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To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia (ALL), we collected the clinical data of 332 patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first complete remission (CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo-HSCT) in CR1. The overall survival (OS) was 43·4% at 1 year, and 16·3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52·5%) achieved a second remission (CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo-HSCT during CR2. Allo-HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone-based (AdVP-type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph-negative ALL is poor. Allo-HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1.
The complete remission (CR) rate of adult patients with acute lymphoblastic leukaemia (ALL) has improved to about 90% with modern intensive chemotherapy. However, many patients eventually relapse, and the long-term leukaemia-free survival rate is only 30–40% (Litzow, 2009). Many relapsed patients receive various salvage therapies after the first relapse, and several studies have reported that 38–56% of relapsed patients can achieve second remission (CR2; Giona et al, 1997; Thomas et al, 1999; Camera et al, 2004; Tavernier et al, 2007; Cornelissen et al, 2009). While allogeneic haematopoietic stem cell transplantation (Allo-HSCT) in CR2 is considered to be the only curative strategy, early relapse and/or organ dysfunction after salvage chemotherapy and the lack of a suitable donor often prevent Allo-HSCT at this stage. Therefore, the prognosis of adult patients with relapsed ALL is extremely poor (Fielding et al, 2007; Tavernier et al, 2007; Oriol et al, 2010; Gokbuget et al, 2012). We collected clinical data after the first relapse in adult patients with Philadelphia chromosome (Ph)-negative ALL who were treated in institutions all over Japan, and performed a retrospective analysis to clarify the prognosis and prognostic factors for the outcome in relapsed patients. Patients with Ph-positive ALL were not included in our analysis because the outcome of treatment in these patients has improved dramatically since tyrosine kinase inhibitors became available (Ottmann & Pfeifer, 2009).
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Several large clinical studies have demonstrated the outcomes of a relatively large number of patients with ALL who relapsed after uniform chemotherapy regimens (Fielding et al, 2007; Tavernier et al, 2007; Oriol et al, 2010; Gokbuget et al, 2012), and the results of uniform salvage chemotherapy regimens have been reported as clinical trials, each of which included a small number of relapsed patients with ALL (Giona et al, 1997; Koller et al, 1997; Montillo et al, 1997; Weiss et al, 2002; Camera et al, 2004; Specchia et al, 2005). The present study investigated the prognosis of relapsed patients with Ph-negative ALL, based on the clinical data of 332 patients from 69 institutions all over Japan. These patients had received various kinds of treatment strategies before and after relapse according to their respective institution, and therefore, these patients should reflect the more general population of relapsed patients with ALL.
Overall survival (OS) at 5 years from relapse was 16·3% in patients who received chemotherapy alone in CR1 and 10·6% in patients who received Allo-HSCT in CR1, and Allo-HSCT in CR1 did not influence the outcome after relapse in our study. These outcomes were comparable to those in three previous reports of large clinical studies (Fielding et al, 2007; Tavernier et al, 2007; Oriol et al, 2010; Table 3). Recently, Gokbuget et al (2012) reported the outcome of 547 relapsed patients in the German Multicentre Study Group for Adult ALL (GMALL). The OS at 5 years from relapse in patients who had received chemotherapy alone in CR1 was significantly better than that in patients who had received Allo-HSCT in CR1 (28% vs. 15%, P < 0·001). This difference might be attributed to the high rate (75%) of Allo-HSCT after relapse in patients who had received chemotherapy alone in CR1. In our study, Allo-HSCT was performed in 55% of the patients who relapsed after they had received chemotherapy alone in CR1. Allo-HSCT in CR2 was associated with a better prognosis after the achievement of CR2, and in addition, some of the patients who received Allo-HSCT even in NR after salvage chemotherapy showed long-term survival (the OS was 20·7% at 5 years). These findings suggested that we should consider Allo-HSCT as much as possible for relapsed patients.
Table 3. Comparison of several studies regarding the outcome of relapsed patients with acute lymphoblastic leukaemia (ALL)
| ||Patients (n)||Rate of CR2 (%)||5-year OS||Prognostic factors for improved OS|
|LALA-94 (Tavernier et al, 2007)||421||44%||8%|| |
Platelet count at relapse >100 × 109/l
|MRC UKALL12/ECOG2993 (Fielding et al, 2007)||609||N.M.||7%|| |
|PETHEMA trials (Oriol et al, 2010)||263||45%||10%|| |
|GMALL trials (Gokbuget et al, 2012)a||547|| || || |
Extramedullary relapse (other than CNS)
(15–25 years vs. 26–45 years vs. 46–55 years)
CR after 1st salvage CTxd
|This study||332|| || || |
WBC count at relapse <10 × 109/le
Age at relapse <35 yearse
Prognostic factors that were associated with a better OS from CR2 were younger age at relapse, lower WBC count at relapse, and Allo-HSCT in CR2 among patients who relapsed after chemotherapy alone in CR1 and achieved CR2 following salvage chemotherapy. None of the factors at diagnosis was associated with OS after relapse. Age and Allo-HSCT were the common factors observed in other studies (Table 3). The duration of CR1 was not associated with better OS in the multivariate analysis in our study. In other studies, the duration of CR1 was associated with not only better OS but also a high rate of achieving CR2 (Thomas et al, 1999; Tavernier et al, 2007; Oriol et al, 2010). Given that our analysis was limited to patients who achieved CR2, the duration of CR1 might not be a significant factor for OS. Although the WBC count at relapse was not analysed in the other studies, it should be considered as an important factor.
We should note that there might be selection bias regarding the performance of Allo-HSCT in CR2, because it depended on each institution's decision. By a multivariate analysis using logistic regression for all covariates, relapse year (after 2003) and younger age at relapse (younger than 36 years) were significantly associated with the performance of Allo-HSCT in CR2. However, a multivariate analysis for OS including relapse year, age at relapse, and Allo-HSCT in CR2 (treated as a time-dependent covariate) as covariates demonstrated that Allo-HSCT in CR2, as well as age at relapse, was still significantly associated with better OS. In addition, there was no significant interactions between Allo-HSCT in CR2 and relapse year and between Allo-HSCT in CR2 and age at relapse (P = 0·36 and P = 0·97, respectively).
Comparisons of different salvage chemotherapy regimens have been limited (Thomas et al, 1999; Tavernier et al, 2007; Oriol et al, 2010). The selection of salvage regimens often depends on the condition of the relapsed patient (Garcia-Manero & Thomas, 2001). In our analyses, the duration of CR1, intensity of chemotherapy at diagnosis, and relapse year were factors that were associated with the selection of salvage regimens. AdVP-type salvage chemotherapy was related to a better OS in patients who had a longer duration of CR1 and a worse OS in those who had a shorter duration of CR1. If we consider that many patients had received induction chemotherapy including doxorubicin, vincristine, and steroids, the duration of CR1 might reflect the sensitivity of ALL to the AdVP-type regimen. Patients who had a longer duration of CR1 might have had ALL that was sensitive to an AdVP-type regimen, and those who had a shorter duration of CR1 might have had ALL that was refractory to an AdVP-type regimen. In patients who relapsed late, the toxicity of moderate-intensity regimens, such as those including high-dose cytarabine, used as the first salvage chemotherapy might offset their effectiveness. Unlike in a previous study (Thomas et al, 1999), the type of chemotherapy at diagnosis did not influence OS following each salvage regimen.
In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. However, Allo-HSCT after the first relapse could improve the prognosis, especially if performed in CR2. The efficacy of different types of salvage chemotherapy might depend on the duration of CR1, and this should be considered in the selection of the salvage regimen.