Efficacy of Chemotherapy-Free Regimens in the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Abstract

Introduction:

The historical standard of care for Ph+ ALL is chemotherapy plus a tyrosine kinase inhibitor (TKI). Recently chemotherapy-free regimens have shown promising efficacy. We performed a meta-analysis to compare the efficacy of chemotherapy-free regimens for Ph+ ALL.

Methods:

We searched PubMed and Embase for chemotherapy-free regimens for Ph+ ALL published between January 2000 and October 2023. Of the 5,348 articles screened, 9 non-randomized clinical trials enrolling 413 patients were included. Two trials (N=117) included treatment with 3 agents (blinatumomab, TKI, and steroid) and 7 trials (N=248) included treatment with 2 agents (TKI and steroids). R software was used to conduct the meta-analysis (PROSPERO registration no. CRD42023482439).

Results:

The pooled complete molecular response (CMR) rate of patients receiving a TKI, blinatumomab, and steroids was 81% (95%CI, 69–89%). TKIs plus blinatumomab were nearly 6 times as likely to have CMR (odds ratio [OR], 5.98; 95%CI, 2.99–11.96) and more than 5 times as likely to be alive at 1-year (OR, 5.1; 95%CI, 1.74–14.9) as compared to TKIs alone. Patients receiving ponatinib were about twice as likely as those receiving dasatinib to achieve CMR (OR, 2.51; 95%CI, 0.72–8.72).

Conclusion:

Adding blinatumomab to TKIs and steroids significantly improved Ph+ ALL patients’ response and survival rates. Regimens with ponatinib elicited higher molecular response rates than those with other TKIs. The high response and survival rates achieved with blinatumomab plus TKIs and steroids suggest that further studies are required to assess the need for intensive treatments like chemotherapy or stem cell transplant in these patients.

Introduction

The Philadelphia chromosome (Ph) with the BCR::ABL1 fusion gene, the most common chromosomal abnormality in acute lymphoblastic leukemia (ALL), occurs in 11–29% of patients.¹ The prognosis of patients with Ph-positive (Ph+) ALL, which was historically poor, has significantly improved with the advent of specific tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 fusion protein. Combinations of these TKIs with high-intensity chemotherapy have achieved high response rates as induction and consolidation therapy and remain the standard of care². However, intensive chemotherapy can cause severe complications, including death, particularly among older patients. Therefore, researchers started investigating the use of lower-intensity, chemotherapy-free regimens as induction or consolidation therapy for patients with Ph+ ALL.

Deep molecular responses and undetectable BCR::ABL1 transcripts are early surrogate markers of survival in patients receiving treatment for Ph+ ALL³. The chemotherapy-free regimens investigated in clinical trials have included three generations of TKIs targeting the BCR::ABL1 fusion protein. Compared with imatinib, a first-generation TKI, second-generation TKIs are more potent inhibitors of BCR::ABL1 and elicit lower relapse rates; however, the emergence of ABL1 kinase domain mutations, such as T315I, can cause resistance to second-generation TKIs. Ponatinib, a third-generation TKI that has activity against almost all single ABL1 kinase domain mutations, is effective against disease with resistance to second-generation TKIs⁴. Some of the chemotherapy-free regimens comprising different TKIs that have been investigated also include blinatumomab, a bispecific T-cell engager. This monoclonal antibody facilitates T-cell–mediated tumor cell lysis by engaging CD3 on cytotoxic T cells, activating them, and binding to CD19 on tumor cells⁵.

The few data about the comparative effectiveness of chemotherapy-free regimens in patients with Ph+ ALL are from non-randomized clinical trials. Therefore, we conducted this meta-analysis to assess the efficacy of chemotherapy-free regimens and compared response rates and 1- and 2-year survival rates among patients receiving different TKIs with or without blinatumomab.

Methods

Study Design

PRISMA⁶ and Cochrane⁷ guidelines were used to perform this systematic review and meta-analysis. The prespecified guidelines were registered with PROSPERO (registration no. CRD42023482439).

Search Strategy

We conducted a comprehensive literature search of the PubMed and Embase databases using the keywords “acute lymphoblastic leukemia,” “Philadelphia chromosome,” and “drug therapy.” We searched for articles published between January 1, 2000, and October 1, 2023. The PICOS (Population, Intervention, Comparison, Outcomes, and Study) framework methodology was used for the literature search⁸ (Supplemental Table 1).

Inclusion and Exclusion Criteria

We included published, peer-reviewed articles reporting clinical trials that provided data on the efficacy and safety of chemotherapy-free regimens used as induction or consolidation therapy in patients with Ph+ ALL. We excluded articles reporting clinical trials in which patients with Ph+ ALL comprised less than 50% of the study population. We also excluded articles reporting clinical trials in which patients underwent stem cell transplant (SCT) before treatment with TKIs and TKIs were used to prevent relapse, as the therapeutic effect of SCT is a confounding factor and the tendency of younger patients proceeding to SCT compared to older patients not undergoing SCT. We excluded published conference abstracts to avoid the inclusion of lower-quality data that might have misleading comparison results.

Study Selection

Two researchers (MAA and WA) independently reviewed each article for inclusion. Any differences in these researchers’ determinations were resolved by a third researcher (KS).

Data Extraction

The primary efficacy outcomes of interest were complete molecular response (CMR; considered to be a reliable predictor of long-term outcomes and survival rates) and overall survival (OS)⁹. CMR definitions varied slightly across each study, however, we collected data for CMR defined as undetectable BCR-ABL1 with a PCR sensitivity of 0.01%. . Secondary outcomes of interest were complete hematological response (CHR), and disease-free survival (DFS). CHR and DFS were study specific and were collected as determined by the authors in each study. The 1-year and 2-year OS and DFS rates, if not provided in the article text, were estimated from the digitalization of Kaplan-Meier curves. Response rates at maximum follow-up after chemotherapy-free induction/consolidation treatment were extracted. Patients’ baseline characteristics, including age, disease status, sex, treatment regimens, and median follow-up time, were extracted from the included clinical trials. Two researchers (MAA and WA) independently extracted the data, and any differences were resolved by a third researcher (SK).

Data Analysis

The R software program (version 4.3.1) was used to run the meta-analysis. (The R codes used for the meta-analysis are available in Supplemental Table 2.) The meta and metafor packages were used to run arguments; metaprop was used for single proportions, and metabin was used for binary proportions¹⁰. Effect sizes and odds ratios (ORs) were calculated using a random effects model. Proportions were commonly logit-transformed to avoid right or left skew, and logit-transformation first calculated ORs before they were pooled. Between-study heterogeneity and sampling error were differentiated by calculating Cochran’s Q¹¹. The study arms were grouped by the type of front-line treatment: TKIs, blinatumomab, and steroids vs. TKIs and steroids only. CMR rates and 1- and 2-year OS and DFS rates with TKIs and blinatumomab were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. Plots summarizing the CMR, DFS, and OS rates achieved with each chemotherapy-free regimen were generated. Subgroup analysis using a multiple fixed effects model and meta-regression using a mixed effects model helped reduce heterogeneity ^12,13. Sensitivity analyses were performed to compare OS, DFS, and CMR among patients who received ponatinib, dasatinib, or imatinib as part of the chemotherapy-free regimen.

Risk of Bias Assessment

Internal validity assessment of the included randomized clinical trials was done using the Cochrane ROB-2 tool¹⁴.

Results

The initial search of Embase and PubMed yielded 5,348 articles. After careful screening, 9 non-randomized clinical trials^15–23 were included in the meta-analysis (Figure 1). The baseline characteristics of each clinical trial included in the meta-analysis are provided in Table 1. These trials enrolled a total of 413 patients with Ph+ ALL, including 103 patients with previously untreated disease who were treated with blinatumomab plus a TKI (63 with dasatinib and 40 with ponatinib), 167 patients with previously untreated disease who were treated with only a TKI (94 with dasatinib, 29 with imatinib, and 44 with ponatinib). A separate analysis was conducted for trials on relapsed/refractory (R/R) patients. 45 patients with R/R disease were treated with blinatumomab alone without TKI. 81 patients with R/R disease were treated with only a TKI (36 with dasatinib and 48 with imatinib). All patients received steroids as part of their treatment. Two studies on TKIs, Vignetti et al., 2007¹⁹, and Martinelli et al., 2022²⁰ enrolled relatively older patients than other studies therefore, OS results should be interpreted with caution and separate regression analysis conducted.

Figure 1:

PRISMA flow sheet of study selection.

Table 1.

Baseline characteristics of the patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) who were enrolled in the clinical trials included in the meta-analysis.

Study	Design	No. of patients	Treatment	Median age (range), y	No. of males (%)	Median follow-up time, months	Patients referred for SCT after induction/consolidation
TKI + blinatumomab as first-line therapy
Foa et al., 202015	Phase II nRCT	63	Dasatinib + blinatumomab + steroids	54 (24–82)	29 (46)	18	24 (38%)
Jabbour et al., 202316	Phase II nRCT	40	Ponatinib + blinatumomab + steroids	57 (38–72)	20 (50)	15	1 (2%)
TKIs as first-line therapy
Xie et al., 202317	Phase II nRCT	41	Dasatinib + steroids	52.8 (16–84)	20 (48.7)	15.4	17 (41%)
Foa et al., 201118	Phase II nRCT	53	Dasatinib + steroids	53.6 (23.8–76.5)	25 (47)	24.8	18 (34%)
Vignetti et al., 200719	Phase II	29	Imatinib + steroids	69 (61–83)	NA	17	NA
Martinelli et al., 202220	Phase II	44 (patients unfit for SCT or chemotherapy)	Ponatinib + steroids	66.5 (26–85)	22 (50.0)	34.9	6 (13%, later deemed fit)
Chemotherapy-free regimens for R/R disease
Jabbour et al., 202316	Phase II nRCT	14	Ponatinib + blinatumomab + steroids	38 (32–50)	9 (64)	22	6 (43%)
Martinelli et al., 201721	Phase II nRCT	45	Blinatumomab + steroids	55 (23–78)	24 (53)	9	7 (15%)
Ottmann et al., 200722	Phase II	36	Dasatinib + steroids	46 (15–85)	23 (64)	8.3	NA
Ottmann et al., 200223	Phase II	48	Imatinib + steroids	50 (22–78)	24 (50)	6	4 (9%)

TKI, tyrosine kinase inhibitor; nRCT, non-randomized clinical trial; R/R, relapsed/refractory.

The pooled response rates and survival rates of patients receiving different chemotherapy-free regimens are shown in Table 2, and the ORs of response rates and survival rates for different treatment groups are shown in Table 3.

Table 2.

Pooled response rates and survival rates of patients receiving different chemotherapy-free regimens.

% (95% CI)
Treatment	No. of patients	CHR	CMR	1-year OS	2-year OS	1-year DFS	2-year DFS
Comparison of TKI vs. TKI + Blina as first-line therapy
TKI + steroids	167	98 (83–100)	39 (25–55)	83 (76–88)	65 (58–72)	56 (48–63)	42 (32–53)
TKI + Blina + steroids	103	98 (92–99)	81 (69–89)	96 (90–99)	95 (89–98)	90 (83–95)	90 (83–95)
Comparison of TKIs in patients with ND disease
Dasa + Blina + steroids	63	98 (91–100)	72 (53–87)	97 (89–100)	95 (87–99)	87 (77–94)	87 (77–94)
Pona + Blina + steroids	40	96 (82–100)	87 (72–96)	95 (82–99)	95 (82–99)	95 (82–99)	95 (82–99)
Dasa + steroids	94	98 (87–100)	51 (40–63)	85 (76–91)	69 (59–78)	59 (48–68)	51 (41–61)
Pona + steroids	44	86 (73–95)	41 (26–57)	84 (70–93)	68 (52–81)	55 (39–70)	32 (19–48)
Imat + steroids	29	100 (88–100)	15 (4–34)	72 (53–87)	48 (29–67)	48 (29–67)	31 (15–51)
Comparison of regimens in patients with R/R disease
Pona + blina + steroids	14	92 (64–100)	79 (49–95)	79 (49–95)	79 (49–95)	57 (29–82)	95 (82–99)
Dasa + steroids	36	42 (26–59)	58 (41–74)	NA	NA	NA	NA
Blina + steroids	45	36 (22–51)	31 (18–47)	44 (30–60)	NA	NA	NA
Imat + steroids	48	29 (17–44)	17 (7–30)	2 (0–11)	NA	2 (0–11)	NA

CI, confidence interval; CHR, complete hematological response; CMR, complete molecular response; OS, overall survival; DFS, disease free survival; ND, newly diagnosed; R/R, relapsed/refractory; TKI, tyrosine kinase inhibitor; Blina, blinatumomab; Dasa, dasatinib; Pona, ponatinib; Imat, imatinib.

Table 3.

Odds ratios (ORs) of response rates and survival rates for different treatment groups.

OR (95% CI)
Treatment group comparisons	CHR	CMR	1-year OS	2-year OS	1-year DFS	2-year DFS
TKIs + Blina + steroids vs. TKIs + steroids	2.24 (0.47–10.77)	5.98 (2.99–11.96)	5.1 (1.74–14.9)	10.22 (3.94–26.5)	7.24 (3.53–14.89)	12.3 (5.98–25.31)
Pona + Blina + steroids vs. Dasa + Blina + steroids	0.44 (0.03–7.22)	2.51 (0.72–8.72)	0.92 (0.34–2.48)	0.9 (0.14–5.65)	2.62 (0.53–13.04)	2.62 (0.53–13.04)
Pona + steroids vs. Dasa + steroids	0.14 (0.03–71)	0.65 (0.3–1.40)	0.59 (0.08–4.37)	0.96 (0.44–2.07)	0.85 (0.41–1.75)	0.45 (0.21–0.95)

CI, confidence interval; CHR, complete hematological response; CHR, complete molecular response; OS, overall survival; DFS, disease free survival; Poni, ponatinib; Blina, Blinatumomab; TKI, tyrosine kinase inhibitor; Dasa, dasatinib.

Risk of Bias

The trials had a high risk of bias, as all trials lacked a comparison group and therefore lacked any blinding or randomization. Two clinical studies by Ottmann et al.—one in 2002²³ and another in 2007²²—did not report survival rates and therefore had some concerns for bias due to the selection of reporting results. The risk of bias in each clinical trial included in the meta-analysis is shown in Figure 2.

Figure 2:

Risk of bias assessment using ROB-II tool.

TKIs Versus TKIs plus Blinatumomab as First-Line Therapy

TKIs with steroids were used as first-line therapy in 167 patients in 4 clinical trials, and TKIs with blinatumomab and steroids were used as first-line therapy in 103 patients in 2 clinical trials.

The pooled CMR rate of patients who received a TKI plus blinatumomab (81%; 95% CI, 69–89%) was substantially higher than that of patients who received a TKI alone (39%; 95% CI, 25–55%) (Supplemental Figure 1). Compared with those receiving a TKI alone, patients receiving a TKI plus blinatumomab were nearly 6 times as likely to have CMR (OR, 5.98; 95% CI, 2.99–11.96) (Supplemental Figure 2).

The pooled 1-year OS rate of patients receiving a TKI plus blinatumomab (96%; 95% CI, 90–99%) was higher than that of patients receiving a TKI alone (83%; 95% CI, 76–88%), and the pooled 1-year DFS rate of patients receiving a TKI plus blinatumomab (90%; 95% CI, 83–95%) was higher than that of patients receiving a TKI alone (56%; 95% CI, 48–63%) (Supplemental Figure 3-4). The pooled 2-year OS rate of patients receiving a TKI plus blinatumomab (95%; 95% CI, 89–98%) was higher than that of patients receiving a TKI alone (65%; 95% CI, 58–72%), and the pooled 2-year DFS rate of patients receiving a TKI plus blinatumomab (90%; 95% CI, 83–95%) was higher than that of patients receiving a TKI alone (42%; 95% CI, 32–53%) (Supplemental Figures 5-6). Compared with those receiving a TKI alone, patients receiving a TKI plus blinatumomab were more than 5 times as likely to be alive at 1 year (OR, 5.1; 95% CI, 1.74–14.9) and more than 7 times as likely to be alive and in continuous remission at 1 year (OR, 7.24; 95% CI, 3.53–14.89) (Supplemental Figures 7-8). Similarly, the odds ratio of 2-year OS and DFS were (10.2; 95% CI, 3.94–26.5) and (12.3; 95% CI, 5.98–25.31), respectively, in favor of TKI plus blinatumomab (Supplemental Figures 9-10). The ORs for CHR are shown in table 3 and forest plots (Supplemental Figures 11-14).

24/63 (38%) patients treated with dasatinib plus blinatumomab and 35/94 (37%) with dasatinib were referred for SCT. While 1/40 (2%) patients treated with ponatinib plus blinatumomab, and 6/44 (13%) patients treated with ponatinib were referred for SCT.

Meta-Regression and Subgroup Analyses

We stratified data by TKI type. The CMR rate was 87% (95% CI, 72–96%) in patients treated with ponatinib and blinatumomab and was 72% (95% CI, 53–87%)in patients treated with dasatinib and blinatumomab (Supplemental Figures 15, 16). Patients who received blinatumomab with ponatinib or dasatinib were similarly likely to be alive at 1 year (OR, 0.92; 95% CI, 0.34–2.48) (Supplemental Figure 7). The pooled CMR rates of patients who received dasatinib (51%) and those who received ponatinib (41%) did not differ significantly, but both were significantly higher than that of patients who received imatinib (15%). Similarly, the 1-year OS rates of patients who received dasatinib or ponatinib were similar (85% and 84%, respectively) and were higher than that of patients who received imatinib (72%) (Supplemental Figures 17-20).

Two studies on TKIs, Vignetti et al., 2007¹⁹, and Martinelli et al., 2022²⁰, included relatively older patients which can be a bias for OS analysis. OR of OS was recalculated after removing these studies and similar results were obtained. OR for 1-year OS and 2-year OS was 4.24 (95% CI, 1.34–13.4) and 8.57 (95% CI, 3.15–23.28), respectively in favor of TKI plus blinatumomab.

Chemotherapy-Free Regimens in Patients with R/R Ph+ ALL

Separate analysis was conducted on R/R patients. The pooled CMR rate of patients with R/R Ph+ ALL who were treated with ponatinib and blinatumomab (79%; 95% CI, 49–95%) was higher than that of those who were treated with dasatinib alone (58%; 95% CI, 41–74%), blinatumomab alone (31%; 95% CI, 18–47%), or imatinib alone (17%; 95% CI, 7–30%).

Discussion

A direct comparison of blinatumomab vs. chemotherapy was conducted in a 2017 randomized clinical trial by Kantarjian et al.²⁴ in patients with R/R ALL. Patients who received blinatumomab had significantly better survival and response rates than those who received chemotherapy. Our results in this meta-analysis suggest that the addition of blinatumomab to TKIs and steroids significantly improves CMR and survival rates for patients with Ph+ ALL. The improvement in survival rates with the addition of blinatumomab is likely related to the higher proportion of patients who have CMR.

In the present study, the pooled CMR rate of patients with Ph+ ALL who received blinatumomab and a TKI was 81%. This rate is similar to those achieved in prior clinical trials of ponatinib and hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; 78%) ²⁵ or higher than dasatinib and lower-intensity chemotherapy (65%) ²⁶. Also, the 2-year survival rate of patients who received chemotherapy-free regimens with blinatumomab and TKIs (95%) in the present study was higher than that of the previously reported patients who received hyper-CVAD with ponatinib (80%). In prior studies, patients receiving the combination of lower-intensity chemotherapy with TKIs had higher relapse rates than patients receiving intensive chemotherapy with TKIs. Our meta-analysis showed that the 2-year DFS rate of patients who received a TKI plus blinatumomab was 90%, which was higher than that of the previously reported patients who received ponatinib with hyper-CVAD (75%). However, our meta-analysis also showed that TKIs and steroids elicited a 2-year DFS rate of only 42% and thus might not be ideal without blinatumomab in patients with ND disease. Because CMR is considered an early predictor of long-term outcomes and survival, the high CMR and DFS rates achieved with blinatumomab in combination with newer-generation TKIs raise the question of whether intensive chemotherapy is needed for these patients. However, our analysis did not directly compare intensive chemotherapy with TKI +/− blinatumomab.

In the present study, a subgroup analysis comparing chemotherapy-free regimens containing different TKIs without blinatumomab revealed that the CMR rate of patients receiving the first-generation TKI imatinib (14%) was lower than those of patients receiving second- or third generation TKIs (41% and 51%, respectively). Therefore, second- and third-generation TKIs should be preferred over first-generation TKIs as induction or consolidation therapy. Ponatinib, a pan–BCR::ABL1 TKI, is active against disease with TKI resistance due to the T315I mutation, which is reported in about 75% of patients whose disease relapses after treatment with a second-generation TKI²⁷. Patients who received ponatinib with blinatumomab had higher CMR and DFS rates than those who received dasatinib with blinatumomab; however, the difference was not significant, which can be related to the small sample sizes or relatively short follow-up time. However, large-scale head-to-head comparison studies are needed to determine these differences if one exists. Major genotype or mutation found to be associated with relapse were the IKZF1plus genotype (deletion of IKZF1 plus deletion of CDKN2A/B and/or PAX5) and T315I mutations²⁸. In a prior clinical trial by Chiaretti et al.²⁹, all Ph+ ALL patients with IKZF1plus genotype relapsed after treatment with dasatinib and steroids only. In the study by Foa et al.¹⁵, Ph+ ALL patients with IKZF1plus genotype had a relapse rate of 64% after treatment with dasatinib plus blinatumomab. These findings suggest that blinatumomab can significantly improve outcomes in such patients. Also in the study by Foa et al.¹⁵, 2 patients with the T315I mutation required an urgent switch from dasatinib to ponatinib and SCT. In a 2016 propensity-matched analysis by Sasaki et al.³⁰, patients receiving ponatinib with hyper-CVAD had significantly better survival and response rates than those receiving dasatinib with hyper-CVAD. Therefore, induction or consolidation therapy with ponatinib plus blinatumomab might be more likely than dasatinib plus blinatumomab to elicit CMR, as the 2 agents target most of the mutations leading to resistance. Large-scale randomized clinical studies with long-term follow-up are needed to confirm these results.

The trend in response rates in patients with R/R Ph+ ALL were similar to those in patients with untreated Ph+ ALL. Among these patients, the CMR rate of patients who received blinatumomab and ponatinib (79%) was higher than those of patients who received either a TKI (58%) or blinatumomab alone (31%).

In the study by Jabbour et al.¹⁶, ponatinib plus blinatumomab was used as induction/consolidation therapy, only 1 patient underwent SCT, and the 1-year DFS rate was 95%. No patient had disease relapse at a median follow-up of 15 months. In contrast, in the study by Foa et al.¹⁵, 24 patients underwent SCT after induction/consolidation therapy, and the 1-year DFS rate was 87%. SCT is frequently used in Ph+ ALL patients however, SCT is also associated with substantial mortality and morbidity and compromises the quality of life ³¹. TKIs and steroids alone are not often used as first line therapy. However, high CMR and DFS rates were achieved in patients treated with addition of blinatumomab to newer generation TKIs without SCT or intensive chemotherapy. Therefore,newer generation TKIs with blinatumomab can be considered as first line therapy in Ph + ALL patients. More large-scale long-term head-to-head comparisons are needed to assess efficacy with SCT-sparing regimen in patients with Ph+ ALL. Furthermore, patients with multiple comorbidities or advanced age might not tolerate or choose not to undergo intensive chemotherapy or SCT. Chemotherapy-free regimens comprising ponatinib, blinatumomab, and steroids might be a feasible and effective option for these patients.

Other chemotherapy-free regimens, including inotuzumab ozogamicin plus bosutinib³³ and ponatinib plus venetoclax,³⁴ have been tested in patients with R/R Ph+ ALL in small-scale clinical trials, and interim analyses have shown promising results. In the phase I trial by Jain et al. (N=18), 10/18 (53%) of the patients treated with inotuzumab ozogamicin and bosutinib had CMR. In the phase I/II study by Short et al. (N=9), 44% of the patients treated with ponatinib and venetoclax had CMR at the time of the interim analysis. Full-term data will provide more information about the feasibility of these newer regimens as induction/consolidation therapy.

The present study had several limitations. The only trial of ponatinib plus steroids enrolled patients unfit for intensive therapy with newly diagnosed Ph+ ALL, and among these patients, 43.2% required dose reductions and 27.3% required ponatinib discontinuation. This meta-analysis relied on study-level data. All the studies included in the meta-analysis were single-arm clinical trials; as such, no direct comparisons among different chemotherapy-free regimens were available, and the comparisons among different clinical trials were indirect. Therefore, the baseline characteristics of the patients enrolled in the trials could have impacted the results of this meta-analysis. Comparisons of long-term survival data might have been affected by the different treatments used after response to chemotherapy-free induction/consolidation therapy (i.e., SCT or chemotherapy) in each trial. Only 9 studies could be included in this meta-analysis; including additional studies would have increased the power to detect significant differences in different subgroups. No significant differences in response or survival were found among patients who received different TKIs, probably because of a smaller number of patients in each group. Despite these limitations, this meta-analysis provides significant results of comparisons of double- and triple-agent chemotherapy-free regimens and provides results of subgroup analyses of patients receiving different TKIs.

Conclusion

Compared with those receiving TKIs and steroids alone, Ph+ ALL patients receiving TKIs and steroids plus blinatumomab had significantly higher rates of CMR and 1- and 2-year survival. Therefore, the addition of blinatumomab to TKIs especially ponatinib should be considered. Given the high response and DFS rates with the chemotherapy-free regimen, large-scale long-term follow-up studies should be considered to assess the necessity of SCT or intensive chemotherapy without compromising responses and outcomes.

Data availability:

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.