Efficacy of Therapies Following Venetoclax Discontinuation in CLL: Focus on B-Cell Receptor Signal Transduction Inhibitors and Cellular Therapies

Mato, Anthony R.; Roeker, Lindsey E.; Eyre, Toby A.; Jacobs, Ryan; Hill, Brian T.; Lamanna, Nicole; Brander, Danielle M.; Shadman, Mazyar; Ujjani, Chaitra S.; Yazdy, Maryam Sarraf; Perini, Guilherme Fleury; Ibarz, Javier Pinilla; Barrientos, Jacqueline C.; Skarbnik, Alan P; Torka, Pallawi; Pu, Jeffrey J.; Pagel, John M.; Gohil, Satyen; Fakhri, Bita; Choi, Michael Y.; Coombs, Catherine C.; Rhodes, Joanna; Barr, Paul M.; Portell, Craig A.; Parry, Helen; Garcia, Christine; Whitaker, Kate J.; Winter, Allison M.; Sitlinger, Andrea; Khajavian, Sirin; Grajales-Cruz, Ariel; Isaac, Krista; Shah, Pratik; Akhtar, Othman Salim; Pocock, Rachael; Lam, Kentson; Voorhees, Timothy J.; Schuster, Stephen J.; Rodgers, Thomas D.; Martínez‐Calle, Nicolás; Munir, Talha; Bhavsar, Erica B.; Bailey, Neil; Lee, Jason C.; Weissbrot, Hanna; Nabhan, Chadi; Goodfriend, Julie M.; King, Amber C.; Zelenetz, Andrew D.; Dorsey, Colleen; Bigelow, Kayla; Cheson, Bruce D.; Fox, Christopher P.; Allan, John N.

doi:10.1182/blood-2019-123747

Cited by 7 publications

(7 citation statements)

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“…11,12 Although prospective studies have demonstrated the efficacy of venetoclax postibrutinib, 13 limited data exist to inform choice of therapy postvenetoclax. [14][15][16][17][18] Here, we report the characteristics and outcomes of patients with R/R CLL who received BTKi after venetoclax discontinuation for PD.…”

Section: Introductionmentioning

confidence: 99%

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax

Lin

Lew

Handunnetti

et al. 2020

Blood

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Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.

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Section: Introductionmentioning

confidence: 99%

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax

Lin

Lew

Handunnetti

et al. 2020

Blood

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“…Anderson et al [30] described ten patients with progressive CLL after venetoclax (including four cases after successful salvage of Richter transformation) treated with BTK inhibitor therapy, with objective responses in nine cases, although cohort follow up was short. Other groups have similarly reported responses to ibrutinib in small patient cohorts progressing after venetoclax therapy with limited follow up [76][77][78][79][80] . In a recent retrospective analysis of 188 patients receiving subsequent therapy after venetoclax, patients receiving BTK inhibitors had an estimated 24-month PFS of 78%, with longer disease control in BTK inhibitor naïve patients.…”

Section: Pitfallsmentioning

confidence: 97%

Promises and pitfalls of targeted agents in chronic lymphocytic leukemia

Lew¹,

Anderson²,

Seymour³

2020

CDR

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Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy. Two classes of agent in particular, the Bruton tyrosine kinase inhibitors (e.g., ibrutinib) and the B-cell lymphoma 2 inhibitor, venetoclax, induce high response rates and durable remissions in the relapsed/refractory and frontline settings. However, maturing clinical data have revealed promises and pitfalls for both agents. These drugs induce remissions and disease control in the majority of patients, often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches. Unfortunately, in the relapsed and refractory setting, both agents appear to be associated with an inevitable risk of disease relapse and progression. Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression. Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients' quality and length of life. Rational drug combinations, optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

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“…3 The largest series to date has been presented in abstract form and comes from a retrospective real-world study that included 326 patients who discontinued venetoclax. 6 A subcohort of 44 patients were BTKi naïve before treatment with venetoclax, and the ORR with subsequent BTKi therapy among these patients was 83.9%, with a median PFS of 32 months. These data are strikingly consistent with the findings of Lin et al…”

mentioning

confidence: 95%

“…The conventional explanation is that platelets with autoantibodies bound to their surface are prematurely destroyed in the spleen, liver, or both through interaction with Fcg receptors. 4 Autoantibodies can also induce complement-mediated 5 or desialylationinduced destruction of platelets, 6,7 as well as inhibit megakaryocyte function. Aged desialylated platelets are cleared via the hepatic Ashwell-Morell receptor (AMR).…”

mentioning

confidence: 99%

“…8 Recent findings support the notion that opsonization of platelets with anti-GPIba antibodies activates the platelets, resulting in the translocation of neuraminidase-1 to the surface, where it desialylates the platelets, thereby leading to Fcindependent hepatic clearance via the hepatic AMR. 6 Despite these elegant blood® 18 JUNE 2020 | VOLUME 135, NUMBER 25 2207…”

mentioning

confidence: 99%

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