Allogeneic Hematopoietic Stem Cell Transplantation Can Improve Prognosis of Extramedullary Infiltration Positive t(8;21) Acute Myeloid Leukemia

Background

In patients with acute myeloid leukemia (AML), t(8;21)(q22;q22) is observed in up to 12% of total AML cases [1]. Compared with other types of AML, the incidence of extramedullary infiltration (EMI) was higher in t(8;21) AML [2]. Moreover, EMI was associated with poor prognosis in t(8;21) AML [3,4]. Hu et al [5] revealed that the complete remission (CR) rate (60% vs 78.4%, P=0.045) and the 3-year relapse-free survival rates (RFS; 68.8±8.8% vs 88.0±3.4%, P=0.004) among patients with EMI were lower than those among patients without EMI; therefore, EMI was an independent risk factor in pediatric t(8;21) AML. Park et al [6] demonstrated that EMI was associated with age ≤45 years, leukocytosis (≥30×109/L), and c-KIT mutation in t(8;21) AML. Gong et al [7] showed that EMI could be indicative of a poor clinical prognosis in t(8;21) AML patients.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is an established treatment modality with curative potential for AML [8]. Hu et al [9] showedthat EMI at diagnosis was associated with a high cumulative incidence of relapse, and allo-HSCT can improve the RFS (P=0.009) in pediatric t(8;21) AML. While, another study showed that 3-year overall survival (OS) was the same regardless of whether a patient underwent allo-HSCT [6]. There is no consensus on whether to consolidate with allo-HSCT or not in EMI-positive t(8;21) AML patients after the first complete remission (CR1). The aim of this study was to evaluate the efficacy of allo-HSCT in EMI-positive t(8;21) AML patients who achieved CR1 and to analyze the prognostic significance of other factors.

Material and Methods

PATIENTS:

Data from 651 Chinese patients with t(8;21) AML were retrospectively collected from 15 AML study groups between 2002 and 2018. Data were obtained using special case report forms. The research was conducted in accordance with the Institutional Review Board guidelines of the participating study groups and the principles of the Declaration of Helsinki.

The criteria for patient exclusion were as follows: (1) 37 patients had no treatment information; (2) 549 patients were without detection of EMI at diagnosis; (3) 11 patients did not achieve CR1; (4) 3 patients were treated with auto-HSCT after CR1. The remaining 51 patients were included in the analysis for this study. Figure 1 provides details on study enrollment and Table 1 summarizes the baseline characteristics of 51 remaining patients in the study.

TREATMENT:

All the 51 remaining patients received 1–2 cycles of the standard ‘7+3’ induction chemotherapy, and achieved CR1 during induction therapy. The regimens of consolidation chemotherapy were either a single Ara-c or Ara-c combined with drugs such as daunorubicin, idarubicin, aclarubicin, mitoxantrone, homoharringtonine, pirarubicin, or fludarabine. The details of the therapeutic regimens have been reported previously [10,11]. Among the 51 remaining patients, 15 patients received allo-HSCT.

CONDITIONING REGIMENS:

Patients were given myeloablative or reduced-intensity conditioning regimens, as previously reported [12]. Myeloablative conditioning regimens included 0.8 mg/kg/6 h busulfan for 4 days, 60 mg/kg/day cyclophosphamide for 2 days, 50 mg/kg/day cyclophosphamide for 2 days, and 800–1000 cGy total body irradiation. Reduced-intensity conditioning regimens included 30 mg/m2/day fludarabine for 5 days, 3.2 mg/kg/day busulfan for 2 days, or reduced-dose TBI. Anti-thymocyte globulin (ATG) was used in patients who accepted haploidentical-related donor transplant or unrelated donor transplant.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS STRATEGIES:

We used mycophenolate mofetil, cyclosporine, and methotrexate to prevent GVHD. Methylprednisolone was added in patients with grades II to IV aGVHD. Patients with extensive cGVHD were treated with prednisone alone or combined with mesenchymal stem cell. Patients with refractory aGVHD were given basiliximab. The details of GVHD prophylaxis strategies were shown in a previous article [13].

INFECTION PREVENTION AND SUPPORTIVE CARE:

Patients with agranulocytosis were given acyclovir and cotrimoxazole for prophylaxis. Red blood cell transfusions were administered in patients when hemoglobin levels <80 g/L, and platelets were used in patients when platelets count <10×109/L. Patients received recombinant human granulocyte macrophage colony stimulating factor after cell infusion. The infection prevention was mentioned in a previous article [13].

MINIMAL RESIDUAL DISEASE (MRD) MONITORING:

Minimal residual disease was monitored on days 30, 60, 90, and 180 after allo-HSCT.

DEFINITIONS OF EVENTS AND END POINTS:

Outcomes were evaluated by using the probability of the overall survival (pOS). The OS of the population was calculated from the date of diagnosis to the date of the last follow-up for alive patients or the date of death for any cause. Response criteria by the International Working Group (IWG) were considered to evaluate treatment response [14]. We defined CR as meeting all of the following response criteria for at least 4 weeks: bone marrow shows normal hematopoiesis, bone marrow blasts < 5%, no blasts with Auer rods or persistence of extramedullary disease, absolute neutrophil count >1×109/L, platelets ≥100×109/L, no residual evidence of extramedullary disease, and transfusion independent [14]. Non-relapse mortality was defined as any death in the first 28 days after transplantation or any death after day 28 in continuous remission.

STATISTICS:

The clinical characteristics were examined using the χ² analysis or Fisher’s exact test for categorical variables. The pOS were estimated by the Kaplan-Meier method and compared using the log-rank test for univariate analysis and using the Cox regression analysis for multivariate analysis. Variables significant at P<0.10 in univariable analyses were entered into an explorative multivariable model. We also adjusted for features that, when added to this model, changed the matched hazard ratio (HR) by at least 10%. All analyses were performed using R (version 3.3.3) and the EmpowerStats (http://www.empowerstats.com, X & Y Solutions, Inc., Boston, MA). Two-sided P value <0.05 was considered statistically significant.

Results

From the 651 t(8;21) AML patients, 65 (10.0%) patients were EMI-positive at diagnosis. And among the 65 patients, 51 (78.5%) patients achieved CR1 after induce treatment. The remaining 51 patients were included in the study. The most frequently involved site was the central nervous system (CNS, 29.4%), followed by bones (15.7%), and skin (9.8%). Fourteen (27.5%) patients had multiple infiltration sites. The FLT3-ITD mutation was detected in 1 patient, but c-KIT mutation was identified in 12 patients. Out of the 51 cases, 19 (37.3%) had t(8;21) alone, 12 (23.5%) had additional loss of a sex chromosome, and 5 (9.8%) had complex karyotype.

Among the remaining 51 patients, 15 patients received allo-HSCT after CR1. We analyzed the characteristics of patients who received allo-HSCT or not. There were no significant differences in age, sex, white blood cells count (WBC), hemoglobin (Hb), platelets (PLT), bone marrow (BM) blasts, EMI sites, numbers of additional abnormal karyotype, type of karyotype, KIT mutation, WT1, or FLT3-ITD between the patients with and without allo-HSCT. The characteristics of patients are summarized in Table 1.

The median follow-up for all the 51 remaining patients was 21.3 months (95% CI; 19.2–35.9). The median OS for the allo-HSCT negative group was 19.7 months (95% CI; 14.7–28.3), whereas the median OS for the allo-HSCT positive group was not reached (Figure 2). Moreover, patients with allo-HSCT had lower mortality (3-year pOS, 52.98%) compared to patients without allo-HSCT (3-year pOS, 21.63%, P=0.0350). The Kaplan-Meier analysis also identified better OS (P=0.0157; Figure 2) in patients who received allo-HSCT. Moreover, patients with allo-HSCT had significantly better pOS compared to patients without allo-HSCT in the univariable models (HR=0.37; P=0.0202; Table 2) and multivariable models (HR=0.32; P=0.0122; Table 3). Overall, these data suggest that EMI-positive patients treated with allo-HSCT had a decreased risk of death compared to patients without allo-HSCT.

Data from 15 patients who received allo-HSCT are shown in Table 4. Disease status at transplantation was: 11 cases (73.3%) that were in CR1, 2 cases (13.3%) that were in second complete remission (CR2), and 2 cases (13.3%) that had no remission (NR) of disease. Among them, 7 cases were matched sibling transplantation, 5 cases were matched unrelated transplantation, and 3 cases were haploidentical transplantation. Among the 3 patients with CNS extramedullary infiltration, 2 (66.7%) experienced post-transplant relapse. The post-transplant relapse incidence rate for all 15 patients who received allo-HSCT was 13.3%, and the non-relapse mortality rate was 0%.

Discussion

In this study, the incidence of EMI in t(8;21) AML was 10.0%. It was similar to other studies, with the incidence of 9.5–10.2% [2,6]. In our study, the CR1 rate was 78.5% in EMI-positive t(8;21) AML patients. Moreover, the CR1 rate was 94.1% and 50% in study of Byrd et al [2] and Park et al [6], respectively. In our study, 51 t(8;21) AML patients with EMI remained at diagnosis. The most frequently involved site was the CNS, which was consistent with the study of Park et al [6]. Moreover, in an article by Byrd et al [2] there were 4 patients with D-spine involvement, 1 patient with sacrum involvement, and 1 patient with meningeal involvement among 8 patients of EMI-positive t(8;21), which was comparable to our data.

Studies showed that EMI is associated with poorer prognosis in t(8;21) AML [15,16]. Although patients with EMI AML and high-risk cytogenetics are candidates for allo-HSCT consensually [17], few report have shown the effects of allo-HSCT in EMI-positive t(8;21) AML patients. In patients with EMI, the median OS of the patients who underwent HSCT was 40.6 months, compared with 9.4 months in patients who did not (P<0.001) [18]. In the article of Fianchi et al [16], the OS of EMI patients who underwent allo-HSCT was significantly different from the OS of EMI patients who did not receive allo-HSCT (16.7 months vs 8.2 months, P=0.02). In another report, there was no significant difference in OS between patients who received or who did not receive HSCT (54.0 months vs 27.2 months, P=0.537) for EMI-positive AML patients in the ELN2017 favorable risk group [19], revealing a significantly better OS for myeloid sarcoma patients proceeding to allo-HSCT as compared to consolidation with chemotherapy only (P=0.029) [20]. However, the EMI-positive individuals enrolled in these articles were not t(8;21) AML only. The patients involved in the article by Ganzel et al [18] and Fianchi et al [16] were patients with all types of AML, they were AML patients in the ELN2017 favorable risk group in the article by Eckardt et al [19], and were myeloid sarcoma patients in study by Shan et al [20]. Moreover, only 26 patients had a favorable karyotype [inv(16), t(16;16), del(16q) or t(8;21)] in the study by Ganzel et al [18]. In the study by Shan et al [20], only 10 of 73 patients had a karyotype of t(8;21). Additionally, of the 38 EMI-positive AML patients, only 1 patient had the karyotype of t(8;21) in study of Fianchi et al [16]. In our study, the remaining 51 EMI-positive t(8;21) AML patients who achieved CR1 after induction therapy were included. Among them, 15 patients received allo-HSCT. In our research, both Kaplan-Meier analysis and the multivariable models showed significantly better OS in patients with allo-HSCT compared to patients without allo-HSCT. Therefore, we suggest that allo-HSCT should be considered initially for outcome improvement of EMI-positive t(8;21) AML. This notion is consistent with the observations of Park et al [6], who also suggested allo-HSCT may be a feasible treatment strategy as a post-remission therapy for treatment of EMI-positive t(8;21) AML. Moreover, Tallman et al [15] suggested aggressive therapy, including HSCT, for EMI-positive t(8;21) AML.

In addition to allo-HSCT, there are other newer treatment options for EMI-positive AML, such as intensive chemotherapy, donor lymphocyte infusion, radiation therapy, CAR T-cell therapy, or gemtuzumab ozogamicin [21–23]. Unfortunately, our study could not compare allo-HSCT with other treatment methods in EMI-positive t(8;21) AML because the number of patients receiving other newer treatment was insufficient. This study has other limitations. The data were collected retrospectively, the patient population was heterogeneous, and patients were treated according to a variety of protocols with different treatment strategies. Despite these limitations, we believe that this study described the clinical characteristics, identified risk factors, and gave a reliable estimate of the effect of allo-HSCT on OS in patients with EMI-positive t(8;21) AML.

Conclusions

In EMI-positive t(8;21) AML, the most involved site was the CNS, followed by bones. Allo-HSCT may improve OS in EMI-positive t(8;21) AML patients.