Combination of venetoclax with BCR-ABL tyrosine kinase inhibitor as a therapeutic strategy for Philadelphia chromosome-positive leukemias

ABSTRACT

Objectives:

Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias.

Methods:

We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias.

Result:

A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy.

Conclusion:

Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.

KEYWORDS:

• Philadelphia chromosome-positive leukemias
• combination of venetoclax with TKI
• hypomethylating agents
• efficacy

Introduction

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 22 and ABL proto-oncogene 1 (ABL1) gene on chromosome 9 [1]. It is ubiquitous in chronic myelogenous leukemia (CML), and is also commonly seen in acute lymphoblastic leukemia (ALL), and, to a lesser extent, mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) [2,3]. The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of Ph + leukemias. These targeted drugs, in comparison with conventional chemotherapy, have a lower toxicity and better direct action against specific oncogenic pathways [4]. However, mutation-driven resistance to TKIs is a critical clinical challenge in CML, causing some chronic patients to progress to the accelerated phase (AP) or a fatal blast phase (BP), which have a poor prognosis and conventional chemotherapy has been much less effective, with a response rate of only 30% and a median survival time of only 3–6 months if untreated [5–8]. Likewise, a proportion of Ph + ALL patients still experience relapse, and allogeneic stem cell transplantation (allo-SCT) remains the primary option for both patients with full-blown relapse and those with persistent or recurrent minimal residual disease (MRD) [9,10]. These patients are considered to have poor outcomes despite the use of TKIs, as well as patients with Ph + MPAL or Ph + AML, although they are seldom reported [11–13]. Therefore, there is an urgent need for novel therapies for managing these patients.

Venetoclax is a potent and selective small molecule BCL-2 inhibitor that has been studied in several hematologic malignancies as both monotherapy and in combination with other agents [14–17]. Preclinical studies have demonstrated that BCL-2 is a key survival factor for CML stem/progenitor cells and that combined inhibition of BCL-2 and BCR-ABL1 tyrosine kinase has the potential to significantly improve the depth of response and cure rates of advanced CML [18]. Lenoard et al. also showed that the combination of TKIs and venetoclax has synergistic antileukemic efficacy in Ph + ALL patient xenografted immunodeficient mice [19]. Moreover, Wang H et al. reported promising clinical results of a series of relapsed Ph + ALL patients harbor the p.T315I mutation treated with venetoclax, ponatinib, and dexamethasone [20]. Therefore, these findings suggest a novel treatment strategy for Ph + leukemias. Here, we conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias.

Patients and methods

Design of the study

This was a retrospective, single-center study conducted at the First Affiliated Hospital of Soochow University, China. Ph + leukemias were established by the identification of either t(9;22) karyotype or BCR-ABL1 fusion transcript. Between February 2021 and April 2022, a total of 18 diagnosed with Philadelphia chromosome-positive patients who received venetoclax and BCR-ABL1 TKI-based regimens were registered in our center. The main aim of the study was to evaluate the efficacy of such a combination. Informed consent was obtained from all the patients. The last follow-up date was May 26, 2022.

The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state [MLFS] + partial response [PR]). Secondary objectives included additional assessments of efficacy, overall survival (OS), and leukemia-free survival (LFS). Response was assessed by bone marrow analysis after each cycle of therapy. CR was defined as the presence of fewer than 5% blasts in the bone marrow, recovery of neutrophil count to ≥1 × 10⁹/L and platelet count to ≥100 x10⁹/L in the peripheral blood, and no extramedullary diseases. The CRi was defined as meeting the criteria for CR except for neutrophil and/or platelet recovery. MLFS was defined as meeting all CR criteria except for a combination of absolute neutrophil count less than 1.0 × 10⁹/L and platelet count less than 100 × 10⁹/L. PR was defined as a percentage of bone marrow blast above 5%, but a reduction of more than 50% of bone marrow blasts when compared to before treatment. No response (NR) indicated the absence of CR, CRi, MLFS, or PR. Relapse was defined as recurrence of more than 5% lymphoblasts in a bone marrow aspirate unrelated to haemopoietic recovery or by the presence of extramedullary disease. Molecular monitoring with BCR-ABL1 was assessed using quantitative real-time polymerase chain reaction (PCR). Complete molecular response (CMR) was defined as undetectable BCR-ABL1 transcripts with ≥100000 ABL copies detected. Major molecular response (MMR) was defined as a 3-log reduction in BCR-ABL1 transcript levels from baseline, but not meeting the criteria for CMR. The cytogenetic response was defined as complete (0% Ph-positive cells, complete cytogenic response (CCyR)), partial (1%-35% Ph + cells), minor (36-65% Ph + cells, mCyR), minimal (66%-95% Ph + cells) or none (95% Ph + cells).

Venetoclax and BCR-ABL1 TKI-based regimens

Venetoclax dosing began at 100 mg on day one and increased stepwise over 4 days to reach the target dose of 400 mg (100, 200, 400 mg) with dose reduction when administered in conjunction with azole antifungal drugs. Reduction of the venetoclax duration from continuous to less than 2 weeks was allowed in cases of myelosuppression. TKI was administered concomitantly with venetoclax. Three patients with a p.T315I mutation were given ponatinib 30 mg daily (n = 1) or 45 mg daily (n = 2). Two patients with CML-BP who failed to respond to second-generation TKIs received 20 mg of olverembatinib alternate dose due to concomitant with CYP3A4 inhibitors. The remaining patients were treated with flumatinib 600 mg daily (n = 6) or dasatinib 100 mg daily (n = 7). Venetoclax and TKI combination regimen was used in 4 relapsed/refractory patients and 2 CML-BP patients. Furthermore, 10 of 18 patients were treated with venetoclax, and TKI in combination with hypomethylating agents (HMAs), including 5 primary Ph + acute leukemia (1 patients with Ph + AML and 4 patients with MPAL), 3 CML-BP and 2 relapse/refractory patients. Azacitidine (75 mg/m²) was administered subcutaneously on Days 1–7 for 3 cases, and decitabine (20 mg/m²) was administered intravenously on Days 1–5 for 7 cases. In addition to venetoclax and TKI-based regimens, dexamethasone (10 mg daily, gradually reducing the amount) was used in two patients with lymphoid blast phase of chronic myeloid leukemia (CML-LBP).

Statistical analyses

Time to event endpoints were estimated using the Kaplan-Meier method. OS was defined as the time from the start of treatment to all-cause death or the last follow-up date. LFS was defined as the time from complete remission (CR) after the combined regimen until relapse, death, or the last follow-up date, whichever occurred first. All statistical analyses were conducted using Prism software version 7.0 (GraphPad Software, La Jolla, CA, USA).

Results

Characteristics of the cohort

Between February 2021 and April 2022, 18 patients with Ph + leukemias were treated with venetoclax and BCR-ABL1 TKI-based regimens. The baseline characteristics of the 18 patients are summarized in Table 1. The median age for the entire group was 37.5 years (range 13 to 86 years), and there were 8 males and 10 females. The majority of the patients had an Eastern Cooperative Oncology Group Performance status of 0–1 (n = 11, 61.1%). There were 3 patients with Ph + AML, 1 patient with Ph + ALL, 5 patients with Ph + MPAL, and 9 patients with CML (6 CML-CP and 3 CML-AP/BP) at the time of their newly diagnosis (Table 1). However, before the initiation of venetoclax and BCR-ABL1 TKI-based therapy, the patients’ disease status changed from that at primary diagnosis, except for five treatment-naive patients (4 had MPAL, 1 had Ph + AML). Of all nine patients with CML, 6 CML-CP and 1CML-AP were progressed to CML-BP while on TKI therapy. Among the 6 relapsed and refractory patients, 2 were diagnosed as CML-BP patients, 1 of whom failed to two courses of standard IA (idarubicin and cytarabine) regimen, and the other relapsed after remission. In addition, one patient with Ph + ALL and one patient with MPAL were relapsed within 1 year after allogeneic transplantation on the basis of TKI maintenance therapy. There were also two cases of Ph + AML, who had achieved remission after treatment but subsequently relapsed.

Table 1. Patients characteristics.

Patient characteristics	No. (%)
No.	18
Gender (male/female)	8/10
Age, years	37.5(13–86)
Primary diagnosis
Ph + AML	3(16.7)
Ph + ALL	1(5.5)
CML-CP	6(33.3)
CML-AP/BP	3(16.7)
MPAL	5(27.8)
Eastern Cooperative Oncology Group Performance status
0–1	11(61.1)
2	7(38.9)
BCR-ABL1 transcript
p190	4(22.2)
p210	14(77.8)
Status at the time of venetoclax and TKI based therapy
newly diagnosed	5(27.8)
CML-BP	7(38.9)
Relapse/refractory	6(33.3)
Previous treatment with TKI
0	5(27.8)
1	8(44.4)
2	3(16.6)
3	2(11.1)
Previous treatment with venetoclax	3(16.6)

Abbreviation: Ph+, Philadelphia chromosome-positive; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; CP, chronic phase; BP, blastic phase; AP, accelerated phase; MPAL, mixed phenotype acute leukemia; TKI, tyrosine kinase inhibitors.

BCR-ABL1 analysis was initially available in all patients; 14 (77.8%) patients encoding for the p210 protein, and only 4 (22.2%) patients encoding for the p190 protein. Beside the Philadelphia chromosome, additional cytogenetic aberrations were identified in 12 patients (66.7%). All but 3 of the newly diagnosed patients were tested for ABL kinase region mutations: 2 had a p.T315I mutation, 1 a p.Y253H mutation, 1 both a p.Y253H and a p.T315I mutation, 1 both a p.E255K and a p.G250E, 1 both a p.Y253H and a p.E255V mutations. Moreover, 11 out of 17 tested patients (64.7%) with next generation sequencing results had one or more adverse risk mutations as defined by the AML ELN 2017 criteria. TP53 mutation was detected in 1 of the patients, and more importantly, RUNX1 mutation was found in 8 patients. Overall, the patients had received a median number of 1 TKI (range, 0–3), i.e.one for 8 patients, two for 3 and three for 3 patients, prior to venetoclax and TKI-based treatment. The specific characteristics of each patient are shown in Table 2.

Table 2. Characteristics and outcomes of individual patients with Philadelphia chromosome-positive leukemia treated with venetoclax and TKI based regimens.

Pt No.	Age (yr)	Primary diagnosis	Status at the time of TKI/vene	No. prior TKI	ABL Mut.	Gene Mut.	ECOG	Type of BCR-ABL protein	Regimen	TKI	Morphologic response	Molecular response	Cytogenetic response	Follow-up
1	53	CML-CP	CML-LBP	2	Y253H/T315I	negative	1	P210	PON + VEN + DEX	PON	NR	NR	not done	In continuous CR under CT
2	29	CML-CP	CML-MBP	3	negative	TET2	1	P210	FLU + VEN + DEC	FLU	MLFS	NR	not done	In continuous CR after HSCT
3	49	Ph + AML	newly diagnosed	0	negative	RUNX1/PTPN11 /BCORL1	1	P210	FLU + VEN + DEC	FLU	CR	MMR	CCyR	In continuous CR after HSCT
4	52	Ph + AML	relapse/refractory	1	negative	CEBPE	2	P210	FLU + VEN*	FLU	CRi	NR	CCyR	In continuous CRi under CT
5	39	CML-AP	CML-MBP	1	E255K/G250E	RUNX1/PTPN11/KRAS /JAK1	1	P210	DAS + VEN + AZA*	DAS	MLFS	NR	mCyR	In continuous CR after HSCT
6	24	Ph + ALL	relapse after transplantation	1	T315I	TET2/TP53/ASXL1/WT1	2	P190	PON + VEN*	PON	CR	CMR	CCyR	In continuous CR after second HSCT
7	59	MPAL	newly diagnosed	0	not done	RUNX1	2	P210	DAS + VEN + DEC	DAS	CR	NR	not done	In continuous CR under CT
8	42	Ph + AML	relapse/refractory	1	T315I	NPM1/WT1/CEBPA	2	P210	PON + VEN + DEC	PON	MLFS	NR	not done	Dead of complications
9	44	MPAL	newly diagnosed	0	negative	CEBPA/RUNX1	2	P210	FLU + VEN + DEC	FLU	CR	MMR	CCyR	In continuous CR after HSCT
10	30	MPAL	newly diagnosed	0	not done	RUNX1	1	P190	FLU + VEN + DEC	FLU	CR	MMR	CCyR	In continuous CR after HSCT
11	30	CML-BP	relapse/refractory	1	negative	not done	1	P210	DAS + VEN + DEC	DAS	CRi	NR	NR	In continuous CR after HSCT
12	36	CML-CP	CML-BP with mixed phenotype	3	negative	U2AF1/ETV6	2	P210	OLV + VEN	OLV	MLFS	NR	mCyR	In continuous CR after HSCT
13	29	MPAL	relapse after transplantation	2	negative	RUNX1	2	P190	DAS + VEN	DAS	NR	NR	not done	In continuous NR under CT
14	13	CML-BP with mixed phenotype	relapse/refractory	2	Y253H	RUNX1/MYC/STAT5B/ATM/UNC13D	1	P210	OLV + VEN	OLV	PR	NR	not done	In continuous CR after HSCT
15	24	MPAL	newly diagnosed	0	not done	negative	1	P190	FLU + VEN + AZA	FLU	CR	CMR	not done	In continuous CR under CT, preparing for HSCT
16	51	CML-CP	CML-MBP	1	negative	negative	1	P210	DAS + VEN	DAS	CR	CMR	not done	In continuous CR under CT
17	86	CML-CP	CML-BP with mixed phenotype	1	Y253H/E255V	RUNX1/RELN/BCOR	1	P210	DAS + VEN + AZA + DEX	DAS	CR	CMR	not done	Dead of disease progression
18	35	CML-CP	CML-MBP	1	negative	NPM1/RUNX1	1	P210	DAS + VEN + AZA	DAS	CR	NR	mCyR	In continuous CR after HSCT

*Previously exposed to venetoclax in combination with other regimens

Abbreviation: CML-LBP, chronic myeloid leukemia in lymphoid blastic phase; CML-MBP, chronic myeloid leukemia in myeloid blastic phase; PON, ponatinib; VEN, venetoclax; DEX, dexamethasone; FLU, flumatinib; DAS, dasatinib; OLV, olverembatinib; AZA, azacytidine; DEC, decitabine; CR, complete remission; CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; PR, partial remission; NR, no response; CMR, Complete molecular response; MMR, Major molecular response; CCyR, complete cytogenic response; mCyR, minor cytogenic response; CT, consolidation therapy.

Efficacy and safety of venetoclax and BCR-ABL1 TKI-based therapy

The treatment regimens and outcomes of individual patients are shown in Table 2 and Figure 1. Responses were evaluated after one cycle of venetoclax and TKI-based therapy. The overall response rate (ORR) in all patients was 88.9%, including 9 patients (50.0%) who achieved CR, 2 patients (11.1%) who achieved CRi, 4 patients (22.2%) who achieved a morphologic leukemia-free state (MLFS), and 1 patient (5.6%) who achieved partial remission (PR). One CML-BP patient with a p.T315I mutation did not respond to venetoclax and ponatinib and achieved remission after subsequent chemotherapy and chimeric antigen receptor T-cell immunotherapy (CART). One patient who failed allogeneic hematopoietic stem cell transplantation (allo-HSCT) without ABL1 mutation was also insensitive to dasatinib and venetoclax, and the subsequent multiline salvage treatment did not achieve remission. At the same time, all patients underwent PCR-based assessment for minimal residual disease, and MMR (or better) was achieved in 7 (38.8%) of all 18 patients. CMR was achieved in 4 patients (22.2%). In addition, five patients (55.6%) achieved a CCyR among 9 evaluable patients, including three primary diagnosed patients. Three patients (33.3%) achieved a mCyR and one patient didn’t respond (Table 3).

Figure 1. Clinical response and results of the venetoclax and TKI based regimens.

Table 3. Overall responses with the combination of venetoclax and TKI based regimens (N = 18).

Overall responses	No. (%)
Morphological response
CR	9(50.0)
CRi	2(11.1)
MLFS	4(22.2)
PR	1(5.6)
NR	2(11.1)
Complete molecular response	4(22.2)
Major molecular response	3(16.6)

Abbreviation: CR, complete remission; CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; PR, partial remission; NR, no response.

All 5 patients who were initially diagnosed with Ph + acute leukemia achieved CR, 4 achieved MMR (or better) after one course of treatment, and 3 of them underwent allo-HSCT after 1–2 consolidation treatments of the original regimen or other regimens. The ORR of the remaining relapsed/advanced patients was 84.6% (11/13), while 6 patients directly proceeded to allo-HSCT, 3 patients were assessed as CR/CRi, 2 as MLFS, and 1 as PR before transplantation. Of the 9 patients who underwent allo-HSCT, they were in continuous complete remission within the duration of follow-up.

With a median follow-up of 7.0 months (range, 2.3-15.6) for alive patients, 15 (83.3%) of the 18 patients were in continuous complete remission at the time of this analysis, for a 1-year OS of 85.6% (Figure 2A), 1-year LFS of 76.7% (Figure 2B), and 1-year CIR of 22.4% (Figure 2C). Early mortality (i.e. death within 4 weeks of starting treatment) did not occur.

Figure 2. Kaplan–Meier survival curves for patients treated with venetoclax and TKI based regimens. (A) Overall survival (OS). (B) Leukemia-free survival (LFS). (C) Cumulative incidence of relapse.

Three patients (16.7%) relapsed after a median of 5.2 months (range, 1.2-6.3) from the start of therapy, including two relapse/refractory patients with a p.T315I mutation and one CML-BP patient with both p.Y253H and p.E255V mutations. At the time of relapse, these three patients were on ponatinib (n = 2) and dasatinib (n = 1). The first patient with Ph + ALL found a p.T315I mutation at the time of first molecular relapse and achieved CR2 after switching TKI to ponatinib combined with CART, followed by haploidentical transplantation. However, a second recurrence occurred 9 months after transplantation, and CR3 was reacquired after ponatinib plus venetoclax. To increase the anti-leukemia efficacy, donor-derived anti-CD19 CART cells were subsequently performed and continued maintenance therapy with ponatinib. Unfortunately, the patient relapsed about 4 months after CART treatment, persisting with the p.T315I mutation, and continued complete remission at the time of this analysis with subsequent secondary transplantation. The second patient had relapsed and refractory Ph + AML with a p.T315I mutation, and reached MLFS after receiving the combined regimen of ponatinib + venetoclax + decitabine, but relapsed after a short time and died of sepsis, gastrointestinal bleeding and cardiac insufficiency during the myelosuppression period after receiving the original regimen. A third patient, aged 86, developed CML-BP with myeloid- and lymphoid- associated antigens, relapsed while on dasatinib 6 months after the start of therapy, and died from disease progression.

The regimen was well tolerated overall, with most adverse events related to cytopenias (mostly grade 1 or 2 in severity), and no tumor lysis syndromes or deaths occurred. Multiple serous effusions occurred in one patient, which was considered to be related to dasatinib. Another patient had mild gastrointestinal bleeding due to thrombocytopenia.

Combination of venetoclax, TKI and HMAs

Ten of 18 patients were treated with venetoclax, TKI and HMA regimens, which included 5 primary Ph + acute leukemia (4 had MPAL, 1 had Ph + AML), 3 CML-BP and 2 relapse/refractory patients. All patients received second-generation TKIs (dasatinib or flumatinib) except one patient with p.T315I mutation who received ponatinib. After one cycle, 7 patients (70.0%) achieved CR/CRi, and 3 patients achieved MLFS. MMR (or better) was achieved in 4 (40.0%) of the 10 patients. For post-remission treatment, 1 patient with CML-BP who previously failed to conventional chemotherapy and 3 patients with CML-BP were directly received allo-HSCT, and 5 primary patients continued to received consolidation therapy with the original regimen or conventional chemotherapy. All the 9 cases were still in continuous complete remission within the duration of follow-up. Another patient with a p.T315I mutation relapsed in a short time, as described above. Anyway, it's worth noting that the combinational regimen showed a high response rate and potential survival advantage in primary diagnosed patients.

Discussion

This is a retrospective study of patients with Philadelphia chromosome-positive leukemias who received venetoclax and a BCR-ABL1 TKI-based regimen. The current report shows the efficacy of the above strategy. Following 1 treatment cycle, the overall response rate was 88.9%, the CCyR rate was 55.6%, and the MMR (or better) was 38.8%. It is really exciting that patients who were newly diagnosed with Ph + acute leukemia treated with venetoclax, TKI and HMA regimen all achieved CR, and 4 achieved MMR (or better). Nine patients who responded to treatment were successfully bridged to allo-HSCT and were in continuous complete remission within the duration of follow-up.

Recently, venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), has shown impressive activity against hematologic malignancies [14–17]. In CML, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly decreased leukemic Lin−Sca-1 + cKit + cell numbers and long-term stem cell frequency and prolonged survival in a murine CML model. Additionally, this combination effectively eradicated chronic myeloid leukemia stem cells [18]. Synergistic effects of this combination were also demonstrated in Ph + ALL, which could decrease cell viability and induce apoptosis. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph + ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy. Furthermore, dasatinib and ponatinib appear to have the added advantage of inducing proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting upregulation of antiapoptotic MCL-1, thereby potentially preventing the development of venetoclax resistance [19]. However, Massimino M and colleagues considered that BCL-2 inhibition, alone or in combination with TKIs, did not reduce the self-renewal of primitive leukemic cells, but strongly induced cell death in primary Ph + ALL [21]. Nevertheless, the antileukemic activity of BCL-2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph + leukemias.

However, until now, there have been relatively few clinical studies on this combination in Ph + leukemias. In 2022, Wang H et al. retrospectively analysed 19 relapsed/refractory (R/R) Ph + ALL patients with the T315I/compound-mutation who were treated with venetoclax, ponatinib and dexamethasone (VPD). After one cycle, 17 patients (89.5%) achieved CR/CRi, 11 MMR, and 8 CMR. At a median follow-up of 259 days, the median EFS and OS of patients starting VPD treatment were 242 and 400 days, respectively [20]. Another study, also for R/R Ph + ALL patients, reported that 5 patients (5/9, 56%) achieved CR (n = 4) or CRi (n = 1), and 3 patients (33%) achieved CMR after the first cycle of venetoclax combined with ponatinib [22]. The promising activity of venetoclax and TKI-based combinations was also shown in Ph + AML and CML in myeloid blastic phase (CML-MBP) by a study from the MD Anderson Cancer Center. The ORR was 43% in Ph + AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML was 2.0 months, and for CML-MBP was 10.9 months [23]. Overall, these studies showed reassuring clinical outcomes, but a large cohort study on this combination is still lacking.

Our study was not restricted to Ph + ALL patients, with clinical R/R disease, but also included patients who were newly diagnosed with Ph + acute leukemia. One interesting and unexpected finding in these treatment-naive patients was a high CR rate, whom treated with venetoclax, TKI, and HMA regimens, and also obtained a good molecular response. One patient did not reach MMR, probably due to the short interval of only 26 days from the start of treatment, but the BCR/ABL1 transcripts was reduced from 8468 to 121 copies/10000 abl copies.

Decitabine and 5-azacytidine are the two HMA drugs approved for use in myelodysplastic syndrome and AML. Venetoclax in combination with HMAs was approved by the Food and Drug Administration (FDA) to treat newly diagnosed AML patients unfit for intensive therapy and represents a significant improvement for the treatment of AML [24,25]. As described, in vitro studies, the drug combination showed high pharmacological synergism at low nanomolar concentrations [26,27]. Azacitidine provokes a change in apoptotic priming. For example, azacitidine indirectly causes downregulation of the pro-survival protein MCL-1 as well as an increased expression of the pro-apoptotic proteins NOXA and PUMA. These changes emphasize the dependence on BCL-2 for AML cell survival [26–28]. As a consequence, pharmacological BCL-2 inhibition results in the release of more proapoptotic proteins, which explains the synergy of azacitidine and venetoclax. Similarly, the combination of HMAs with TKIs for the treatment of CML-MBP is intriguing given the HMA’s proven efficacy and modest sustained response rates demonstrated in patients with MDS or AML. A phase-2 trial conducted between 2012 and 2017 investigated decitabine’s combination with dasatinib for advanced-phase CML and Ph + AML [29]. The favorable response rates presented in this study, along with the evidence that achieving a hematologic response prolongs the survival of advanced-phase CML patients, encourages us to put the decitabine + dasatinib combination forward for review as the induction treatment of CML-MBP. Another retrospective study, published in 2021 evaluated the outcomes of all CML-MBP treated at the MD Anderson Cancer Center in the last 20 years [30]. The study reported that compared to patients treated with TKI alone for CML-MBP, treatment with intensive chemotherapy + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. However, its feasibility and efficacy when venetoclax and HMAs combined with TKIs for Ph + leukemias has not yet been studied adequately. In our research, 10 patients were treated with the combination of three drugs, including 2 primary Ph + AML, 4 MPAL, and 4 CML-MBP patients. After one cycle, 7 patients (70.0%) achieved CR/CRi, and 3 patients achieved MLFS. MMR (or better) was achieved in 4 (40.0%) of all 10 patients. Here, we demonstrated for the first time that the combination appears to have significant activity and safety in Ph + leukemias, although the molecular mechanisms of the interaction remain to be elucidated.

This retrospective study which included 18 Ph + leukemias who received a combination of venetoclax and a BCR-ABL1 TKI-based regimen, appeared tolerable with promising efficacy. However, the study has several limitations. First, this is a retrospective study; thus, our findings need to be confirmed in future work. Second, the reliability of the results is limited by the short follow-up period and small number of patients. Third, the heterogeneity of treatment in terms of schedule, dosing, or consolidation, as well as potential reporting bias, also need to be improved. Therefore, prospective studies are needed to properly assess the safety, tolerability and efficacy for this combination therapy.

In summary, venetoclax and TKI-based combination regimens are a feasible approach to treat Ph + leukemias, and are associated with a high CR rate and decent LFS and OS. Moreover, combination of venetoclax, TKI and HMAs, to be used for induction or salvage therapy, is rational and exciting, deserving rapid expansion of evidence to establish its place in practical decision-making.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Jiangsu Overseas Visiting Scholar Program for University Prominent Young & Middle-aged Teachers and Presidents: [Grant Number]; National Natural Science Foundation of China: [Grant Number 81970138]; National Natural Science Foundation of China: [Grant Number 81900130]; Translational Research Grant of NCRCH: [Grant Number (2020ZKMB05)]; Social Development Project of the Science and Technology Department of Jiangsu: [Grant Number BE2021649].