLT3-ITD), despite the limited sample size, we found that OS was significantly influenced by q-MRD pre-HSCT in FLT3-ITD (63% versus 100% for q-MRD negative patients, p=0.019) and in t(8;21)RUNX1-RUNX1T1 rearranged patients (50 % versus 84% for q-MRD negative patients, p=0.048). We further investigated the impact of higher levels of q-MRD: we found that the 17 patients showing a pre-transplant q-MRD reduction lower than 1x10-2 (2-log), with respect to either diagnosis or relapse value, had a worse outcome (OS=39%) when compared to the 91 patients who reduced q-MRD values more than 2-log (OS=78%, p=0.0019). These 17 patients, transplanted in CR1 (n=8) or CR2 (n=9), were heterogeneous in terms of genetic lesions (t(8;21) n=7, inv(16) n=2, t(9;11) n=5 and FLT3-ITD n=3). Applying this 2-log cutoff by genetic subgroups, we found that cases with RUNX1-RUNX1T1 with q-MRD reduction above 2-log had the worst prognosis (OS 29% for q-MRD>2-log versus 73% for q-MRD<2-log, p=0.016). Overall, cases with FLT3-ITD, KMT2A-MLLT3 or CBFB-MYH11 more often achieved a q-MRD reduction greater than 2-log. In line with these results we combined the two measurement approaches and proposed a model where the two cutoffs generate 3 risk groups stratification, namely low (q-MRD<2.1x10-4, LR), intermediate (q-MRD>2.1x10-4 and <2-log, IR) or high risk (q-MRD>2-log, HR). This combined stratification by q-MRD resulted into a better subdivision of the OS probability, which was 83%, 69% and 39% for LR, IR and HR respectively (p=0.004). Finally, a multivariate Cox regression model revealed that, together with CR status at time of the allograft (CR2, hazard ratio 4.4, p=0.001), q-MRD was an independent factor (hazard ratio 0.5, p=0.001) predicting HSCT outcome. In conclusion, this study supports the role of q-MRD pre-HSCT as a useful prognostic tool in childhood AML, able to provide information to tailor transplant strategies involving conditioning regimen intensity and graft-versus-host disease prophylaxis. Disclosures Reinhardt: AbbVie: Consultancy; Novartis: Consultancy, Other: Institutional Research Funding; Jazz: Consultancy, Other: Institutional Research Funding; Celgene: Consultancy, Other: Institutional Research Funding; bluebird bio: Consultancy; Roche: Consultancy, Other: Institutional Research Funding; Biotest: Other: Institutional Research Funding; Novo Nordisk: Other: Institutional Research Funding; Behring: Other: Institutional Research Funding. Merli:Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Sanofi-Genzyme: Honoraria; Atara Therapeutics: Honoraria.

Impact of Minimal Residual Disease (MRD) By Multiparameter Flow Cytometry (MFC) and Next-Generation Sequencing (NGS) on Outcome: Results of Newly Diagnosed Transplant-Eligible Multiple Myeloma (MM) Patients Enrolled in the Forte Trial

Impact of Minimal Residual Disease (MRD) By Multiparameter Flow Cytometry (MFC) and Next-Generation Sequencing (NGS) on Outcome: Results of Newly Diagnosed Transplant-Eligible Multiple Myeloma (MM) Patients Enrolled in the Forte Trial

AML-180: The Adverse Impact of Minimal Residual Disease Measured Before Allogeneic Hematopoietic Stem Cell Transplantation on the Outcome of Acute Leukemia Patients

Context One of the main causes of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia (AL) patients is the disease relapse. Minimal residual disease (MRD) detected by multiparameter flow cytometry (MFC) is a strong prognostic marker of increased risk of relapse. Objective To determine the impact of MRD detected by MFC before allo-HSCT on clinical outcomes of acute leukemia patients. Patients and methods To assess the impact of MRD status before transplantation we included 84 AML patients and 46 ALL patients in their first or second morphologic remission who underwent allo-HSCT between July 2016 and April 2020. 6-color MFC was performed on bone marrow samples obtained before allo-HSCT. Positive MRD was identified as a cell population deviating from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation for all patients. For patients with LAIP at diagnosis, positive MRD was also defined as a cell population carrying LAIP markers at diagnosis. The probabilities of overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR) were estimated using the Kaplan–Meier method. Results Among 84 AML patients before allo-HSCT 23 patients (27.4%) were identified as MRD+. 11 out of 46 ALL patients (23.9%) before allo-HSCT were MRD+. Subsequently, 9 out of in 23 MRD+AML patients and 4 out of 61 MRD−AML patients relapsed (CIR 50.6% vs. 10%, p Conclusions Despite the presence of morphological complete remission before allo-HSCT, MRD persistence before allo-HSCT influences OS and RFS in patients with AL. Because of the association between MRD and relapse risk, MRD-testing before allo-HSCT may help to identify a subgroup of acute leukemia patients who need preemptive treatment.

Outcomes and impact of minimal residual disease (MRD) in pediatric, adolescent and young adults (AYA) with acute lymphoblastic leukemia treated with modified MCP 841 protocol

Background: The impact of minimal residual disease (MRD) on overall survival (OS) is insufficiently studied in pediatric, adolescent, and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with modified MCP 841 protocol. Objectives: We planned to evaluate the outcomes (post-induction response rates, MRD, and OS) with modified MCP 841 in pediatric and AYA ALL. Materials and Methods: This was a retrospective audit of patients with ALL registered between March 01, 2017, and August 31, 2019. Patients who received at least 7 days of therapy on modified MCP 841 protocol were analyzed. Response evaluation was done on day 35 of induction with bone marrow aspiration, and MRD was assessed with flow cytometry with Results: 130/167 (78%) patients were started on MCP 841 protocol; the remaining 37 (22%) patients defaulted after the first visit. B-cell ALL was more common at 78 (60%). 94 (72%) had National Cancer Institute High Risk. Day 8 good prednisolone response (GPR) was seen in 76 (58%) patients. Morphological remission was noted in 90/107 (84%) patients. MRD status was available in 84 (78%) patients. 46 (43%) patients achieved MRD-negative status. The median follow-up was 21 months (range, 10–31 months). The median OS was 30 months (95% CI, 15.5–42.8 months). One-year and 2-year survival was 87% and 60%, respectively. Patients who were MRD negative did better than those with MRD positive, 29 versus 22 months (P = 0.03). GPR performed better than those with Poor Prednisolone Response (PPR), 29 versus 15 months (P = 0.01). Conclusion: Post-induction MRD is a useful prognostic tool for ALL patients treated with modified MCP 841 protocol. Outcomes are suboptimal compared to those reported from the developed western world.

Impact of Minimal Residual Disease Detected By Multiparameter Flow Cytometry on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be curative for acute myeloid leukemia (AML) patients. However, the disease relapse after allo-HSCT lead to poor outcomes almost in all cases. Minimal residual disease (MRD) is a strong prognostic marker of increased risk of relapse and reflects overall (OS) and relapse-free survival (RFS) in patients with AML. Immunophenotypic evaluation using multiparameter flow cytometry (MFC) is an important strategy for detecting MRD, because of its simplicity and wide availability. Aim. Determine the impact of MRD detected by MFC before allo-HSCT on clinical outcomes. Patients and methods. To assess the impact of MRD status before transplantation we include 56 AML patients who underwent allo-HSCT in National Research Center for Hematology between July 2016 and June 2019. Patient's characteristics are shown in table 1. All these patients were in first compete morphologic remission at the time of allo-HSCT. MRD was evaluated by MFC. Bone marrow samples were obtained before allo-HSCT and were analyzed by 6-color MFC (BD FACS Canto II, USA). Positive MRD was identified as a cell population deviating from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation for all patients. In addition, for patients with LAIP at diagnosis, positive MRD was also defined as a cell population carrying LAIP markers at diagnosis. The probabilities of OS and RFS were estimated using the Kaplan-Meier method. Results. Among 56 AML patients before allo-HSCT (all were in CR at the time of MRD analysis). Median of follow-up was 9.3 months.11 patients (19,6%) were identified as MRD+ (0,011%-5,08%, mean 1%). And 5 of them relapsed (45,5%). Out of 45 MRD negative patients before HSCT relapse was registered in one (relapse rate 2,2%). Statistical analysis revealed significant differences between MRD- and MRD+ patients: MRD+ had much worse OS (22,9% vs. 85.5%, p=0.0047, Fig.1A) and RFS (26% vs. 97.4%, p<0,0001, Fig.1B). Conclusions. Despite the presence of morphological CR before allo-HSCT, MRD persistence can lead to worse probabilities of OS and RFS, which is comparable to patients who were transplanted in relapse. Because of the association between MRD and relapse risk, it can be assumed, that testing for MRD before allo-HSCT may help to identify a subgroup of patients at high risk of relapse who might benefit from preemptive posttransplantation treatment. Disclosures No relevant conflicts of interest to declare.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for the Treatment of Newly Diagnosed AL Amyloidosis: Impact of Response on Survival Outcomes

BackgroundCyBorD (cyclophosphamide, bortezomib, and dexamethasone) is an effective regimen for the treatment of patients with newly diagnosed immunoglobulin light chain (AL) amyloidosis. CyBorD can induce rapid hematologic responses (HRs). However, it remains inadequate to enhance outcomes in high-risk groups. In addition, minimal information is available on the impact of minimal residual disease (MRD) in overall survival. Patients and MethodsAll consecutive patients with newly diagnosed AL amyloidosis treated with CyBorD from January 2012 to August 2018 were evaluated. HR and organ response was assessed as per standard guidelines. Further, MRD was evaluated by multiparameter flow cytometry in patients with confirmed complete response (CR). ResultsAfter a median of 4 cycles, HR was seen in 31 (91.2%) cases, including CR in 9 (26.5%), very good partial response in 9 (26.5%), and partial response in 13 patients (38.2%). Organ response at 6 months was documented in 11 (32.4%) cases. With respect to cardiac response, a > 30% decrease of NT-proBNP was observed in 4 (19%) of 21 evaluable cases (NTproBNP > 650 ng/L) at a median of 6 months. The median progression-free survival was 26.7 months. Patients who achieved CR exhibited a better overall survival compared with those without CR (P = .001). No difference on overall or progression-free survival among cases achieving CR irrespective of their MRD status was observed (P > .05). ConclusionsIn summary, CyBorD showed a ≥ very good partial response rate of 53% with 26.5% achieving CR, which is similar to that seen in previous studies. In addition, MRD negativity assessed by multiparameter flow cytometry in patients with CR resulted in no difference on survival outcomes.

Longitudinal Evaluation of Minimal Residual Disease in Patients with Multiple Myeloma who Achieve Complete Response After First Line Therapy

Novel treatments have significantly increased the rates of complete response (CR) in patients with multiple myeloma (MM), however most of them will eventually relapse. The presence of minimal residual disease (MRD) has emerged as a valuable biomarker as it discriminates patients with a higher risk of progression despite the achievement of CR. Previous studies have highlighted the prognostic value of MRD negativity at the time of CR after frontline therapy; there is limited data on the impact of MRD in patients achieving long-term CR.

PS1564 HAPLOIDENTICAL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA PATIENTS WITH DETECTABLE DISEASE AT TRANSPLANT

Background:Patients with acute myeloid leukemia (AML) with minimal residual disease (MRD) and not in complete remission (CR) have inferior outcomes after HLA‐matched allogeneic stem cell transplantation (SCT). Haploidentical SCT (HSCT) is being increasingly used worldwide as an alternative donor source for patients who lack an HLA matched donor. The impact of MRD and disease status at transplant on HSCT outcomes for patients with AML are unknown.Aims:To determine the impact of pre‐transplant disease status on AML outcomes after HSCT.Methods:All consecutive patients with AML who underwent HSCT with post‐transplantation cyclophosphamide (PTCy)‐based graft‐versus‐host‐disease (GVHD) prophylaxis between 02/2009–10/2018 were included. MRD status was measured using flow cytometry and/or presence of cytogenetic/molecular abnormalities at time of SCT. Primary endpoints: progression‐free survival (PFS) and overall survival (OS). Secondary endpoints: cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM). Kaplan‐Meier estimates, Cox proportional hazards and competing risks regression were used.Results:A total of 143 patients with a median age of 52 (18–72) were identified. Patients received conditioning with fludarabine 160 mg/m2, melphalan 100 or 140 mg/m2 and 2GyTBI, as previously described by our group (Gaballa S. Cancer. 2016). With a median follow up of 29 months, the median PFS and OS of all patients were 10 and 18 months, respectively. The 2‐year PFS and OS were 41% and 47%, respectively. Compared to patients in CR at transplant, those with active disease (n = 29) and CR with incomplete count recovery/hyoplastic marrow [CRi] (n = 39) have worse 2‐year PFS hazard ratios (HR) of 3.5 (95% CI: 2.05–6.1; p < 0.001) and 2.3 (95% CI: 1.3–3.9; p = 0.002), respectively (Figure). Likewise, patients with active disease (HR 3.7, 95% CI: 2.1–6.6; p < 0.001) and CRi (HR 2.1, 95% CI: 1.2–3.8; p = 0.01) had inferior 2‐year OS. Patients with active disease and CRi at transplant have statistically significant worse CIR, but comparable NRM compared to patients in CR. The median PFS and OS for patients in CR at transplant were not reached, compared to 4.3 and 6.5 months, respectively, for those with active disease and 7.1 and 10.3 months, respectively, for those with CRi.When we subgrouped patients in CR by MRD status at transplant, there was no statistically significant differences between MRD+ve (n = 24) and MRD–ve (n = 41) in both 2‐year PFS (HR 1.85, 95% CI: 0.9–4.0; p = 0.1) and OS (HR 2.1, 95% CI: 0.9–4.8; p = 0.08). In multivariable analysis, only age was predictive for outcomes (Figure). For ≤50 years, MRD status has no influence on outcomes with 2‐year PFS and OS of 65% and 76% and 2‐year OS of 89% and 76% for those with MRD+ve and MRD–ve, respectively (p = NS). Patients older than 50 year and with MRD+ve disease had the worst outcomes with 2‐year PFS and OS of 29% (p = 0.005) and 26% (p = 0.002), respectively.Summary/Conclusion:Our findings suggest that patients with MRD+ve have excellent outcomes with HSCT and melphalan‐based conditioning with PTCy‐based GVHD prophylaxis, especially in younger patients. Proceeding to a HSCT in patients with MRD+ve disease does not appear to compromise transplant outcomes and are better than reported outcomes with HLA matched donor transplants. Haploidentical grafts might be a preferred donor source for MRD+ve AML patients who frequently may need to proceed urgently to transplant.image

Role of Minimal Residual Disease in the Clinical Course of T cell Acute Lymphoblastic Leukemia in Pediatric Patients

Background Minimal Residual Disease (MRD) is the most important prognostic parameter in pediatric precursor B cell- Acute Lymphoblastic Leukemia (B-ALL). However, the feasibility of flow cytometry in the detection of Minimal Residual Disease (MRD) in T cell- Acute Lymphoblastic Leukemia (T-ALL) is not well defined. Objectives We aimed to investigate the prognostic impact of Flow Cytometry-MRD in T-ALL measured at different time points post-induction. Patients and methods In the current study, the impact of MRD was investigated in 58 newly diagnosed pediatric ALL at day 15, 28 and 42 post induction treatment in relation to other clinical and hematological parameters as well as disease-free survival. Results At day 15, day 28 and day 42 patients with MRD level ≥ 0.1% had inferior Disease-Free Survival (DFS) compared to patients with lower MRD levels which was significant for day 15, day 28 and 42 (p=0.007, p=0.0148 and p=0.0004 respectively). No association was detected between MRD status and different clinical and laboratory parameters. Conclusion Post-induction MRD detection is sensitively reflecting the disease progression in pediatric (T-ALL). This is most evident at day 42 followed by day 15.

Impact of Minimal Residual Disease and Achievement of Complete Remission/Complete Remission with Partial Hematologic Recovery (CR/CRh) on Overall Survival Following Treatment with Gilteritinib in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) with FLT3 Mutations

Impact of Minimal Residual Disease and Achievement of Complete Remission/Complete Remission with Partial Hematologic Recovery (CR/CRh) on Overall Survival Following Treatment with Gilteritinib in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) with FLT3 Mutations

Depth of Response and Outcomes in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Background: For multiple myeloma (MM) patients, depth of response after induction therapy and after autologous hematopoietic stem cell transplantation (AHCT) has been shown to be important for progression free (PFS) and overall survival (OS) in some studies. Furthermore, the impact of minimal residual disease (MRD) on outcomes and treatment decisions has been widely discussed. We aimed to evaluate outcomes by depth of response after induction and AHCT.Methods: MM patients who received their first AHCT within 1 year of starting induction were identified from the institutional registry. MRD was assessed by non-10 color flow cytometry. Response was defined by the International Myeloma Working Group criteria. Summary statistics were used to describe the population. Kaplan-Meier methodology estimated PFS and OS by response status pre-AHCT and at post-AHCT restaging.Results: Between 2012 - 2014, 182 MM patients met our inclusion criteria, with 83% alive at last follow-up. The median age at AHCT was 60 years (range 29-76) with 57% male. By the International Staging System (ISS), 50% were stage I, 26% stage II, and 24% stage III. High risk cytogenetics were detected in 24%. Isotype was IgG in 55%, IgA 21%, Kappa Free Light Chain (KFLC) 11%, and lambda FLC (LFCL) 9%. First induction therapy included bortezomib in 90% and lenalidomide in 79%. Median time to AHCT was 5.5 months (range 2.8-11.7). The median follow-up from AHCT was 3.7 years (range 0.22 - 4.6 years), with 84% of patients receiving lenalidomide maintenance, and 9% receiving an additional autologous or allogenic transplant at relapse.Response prior to the initial AHCT was a complete remission (CR) in 13.7% (MRD negative 6.6%, positive 4.4%, unknown 2.7%), very good partial remission (VGPR) 38%, partial remission (PR) 40%, stable disease (SD) 5%, and progressive disease (PD) 4%. At post-AHCT restaging, responses had improved to 42% CR (MRD negative 23%, positive 6%, unknown 13%), 35% VGPR, 19% PR, 2% SD, and 3% PD.Median PFS from AHCT for the entire cohort was 3.2 years (95% CI 2.4 - 4 years) with 1-year and 3-year PFS 85% and 52%, respectively. Median OS was not reached (NR) (95% CI 4.4 years - NR) with 1-year and 3-year OS 97% and 88%, respectively (Figure 1).PFS from AHCT was significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached (95% CI 1.7 - NR) compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.64 years (95% CI 1.09-3.64), 3.46 years (95% CI 2.4 - NR), and 2.44 years (1.68-3.56 years), respectively, p=0.048] (Figure 2A). From post-AHCT restaging, PFS was also significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.49 years (95% CI 0.86-3.49), 3.56 years (95% CI 2.5 - NR), and 2.4 years (1.6-3.33 years), respectively, p=0.026] (Figure 2B). However, there was no difference in PFS based on the post-AHCT restaging with median PFS in MRD negative CR, MRD positive/unknown CR, VGPR, and ≤ PR of 3.49 years (95% CI 2-NR), not reached (95% CI 1.4-NR), 2.96 years (95% CI 1.7-NR), and 2.86 years (95% CI 1.7 - NR) (p=0.78, Figure 2C), respectively.OS from AHCT was not significantly different by pre-AHCT response, and the median was not reached in any group (p=0.33, Figure 3A). Finally, the median OS from post-AHCT restaging by pre-AHCT response or by post-AHCT response was also not reached in any group (p=0.32 and 0.31, respectively; Figure 3B & C).Conclusion: For MM patients, AHCT deepened responses and increased the CR rate. We were unable to show a significant difference in outcomes at post AHCT restaging, which may be due to the effect of maintenance therapy, the small numbers of MRD negative patients, or the sensitivity of the MRD assay available during this time period, though potentially show that MRD positive patients do as well as MRD negative patients after AHCT. We plan to add additional patients treated in the more recent years who were assessed by more sensitive methods. DisclosuresShah:Janssen: Research Funding; Amgen: Research Funding. Korde:Amgen: Research Funding. Lesokhin:Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Squibb: Consultancy, Honoraria. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

The Impact of Minimal Residual Disease (MRD) Status at Day 28 in Predicting Relapse in Adults with Acute Lymphoblastic Leukemia in the Real World Setting

BackgroundAcute lymphoblastic leukemia (ALL) requires intensive systemic and intrathecal (IT) therapy for a prolonged period to prevent relapse [1, 2]. MRD negativity has been associated with long-term disease-free survival.[3] However, most published data are in patients treated in a clinical trial setting. Real-world data are lacking. We performed a retrospective cohort analysis of our database of ALL patients to determine the impact of MRD measurement on the pattern of relapse.[3-5]MethodsWe conducted a retrospective cohort analysis of patients with ALL treated at our institution between December 2001 and September 2015. We interrogated the database for patient and disease characteristics, treatment protocols, and outcomes. In all cases, MRD reported was obtained by way of multi-color flow cytometry on bone marrow biopsy samples. Data were stored in the RedCap database and simple, descriptive statistics were utilized for analysis. Chemotherapy consisted of standard regimens including E2993, Hyper-CVAD, the Vanderbilt ALL protocol, multiple pediatrics protocols, and multiple regimens not otherwise specified. [3-5]ResultsWe identified 147 patients over the time period specified, consisting of 91 males and 56 females. The median age of the cohort was 42 years. The most common chemotherapy regimens used included Hyper-CVAD (31%), E2993 (24%), the Vanderbilt ALL protocol (23%) and pediatric protocols (19%). Among the patients in morphologic CR, 55 (37%) had MRD measured at day 28 (+/- 7 days). Of those patients, 38 (83%) were MRD-negative and 17 (13%) were MRD-positive. In the MRD-negative cohort, 2 (5.3%) relapses occurred within the first year while 8 (21%) ocured later. In the MRD-positive cohort, 3 (38%) relapsed within the first while 2 (12%) occurred later.DiscussionOur results underscore the importance of early measurement of MRD in ALL patients in predicting early relapse. In those patients with no detectable MRD on flow cytometry of the bone marrow at day 28, only 5.3% relapsed within one year compared to 38% of those with detectable MRD. This difference is actually more pronounced than those observed in some clinical trials, validating early MRD measurement across treatment regimens in the real world setting. Notably, 2 patients with detectable MRD at day 28 were continued on the same protocol and did not relapse at 7-year follow-up. This suggests a potential role for serial MRD measurement in select, low-risk patients with MRD close to negative. Our study is limited as it is a retrospective analysis with a small sample size and at a single tertiary academic medical center which may diminish its applicability to other practice settings.

Achieving a Difference in Involved and Uninvolved Light Chains (dFLC) of Less Than 10mg/L Is the New Goal of Therapy in Systemic AL Amyloidosis: Analysis of 916 Patients Treated Upfront with Bortezomib-Based Therapy

BackgroundBased on international consensus criteria (ICC), the treatment goal in AL amyloidosis (AL) is at least a very good partial response (VGPR, defined by dFLC<40mg/L), associated with better organ responses and overall survival (OS). In patients presenting with low dFLC (<50mg/L), a low-dFLC partial response (PR, dFLC<10mg/L) predicts better renal and OS. Given emerging data on the impact of minimal residual disease in AL, we posited that a target of dFLC<10mg/L may be important in all AL patients, irrespective of baseline light chain levels. We therefore report outcomes in the largest cohort treated with upfront bortezomib-based therapy and explore the impact of dFLC<10mg/L as a potential therapy goal in AL.MethodsAll patients from a prospective observational study of newly diagnosed AL treated with upfront bortezomib regimes from 2010-2017 were included. All underwent serial organ function assessment and biomarkers. Organ responses were defined by ICC. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis. Haematologic responses were assessed by ICC and absolute dFLC. Patients with presentation dFLC 20-50mg/L were regarded as achieving a low-dFLC PR if dFLC<10mg/L after treatment. Progression-free survival (PFS) was defined as time to death or progression to next therapy. Time-to-next-treatment (TNT) was defined as time from first-line therapy to second-line.Results916 patients were included. Median age was 66 years (29-89), M:F 59%:41%. The number of patients with cardiac, renal, liver, peripheral nerve and autonomic involvement was: 71%, 68%, 14%, 6% and 6%. The number of patients with Mayo Stage 1, 2 and 3 disease was 16%, 33% and 51%. The median NT-proBNP and dFLC were 2228ng/L (range 29-93776) and 180mg/L (0-15898), respectively. All received bortezomib-based therapy: CyBorD 95%, bortezomib-dexamethasone 3%, bortezomib-thalidomide-dexamethasone 1.3%, bortezomib-melphalan-prednisolone 0.3%, bortezomib-lenalidomide-dexamethasone 0.3% and bortezomib-melphalan-thalidomide-dexamethasone 0.1%. The median number of chemotherapy cycles was 5 (1-9).ITT haematologic responses by ICC at 6 months were: complete haematologic response (CR) 15%, VGPR 30%, partial response (PR) 16%, low-dFLC PR 4%, non-response 35% (including deaths 25%). Evaluable haematologic responses were: CR 21%, VGPR 40%, PR 21%, low-dfLC PR 5% and non-response 13%. Absolute dFLC responses were: dFLC <10 mg/L 30%; dFLC 10-20mg/L 11%; dFLC 20-30mg/L 6%; dFLC 30-40mg/L 5%, dFLC 40-50mg/L 3%, dFLC>50mg/L 20% and deaths 25%.Median OS, PFS and TNT were 72 months, 22 months and not reached (55% of evaluable patients not having progressed to next treatment at 7 years). Median OS was not reached in patients in a CR, VGPR or low-dFLC PR; median OS was 71 and 39 months in patients in a PR and non-response, respectively. Median OS in patients with 6 month dFLC<10mg/L, dFLC 10-40mg/L, and dFLC>40mg/L was not reached (86% alive at 6 years), not reached (61% alive at 6 years) and 53 months, respectively. Median PFS was not reached in patients in a CR or low-dFLC PR, and it was 48, 17 and 13 months in patients in a VGPR, PR and non-response, respectively. Median PFS in patients with 6 month dFLC<10mg/L, 10-40mg/L and dFLC> 40mg/L was not reached, 33 and 14 months, respectively. Median TNT in patients in a CR, VGPR and “low-dFLC” response was not reached; it was 16 and 13 months in those in a PR and non-response, respectively (Fig. 1A). Median TNT in patients with a 6 month dFLC<10mg/L, 10-40mg/L and dFLC>40mg/L was not reached, 38 months and 13 months (Fig. 1B).Median OS, PFS and TNT at 3 and 5 years in patients achieving CR vs dFLC<10mg/L was: 76% vs 82%, and 67% vs 76%. 32% achieved cardiac responses in total, compared to 61% in those with 6 month dFLC<10mg/L (p<0.0001). 15.4% achieved renal responses overall, compared to 27.4% in the 6 month dFLC<10mg/L group (p=0.0003).ConclusionIn this study, we report the largest cohort of AL patients treated with upfront bortezomib. On an evaluable basis, 66% of patients achieved CR/VGPR/low-dFLC response. The OS, PFS and TNT in patients in a CR are akin to those previously reported in ASCT. Strikingly, PFS, TNT and organ responses are markedly better in patients with dFLC<10mg/L after treatment, even compared to patients in a standard CR. We propose that dFLC<10mg/L should be evaluated in an international collaboration as the new therapy goal in AL. [Display omitted] DisclosuresWechalekar:Janssen: Honoraria.

RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

AbstractImproving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: systematic review and meta-analysis

BackgroundThis meta-analysis was performed to explore the impact of minimal residual disease (MRD) prior to transplantation on the prognosis for patients with acute lymphoblastic leukemia (ALL).MethodsA systematic search of PubMed, Embase, and the Cochrane Library was conducted for relevant studies from database inception to March 2016. A total of 21 studies were included.ResultsPatients with positive MRD prior to allogeneic stem cell transplantation (allo-SCT) had a significantly higher rate of relapse compared with those with negative MRD (HR = 3.26; P < 0.05). Pre-transplantation positive MRD was a significant negative predictor of relapse-free survival (RFS) (HR = 2.53; P < 0.05), event-free survival (EFS) (HR = 4.77; P < 0.05), and overall survival (OS) (HR = 1.98; P < 0.05). However, positive MRD prior to transplantation was not associated with a higher rate of nonrelapse mortality.ConclusionsPositive MRD before allo-SCT was a predictor of poor prognosis after transplantation in ALL.Trial registrationNot applicable.

Impact of minimal residual disease (MRD) status in clinical outcomes of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin (InO) in the phase 3 INO-VATE trial.

7013Background: MRD negativity is a key prognostic indicator of patient (pt) outcome in ALL and is predictive of improved survival and disease-free status. In the INO-VATE ALL trial (Kantarjian, NE...

Prognostic significance of flow cytometric minimal residual disease in acute myeloid leukemia during aplasia

目的探讨急性髓系白血病（AML）患者诱导化疗后骨髓抑制期，采用多参数流式细胞术（MPFC）检测的骨髓微小残留病（MRD）在疗效判断及预后中的价值。方法回顾性分析85例初诊并于诱导化疗后第7～8天采用八色MPFC检测了骨髓MRD的AML（非急性早幼粒细胞白血病）患者临床资料，对其与疗效及预后的关系进行统计学分析。结果在85例患者中，男42例（49.4%），女43例（50.6%），中位年龄35（15～54）岁，诱导化疗后第7～8天MRD中位数0.58%（0～81.11%），1个疗程诱导治疗后完全缓解（CR）患者70例（82.4%）。根据受试者工作特征曲线（ROC曲线）得到MRD的阈值为2.305%（Se＝0.867，Sp＝0.800）。MRD<2.305%的患者1个疗程CR率为96.6%（56/58），MRD≥ 2.305%的患者1个疗程CR率为51.9%（14/27），两组CR率差异有统计学意义（χ2＝22.348，P<0.001）；两组无复发生存率差异无统计学意义（χ2＝1.08，P＝0.299）；两组总生存率差异无统计学意义（χ2＝0.42，P＝0.516）。多因素分析结果显示，以2.305%为界的MRD（OR＝21.560，95% CI 4.129~112.579，P<0.001）是第1个疗程诱导疗效的唯一独立预后因素。结论AML患者诱导化疗后骨髓抑制期，采用MPFC检测骨髓MRD以2.305%为界能够预测诱导化疗疗效。

DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia.

We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3Amut transcript levels (log10-transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in BM than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004) and consolidation II (P=0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission.

Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML to reduce risk of relapse.

7018 Background: Persistence of minimal residual disease (MRD) post therapy is a powerful predictor of outcome in patients with AML treated with traditional cytarabine and anthracycline based regimens. The clinical relevance of MRD in the context of hypomethylating agents has not been evaluated extensively. Methods: Among 194 patients with AML treated with single agent azacytidine, decitabine, or gaudecitabine, 116 (median age 76, range 60 - 92) had MRD analysis performed on bone marrow specimens obtained at time of assessment of response or thereafter; among them 69 (59%) achieved either morphologic complete remission (CR) or CR with incomplete recovery of platelets (CRp) or counts (CRi), and 61 (53%) had evaluable MRD data; MRD was assessed using an 8-color flow panel, with a detection sensitivity of 0.01%. Results: Median cycles to achieving response was 2 (range, 1-6). Sixty one patients had evaluable MRD data at the time of response, of whom 19 (28%) became MRD negative (-). This was associated with a reduced cumulative risk of relapse (p = 0.012) but did not translate to an improved relapse-free survival (RFS; p = 0.17) or overall survival (OS; p = 0.79) due to high frequency of non-relapse deaths (attributable to comorbidities and infections) in the MRD- group. Patients who achieved a MRD- state at the time of achieving response had a higher mortality [5/8 (62%)] when compared with those who achieved a MRD- state in subsequent cycles [1/13 (7.6%); p = 0.01], resulting in an inferior OS (6.2 months (mo) vs 20 mo, p = 0.012). Similarly, achieving negative MRD at CR and at any time up to 3 months post response was not associated with improved RFS or OS despite a lower cumulative risk of relapse (p = 0.045). There was no impact of MRD, on OS, whether the MRD- state was achieved after 1st, 3rd or 6thcycle of therapy. Association between depth of MRD response at time of remission and RFS was borderline significant (p = 0.08). On multivariate analysis, response (CR vs CRi/CRp), but not a negative MRD, was predictive for RFS or OS. Conclusions: In this cohort of older AML patients treated with hypomethylating agents, achieving a MRD- state was associated with a reduced risk of relapse but not improved RFS or OS.

380 Determination of molecular remission in patients with mycosis fungoides (MF) and Sezary Syndrome (SS) following allogeneic transplant using high throughput sequencing (HTS)

Allogeneic stem cell transplantation (ASCT) is the only potentially curative therapy in pts with advanced stage MF/SS. Currently, we lack predictive markers associated with clinical outcome after ASCT. We utilized HTS of TCRß to evaluate the impact of minimal residual disease (MRD) after ASCT in a prospective clinical trial. Our study included 12 pts with MF and 20 with SS. Median age was 62 (range 20-75). Twenty six pts (81%) had stage IV disease and none achieved complete response from last systemic therapy immediately prior to conditioning. All received non-myeloablative conditioning with total skin electron beam therapy (TSEBT), total lymphoid irradiation (TLI, 8 Gy) and anti-thymocyte globulin (ATG). Pts tolerated ASCT extremely well with 1-year transplant-related mortality of 3%. At 3-months post-transplant, 19 pts achieved complete clinical response and 10 pts had a partial response. Of the 27 pts assessed by the specific and ultra-sensitive (detecting 1 in 150,000 cells) HTS of TCRß, 12 pts (44%) achieved molecular remission in the blood after ASCT. The median time to molecular remission in the blood was 120 days (range 30-730). Of these 12 pts, 11 of them also achieved molecular remission in the skin. Pts who achieved molecular remission in both blood and skin had less chance of disease progression/relapse than those who had MRD, with cumulative incidence of progression/relapse of 13% and 92%, respectively (p=0.0005). Herein, we demonstrate that a non-myeloablative ASCT utilizing our unique TSEBT/TLI/ATG conditioning is safe and effective in treating patients with advanced stage MF/SS. Our findings show that close to half of the pts achieved molecular remission after transplant as determined by HTS of TCRß, which correlated with a very low likelihood of disease progression/relapse. This is the first report of a systematic, rigorous investigation of a clinically meaningful impact of molecular remission in this pt population.