Prognostic Implication of Early Minimal Residual Disease Evaluation in Patients with Chronic Myelomonocytic Leukemia

doi:10.21203/rs.3.rs-1454975/v1

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Research Article

Prognostic Implication of Early Minimal Residual Disease Evaluation in Patients with Chronic Myelomonocytic Leukemia

https://doi.org/10.21203/rs.3.rs-1454975/v1

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posted 18 Mar, 2022

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Background: This article is performed to assess the significance of minimal residual disease (MRD) after one course of therapy in patients with chronic myelomonocytic leukemia (CMML).

Methods: From January 2010 to January 2022, a total of 158 patients who were newly diagnosed with CMML were enrolled, in which 58/158 (37%) patients were conducted by multiparameter flow cytometry (FCM) assessed MRD analysis after on cycle treatment and were included in this study. MRD was detected by six- to eight- colour FCM.

Result: After one course of therapy, twenty-one (36%) patients achieved MRD<0.01% (MRD1-) and thirty-seven (64%) were MRD>0.01% (MRD1+). The patients in the MRD1+ group had lower platelet counts, higher 𝛽2-microglobulin, ferritin and BM1 myeloblasts (bone marrow myeloblasts after one cycle of therapy) than that of the MRD1- group (P=0.005, P=0.023, P=0.026 and P=0.007, respectively). Furthermore, a greater propotion of patients had JCK2 and SETBP1 mutation in MRD1- patients than in MRD1+ group (both P=0.037). At a median follow up time of 25.8 months (95%CI, 15.01-36.59), those patients who achieved MRD<0.01% after one course of therapy fared better prognosis in terms of both OS (overall survival, 54.9 months vs. 17.5 months; P<0.001) and PFS (progression-free survival, 52.3 months vs 11.9 months; P=0.006) than those of MRD>0.01%, and 2-year OS rate (90% vs. 30%; P<0.001) and 2-year PFS rate (70% vs. 7%; P=0.004) were also higher. MRD1 status could determine the likelihood of progression after hematopoietic stem cell transplantation (HSCT), the 2-year PFS rate (100% vs. 24%, P=0.04) was higher in MRD1+ group than MRD1- group at the post-HSCT assessment. In addition, MRD1 status were independent prognostic factor of both PFS (HR, 3.326 [95%CI, 1.340-8.259]; P=0.01) and OS (HR, 4.614 [95%CI, 1.266-16.812]; P=0.02).

Conclusion: MRD is highly predictive of prognosis, and it may help identify patients at increased risk for progression to further improve the management of patients with CMML. Large-scaled investigations are warranted to validate our conclusions and its potential in clinical practice.

chronic myelomonocytic leukemia

minimal residual disease

hematopoietic stem cell transplantation

prognosis

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that overlaps the features of myelodysplastic syndromes and myeloproliferative neoplasms (MDS/MPN), which carrying an inherent risk for developing blast transformation and the approximated incidence is 15%–30% over 3–5 years.(1, 2) Numerous pretreatment prognostic models are well established so far by bone marrow (BM) blasts, abnormal karyotypes, and genetic mutations, which closely associated with clinical prognosis of patients with newly diagnosed CMML and developing adapted treatment strategy.(3, 4) Response criterias proposed by International Working Group (IWG) in 2015 according to morphologic analysis also provides much disease specific prognostic information and reflects chemotherapy sensitivity of leukemia.(5) However, they are not ideal for capturing responses associated with the myeloproliferative features of the disease, such as increased leukocyte and/or monocyte counts and splenomegaly.(4) The lack of adequate predictors of response has limited the standard hypomethylating agents for CMML.(6) In the context of precision medicine, however, further improvement of predicting response may be accomplished through assessment of measurable residual disease (MRD), which refers to a small subpopulation of neoplastic cells that is incapable to detect by conventional morphology analysis,(7, 8) whereas they remains intratumoral heterogeneity of the primary tumor, allowing them to develop drug-resistance and evolution under continuous drug environment, and then regrow to become the dominant tumor population, (9) subsequently drive disease progression. The persistence of MRD has been showed to be correlated with early relapse and poor survival in several malignant hematologies, including acute leukemia,(10-12) chronic lymphocytic leukemia (CLL),(13) and multiple myeloma (MM)(14, 15) and so on. Moreover, in the latest published European Leukemia Net MRD guidelines, it noted MRD-negative complete remission in acute myeloid leukemia (AML) could serve as a potential surrogate end point in clinical trials.(10) Furthermore, MRD detectable before or after hematopoietic stem cell transplantation (HSCT) is an established, independent indicator of inferior survival.(16) By contrast, little information is currently available concerning MRD profiles in CMML and the relationship between MRD and prognosis has not yet taken a hold.

In the current retrospective analysis, we aimed to examine the significance of MRD1 status so as to evaluate relavant prognosis in CMML patients. It may help improve clinical risk stratification and decision-making in patients with CMML.

Patients

A total of 158 patients who were newly diagnosed with CMML at the First Affiliated Hospital of Zhejiang University from January 2010 to January 2022 were examined, patients were included in this study if they (1) had received a diagnosis of CMML, (2) had received therapy and (3) had a MRD parameter conducted by multiparameter flow cytometry (FCM) after the first course of treatment. Exclusion criteria included the following: (1) lacked of any medical data, (2) left hospital without any therapy, (3) censored after one cycle therapy, (3) lacked of MRD1 data. The diagnosis of CMML was established according to the current WHO criteria by a combination of clinical findings, morphologic evaluation of peripheral blood and bone marrow aspirate samples, and conventional cytogenetic and molecular analysis. The endpoint of last follow-up was January 30, 2022. The study was approved by the institutional Ethics Committee and it was conducted per the ethical principles of the Declaration of Helsinki.

Endpoint and definitions

Measured outcomes were progression-free survival (PFS) and overall survival (OS). Relapse and blast transformation was defined by morphologic evidence in the peripheral blood, marrow, or extramedullary sites. PFS was defined as the date from diagnosis to relapse or blast transformation or death, or censored at the last follow up. OS was defined as the date from dieases newly diagnosed to death due to any cause or censored at the last follow up. BM1 myeloblasts was defined as the percent of myeloblasts in bone marrow after one course therapy. The MRD level of 0.01% was used as a threshold to distinguish MRD- positivity (MRD+) from MRD-negativity (MRD−). MRD1 were defined as MRD by MFC after one course therapy. Those achieved MRD negativity after one cycle therapy were considered MRD1-, likewise, those with MRD positive were considered MRD1+.

MRD assessments

We used six- to eight-colour FCM for bone marrow samples MRD levels assessement after each course of treatment, which is able to identify cluster differentiation 1a (CD1a), CD2, sCD3, cCD3, CD4, CD5, CD7, CD8, CD34, CD45, CD56, CD99, CD117, HLA-DR and terminal deoxynucleotidyl transferase (TdT). MRD positives were defined as the detection at diagnosis of a cluster of >20 cells expressing two or more leukemia-associated immunophenotypic (LAIP) markers. When patients lack LAIP markers expression at diagnosis, MRD was considered as a population of cells where antigen expression of a particular cell line deviates from the normal pattern at a particular stage of maturation compared to normal or regenerated BM. A lower limit of MRD detection was 0.01%. At least 200000 samples were collected for MRD analysis routinely. Homotypic control monoclonal antibodies were applied. Standardized measurements and routine quality control were carried out according to manufacturer recommendations. Samples were collected by a three-laser Navios instrument (Beckman Coulter, Fullerton, CA, USA).

Cytogenetic and molecular analysis

Cytogenetic and molecular analyses were routinely performed at initial diagnosis in the Institute of Hematology in our hospital. Cytogenetic analyses were detected with Giemsa staining and reverse banding techniques and fluorescence in situ hybridization. Molecular markers were performed by polymerase chain reaction and next-generation sequencing.

Statistical analysis

Continuous variables were compared using the Mann-Whitney test and categorical variables were compared using the Chi-square test to compare characteristics among groups. The Kaplan-Meier method and the log-rank test were used in the survival analysis. Correlation between MRD and BM1 myeloblasts was measured using the Spearman’s rank correlation test. Cox's proportional hazard univariate and multivariate regression model was applied for the identification predictors of CMML prognosis. Patients who were lost to follow-up were censored at the last contact date. All tests were 2-sided, with P-value of 0.05 or less was considered to be statistically significant. All the analysis mentioned above were performed using the SPSS (version 26; SPSS, IBM).

Patient baseline characteristics

A total of 58 consecutive patients who conformed to the inclusion criteria were enrolled in this study. Figure 1. Patients baseline clinical characteristics are summarized in Table 1. With median age of 62 years (range: 22–81 years), and male to female ratio is 38:20. The initial treatment protocols included hypermethylation monochemotherapy in 44 cases, hydroxyurea in 2, combination chemotherapy in 10. Thirteen (22%) patients carried with additional cytogenetic abnormalities, four (7%) patients with complex karyotype, two (3%) patients with + 8, and del (13), -Y, -21, -18, t(4, 11), inv(2), del (9) in 1 patient each. Following the CPSS cytogenetic risk groups, forty-six patients (80%) categorized to the low-risk group, six patients (10%) to the intermediate risk group, and six patients (10%) to the high-risk group. Genetic mutation data were available in 49 patients, as shown in Fig. 2. TET2 mutations were the most common (16, 33%) followed by ASXL1 (11, 22%), SRSF2 (9, 18%), DNMT3A (7, 14%), KRAS (6, 12%) and NRAS (6, 12%). After one course of therapy, 21 patients achieved MRD negative (MRD1-) and 37 patients were MRD positive (MRD1+). We then compare the characteristics of patients with MRD1- and MRD1+. Table 1. There were few notable differences in baseline characteristics within each MRD subgroups, like gender, age, baseline BM myeloblasts, hemoglobin, white blood cell count, monocyte count, population distribution of CMML-specific risk classification, cytogenetic risk group, 2016 WHO subtype and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, there was no difference in the chemotherapy schedule before MRD testing. However, the patients in the MRD1 + group had lower platelet counts, higher 𝛽2-microglobulin (𝛽2-MG), ferritin and BM1 myeloblasts than that of the MRD1- group (P = 0.005, P = 0.023, P = 0.026 and P = 0.007, respectively). Furthermore, a greater propotion of patients had JCK2 and SETBP1 mutation in MRD1- patients than in MRD1 + group (both P = 0.037). Figure 2.

Table 1

Patients Baseline Characteristics
Characteristic	Patients (N = 58)	MRD1-(N = 21)	MRD1+(N = 37)	P value
Sex, n (%) Male Female	38 (65.5) 20 (34.5)	13 (61.9) 8 (38.1)	25 (67.6) 12 (32.4)	0.658
Age, years Median, (range) ≤ 60 > 60	62 (22–81) 27 (46.6) 31 (53.4)	64 (30–78) 9 (42.9) 12 (57.1)	61 (22–81) 18 (48.6) 19 (51.4)	0.671
Baseline BM myeloblasts, % Median, (range)	9.25 (1.5–19)	8 (1.5–17.5)	9.5 (3–19)	0.209
WBC, x 10⁹/L Median, (range)	19.4 (1.5-209.8)	18.9 (4.1-209.8)	19.9 (1.5-157.9)	0.929
Hemoglobin, g/L Median, (range)	93 (41–151)	98 (41–151)	78 (43–140)	0.271
Platelets, x 10⁹/L Median, (range)	66 (4-443)	135 (23–443)	56 (4-358)	0.015
Monocyte count, x 109/L Median, (range)	4.37 (0.3–33.5)	3.99 (0.9–33.5)	4.39 (0.3–31.5)	0.837
APTT, s, median, (range)	29.25 (13.7–41.5)	31.1 (13.7–41.5)	28.2 (20.9–39.0)	0.054
𝛽2-MG, mg/L, median, (range)	2070 (579-11931)	1200 (651–4491)	2310 (579-11931)	0.023
Ferritin, ng/ml, median, (range)	524.78 (13.6-10649.7)	348.1 (13.6-1003.3)	663.6 (66.0-10649.7)	0.026
CPSS cytogenetic risk groups, n (%) Low Intermediate High	46 (80) 6 (10) 6 (10)	19 (33) 2 (3) 0	27 (47) 4 (7) 6 (10)	0.156
CMML-specific risk classification: n (%) Low Intermediate1/2 High	5 (9) 50 (86) 3 (5)	1 (2) 20 (34) 0	4 (7) 30 (52) 3 (5)	0.353
2016 WHO subtype, n (%) CMML-0 CMML-1 CMML-2	5 (9) 20 (34) 33 (57)	3 (5) 6 (10) 12 (21)	2 (4) 14 (24) 21 (36)	0.458
Allo-HSCT, n (%) Yes No	14 (24) 44 (76)	6 (10) 15 (26)	8 (14) 29 (50)	0.552
First line of treatment, n (%) Hydroxyurea Mono-HMAs Combined chemotherapy	2 (4) 45 (77) 11 (19)	2 (4) 17 (29) 2 (4)	0 28 (48) 9 (15)	0.106
BM1 myeloblasts, %, Median, (range)	5 (0.5–28)	3 (0.5–20)	6 (1–28)	0.007
WBC white blood cell, APTT activated partial thromboplastin time, 𝛽2-MG 𝛽2-microglobulin, BM bone marrow, HMAs hypomethylating agents.

Overall Treatment Results

During the median follow up time of 25.8 months (95%CI, 15.01–36.59), thirty-three (57%) patients experienced progression, with median PFS of 15.6 months (95%CI, 6.64–24.55), among them 14 patients (24%) developed blast transformation and 10 (17%) patients relapsed, in which 2 undergone blast transformation after relapsed. At last follow up, twenty-five (43%) patients expired, with median OS of 37.9 months (95%CI, 7.69–68.11) and OS rate was 57%. The 1 year OS and PFS rates were 73% and 59%, 2 year OS and PFS rates were 52% and 35%, respectively.

Furthermore, in our entire cohort, 14 patients subsequently undergone allo-HSCT, at a median follow up of 16.3 months (95%CI, 13.19–19.44) after HSCT, 78.6% of them patients remain alive, with a median OS not reached. Two expired because of HSCT related complications in 2.3 months and 2.5 months after HSCT, respectively. One patients undergone blast transformation 6.3 months after HSCT and died of salvage therapy failure. One relapsed 19.1 months thereafter and was still alive. The 2-year PFS and OS after HSCT were 58% and 75%, respectively.

Mrd1 Statu Is Predictive Of Outcome In Patients With Cmml

Among the cohort, twenty-one (36.2%) patients achieved MRD1-, with 8 patients progressed and 4 died during follow up time of 27.67 months (95%CI, 24.68–30.65). Thirty-seven (63.8%) were MRD1+, with 25 patients progressed and 21 died during median follow up time of 18.77 months (95%CI, 14.12–23.41). The MRD1- was associated with improved OS (54.9 months vs. 17.5 months; P < 0.001) and PFS (52.3 months vs 11.9 months; P = 0.006). MRD1- group also had a higher 2-year OS rate (90% vs. 30%; P < 0.001), as well as 2-year PFS rate (70% vs. 7%; P = 0.004). Figure 3.

In MRD1- group, 6 patients undergone allo-HSCT, no patients progression and all of them continue to remain alive, even though 2 patients received allo-HSCT after transformed to acute leukemia. On the contrary, in the MRD1 + group, 8 patients undergone allo-HSCT, all of the death and progression events forementioned happened in this group. The MRD1- had a higher 2-year PFS rate (100% vs. 24%, P = 0.04) than the MRD1 + at the post-HSCT assessment, whereas the 2-year OS rate (100% vs. 58%, P = 0.091) was not significant difference.

The optimal cutoff values of BM1 myeloblasts and ferritin obtained using the ROC curve were 3.5% (sensitivity 83.3%, specificity 46.9%, AUC 0.661, P = 0.041) and 344ng/ml (sensitivity 90%, specificity 51.6%, AUC 0.655, P = 0.064), respectively. In univariate analysis, MRD1+, male and BM1 blast > 3.5% were associated with OS and PFS, ferritin > 344ng/ml was also correlated with shorter OS. Table 2 and Table 3.

Table 2

Univariate analysis and multivariate analysis for overall survival
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Male	2.373 (1.041–5.406)	0.04	2.841 (1.128–7.155)	0.027
MRD1+ Age ≥ 60 years WBC ≥ 10 x10⁹/L Hemoglobin < 100 g/L Platelet count < 100 x10⁹/L	6.780 (1.925–23.881) 0.911 (0.432–2.272) 0.874 (0.326–2.343) 1.910 (0.811–4.498) 1.415 (0.579–3.461)	0.003 0.983 0.789 0.139 0.447	4.614 (1.266–16.812)	0.020
BM1 myeloblasts > 3.5%	3.191 (1.076–9.465)	0.036
Ferritin > 344 ng/ml	6.754 (1.559–29.252)	0.011	5.997 (1.351–26.613)	0.018

Table 3

Univariate analysis and multivariate analysis for progression-free survival
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Male	2.116 (1.043–4.296)	0.038	2.079 (1.021–4.233)	0.044
MRD1+ Age ≥ 60 years WBC ≥ 10 x10⁹/L Hemoglobin < 100 g/L Platelet count < 100 x10⁹/L	3.343 (1.358–8.230) 1.126 (0.561–2.261) 0.919 (0.397–2.126) 1.417 (0.690–2.912) 1.194 (0.571–2.495)	0.009 0.739 0.843 0.343 0.638	3.326 (1.340–8.259)	0.010
BM1 myeloblasts > 3.5%	2.406 (1.023–5.659)	0.044
Ferritin > 344 ng/ml	2.088 (0.887–4.915)	0.092

. By Spearman’s rank correlation test, there was a strong correlation between BM1 myeloblasts and MRD1 statu (r = 0.365, P = 0.007). Therefore, only MRD1 status incorporated into a multivariate analysis with other clinical features. In multivariate analysis, MRD1 + remained independent prognostic factor of both PFS (HR, 3.326 [95%CI, 1.340–8.259]; P = 0.01) and OS (HR, 4.614 [95%CI, 1.266–16.812]; P = 0.020). Table 2 and Table 3.

The results from this present study showed MRD1 positivity was an independent prognostic factor for progression and survival in patients with CMML, and MRD1 status was associated with clinical outcome after HSCT, such as PFS. Our findings added novel evidence for predictive survival and may help guide treatment decisions for patients with CMML. To our knowledge, the present study is the first one evaluating the prognostic value of MRD focussing on patients with CMML.

It is widely acceptance that early response to therapy is an important prognostic message in leukemia,(17) which reflecting chemotherapy sensitivity. In our study, patients who were MRD1- had a higher 2-year PFS rate than MRD1 + patients (70% vs. 7%; P = 0.004) and prolonged PFS (52.3 months vs. 11.9 months; P = 0.006). MRD1- group also had a higher 2-year OS rate (90% vs. 30%; P < 0.001), with OS improved (54.9 months vs. 17.5 months; P < 0.001). Our finding was in agreement with the professor Feller’s, though differed in diseases and MRD threshold, the percentage of MRD (cutoff level of 1%) in BM after the first cycle therapy strongly correlated with relapse-free survival (P = 0.002) in AML.(18) Furthermore, according to the latest reseaches of dynamic MRD assessment in intermediate-risk AML, MRD1 status had no significant influence in survival.(19, 20) The main reason may be that these studies were based on morphologic complete remission patients, while our study only concentrated on MRD status, regardless of morphilogic outcome. In a way that makes a larger significant difference in prognostic. Second, it may be due to the different biology of AML and CMML. MRD in this study was also a powerful predictor of clinical outcome independent of other well-known risk factors.(2, 4) Multivariate analysis confirmed the significant independent association of MRD1 status with PFS (HR, 3.326 [95%CI, 1.340–8.259]; P = 0.01) and OS (HR, 4.614 [95%CI, 1.266–16.812]; P = 0.020). Therefore, a MRD-driven personalized therapeutic strategies could be designed. For patients who are MRD1-, maintenance therapy or allo-HSCT could theoretically suppress the emergence of residual leukemic clones that may eventually lead to disease relapse likewise AML.(11, 19, 20) For MRD1 + patients, early treatment plan changes should be considered such as dose-adapted hypomethylating agents (HMAs), AML-like induction therapy and allo-HSCT. Clinical trials is also an attractive alternative approach and should be considered if available because the overall outcome of therapeutic interventions are far from optimal.(21, 22)

There unfortunately prospective data were rare to analyze the prognostic relationship between MRD and HSCT in CMML. Our present study revealed that the MRD1 status could determine the likelihood of progression after HSCT for the patients with CMML, which different from factors previously identified such as blast percentage, cytogenetic abnormalities, time to alloHCT, disease control at the time of alloHCT and acute and chronic graft vs. host disease (GVHD).(23) Studies do exist on the effect of MRD on CMML relapse after HSCT, but most have analyzed the effect of pre- and post-HSCT MRD on relapse after HSCT,(24) rather than the early MRD response. Our results showed that CMML patients with MRD1- had a higher 2-year PFS than the MRD1 + group after HSCT (100% vs. 24%, P = 0.04), suggesting early response also of high value of progression evaluation after HSCT. Based on our present results and the significant adverse prognostic role played by MRD1 + in AML(10) indicates that some intervention options (such as post–allo-HCT maintenance treatment or donor lymphocyte infusions) should be be considered for patients who are MRD1 + after transplantation, and they might reduce the post-transplantation progression risk.

In conclusion, early MRD assement can offer reliable prognostic imformation in CMML. MRD1 statu was an independent predictive factor for PFS and OS, it also has potential to identify CMML patients who at high risk progression. In future studies, risk stratification should be based not only on risk assessment at diagnosis, but also on MRD as a treatment-dependent prognostic factor. MRD assessment will serve as a gateway to better therapeutic schedules in CMML. However, this study exists several limitations mainly related to cohort design and its retrospective nature, thereby allowing intrinsic biases that may affect the results. First, given the rarity of CMML, a relatively small sample size of 58 patients had MRD data available for analysis, no definitive conclusion can be drawn. Second, we only conducted MRD analysis after the first cycle of treatment, without considering the impact of subsequent therapy and dynamic MRD changes. Finally, our findings that rely on the clinical manifestation and laboratory test results require external validation. Multicenter and large-scaled studies are warranted to validate our conclusions and its potential in clinical practice.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

All patients provided written informed consent prior to study commencement. The study was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University.

Consent for publication

Not applicable

Disclosure

The authors declare that they have no competing financial interests.

Acknowledgments

We would like to thank all patients included in this study.

Funding

This study was supported by the Natural Science Foundation of China (NO. 81900152), the Natural Science Foundation of Zhejiang Province (NO. LQ19H080005 and NO. LY19H080005), and the Health Department of Zhejiang Province (NO. 2020KY113).

Author Contributions

XJY and XBH conceived the study, LLW and RRC collated and analyzed the data and draft the article, LL collected and selected the references and revised the manuscript, LXZ screened patients and revised the manuscript. All the authors have read and approved the manuscript. All the authors have contributed to conceiving, drafting or revising the manuscript, have agreed on the journal to which the article will be submitted, have provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work.

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No competing interests reported.

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Prognostic Implication of Early Minimal Residual Disease Evaluation in Patients with Chronic Myelomonocytic Leukemia

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Abstract

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Introduction

Material And Methods

Results

Patient baseline characteristics

Overall Treatment Results

Mrd1 Statu Is Predictive Of Outcome In Patients With Cmml

Discussion

Declarations

References

Competing Interests

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