Pre-transplant molecular minimal residual disease (MMRD) is associated with inferior outcomes in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7547-7547
Author(s):  
Muhammad Husnain ◽  
Krishna Komanduri ◽  
Jeremy Ramdial ◽  
Lazaros J. Lekakis ◽  
Trent Peng Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Molecular Data ◽  
Cell Transplant ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Risk Patients ◽  
The Impact ◽  
Minimal Residual

7547 Background: Allogeneic Stem Cell Transplant (alloSCT) continues to be the optimal consolidation strategy for many patients with AML; cytogenetic and molecular abnormalities are known predictors of post-transplant outcomes. There is increasing evidence that Molecular Minimal Residual Disease (MMRD) following induction has important prognostic implications and its value in the prediction of post-transplant relapse continues to be elucidated. We aim to evaluate the impact of genetics and pre-transplant MMRD on clinical outcomes following alloSCT. Methods: We retrospectively evaluated eighty-nine patients, ≥18 years with a diagnosis of AML in complete morphologic remission (i.e. < 5% BM blasts by morphologic assessment) who received alloSCT between 01/2012-05/2018 at the University of Miami and for whom cytogenetic and comprehensive molecular data was available prior to transplantation. Patients were stratified into favorable, intermediate and poor-risk categories based on 2017 ELN criteria. MMRD was defined as persistent leukemia-specific mutations prior to transplantation (i.e. NPM1, FLT3, CEBPA, IDH1-2, RUNX1 and TP53). Persistence of DTA mutations (DNMT3A, TET2 and ASXL1) was not considered MMRD, patients with unavailable cytogenetic/molecular data at diagnosis were excluded. Results: Seventy-four (83%) patients were transplanted in CR1, myeloablative conditioning was used in 72% of patients. Two-year OS and LFS were 69.4% and 78.2%, respectively. Stratification by ELN criteria resulted in prognostic separation for patients transplanted in CR1: 2-year OS for favorable (87%), intermediate (68%) and adverse risk (51%) patients (p = 0.0417). The presence of MMRD was the strongest predictor of post-transplant outcomes for the whole cohort with 2-year OS and LFS of 29.4% and 37.1% (HR 5.45 [95%CI 2.43-12.3] p = 0.0001; HR 12.4 [95%CI: 3.76 to 39.8] p = 0.0001); respectively. Subgroup analysis confirmed that MMRD was associated with significantly inferior LFS for IM/favorable and adverse risk patients (HR: 6.76 [95% CI 1.12 to 40.9], p = 0.038). Conclusions: Pre-transplant MMRD was the most important prognostic factor for relapse and survival in our cohort of AML patients undergoing alloSCT. Correlation of MMRD with other transplant variables such as conditioning intensity, MRD status by MFC and the impact of pre-emptive/therapeutic strategies in high-risk patients continues to be explored.

Intensive minimal residual disease monitoring to drive early intervention after allogeneic hematopoietic stem cell transplant for pediatric acute leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18531-e18531
Author(s):  
Thomas Pincez ◽  
Raoul Santiago ◽  
Henrique Bittencourt ◽  
Isabelle Louis ◽  
Pierre Teira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Minimal Residual Disease ◽  
Therapeutic Intervention ◽  
Residual Disease ◽  
Cell Transplant ◽  
Rt Pcr ◽  
The Impact ◽  
Minimal Residual

e18531 Background: Relapse of acute leukemia (AL) remains the main cause of death after allogeneic stem cell transplantation (HSCT) in children. Minimal residual disease (MRD) allows to detect leukemia cells in the bone marrow at low level. The impact of post-HSCT MRD monitoring to detect early leukemia recurrence, to guide therapeutic intervention, and to prevent overt relapse is unknown. We report our experience of systematic MRD monitoring after pediatric HSCT. Methods: All patients who underwent HSCT from January 2012 to December 2017 for an AL had bone marrow MRD performed for 2 years (months 1, 2, 3, 5, 7, 9, 12, 15, 18, 21 and 24). MRD was assessed by flow-cytometry (FC) and, when a molecular alteration was present, by nested RT-PCR. Results: Seventy-one HSCT were performed for AL of myeloid (n=38), lymphoid (n=31) or mixed (n=2) lineage in 59 patients at a median (range) age of 6.5 (0.7-18.4) years. Nine cases did not engraft or had a refractory disease at month+1 evaluation. In all other cases (n=62) MRD was monitored using FC (n=58) and/or RT-PCR (n=34). Thirty-three cases had a MRD detection and/or an overt relapse (≥5% blasts). In 23/33 cases (70%), MRD was detected without simultaneous overt relapse. In the 10 others, an overt relapse occurred without prior MRD detection. Among the cases monitored with RT-PCR, only one relapse occurred without a prior MRD detection. The follow-up protocol was not respected in this particular case. On early MRD detection, 20/23 cases underwent therapeutic intervention, the most frequent being the discontinuation of immunosuppressive drugs (n=13), with subsequent undetectable MRD in 6. Other interventions included chemotherapy (n=8), donor lymphocyte infusion (n=6) and/or interferon ± interleukine 2 (n=3), leading to an undetectable MRD in 3 cases. Overall after first MRD detection, 9/23 (39%) cases never experienced a subsequent overt relapse. Conclusions: Intensified MRD monitoring detected 70% of leukemia recurrences before overt relapse. Therapeutic intervention were taken in most of the cases and 39% never experienced overt leukemia relapse. More efficient immunotherapies may improve the impact of preemptive interventions.

scholarly journals Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2909-2909
Author(s):  
Guldane Cengiz Seval ◽  
Klara Dalva ◽  
Dilek Oz ◽  
Sule Mine Bakanay ◽  
Ender Soydan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Post Induction ◽  
Sensitivity Level ◽  
Stem Cell Graft ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics. Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD. Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p&lt;0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2). Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. Figure 1 Figure 1. Disclosures Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.

Autologous Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Achieves Outcomes Similar to Allogeneic Transplantation - Results of CALGB 10001 (Alliance)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 816-816 ◽  
Author(s):  
Meir Wetzler ◽  
Dorothy Watson ◽  
Wendy Stock ◽  
Kouros Owzar ◽  
Gregory Koval ◽  
...  
Keyword(s):  
Stem Cell ◽  
Minimal Residual Disease ◽  
Stem Cell Transplant ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Molecular Response ◽  
Cell Transplant ◽  
Major Molecular Response ◽  
Disease Free ◽  
Minimal Residual

Abstract Abstract 816 We hypothesized that imatinib plus sequential chemotherapy would result in significant leukemia cell cytoreduction (molecular remission) in patients with Ph+ acute lymphoblastic leukemia (ALL), allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL+ lymphoblasts and thus reduce the likelihood of relapse after autologous (auto) stem cell transplant (SCT) for patients <60 years old without sibling donors. Cancer and Leukemia Group B (CALGB) study 10001 enrolled 58 patients who received 3–4 courses of imatinib (400 mg twice daily) plus sequential chemotherapy followed either by total body irradiation (TBI, 1320 cGy)/etoposide (60 mg/kg) and an allogeneic (allo) SCT from a matched sibling donor or by TBI/etoposide/cyclophosphamide (100 mg/kg) and auto-SCT. Fifteen had an allo-SCT on study using their matched sibling donor; others were transplanted off study using unrelated donors or received alternative therapy. Nineteen have undergone auto-SCT. Imatinib plus chemotherapy resulted in reverse-transcriptase polymerase chain reaction (RT-PCR) negative stem cells (complete molecular response, CMR) in 9 of the 19 patients; 4 remained minimally positive (major molecular response, MMR; <0.001) and 6 were not evaluable. RT-PCR status of the stem cell products had no effect on overall survival (OS) or disease-free survival (DFS) after auto-SCT (CMR vs. MMR P=0.77 for DFS and P=0.50 for OS). We studied the effect of minimal residual disease (MRD) detection on outcome following auto-SCT. At day +120 post auto-SCT, DFS and OS were longer in patients who achieved at least a MMR (n=8) than patients who did not have a MMR (n=6) at that time point (P=0.045 and P=0.011; Panels A and B). After allo-SCT, 7 of 10 patients who survived >120 days had CMR; 2 additional patients achieved MMR, and 1 patient had residual MRD >0.001 (less than MMR); however, the sample size was too small to analyze the effect of MRD on outcome. After a median follow up time of 5.1 years, 9 (47%) of 19 auto-SCT patients and 7 of 15 (47%) of the allo-SCT patients remain alive in continuous CR. Ten of the transplanted patients have relapsed (8 following auto-SCT and 2 following allo-SCT); relapses occurred at a median of 5.9 months following auto-SCT. The DFS (median, 5.5 vs 4.1 years; P=0.84) and OS (median, 6.0 years vs. not reached at >6 years; P=0.90) were similar between those who underwent auto- or allo-SCT (Panels C and D). We conclude that patients who have MRD at levels lower than or equal to MMR following auto-SCT have prolonged survival and that auto-SCT represents a safe and effective alternative to allo-SCT for Ph+ ALL patients without sibling donors. The intergroup trial CALGB 10701 (Alliance) is now testing this strategy in Ph+ ALL patients >50 year old, using dasatinib as the BCR/ABL inhibitor. Figure: Disease-free (A, C) and overall (B, D) survival, stratified by minimal residual disease (MRD) at Day +120 and by transplant type. (A, B) MRD ≤0.001 (major molecular response) vs. >0.001 at day +120 for patients undergoing autologous-stem cell transplant (SCT); (C, D) allogeneic (allo) vs. autologous (auto) SCT. Figure:. Disease-free (A, C) and overall (B, D) survival, stratified by minimal residual disease (MRD) at Day +120 and by transplant type. (A, B) MRD ≤0.001 (major molecular response) vs. >0.001 at day +120 for patients undergoing autologous-stem cell transplant (SCT); (C, D) allogeneic (allo) vs. autologous (auto) SCT. Disclosures: Wetzler: BMS: Research Funding; Novartis: Research Funding. Off Label Use: Dasatinib is off label but in a clinical trial. 615A Oral Session 1 (3 abstracts) Acute promyelocytic leukemia 622A Oral Session 1 (3 abstracts) Autologous and Allogeneic Transplantatin CLL - Biology and Pathophysiology, excluding Therapy: Cell Signaling Leukemias - Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Chronic Lymphoid and Myeloid Leukemias 111. Hemoglobinopathies, excluding Thalassemia IV

Incidence and Kinetics Of Full Donor Chimerism and The Impact Of Minimal Residual Disease Status Following Outpatient Non-Myeloablative Allogeneic Stem Cell Transplantation For Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2129-2129
Author(s):  
Philip Campbell ◽  
Tongted Das ◽  
David Kipp ◽  
Patricia A. Walker ◽  
Jenny Muirhead ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Entire Cohort ◽  
High Risk Disease ◽  
The Impact ◽  
Kinetics Of ◽  
Minimal Residual

Abstract Background Chimerism analysis is routinely performed following allogeneic haemopoietic stem cell transplantation (allo HSCT) as a means of monitoring donor engraftment and relapse risk, although its role in the management of allografted myeloma patients is controversial. Multiparameter flow cytometry (MFC) assessment of minimal residual disease has been demonstrated to predict outcome following myeloblative autologous stem cell transplantation (ASCT) in multiple myeloma (MM). Relapse and disease progression is the principle cause of allograft failure and the detection of minimal residual disease (MRD) following tandem autologous/non-myeloablative(NMA) allo HSCT may potentially identify patients at risk of early relapse and provide a platform for early post-allograft therapy designed to further cytoreduce or enhance alloreactive T cell function and graft versus myeloma effect. Aim To evaluate the impact of MRD assessment performed at 3 months post-allo HSCT on PFS and OS and document the incidence and kinetics of full donor chimerism (FDC) in a cohort of myeloma patients undergoing tandem ASCT/outpatient non-myeloablative (NMA) allogeneic HSCT for MM. Methods Retrospective analysis of 33 MM patients referred to our centre for tandem ASCT/outpatient NMA HSCT between May 2008 and December 2012. Patients were transplanted as part of their front line management (upfront) (n=18) if they had one or more high risk disease features (poor prognosis cytogenetics/FISH abnormalities, elevated LDH, stage III disease or less than a PR following a novel agent-containing induction regimen) or as a ‘deferred’ procedure (n=15), if relapsing/progressing after an initial ASCT and maintenance/consolidation. Allo HSCT was undertaken as an ambulatory procedure and conditioned with oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0 followed by donor stem cell infusion, with a target CD34 dose of 2 x 106/kg and T cell dose of 3 x 108/kg. Sequential peripheral blood monitoring of CD3+ and CD33+ donor-specific chimerism was performed on days 30, 60, 90, 180 and 365 following allo HSCT. Bone marrow samples were collected for MRD analysis using MFC incorporating a CD56/CD19/CD45 panel following CD38/CD138 gating on plasma cells. MRD assessment was performed every 3 months during the first 12 months, 6 monthly during the second year and annually thereafter. Results The median age for the entire cohort (M 19, F 14) was 52 years (range 39-65) and the analysis performed after a median follow up of 719 days (50-1733). All patients were transplanted using matched sibling (20/33) or unrelated donors (13/33). Non-relapse mortality was 0% at 1 year and 6% overall. At the time of analysis, 26 (79%) patients were alive including 15 (45%) in CR. The median PFS for all patients was 2.8 years and although the median OS for the entire cohort has not been reached, the estimated probability of overall survival at 4 years is 67% (95% CI: 38-85%). 29/33 (88%) patients had MRD assessments performed at least once post-allo HSCT and 4 patients progressed within 3 months prior to MRD evaluation. At the first 3 month assessment, 11/29 (38%) were MRD +, 12/29 (41%) were MRD – , results were unavailable in 3/29 (10.5%) and 3 (10.5%) patients had morphological evidence of disease. Patients achieving MRD negativity at 3 months had superior PFS in comparison to those who remained MRD positive (median 2.81 years v 1.02 years; p=0.01) but this has yet to translate into an OS advantage. The MRD + patients transplanted as a deferred procedure (n=6) had a median PFS of less than 6 months (0.47 years), suggesting this subset of patients have a particularly poor outcome, although overall numbers are insufficient to directly compare outcome according to MRD status and transplant timing. 30 (91%) patients achieved FDC (16 and 14 in the upfront and deferred groups respectively) with 2 patients not assessed. The median time to FDC for the entire cohort was 180 days (range 30-730) and there was no significant difference according to transplant timing or relationship between FDC and MRD status, GVHD, PFS or PS. Conclusion The majority of patients undergoing outpatient-based tandem ASCT/NMA allo HSCT for myeloma achieve FDC. MRD status as assessed by MFC at 3 months post-allo HSCT appears to predict PFS and may be a useful early trigger for additional post-allograft therapy, particularly in patients with high risk disease or those transplanted later in their disease course. Disclosures: Spencer: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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