CLL-358: Adaptation of Chronic Lymphocytic Leukemia to Ibrutinib Is Mediated by Epigenetic Plasticity of Residual Disease and Bypass Signaling via the MAPK Pathway

Inhibitors of Bruton's tyrosine kinase (BTKi) and phosphatidylinositol 3-kinase delta (PI3Kδi) that target the B cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While mutations associated with resistance to BTK inhibitors have been identified, limited data are available on mechanisms of resistance to PI3Kδi. Here we present findings from longitudinal whole-exome sequencing of multiply relapsed CLL patients (Ncases=28) enrolled in PI3Ki trials. The non-responder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF and KRAS in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in non-responder CLL cells with and without mutations, while treatment with MEKi rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδi in CLL and provide rationale for combination therapy with PI3Kδ and ERK inhibitors.

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Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2006-07-033274 ◽

2006 ◽

Vol 109 (2) ◽

pp. 405-411 ◽

Cited By ~ 229

Author(s):

Neil E. Kay ◽

Susan M. Geyer ◽

Timothy G. Call ◽

Tait D. Shanafelt ◽

Clive S. Zent ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Hematologic Toxicity ◽

Color Flow ◽

Significant Clinical Activity ◽

Minimal Residual

Abstract Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

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Advances in the biology and treatment of B-cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v85.2.307.bloodjournal852307 ◽

1995 ◽

Vol 85 (2) ◽

pp. 307-318 ◽

Cited By ~ 3

Author(s):

S O'Brien ◽

A del Giglio ◽

M Keating

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Autologous Bone Marrow ◽

Marrow Transplant ◽

Lymphocytic Leukemia ◽

Western Hemisphere ◽

Molecular Heterogeneity ◽

Prognostic Information ◽

New Agents ◽

History Of

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the western hemisphere. Diagnosis and staging of CLL are usually straightforward, but predicting an individual patient's prognosis is still a challenge. Cytogenetic abnormalities provide important prognostic information in CLL and may show its molecular heterogeneity. A search for oncogene abnormalities continues, although no consistent defects have been identified. New agents such as fludarabine produce high complete remission rates and have generated interest in earlier treatment as a first step in a potential cure. Fludarabine also makes autologous bone marrow transplant feasible as a consolidation therapy. Immunologic abnormalities and minimal residual disease persist in most patients in remission. Combining fludarabine with other active agents and devising effective postremission strategies may change the natural history of CLL.

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How I treat chronic lymphocytic leukemia after venetoclax

Blood ◽

10.1182/blood.2020008502 ◽

2021 ◽

Author(s):

Thomas E Lew ◽

Constantine S. Tam ◽

John F. Seymour

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Treatment Options ◽

Cell Receptor ◽

Resistance Mechanisms ◽

Lymphocytic Leukemia ◽

Bcl2 Family ◽

Clinical Scenarios ◽

Car T

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease (uMRD) and facilitating time-limited treatment without utilizing chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory (RR) disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease (PD) is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins and genomic instability. Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors (BCRis), allogeneic stem cell transplantation (SCT), chimeric antigen receptor (CAR) T-cells, and venetoclax re-treatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.

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Italian Cytometry Society (GIC) endorsement of consensus recommendations for measurable residual disease in chronic lymphocytic leukemia

International Journal of Laboratory Hematology ◽

10.1111/ijlh.13766 ◽

2021 ◽

Author(s):

Giovanni D'Arena ◽

Silvestro Volpe ◽

Rachele Amodeo ◽

Virginia Tirino ◽

Fiorella D'Auria ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Consensus Recommendations ◽

Measurable Residual Disease

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Fine-tuning front-line therapy in chronic lymphocytic leukemia

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-020-00615-y ◽

2020 ◽

Vol 13 (3) ◽

pp. 259-265 ◽

Cited By ~ 1

Author(s):

Jan-Paul Bohn ◽

Dominik Wolf

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Kinase Inhibitor ◽

Residual Disease ◽

B Cell Lymphoma ◽

Outcome Data ◽

Lymphocytic Leukemia ◽

Fine Tuning ◽

Targeted Drugs ◽

First Line ◽

Good Tolerability

Summary A deeper understanding of disease biology and the advent of targeted drugs have implemented chemotherapy-free treatment options in chronic lymphocytic leukemia (CLL). With consistently superior outcome data and good tolerability, the Bruton’s kinase inhibitor ibrutinib as well as the B‑cell lymphoma 2 inhibitor venetoclax +/− CD20 antibody have recently been licensed for first-line treatment independently of TP53 status and are currently recommended as therapy of choice in most patient subgroups according to international management guidelines. Survival curves, however, have not reached a plateau and relapse due to acquired resistance or drug intolerance remain major hurdles in CLL treatment. Clinical trials currently focus on the most promising combinations and sequences of highly effective targeted drugs aimed at avoiding drug resistance by further enhancing eradication of minimal residual disease and optimizing drug tolerability. This brief review provides an update on the recently presented clinical trial data in first-line CLL at ASH 2019 and discusses clinically relevant obstacles to overcome.

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