Venetoclax therapy in chronic lymphocytic leukaemia patients relapsed after allogeneic haematopoietic stem cell transplantation

Summary

Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains an option for young and fit chronic lymphocytic leukaemia (CLL) patients with high‐risk disease features. However, allotransplanted patients are generally excluded from clinical trials, making data regarding the use of venetoclax after alloHSCT extremely rare. We report data from 7 CLL patients who received venetoclax after alloHSCT among 53 Italian centers. These patients underwent alloHSCT between 2006 and 2021 after failing chemoimmunotherapy (7/7), ibrutinib (5/7) and/or idelalisib (1/7). Of note, 3/7 patients had already received venetoclax‐based therapy before alloHSCT. Post‐allo HSCT venetoclax treatment resulted safe, with adverse events not different from what reported in clinical trials. Importantly, no meaningful impact on graft versus host disease (GvHD) course was observed: 4/7 patients with pre‐existing chronic GvHD had no exacerbation after venetoclax start, and only one patient developed GvHD during venetoclax therapy, that was managed as per standard clinical practice. Concerning efficacy, 5/7 patients presented a clinical response to venetoclax, with two patients achieving an undetectable minimal residual disease. To our knowledge, this is the largest reported series of CLL patients treated with venetoclax after alloHSCT. In these heavily pretreated and high‐risk patients, previous alloHSCT did not compromise the feasibility of venetoclax therapy, that lacked unexpected toxicities and did not exacerbate GvHD.

Treatment strategies for chronic lymphocytic leukaemia (CLL) have evolved over time, and traditional chemotherapy‐based approaches have been gradually replaced by the advent of targeted therapies. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option with curative potential for young and fit CLL patients with high‐risk disease features (e.g. del(17p) and/or TP53 mutations) and showing resistance to both chemotherapy‐ and novel agents‐based treatment regimens. ¹ However, most CLL patients are not eligible for alloHSCT based on age and/or comorbidities, and patients who previously underwent alloHSCT are generally excluded from clinical trials, making data regarding the safety and efficacy of targeted agents after alloHSCT extremely rare.

Venetoclax has been part of the European clinical practice since 2016, presenting—both in clinical trials and in real‐world experiences—high rates of responses with undetectable minimal residual disease (MRD) when administered in combination with anti‐CD20 monoclonal antibodies, in both pretreated and treatment‐naïve CLL patients. ² , ³ , ⁴ , ⁵ Despite its wide use, to date there are few data on its application in patients with CLL relapsing after alloHSCT. ⁶ , ⁷

Here, we report a case series of seven patients with CLL who were treated with venetoclax as subsequent therapy after alloHSCT. The patients were identified through a specific survey sent to 53 Italian haematology centres specialized in the care of CLL. Thirty‐five centres responded, among which seven centres had patients who received venetoclax in this setting.

Patients' clinical history and subsequent lines of treatment are illustrated in Figure 1, while main aspects of alloHSCT and venetoclax therapy are summarized in Table 1.

FIGURE 1.

Patients' clinical history. Patients' clinical history with timing of subsequent lines of therapy, including allogeneic haematopoietic stem cell transplantation and venetoclax treatment. ALZ, alemtuzumab; CAR‐T, chimeric antigen receptor T cells; CIT, chemoimmunotherapy; CT, chemotherapy; DLI, donor lymphocyte infusion; HSCT, allogeneic haematopoietic stem cell transplantation; Ibr, ibrutinib; Len, lenalidomide; Obi‐Ven, venetoclax plus obinutuzumab; R‐idela, rituximab plus idelalisib; RT, radiotherapy; RTX, rituximab; and Ven, venetoclax.

TABLE 1.

Patients' characteristics and main aspects of alloHSCT and venetoclax therapy.

	Date of CLL diagnosis	CLL prognostic features1	Date of alloHSCT	Type of alloHSCT	Conditioning regimen of alloHSCT	Date of venetoclax start	BM chimerism status at venetoclax start (% donor)	Relevant AEs during venetoclax therapy	cGvHD during venetoclax therapy	Best response to venetoclax	Date of venetoclax discontinuation	Reason for venetoclax discontinuation	Duration of venetoclax therapy	Last follow‐up
Patient 1	01/06/09	FISH: del13, del17 TP53: NA IgHV: NA	14/01/15	MUD 10/10	Non‐myeloablative	15/04/19	50%	Neutropenia G4	/	NR	16/08/19	PD	4 months	16/08/19
Patient 2	23/12/09	FISH: del13, del17 TP53: MUT IgHV: UM	27/04/15	MUD 9/10	Non‐myeloablative	03/05/19	0%	Neutropenia G3	/	PR	09/09/19	PD	4 months	17/09/19
Patient 3	01/02/11	FISH: del17 TP53: NA IgHV: UM	02/04/15	Sibling	Non‐myeloablative	14/08/21	NA	Neutropenia G4	Skin G2	PR	20/01/22	PD	5 months	31/05/22
Patient 4	20/12/16	FISH: neg TP53: MUT IgHV: NA	17/06/20	MUD 7/8	Myeloablative	25/02/21	99%	Infection G2	Skin NA	PR MRD neg	10/03/22	PD	12 months	19/03/23
Patient 5	15/03/08	FISH: del13, del11, del17 TP53: MUT IgHV: UM	13/07/17	MUD 10/10	Non‐myeloablative	11/11/17	1%	/	Lung G2	NR	04/06/18	PD	6 months	19/03/23
Patient 6	01/01/05	FISH: del17 TP53: MUT IgHV: UM	12/01/21	Sibling	Non‐myeloablative	01/04/21	99%	Neutropenia G3	Skin G2	PR MRD neg	15/04/23	MRD neg	24 months	14/09/23
Patient 7	01/12/02	FISH: del11, del13 TP53: NA IgHV: UM	09/03/06	MUD 10/10	Myeloablative	26/08/20	NA	/	Ocular G3	PR	19/10/23	PD	38 months	13/11/23

Note: 1 = Last available before venetoclax start.

Abbreviations: alloHSCT, allogeneic haematopoietic stem cell transplantation; BM, bone marrow; cGvHD, chronic graft versus host disease; CLL, chronic lymphocytic leukaemia; MRD, minimal residual disease; MUD, matched unrelated donor; MUT, mutated; NA, not available; NR, non‐responder; PD, progression disease; PR, partial response; UM, unmutated.

All the patients were diagnosed with CLL between 2002 and 2016 and presented high‐risk features (TP53 deletion and/or mutation in six of six patients for whom data were available and IgHV‐unmutated status in five of five patients for whom data were available). AlloHSCT was performed between 2006 and 2021 after failure of chemoimmunotherapy regimens (patients 1, 2, 3, 5, 6 and 7), covalent Bruton tyrosine kinase inhibitors (BTKi) (patients 2, 3, 4, 5, 6) and idelalisib (patient 5). Interestingly, a subset of patients (patients 4, 5 and 6) also received venetoclax as a bridging therapy before alloHSCT, with the aim of achieving the deepest possible clinical response prior to transplant. The duration of venetoclax therapy was 6 months for patients 5 and 6, while patient 4 received only 1 month of treatment. At the time of alloHSCT, all three patients were in partial response (PR), with patient 5 showing an undetectable MRD in the bone marrow. Patients 1, 2, 4, 5 and 7 underwent alloHSCT from matched unrelated donors, and only two patients (patients 4 and 7) received a myeloablative conditioning regimen. Of note, at the time of relapse after alloHSCT, 4 of 7 patients (patients 1, 2, 3 and 7) received other regimens before starting venetoclax, further increasing the exposure to different treatments. Among patients who had already received venetoclax prior to alloHSCT, patients 4 and 5 started venetoclax at the time of relapse post‐alloHSCT, while patient 6 resumed venetoclax 90 days after alloHSCT in an attempt to eradicate persistently detectable MRD. Venetoclax was administered at full dose to all patients except for patients 1 and 6, who received the dose of 200 mg and 300 mg daily, respectively, due to the occurrence of haematological toxicity, as per the treating physician's decision. Venetoclax was administered in combination with obinutuzumab in patient 4, while the other patients received venetoclax as single agent.

The use of venetoclax in these heavily pretreated patients who had undergone post‐alloHSCT proved to be safe. The observed adverse events (AEs) were consistent with those reported in clinical trials for CLL ² , ³ , ⁸ , with neutropenia being the most relevant one, occurring in 4 out of 7 patients (all G ≥ 3). No clinical or laboratory signs of tumour lysis syndrome were observed. Interestingly, venetoclax did not seem to meaningfully impact graft‐versus‐host disease (GvHD). Four of seven patients (patients 3, 5, 6 and 7) had pre‐existing chronic GvHD, and they did not present GvHD exacerbation after venetoclax start. Indeed, during venetoclax therapy, two of four patients presented an improvement in GvHD symptoms and two of four reduced dose of steroid therapy. Only one patient (patient 4) developed GvHD after venetoclax start, which was treated as standard clinical practice.

Concerning the efficacy, five of seven patients presented a clinical response to therapy (PR) according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, ¹ with patients 3 and 7 achieving undetectable MRD in the bone marrow. Patients 1, 2, 3 and 5 experienced an early disease progression during venetoclax treatment. Patients 1 and 2 had no other lines of therapy after venetoclax and deceased from disease progression. After failing venetoclax, patient 3 received the non‐covalent BTKi pirtobrutinib followed by idelalisib plus rituximab, while patient 5 underwent an experimental therapy with Chimeric antigen receptor T cells followed by pirtobrutinib. Patient 4 achieved a PR with undetectable MRD that lasted 12 months but then presented a Richter transformation, which was managed accordingly. Patient 7 relapsed after more than 3 years of venetoclax therapy, and at the time of data collection was receiving an experimental drug within a clinical trial. Patient 6 stopped venetoclax therapy after 2 years of treatment thanks to the achievement of a persistent undetectable MRD; at the time of data collection, he was still alive and in complete response.

To date, the use of venetoclax in CLL patients relapsing after alloHSCT is still anecdotal. Al‐Sawaf and colleagues reported on venetoclax activity in a small series of five highly pretreated CLL patients who relapsed after alloHSCT, including one patient with Richter syndrome. ⁶ In their series, venetoclax was administered in combination with anti‐CD20 monoclonal antibody (rituximab or obinutuzumab). Similar to our data, under venetoclax‐based regimen, no severe AEs were reported, and importantly, there was no evidence of GvHD. ⁶ More recently, another case of a patient with CLL who relapsed after alloHSCT together with the onset of cutaneous and liver GvHD was described. ⁷ The patient was treated with venetoclax plus rituximab, obtaining an initial response. Also in this case, during venetoclax therapy, there was no exacerbation of GvHD, which was controlled without the need for immunosuppressive therapy. ⁷

Differently from venetoclax, the use of ibrutinib in CLL patients relapsing after alloHSCT has been more widely investigated. Use of ibrutinib was feasible and effective in a cohort of 27 patients with CLL relapsing after alloHSCT, ⁹ and similar data were reported by the European Society for Blood and Marrow Transplantation Registry. ¹⁰ More recently, a retrospective Italian study compared the outcome of 157 CLL patients, showing that the addition of a BTKi may improve the outcome of high‐risk CLL patients undergoing alloHSCT. ¹¹

Thanks to its renowned off‐tumour immunomodulatory properties, ¹² ibrutinib provides benefits in steroid‐dependent or refractory chronic GvHD, and today it is approved for the treatment of chronic GvHD after at least one line of systemic therapy. ¹³ On the contrary, little is known about the possible influence of venetoclax on GvHD. Recently, in acute myeloid leukaemia (AML) preclinical models, the administration of venetoclax prior to alloHSCT was capable of inducing NK‐cell depletion, resulting in durable engraftment and reduced pro‐inflammatory cytokines production, thus suggesting its potential protective role against GvHD. ¹⁴ In line with these preclinical observations, a monocentric experience of post‐alloHSCT administration of venetoclax maintenance to AML patients did not result in an increased incidence of GvHD compared to untreated controls. ¹⁵

To our knowledge, we have reported the largest series, to date, of CLL patients treated with venetoclax after alloHSCT. In these heavily pretreated and high‐risk patients, venetoclax therapy was feasible, lacked unexpected toxicities and did not exacerbate GvHD. Considering the very limited cohort of patients included that present very different disease histories, it is difficult to draw a conclusion on the therapy efficacy. More data on a larger cohort would be needed to investigate the use of venetoclax as a treatment option after alloHSCT.

AUTHOR CONTRIBUTIONS

F.P., C.V. and M.C. designed the research, analysed and interpreted the data and wrote the manuscript. F.P. provided patient care and collected data; C.V. and M.C. provided patient care and supervised the study. C.V. and M.C. equally contributed to this work. E.B., M.C.M., G.C., A.M.F., I.I., R.M., F.M.Q. and G.Q. collected data and provided patient care; G.G., M.K., M.L., L.L., A.R., A.T. and B.B. contributed to data interpretation. All the authors discussed results, contributed to manuscript revision and approved the submitted version.

CONFLICT OF INTEREST STATEMENT

E.B. received honoraria from Amgen and BeiGene. A.M.F. served on advisory boards for AbbVie, Janssen, BeiGene and AstraZeneca. R.M. served on advisory boards for BeiGene and AbbVie. G.G. took part in speaker's bureau for AstraZeneca, BeiGene, Hikma and Johnson & Johnson and served on advisory boards for Abbvie, AstraZeneca, BeiGene, Hikma, Incyte, Johnson & Johnson and Lilly. B.B. received honoraria from Amgen, Janssen, Novartis, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Jazz Pharmaceuticals, AstraZeneca and Incyte and served on advisory boards for Amgen and Jazz Pharmaceuticals. C.V. received consultancy fees from AbbVie and AstraZeneca. M.C. received consultancy fees from AbbVie, AstraZeneca, BeiGene and Janssen and research funding from AbbVie and Janssen. The other authors declare no conflicts of interest.

ETHICS STATEMENT

This study was approved by the Ethics Committee of AOU Città della Salute e della Scienza di Torino (Protocol ID: UNITO‐CLL07; Reference Number 358/2021) in compliance with the ethical standards outlined in the Declaration of Helsinki.

PATIENT CONSENT STATEMENT

Informed consent was obtained from all participants involved in the study, in accordance with International Council for Harmonisation‐Good Clinical Practice (ICH‐GCP).

Perutelli F, Boccellato E, Montalbano MC, Catania G, Deodato M, Frustaci AM, et al. Venetoclax therapy in chronic lymphocytic leukaemia patients relapsed after allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2025;206(3):924–929. 10.1111/bjh.19976

DATA AVAILABILITY STATEMENT

Data that support the findings of this study are available from the corresponding author upon reasonable request.