Different impact of BCR‐ABL transcripts on allogeneic hematopoietic cell transplantation from different graft sources for Ph + ALL with minimal residual disease
Authors: Satoshi Nishiwaki, Shuichi Mizuta, Kazuteru Ohashi, Takahiro Fukuda, Naoyuki Uchida, Takayoshi Tachibana, Makoto Onizuka, Yukiyasu Ozawa, Yasushi Onishi, Satoshi Takahashi, Tetsuya Eto, Hirohisa Nakamae, Junji Tanaka, Tatsuo Ichinohe, Yoshiko Atsuta, Shinichi Kako
Journal: American Journal of Hematology (2019)

In two thirds of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), the BCR-ABL transcript is minor (p190), and it is major (p210) in one third. The frequency of BCR-ABL1-positive cells outside the B-lineage compartment was different according to BCR-ABL transcripts.1 Although this could suggest the possibility of biological differences, the prognostic significance of a difference in transcripts has not been confirmed. Allogeneic hematopoietic cell transplantation (allo-HCT) is still a popular treatment option for Ph + ALL, in the era of tyrosine kinase inhibitors (TKIs).2, 3 Different effect of different unrelated graft source has been reported on the outcome of allo-HCT among patients with minimal residual disease (MRD) in a recent study.4 Therefore, in this study, we analyzed the impact of BCR-ABL transcripts according to unrelated graft source on the outcome of allo-HCT for Ph + ALL with MRD. Data for 242 adult Ph + ALL patients who underwent their first unrelated allo-HCT in the first hematological complete remission with MRD were analyzed using the Japanese database. Patients with no history of chronic myeloid leukemia in chronic or accelerated phase were included in this study. The copy numbers of BCR-ABL transcripts in each sample are reported as normalized values by means of GAPDH. The cut-off for MRD(+) was 50 copies/μg RNA in this study, which corresponded to a minimal sensitivity of 10−5.2 The MRD at the time of allo-HCT was evaluated by the results of RQ-PCR within 30 days before transplantation.3 Determination of whether to prescribe a TKI after allo-HCT was made by each institution. Relapse was defined as hematological leukemia recurrence. Non-relapse mortality (NRM) was defined as death during continuous remission. For analyses of overall survival (OS), failure was death from any cause, and surviving patients were censored at the date of last contact. The OS rates were estimated by the Kaplan-Meier method, and P values were calculated using a log-rank test. Cumulative incidences of relapse, NRM, and GVHD were calculated by Gray's method. Death without relapse was considered as a competing event for relapse, and relapse was considered as a competing event for NRM. A significance level of P < .05 was used for all analyses. Of the 242 patients, 180 patients (74%) had p190, and 62 (26%) had p210. Graft source was unrelated bone marrow or peripheral blood transplantation (UBMT) in 151 patients (62%) and unrelated cord blood transplantation (UCBT) in 91 patients (38%) (Table S1). The median follow-up period for survivors was 44 months. The OS rates at 4 years were 64% in patients with p190, and 41% in those with p210 (P = .01) (Figure 1). The multivariate analysis for OS showed that the BCR-ABL transcript was a significant risk factor (Table S2). The cumulative incidence of relapse was not significantly different between patients with p190 and those with p210 (28% in p190 and 29% in p210 at 4 years, P = .81) (Figure 1). The multivariate analysis for relapse showed that posttransplant TKI and year of allo-HCT were significant risk factors. The BCR-ABL transcript was not a significant risk factor for relapse (Table S2). Sixty-nine patients (29%) received posttransplant TKI, and the reason for starting administration was documented in 47 patients (68%). Molecular relapse was the cause in 80% of patients with p210, and 49% of those with p190 (not significant). The cumulative incidence of NRM was significantly different between patients with p190 and those with p210 (18% in p190 and 41% in p210 at 4 years, P = .004) (Figure 1). The multivariate analysis for NRM showed that patient sex and the BCR-ABL transcript were significant risk factors (Table S2). The cumulative incidence of grade III-IV acute GVHD was not significantly different between patients with p190 and those with p210 (9.8% in p190 and 18% in p210 at day 100, P = .09). Among evaluable patients who survived at least 100 days after allo-HCT, no significant difference was observed in the incidence of chronic GVHD between patients with p190 and those with p210 (31% in p190 and 26% in p210 at 4 years, P = .44). The three major causes of death were relapse, infection, and organ failure. Nineteen of 180 patients with p190 (11%), and eight of 62 with p210 (13%) died of leukemia (P = .64), 13 (7.2%) and 11 (18%) died of infection (P = .03), and six (3.3%) and six (9.7%) died of organ failure (P = .08). The OS and NRM were significantly different between patients with p190 and those with p210, among patients who underwent UBMT (OS: 65% in p190 vs 37% in p210, P = .001; NRM: 14% in p190 vs 44% in p210 at 4 years, P < .001) (Figure 1). However, these were not significantly different between patients with p190 and those with p210, among patients who underwent UCBT (OS: 51% in p190 vs 55% in p210, P = .76; NRM: 23% in p190 vs 34% in p210 at 4 years, P = .99). Among 151 patients who underwent UBMT, BCR-ABL transcript was a significant risk factor for both OS and NRM in the multivariate analyses (Table 1A). However, it was not a significant risk factor for relapse. On the other hand, among 91 patients who underwent UCBT, the BCR-ABL transcript was not a significant risk factor for OS, relapse or NRM in the multivariate analyses (Table 1B). The cumulative incidence of grade III-IV acute GVHD was significantly higher in patients with p210 who underwent UBMT, than those with p190 (9.8% in p190 vs 24% in p210 at day100, P = .03). However, there was no distribution difference of known risk factors for acute GVHD, such as HLA disparity (P = .76), frequency of female donor to male recipient (P = .48), and patient age (P = .18),5 between patients with p190 and those with p210 who underwent UBMT. On the other hand, the cumulative incidence of grade III-IV acute GVHD was not significantly different between patients with p190, and those with p210 who underwent UCBT (9.7% in p190 vs 5.3% in p210 at day 100, P = .54). In UBMT, 7 of 108 patients with p190 (6.5%) and 10 of 43 with p210 (23%) died of infection (P = .001), and four with p190 (3.7%) and five with p210 (12%) died of organ failure (P = .04). To our knowledge, this is the first study to report the possibility of a significant impact of BCR-ABL transcripts on transplant outcome in patients with MRD(+) at allo-HCT. In addition, in patients who underwent UBMT, p210 was associated with a higher NRM than p190, which led to differences in survival due to BCR-ABL transcripts. One reason was a higher incidence of severe acute GVHD in patients with p210, who underwent UBMT than those with p190, which led to a higher incidence of infection and/or organ failure. However, the reason for the higher incidence of severe acute GVHD in such patients is unclear. The influence of pre-transplant treatment is another reason. More patients with p210 underwent allo-HCT with MRD(+) status than those with p190 in our previous analysis [MRD(+) at allo-HCT: 62 (25%) in p210 vs 77 (17%) in p190, P = .007]. The time from diagnosis to allo-HCT was longer in patients who underwent UBMT than those who underwent UCBT. Taken together, it was possible that for patients with MRD(+) at UBMT, intensified pre-transplant treatment was performed over a longer period due to persistent MRD, which might have led to an increase in NRM. In addition, although there was no significant difference, cytarabine was used as preparative regimen for more patients with p210 than those with p190, which might have supported the increased NRM in patients with p210.6 As a strategy for Ph + ALL, especially in patients with p210 who had poor molecular response after induction therapy, NRM could be reduced by achieving early molecular remission using second or third generation TKIs and performing all-HCT as soon as possible. As for relapse, there was no difference depending on BCR-ABL transcripts. Because hematological relapse was treated as an event of relapse, attention should be paid to the fact that patients who received therapeutic intervention at molecular relapse and did not reached hematological relapse were not counted as relapse in this study. Although it is speculation from a relatively small amount of data, relapse might have been detected at the molecular stage in more patients with p210 than those with p190, and early treatment intervention at molecular relapse including fast reduction of immunosuppressant was performed for more patients with p210, which might have led to increased NRM. The most important limitation of this retrospective study is the selection biases. Because selection of graft source and both pre- and post-transplant treatments were at the physicians’ discretion, differences in treatment intervention could have resulted in the differences of NRM. However, it was highly likely that the result was not a mere coincidence but had some meaning considering that this study included a large number of Ph + ALL patients from transplant centers throughout Japan. Although the mechanism should be clarified in another study, our results could provide a rationale to perform a future clinical trial considering BCR-ABL transcripts and MRD status as parameters. In conclusion, this study demonstrated the impact of BCR-ABL transcripts on transplant outcomes according to graft source in Ph + ALL patients with MRD(+) at unrelated allo-HCT. Although it is necessary to elucidate the reasons including biological differences, further investigation would lead to more specialized treatment for Ph + ALL. The authors declare no competing financial interests. The authors thank Dr Akihito Shinohara for a thoughtful discussion. This study was supported in part by JSPS KAKENHI Grant Number JP17K16186. TABLE S1 Patient characteristics of adult Ph + ALL patients undergoing unrelated allo-HCT in CR1 with MRD Table S2 Impact of BCR-ABL transcript among MRD(+) adult Ph + ALL patients undergoing unrelated allo-HCT in CR1: Multivariate analyses Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.