Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1 ‐mRNA expression in patients with AML and MDS

Abstract Introduction Allogenic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) is a curative option in patients with intermediate/high risk disease who achieve morphologic complete remission (CR) after induction chemotherapy. Patients in CR but with positive measurable residual disease (pMRD) prior to HCT had high relapse risk(RR) (67% vs 65%) and low 3 year overall survival (OS) (26% vs 23%),similar to those with active disease in a single institution study (Araki et.al; Volume 34, Feb 1,2016, JCO). However, this study included only patients who received myeloablative conditioning (MAC) and included both peripheral blood and marrow grafts. A single institution retrospective study showed that use of MAC compared to reduced intensity conditioning (RIC) improved 3 year RR(19% v 67%; P < .001) and OS( 61% v 43%; P = .02) in patients with pMRD/CR(determined by molecular analysis of limited gene mutational panel)(Hourigan et.al. Volume 38, April 20,2020, JCO). We analyzed a cohort of AML patients that underwent either MAC or RIC followed by peripheral blood stem cell grafts and post-transplant cyclophosphamide (PTCy) based GVHD prevention regimen at our institution to determine the effect of pMRD on transplant outcomes. Methods: To evaluate the impact of pMRD on transplant outcomes, we analyzed AML patients who underwent HCT at Levine Cancer Institute between June 2014 and April 2020 with MRD testing performed within 1 month prior to HCT. MRD testing was performed at University of Washington by using multiparametric flow cytometry (MPC). The overall sensitivity of the assay is conservatively estimated as 0.1%. In our institution, all patients received MAC (Bu/Flu) or RIC (Bu/Flu or Flu/Cy/TBI) regimens followed by peripheral blood stem cell grafts and identical PTCy-based GVHD prophylaxis regimens that included tacrolimus and mycophenolate. Patient and transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Fisher's exact test for categorical variables and nonparametric Mann-Whitney U test for continuous variables. Relapse-free survival (RFS) and OS were estimated using the Kaplan Meier method. All statistical tests were two sided, and a P-value < 0.05 was considered statistically significant. Results From June 2014 to April 2020, 105 patients with AML underwent HCT. Eighty-three patients with MRD results were included in the final analysis - 52 (63%) with negative MRD (nMRD)/CR, 16 (19%) with pMRD/ CR and 15 (18%) with active disease (no CR). Baseline characteristics were similar except for presence of significantly greater number of high risk patients, based on ASTCT disease classification in the active disease group compared to pMRD/CR and nMRD/CR cohorts( 87% vs 19% vs 0%, P =< 0.001). Median follow up for the entire cohort was 32.7 months. RFS was superior in patients with nMRD/ CR compared to pMRD/ CR or active disease (56.4% vs 19.4% vs 35%, P= 0.005). In addition, OS was superior in nMRD/ CR compared to pMRD/CR or active disease (56.7% vs 35.2% vs 40%, P= 0.014). The use of MAC compared to RIC did not improve RFS (0% vs 32%, P= 0.018) and OS (0% vs 44%, P= 0.071) in pMRD/CR cohort. The use of MAC or RIC did not significantly impact RFS (69% vs 52%, P=0.729) or OS (61% vs 53%, P=0.739) in nMRD/CR patients. Conclusion: Our study validates the previous data that prognosis of patients with pMRD/CR (determined by MPC) prior to HCT is not significantly better than those having active disease. The outcomes were poor regardless of conditioning regimen intensity and PTCy based GVHD prophylaxis used at our institution. These patients might benefit from additional chemotherapy or targeted treatments to achieve nMRD prior to HCT and/or maintenance therapy post HCT. Patients with nMRD/CR disease had similar outcomes with MAC or RIC. This finding suggests that less aggressive conditioning regimens incorporating PTCy could be considered in a subset of patients with nMRD/CR, thereby sparing them from complications associated with MAC. Prospective trials are needed to further study these findings. Figure 1 Figure 1. Disclosures Copelan: Amgen: Consultancy. Grunwald: Astellas: Consultancy; Karius: Consultancy; PER: Other; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; PRIME: Other; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Sierra Oncology: Consultancy; Med Learning Group: Other; Cardinal Health: Consultancy; MDEdge: Other; Agios: Consultancy.

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Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia

Bone Marrow Transplantation ◽

10.1038/s41409-021-01453-0 ◽

2021 ◽

Author(s):

V. Rocha ◽

L. J. Arcuri ◽

A. Seber ◽

V. Colturato ◽

V. G. Zecchin ◽

...

Keyword(s):

Stem Cells ◽

Cell Transplantation ◽

Peripheral Blood ◽

Acute Leukaemia ◽

Hematopoietic Cell Transplantation ◽

Residual Disease ◽

Peripheral Blood Stem Cells ◽

Blood Stem Cells ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Measurable Residual Disease

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How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring

Biomedicines ◽

10.3390/biomedicines9080953 ◽

2021 ◽

Vol 9 (8) ◽

pp. 953

Author(s):

Annalisa Talami ◽

Francesca Bettelli ◽

Valeria Pioli ◽

Davide Giusti ◽

Andrea Gilioli ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Disease Onset ◽

Working Party ◽

Fusion Transcript ◽

Prognostic Impact ◽

End Of Treatment ◽

Measurable Residual Disease ◽

Acute Myeloid

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB-MYH11, belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with CBFB-MYH11 AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low-level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize post-remission monitoring and to define effective MRD-based therapeutic strategies.

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Measurable residual disease affects allogeneic hematopoietic cell transplantation in Ph+ ALL during both CR1 and CR2

Blood Advances ◽

10.1182/bloodadvances.2020003536 ◽

2021 ◽

Vol 5 (2) ◽

pp. 584-592

Author(s):

Satoshi Nishiwaki ◽

Yu Akahoshi ◽

Shuichi Mizuta ◽

Akihito Shinohara ◽

Shigeki Hirabayashi ◽

...

Keyword(s):

Risk Factor ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Residual Disease ◽

Survival Rates ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Prognostic Impact ◽

Significant Difference ◽

Measurable Residual Disease

Abstract Although measurable residual disease (MRD) at the time of allogeneic hematopoietic cell transplantation (allo-HCT) has been reported to be an important prognostic factor for Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) during first complete remission (CR1), the prognostic impact of MRD is unclear during second CR (CR2). To clarify the impact of MRD for both CR1 and CR2, we analyzed data from a registry database including 1625 adult patients with Ph+ ALL who underwent first allo-HCT during either CR1 or CR2 between 2002 and 2017. Adjusted overall and leukemia-free survival rates at 4 years were 71% and 64%, respectively, for patients undergoing allo-HCT during CR1 with MRD−, 55% and 43% during CR1 with MRD+, 51% and 49% during CR2 with MRD−, and 38% and 29% during CR2 with MRD+. Although survival rates were significantly better among patients with CR1 MRD− than among patients with CR2 MRD−, no significant difference was observed in survival rate between patients with CR1 MRD+ and CR2 MRD−. Relapse rates after 4 years were 16% in patients with CR1 MRD−, 29% in CR1 MRD+, 21% in patients with CR2 MRD−, and 46% in patients with CR2 MRD+. No significant difference was identified in relapse rate between patients with CR1 MRD− and CR2 MRD−. CR2 MRD− was not a significant risk factor for relapse in multivariate analysis (hazard ratio, 1.26; 95% confidence interval, 0.69-2.29; P = .45 vs CR1 MRD−). MRD at time of allo-HCT was an important risk factor in patients with Ph+ ALL during both CR1 and CR2.

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Prognostic Impact of Peripheral Blood Involvement during Early Time Points of Childhood ALL Treatment.

Blood ◽

10.1182/blood.v112.11.1489.1489 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1489-1489

Author(s):

Jana Volejnikova ◽

Eva Fronkova ◽

Ester Mejstrikova ◽

Katerina Muzikova ◽

Leona Reznickova ◽

...

Keyword(s):

Peripheral Blood ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Receptor Gene ◽

Univariate Analysis ◽

Induction Treatment ◽

Prognostic Impact ◽

Childhood All ◽

Paired Samples ◽

All Treatment

Abstract Minimal residual disease (MRD) testing performed on bone marrow (BM) samples has become a part of the risk group stratification procedure in several of the most progressive acute lymphoblastic leukemia (ALL) treatment protocols. MRD testing of peripheral blood (PB) instead of BM is not routinely performed, although PB sampling could cause less discomfort especially in children. It is well established that the level of MRD in PB and BM correlates well in T-ALL; the data concerning B-cell precursor (BCP)-ALL remain controversial, with most studies lacking sufficient number of samples taken during the early phase of treatment with quantifiable MRD in both compartments. We simultaneously evaluated MRD in BM and PB using immunoglobulin and T-cell receptor gene-based RQ-PCR. 221 paired samples from 47 children with BCP-ALL treated according to the Berlin-Frankfurt-Muenster (BFM) ALL IC-BFM 2002 protocol were taken at diagnosis (dg, n=47), day 8 (d8, n=39), day 15 (d15, n=44), day 33 (d33, n=34), week 12 (w12, n=31) and at the end of maintenance therapy (post-MT, n=26). As in the BM at d15, patients with lower MRD in PB at d15 were more likely to achieve MRD negativity in BM at d33 in the univariate analysis (p=0.01, Mann Whitney). Patients younger than 10 yrs had lower MRD in PB at d8 and at d15 than other patients (p=0.03 and p=0.01, respectively). Unlike in BM, patients with hyperdiploidy had lower MRD in PB at d15 than other patients excluding TEL/AML1 cases (p=0.05). There were no significant associations with diagnostic white blood cell count (WBC), sex, immunophenotype (cALL/prae-B ALL) or presence of TEL/AML1 fusion at any time point. Patients with MRD<1E-04 in PB at d15 had a 5-year relapse-free survival (RFS) of 100% vs. 62.5±9.9% for those with a higher MRD (p=0.0089). No such threshold could be set for dg, d8 and d33 PB MRD level. Low numbers of MRD-positive results at w12 and post-MT samples precluded statistical analysis. In 125 paired samples MRD was detected in both tissues, in 18 pairs in BM only and in 5 pairs in PB only. MRD levels in PB varied greatly and were a mean of 149-fold lower than in BM (range 0.04–8293). We next examined the prognostic impact of BM/PB MRD ratio. Patients having MRD levels in PB similar to those in BM (BM/PB MRD<10) at d8 and d15 were more likely to relapse (d8: RFS 88.1±6.4% vs. 61.5±13.5%, p=0.04; d15: RFS 89.5±5.7% vs. 54.5±15%, p=0.01). No such relationship was observed for dg or d33. In conclusion, our data show that in childhood BCP-ALL, MRD in PB is not simply proportional to the BM level and provides additional prognostic information. A higher relapse rate in patients with PB MRD level similar to that in BM suggests that leukemic blasts with the propensity for massive escape from BM to PB during the induction treatment have a great potential for giving rise to relapse.

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