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We report here the largest study to date of adult AML patients tested for measurable residual disease (MRD) at the time of autologous hematopoietic cell transplantation (auto-HCT). Seventy-two adult patients transplanted between 2004-2013 at a single academic medical center (UCSF) were eligible for this retrospective study based on availability of...
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... The higher overall efficacy of the patients in our study may be related to the following factors: (1) all patients in the study were at CR1 except 2 AML-M3 patients at CR2, and all patients had negative MRD before transplantation, and 17 AML patients with non-APL had negative MRD after 1 or 2 course of consolidation therapy; Both MRD status before auto-HSCT and MRD status after 1 course of consolidation therapy were independent prognostic factors affecting OS and LFS after auto-HSCT Frontiers in Pharmacology frontiersin.org (Mulé et al., 2016;Yao et al., 2017;Buccisano et al., 2019;Percival and Estey, 2019); (2) compared with FLU, the addition of CLAD to the conditioning regimen enhanced the anti-leukemia effect of conditioning; ...
This is a small phase I study examining the safety and efficacy of a cladribine (CLAD)-containing conditioning regimen prior to autologous hematopoietic stem cell transplantion (auto-HSCT) for patients with acute myeloid leukemia (AML). All patients, aged 15–54 years (median 32 years), had favorable/intermediate risk AML (n = 20) or acute promyelocytic leukemia (APL; n = 2) and no evidence of minimal residual disease (MRD) prior to transplantation. Fourteen of the 22 patients received the conditioning regimen as follows: busulfan (Bu) + cyclophosphamide (Cy) + CLAD + cytarabine (Ara-c) or idarubicin. The conditioning regimen of 8 patients was without Cy nor idarubicin to reducing adverse cardiac reaction: the regimen of Bu + CLAD+ Ara-c for 6 patients; and the regimen of Bu + melphalan + CLAD + Ara-c for the other 2 patients. All 22 AML patients received peripheral blood stem cell transplantation. The number of infused mononuclear cells and CD34+ cells was 10.00 (2.88–20.97) × 108/kg and 1.89 (1.52–10.44) × 106/kg, respectively. Hematopoietic reconstitution was achieved in all patients, with a median time of 13 (10–34) days for neutrophils and 28 (14–113) days for platelets. Two patients suffered from pulmonary infection, 4 patients suffered from septicemia during the neutropenic stage, and the others suffered from infection or gastrointestinal reaction without exceeding grade 3 after conditioning, which were all alleviated by anti-infection and other supportive treatment. None of the patients died of transplantation-related complications. At a median follow-up of 29.5 (ranging from 4.0 to 60.0) months, three patients relapsed after auto-HSCT at a median time of 6 (ranging from 0.5 to 10.0) months. One patient died due to relapse at 18 months after auto-HSCT. The remaining 21 patients were all alive, including 19 patients with negative MRD. The other 2 patients achieved negative MRD after allogeneic HSCT or chemotherapy. The estimated 2-year survival, relapse, and Leukemia-free survival rates were 94.1 ± 5.7%, 14.7 ± 7.9% and 85.3 ± 7.9%, respectively. A CLAD-combination conditioning regimen is efficient and safe for auto-HSCT, indicating an effective approach for AML treatment.
... There are also a few studies analyzing WT1 expression in peripheral blood stem cell (PBSC) harvest, in patients eligible for autologous stem cell transplantation (Auto-SCT), to detect PBSC contamination with leukemic cells [50,51]. ...
... However, in another study including 72 AML patients, Mulé et al. did not observe differences in RFS between patients who received WT1-positive PBSC grafts and those who received WT1-negative PBSC grafts (using both the 80 and 50 WT1 copies/10 4 ABL as cut-off values) [51]. The authors also reported that the administration of G-CSF could falsely enhance WT1 expression in PBSC even from healthy donors, a result in contrast to what was previously reported by Cilloni et al. and by Messina et al. [4,50,51]. ...
... However, in another study including 72 AML patients, Mulé et al. did not observe differences in RFS between patients who received WT1-positive PBSC grafts and those who received WT1-negative PBSC grafts (using both the 80 and 50 WT1 copies/10 4 ABL as cut-off values) [51]. The authors also reported that the administration of G-CSF could falsely enhance WT1 expression in PBSC even from healthy donors, a result in contrast to what was previously reported by Cilloni et al. and by Messina et al. [4,50,51]. ...
The Minimal Residual Disease(MRD) monitoring in acute myeloid leukemia (AML) is crucial to guide treatment after morphologic complete remission, to define the need for consolidation with allogeneic stem cell transplantation (Allo-SCT), and to detect impending relapse allowing early intervention. However, more than 50% of patients with AML lack a specific or measurable molecular marker to monitor MRD. We reviewed the key studies on WT1 overexpression as a marker of MRD in AML patients undergoing an intensive chemotherapy program, including Allo-SCT. In addition, we provided some practical considerations on how to properly use WT1 expression as an MRD marker, considering its strengths and weaknesses. In order to achieve the best sensitivity and specificity, it is recommended to refer to the standardized method of European LeukemiaNet and its defined threshold (250 WT1 copies/104 Abelson (ABL) on Bone Marrow-BM and 50 WT1 copies/104 ABL on Peripheral Blood-PB), which has been validated in a large and multicenter cohort of patients and normal controls.
... The ability to accurately monitor disease burden during therapy, commonly referred to as minimal/measurable residual disease (MRD), is fundamentally important in CML as well as other leukemias (ALL, AML, MPN, APL) and transplant monitoring [46][47][48][49][50]. Additionally, MRD monitoring by liquid biopsy is actively being investigated for solid tumors (NSCLC, CRC, Breast, Melanoma) [51][52][53][54][55]. Indeed academic, regulatory, and pharmaceutical interests are aligning to use accurate and sensitive disease monitoring as early measures of drug efficacy. ...
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy that accounts for 15–20% of all cases of leukemia. CML is caused by a translocation between chromosomes 9 and 22 which creates an abnormal fusion gene, BCR :: ABL1 . The amount of BCR :: ABL1 transcript RNA is a marker of disease progression and the effectiveness of tyrosine kinase inhibitor (TKI) treatment. This study determined the analytical and clinical performance of a droplet digital PCR based assay (QXDx BCR-ABL %IS Kit; Bio-Rad) for BCR :: ABL1 quantification. The test has a limit of detection of MR4.7 (0.002%) and a linear range of MR0.3–4.7 (50–0.002%IS). Reproducibility of results across multiple sites, days, instruments, and users was evaluated using panels made from BCR :: ABL1 positive patient samples. Clinical performance of the assay was evaluated on patient samples and compared to an existing FDA-cleared test. The reproducibility study noted negligible contributions to variance from site, instrument, day, and user for samples spanning from MR 0.7–4.2. The assay demonstrated excellent clinical correlation with the comparator test using a Deming regression with a Pearson R of 0.99, slope of 1.037 and intercept of 0.1084. This data establishes that the QXDx ™ BCR-ABL %IS Kit is an accurate, precise, and sensitive system for the diagnosis and monitoring of CML.
... This is also true for patients after HDCT/autologous HCT, with relapse rates up to 50% [12]. MRD testing is increasingly performed in patients with a higher risk of post-autologous HCT relapse, e.g., due to MRD positivity following induction therapy [13,14], and has triggered the interest in maintenance strategies post-transplant. Hypomethylating agents or (in case of the respective mutation) FLT3 inhibitors have demonstrated promising results for patients with an increased relapse risk after allogeneic HCT [15][16][17][18], whereas these options still await exploration in patients after autologous HCT. ...
Autologous hematopoietic cell transplantation (HCT) is suitable for consolidation of favorable-/intermediate-risk AML patients in CR1. However, ~50% of AML patients relapse after autologous HCT, and efficacy of subsequent salvage strategies including allogeneic HCT remains unclear. We studied 123 consecutive patients with newly diagnosed AML undergoing high-dose chemotherapy (HDCT)/autologous HCT in CR1. In relapsing patients afterwards, we analyzed salvage treatments and outcomes focusing particularly on salvage allogeneic HCT. Of 123 patients, 64 (52%) relapsed after autologous HCT. Subsequently, 13 (21%) received palliative therapy, whereas 51 (79%) proceeded to salvage therapy with a curative intent. Of the 47 patients with a curative intent and who did not proceed directly to allogeneic HCT, 23 (49%) achieved CR2 or had ongoing hematologic CR1 despite molecular relapse. Finally, 30 patients (47%) received allogeneic HCT with estimated 3-year leukemia-free and overall survival rates of 33% and 43%. Hematologic remission at allogeneic HCT and lack of acute GvHD had a positive impact on OS and LFS (p < 0.05). Our study suggests that almost 80% of AML patients can undergo salvage therapy following relapse after front-line HDCT/autologous HCT. Allogeneic HCT can provide cure in one third of patients relapsing after front-line HDCT/autologous HCT.
... Therefore, only selected patients with chemosensitive disease can take advantage of ASCT. Among these, patients Core-Binding-Factor (CBF) AML and AML with a NMP1 mutation in absence of an FLT3 one are the ideal candidates to receive ASCT [32][33][34]. Notwithstanding, even in this setting, the role of ASCT remains unclear, although most studies that have compared ASCT with intensive consolidation chemotherapy (ICC) demonstrated a significantly lower rate of relapse following ASCT [17][18][19][20][21][22]. However, results in terms of survival were less encouraging because of transplant-related deaths and the low rate of second CR in patients who relapsed after ASCT; therefore, in the last year, ASCT has become less popular both in Europe and the USA. ...
After intensive induction chemotherapy and complete remission achievement, patients with acute myeloid leukemia (AML) are candidates to receive either high-dose cytarabine-based regimens, or autologous (ASCT) or allogeneic (allo-SCT) hematopoietic stem cell transplantations as consolidation treatment. Pretreatment risk classification represents a determinant key of type and intensity of post-remission therapy. Current evidence indicates that allo-SCT represents the treatment of choice for high and intermediate risk patients if clinically eligible, and its use is favored by increasing availability of unrelated or haploidentical donors. On the contrary, the adoption of ASCT is progressively declining, although numerous studies indicate that in favorable risk AML the relapse rate is lower after ASCT than chemotherapy. In addition, the burden of supportive therapy and hospitalization favors ASCT. In this review, we summarize current indications (if any) to ASCT on the basis of molecular genetics at diagnosis and minimal residual disease evaluation after induction/consolidation phase. Finally, we critically discuss the role of ASCT in older patients with AML and acute promyelocytic leukemia.
... Autologous transplantation can potentially allow a selected group of patients, especially with low and potentially intermediate genetic risk, to avoid over-treatment with allogeneic transplantation, providing 50-60% probability of long-term LFS [74]. The recently published excellent outcomes of autologous transplantation in MRD negative patients with low or intermediate genetic risk [75][76][77][78] prompt re-evaluating the role of autologous transplantation in AML. In this regard, a group from China compared retrospectively autologous to allogeneic HSCT in AML patients with favorable or intermediate genetic risk [76]. ...
... Two other groups studied the significance of residual leukemic cells detected in cryopreserved autografts. In a retrospective analysis of AML patients who underwent autologous HSCT at University of California, MRD assessed by RQ-PCR for a multigene panel in cryopreserved autograft appeared to be highly predictive for relapse in patients with known chromosomal abnormalities or mutations, including WT1, mutated NPM1, t(8;21), inv (16), and t(15;17) [77]. In the first year after autologous HSCT, there were no relapses in MRD-negative patients compared to 83% relapse incidence in MRD-positive patients. ...
The significance of measurable residual disease (MRD) in hematopoietic stem cell transplantation (HSCT) is well recognized in different hematological malignancies, but the evidence indicate that pre-transplant MRD status is of particular importance in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In ALL, inadequate response at the level of MRD is a commonly accepted risk factor for relapse and thus an indication for allogeneic HSCT. Similarly, growing evidence from the literature strongly suggest that MRD detected by multiparameter flow cytometry or molecular techniques should be also used for risk stratification in AML at the time of HSCT. Despite the well-defined association of MRD and outcomes of HSCT in acute leukemias, there are still many open issues such as the role of additional pre-transplant consolidation for MRD eradication, the ability of HSCT to overcome negative influence of MRD positivity on survival, the impact of conditioning regimen intensity on MRD clearance post HSCT, and transplantation outcomes or the selection of optimal donor with regards to MRD status. In addition, the role of MRD assessment in guiding post-transplant maintenance treatment should also be addressed in prospective trials. These open issues mostly awaiting further clinical studies will be discussed in our current review.
... In this light, the integration of cytogenetic and molecular profiles can further refine the risk stratification of patients undergoing autologous HCT, making it an issue for ongoing research. It is also worth noting that MRD status before autologous HCT has been shown to have predictive value for post-transplant outcomes [43,44], and thus warrants further investigation. While acknowledging its potential limitations, we consider its focus on AML in adults consecutively registered over a 25-year period to represent the unique strength of this kind of study. ...
Autologous hematopoietic cell transplantation (HCT) has not gained universal popularity in the treatment of acute myeloid leukemia (AML), and its status remains unclear. To determine the implementation status and outcomes of autologous HCT for adults with AML in Japan, we analyzed data from 1,174 patients (including 446 with acute promyelocytic leukemia [APL]) who underwent autologous HCT between 1992 and 2016 consecutively reported to the Japanese nationwide transplantation registry. The annual number of transplantations peaked at 82 cases in 1997, and has recently remained at around 40 cases. The percentage of APL has increased sharply since 2004, and currently exceeds 70%. While most non-APL patients underwent autologous HCT during first complete remission (CR), transplantation during second CR has become mainstream for APL patients since the early 2000s. The 5-year survival, relapse, and non-relapse mortality rates were 55.3%, 42.1%, and 8.6% for non-APL patients, and 87.6%, 12.9%, and 3.4% for APL patients, respectively. Patients transplanted in the later period showed better survival than those transplanted in the earlier period, both for non-APL (P < 0.001) and APL (P = 0.036). These results clearly show the various changes in transplantation practice and post-transplant outcomes in Japan over the past 25 years.
... 32,33 Similarly, the quality of CR1 seems to affect autoHCT outcomes. 10,23,34,35 It is therefore conceivable that as our ability to detect and monitor measurable residual disease (MRD) in AML gets refined and standardized, MRD status after induction could guide the selection of the optimal consolidation strategy, with autoHCT reserved as a valuable option for patients with MRDnegative remission, ideally as part of a well designed clinical trial. ...
Introduction
In the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non-high-risk acute myeloid leukemia (AML) when allogeneic HCT (alloHCT) is unfeasible, which is common in racial minorities due to donor registry underrepresentation and socioeconomic challenges. We compared autoHCT consolidation outcomes to chemotherapy alone in a minority-rich cohort in the Bronx.
Materials and Methods
We identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 cases consolidated with ≥2 cycles of chemotherapy, of which 28 received autoHCT.
Results
The cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS) (43 vs. 11 months, p=0.003) and overall survival (OS) (not reached vs. 36 months, p=0.043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (HR 0.53, 95% confidence interval [CI] 0.37 – 0.75, p<0.001) and OS (HR 0.61, 95% CI 0.40 – 0.95, p=0.027).
Conclusion
In this inner-city non-high risk AML cohort, autoHCT provided OS and RFS benefit compared to chemotherapy alone. AutoHCT may constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, while integration of measurable residual disease can help select patients more likely to benefit.
... [53], consistent with the results published by Yoon et al [21]. In addition, Mule et al [54] reported that individualized MRD parameters, combined with WT1 and other non-leukemia-specific genes, such as PRAME and MSLN, can predict prognosis after ASCT in patients with AML with high sensitivity. They monitored MRD in peripheral blood autografts pre-ASCT in a subset of patients with AML and found that WT1 alone had limited predictive value for the RR, whereas multiparameter MRD [considering inv (16), t(8;21), NPM1 mutation, WT1, PRAME, and MSLN] was more sensitive for predicting leukemia recurrence, showing 52% sensitivity and 83% specificity for predicting early relapse in patients with AML who underwent ASCT. ...
The clinical outcomes of autologous hematopoietic stem cell transplantation (ASCT) in acute myelogenous leukemia (AML) have improved over time. Indeed, numerous studies have demonstrated that ASCT is associated with a lower relapse rate and acceptable nonrelapse mortality compared with chemotherapy alone in patients with AML. In addition, ASCT is also associated with comparable overall survival outcomes to those of allogeneic hematopoietic stem cell transplantation in some patients with AML. To date, age, cytogenetic and molecular risk stratification, and minimal residual disease (MRD) status have been shown to be closely related to clinical outcomes following ASCT. ASCT is recommended for patients with favorable-risk and intermediate-risk AML in first complete remission and patients with acute promyelocytic leukemia in second complete remission for whom a matched sibling donor is not available. MRD status pre-ASCT is the most important factor to consider when determining whether a patient is eligible for ASCT and can effectively predict clinical outcomes after ASCT. Advanced age is not an absolute contradiction for ASCT. In this review, we describe the literature and clinical trials evaluating the outcomes of ASCT in patients with AML and discuss the indications for ASCT therapy. Because the greatest concern in ASCT recipients is early relapse, important factors that should be monitored before ASCT and future perspectives in this area are also presented.
... In young adults and children, the relapse risk increases from around 15-25% in MRD-negative patients to about 40-60% in MRD-positive patients (19,20,23). For older patients, the relapse risk for MRD-positive patients may be even higher, approaching 80% or more (18,78,(80)(81)(82)(83). In multivariate analyses, MRD has consistently been shown to be an independent predictor of relapse (18-20, 22, 23, 78, 84). ...
This review summarizes – with the practicing hematologist in mind – the methods used to determine measurable residual disease (MRD) in everyday practice with some future perspectives, and the current knowledge about the prognostic impact of MRD on outcome in acute myeloid leukemia (AML), excluding acute promyelocytic leukemia. Possible implications for choice of MRD method, timing of MRD monitoring, and guidance of therapy are discussed in general and in some detail for certain types of leukemia with specific molecular markers to monitor, including core binding factor (CBF)‐leukemias and NPM1‐mutated leukemias.
