Ph + ALL is the most common group of cytogenetic abnormalities in adult ALL and is a subtype with a poor prognosis. In the pre-TKI era, conventional chemotherapy regimens were used to treat adults with Ph + ALL with a long-term survival rate of only 10% (Leoni & Biondi, 2015), characterized by low CR, short duration of remission, low long-term survival rates, and high relapse rates. Using TKIs, the treatment pattern, efficacy, and prognosis of patients with adult Ph + ALL have changed dramatically, with CR rates of over 90% and OS rates of 40–60%, significantly improving the disease outcome and prognosis (Fielding & Zakout, 2013).
In this study, univariate and multivariate analyses of disease data at presentation in the 205 patients with Ph + ALL showed that WBC count, age, and CR in induction chemotherapy were independent prognostic factors affecting OS and DFS, a result consistent with that reported by Fielding et al. (Fielding et al., 2009) in 2009, suggesting higher WBC count and older age were associated with worse prognosis.
One of the reasons for the poor prognosis of patients with Ph + ALL is the low rate of induction remission. In the era of TKIs, TKIs combined with chemotherapy has become the first-line induction chemotherapy regimen for patients newly diagnosed with Ph + ALL, improving the CR rate and OS and DFS rates while reducing treatment-related mortality (Fielding, 2010; Fielding et al., 2014). Additionally, this has led to the consideration of chemotherapy regimens and whether high-intensity chemotherapy is still needed for induction remission with potent targeted agents, especially in elderly patients, where complications such as severe myelosuppression or infection caused by high-intensity chemotherapy often cause interruption of chemotherapy or early death in some patients. Hence, several international clinical studies of TKIs with reduced-dose chemotherapy have been conducted. The EWALL studied the clinical efficacy of dasatinib combined with low-dose chemotherapy, enrolling 71 elderly patients with a median age of 69 (55–83) years and with CR rate, CMR rate, and MMR rates of 96%, 24%, and 65%, respectively. Moreover, only 10% of patients underwent allo-HSCT, with 5-year RFS and OS rates of 28% and 36%, respectively (Rousselot et al., 2016). In the European study by Foà et al., dasatinib (70 mg twice daily) was used combined with prednisone (10–60 mg/m2) for 84 days. In this trial, 53 patients were enrolled, with a median age of 54 (24–76) years and CR, MMR, CMR, and OR rates of 93%, 52%, 15%, and 69% at 20 months, respectively (Foà et al., 2011). Similar results were obtained in another clinical trial with a CR rate of 96% and a 3-year OS rate of 59.1% in 49 patients (Chiaretti et al., 2016). In addition to dasatinib, the clinical efficacy of ponatinib with glucocorticoids has been studied. In the GIMEMA LAL 1811 clinical trial, 42 patients (median age, 68 years) had CR, CMR, and 1-year OS rates of 95%, 46%, and nearly 87%, respectively, after using ponatinib with glucocorticoids (Martinelli et al., 2017). The above study showed that reducing the intensity of chemotherapy did not reduce the remission rate or survival time of patients. Rather, the reduced intensity of chemotherapy allowed patients to achieve high CR while significantly reducing the toxic side effects of chemotherapy and reducing the associated mortality. In this study, patients were divided into the TKIs with reduced-dose chemotherapy group (62 patients) and the TKIs with standard chemotherapy group (143 patients) based on the induction chemotherapy, with CR rates (88.7% vs 83.9%, P = 0.372) and early mortality (3.2% vs 3.5%, P = 0.922) in both groups not statistically significant. Thus, it was observed that the induction chemotherapy of TKIs combined with low-dose chemotherapy had a high CR and an early mortality rate of < 5%. However, the present study was a retrospective analysis, and the induction regimen was not standardized. Therefore, strategies on how to optimize post-remission outcomes for patients who cannot tolerate strong chemotherapy need to be determined in the future.
Ph + ALL is a hematological malignancy and a chronic disease that requires repeated hospitalization, resulting in high hospitalization costs and seriously threatening individuals’ quality of life. A cost statistics shows that the mean total costs of childhood ALL were between $115,858 and $163,350 per patient. The important drivers of overall costs were hospital admissions (57%) and medication (11–17%) (van Litsenburg, Uyl-de Groot, Raat, Kaspers, & Gemke, 2011). The financial burden of high costs is one of the most significant factors affecting patient compliance and has a direct impact on patients’ willingness to be treated. Therefore, paying attention to the possible strategies on how to control hospitalization cost is considered beneficial. A number of international studies have estimated the hospitalization costs of patients with leukemia (DiNofia et al., 2018; Kaul et al., 2016; Tong et al., 2013). The results show that the number of days of hospitalization directly affects their hospitalization costs and treatment outcomes, with a positive correlation between the two. A retrospective analysis of the direct economic losses of 362 patients with acute leukemia by national researchers (王书会, 王静娜, 刘芸宏, 吴晓慧, & 李颖霞, 2015) has shown that the average total hospitalization cost was 34394 yuan for patients in the infected group and 14049 yuan for patients in the non-infected group, and the average hospitalization days was longer in the infected group (P < 0.05). It was concluded that the occurrence of hospital infection increased the economic burden of patients. In this study, we investigated the number of hospital days, hospital costs, type of infection, and antibiotic use in 205 patients with Ph + ALL at our hospital. It was observed that in the low-intensity chemotherapy group, due to the reduced intensity of chemotherapy, the degree of suppression of the bone marrow by chemotherapy drugs is reduced and that the duration of bone marrow suppression after chemotherapy is shortened, thus reducing the severity of hospital infections in patients, as evidenced by the reduction of serious infections and the use of fewer types and lower intensity of antibiotics, thus shortening the number of hospital days and controlling the cost of antibiotic drugs and total costs. Currently, there is a paucity of the literature on the comprehensive cost analysis of acute leukemia treatment. Most of the available literature examine the cost-effectiveness of treatment methods; however, few of it analyze the impact of financial burden on patient survival.
Patients with Ph + ALL are mostly older, have high WBC count, are at risk of central nervous system involvement, and are more likely to relapse with chemotherapy alone (Faiz, Iqbal, & Qureshi, 2015). Therefore, allo-HSCT is recommended for patients with Ph + ALL who have achieved CR when possible. Although the advent of TKIs has changed the management of patients with Ph + ALL, chemotherapy combined with TKIs has been widely used to treat patients with Ph + ALL, improving the CR and long-term survival time and reducing the risk of relapse (Malagola, Papayannidis, & Baccarani, 2016), bringing into question the status of allo-HSCT in the treatment of Ph + ALL. However, several national and international studies still demonstrate the survival benefit of allo-HSCT compared to combination chemotherapy in both the pre- and post-TKIs eras. The clinical significance of allo-HSCT was confirmed by the international randomized study GRAAPH-2005, which showed that among patients treated with imatinib in combination with chemotherapy (median age, 47 years), allogeneic transplantation in first remission prolongs RFS and OS (Y. Chalandon et al., 2015). Moreover, RFS and OS were shown to benefit allogeneic transplantation patients compared to those receiving vincristine and prednisone combined with dasatinib in a multicenter study in the USA (F. et al., 2016). In an analysis of 145 patients (median age, 37; range, 14–65 years) with Ph + ALL at the Peking University People’s Hospital treated with imatinib in combination with chemotherapy during the induction phase, 57.9% (77) of patients underwent allo-HSCT after remission, and the 4-year cumulative relapse, DFS, and OS rates in the transplant groups were 29.4%, 60.9%, and 69.2%, respectively, a significant advantage over the non-transplant group, especially in those with persistent MRD level (Wang et al., 2018). Our study compared the survival of transplanted and non-transplanted patients during treatment and showed that OS and DFS were significantly better in the transplant group than those in the non-transplant group, further suggesting that allo-HSCT can significantly improve long-term survival and prognosis in adults with Ph + ALL.
This study had a few limitations. According to MD Anderson et al. (Y Chalandon et al., 2015; Ravandi et al., 2013; Ravandi et al., 2015), more potent TKIs, for example, nilotinib and ponatinib, used as frontline therapy in combination with chemotherapy to reduce minimal residual disease significantly prolong patient survival. However, considering the small sample size in our study, the roles of second- and third-generation TKIs in combination chemotherapy were not analyzed in this study. Moreover, in this study, the median age of patients in the transplant group was younger than that in the non-transplant group, and the non-transplant group included more patients with advanced disease, such as those with poor systemic status or refractory relapses, who were often lost to transplantation, which may have masked the efficacy of some TKIs combined with chemotherapy regimens.
In summary, WBC count, age, and CR in induction chemotherapy are independent prognostic factors affecting OS and DFS in patients with Ph + ALL. Furthermore, this study suggests that TKIs combined with reduced-dose chemotherapy is a practical option for patients with Ph + ALL because it reduces chemotherapy-related adverse effects, lowers hospital costs, reduces patients’ financial burden, and improves patient compliance without reducing CR rate and long-term survival. Moreover, the study showed that SCT in CR1 remains a good option for patients with Ph + ALL. These findings need to be further validated by multicenter, prospective clinical studies with larger sample sizes. Additionally, the treatment of Ph + ALL continues to face serious problems of disease relapse and drug resistance, and further studies of novel biologic agents and antileukemic regimens such as immunotherapy will improve the outcome and prognosis of patients with Ph + ALL.