Novel agents and therapies for CLL
Eugen Tausch , Jasmin Bahlo , Sandra Robrecht , Christof Schneider ,GENETIC MARKERS AND OUTCOME IN THE CLL14 TRIAL OF THE GCLLSG COMPARING FRONT LINE OBINUTUZUMAB PLUS CHLORAMBUCIL OR VENETOCLAX IN PATIENTS WITH COMORBIDITY
Conclusion: Prognostic value of genomic aberrations, IGHV and gene mutations were confirmed for G-Clb, while with Ven-G only del(17p) and TP53mut were associated with short PFS and only del(17p) with short OS. Unmutated IGHV was identified as a predictive factor characterizing a group of patients with particular benefit from Ven-G.
Othman Al-Sawaf, Esther Lilienweiss, Jasmin Bahlo, Sandra Robrecht, et al.
HIGH EFFICACY OF VENETOCLAX PLUS OBINUTUZUMAB IN PATIENTS WITH COMPLEX KARYOTYPE (CKT) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PROSPECTIVE ANALYSIS FROM THE CLL14 TRIAL
Conclusion: CKT can be frequently observed in older, treatment-naïve CLL pts. While CKT correlates well with CLL-IPI high/very high risk, 2/3 of these pts do not show TP53 aberrations. Presence of CKT in pts treated with ClbG is associated with shorter PFS and OS, including pts without TP53 aberrations. In contrast, VenG is able to overcome the adverse risk associated with CKT. These findings support the clinical importance of chromosome analysis before choosing frontline therapy, and underline the particular value of VenG in CLL CKT pts.
Alessandra Tedeschi, Jan Burger, Paul M. Barr, Tadeusz Robak, et al.
FIVE-YEAR FOLLOW-UP OF PATIENTS RECEIVING IBRUTINIB FOR FIRST-LINE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA
Conclusion: Single-agent ibr had sustained PFS and OS benefit, including for pts with high-risk genomic features, in the longest follow-up to date from a phase 3 study of first-line BTK-directed therapy. Responses to ibr improved over time with nearly three-fold more pts achieving CR/CRi with long term follow up. With up to 66 months follow up, more than half of pts remain on long-term continuous ibr treatment. No new safety signals emerged.
Arnon P Kater, Julie Dubois, Sabina Kersting, Lisbeth Enggaard, et al.
SAFETY ANALYSIS OF VENETOCLAX AND IBRUTINIB FOR PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL): SECOND INTERIM ANALYSIS FROM THE PHASE II VISION HO141 TRIAL
Conclusion: Treatment with ibrutinib and venetoclax in the setting of R/R CLL shows a favorable benefit-risk profile and a complete remission in 61% of patients after 9 cycles of treatment with an increasing uMRD rate to 52% after one year of treatment. The DSMB recommends continuing of the study.
Tanya Siddiqi, Kathleen Dorritie, Jacob Soumerai, Deborah Stephens, et al.
TRANSCEND CLL 004: MINIMAL RESIDUAL DISEASE NEGATIVE RESPONSES AFTER LISOCABTAGENE MARALEUCEL (LISO-CEL) IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA OR SMALL LYMPHOCYTIC LYMPHOMA
Conclusion: In this study of heavily pretreated patients with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs) were manageable. Patients rapidly achieved CR/CRi and uMRD. The phase 2 component of the study is currently enrolling patients for treatment at dose level 2. Additional follow-up will be presented.
Jenny Wu, Christopher Bolen, John F Seymour, Peter Hillmen, et al.
IMPACT OF MAJOR GENOMIC ALTERATIONS ON OUTCOME OF RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH VENETOCLAX PLUS RITUXIMAB IN THE PHASE 3 MURANO STUDY
Conclusion: We assessed the mutational landscape of R/R CLL by WES and confirmed prior mutation frequency reports. A superior PFS benefit was observed for VenR vs BR in all clinical and molecular subgroups assessed, including the key CLL driver mutations reported here. NOTCH1 mutations may define a new high-risk pt subgroup for VenR. MVA, further validation and deep sequencing for subclones are needed, given the small size of the mutated cohort, and to address the biological basis of the findings.
Richard Greil, Graeme Fraser, Brian Leber, Reinhard Marks, et al.
EFFICACY AND SAFETY OF IBRUTINIB IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS PREVIOUSLY TREATED WITH VENETOCLAX IN THE MURANO STUDY
Conclusion: IBR demonstrated an acceptable tolerability profile with no new safety signals as well as good clinical activity in this series of R/R CLL pts who received IBR following VenR treatment in MURANO. IBR treatment, therefore, seems an acceptable option for pts with CLL who relapse following VenR. More data will be gathered from the MURANO study for pts treated with VenR who progress and subsequently receive treatment with IBR.
Farrukh Awan, Rebecca Chan, Lin Gu, Guan Xing, et al.
TREATMENT EMERGENT ADVERSE EVENTS VARY WITH DIFFERENT PI3K INHIBITORS
Conclusion: Although the approved PI3Kδ inhibitors may be perceived to be associated with synonymous AE profiles (“class effect”), this intra-class comparison highlights specific AE risks associated with each compound. The potential emergence of specific AEs associated with each agent should be considered when selecting a PI3Kδ inhibitor, though drug exposure differences and major limitations of cross-trial comparisons should be noted.
Max Gordon, Julie Huang, Pankaj Bhargava, Alexey Danilov
IMPACT OF COMORBIDITIES ON OUTCOMES OF THERAPY WITH IDELALISIB (IDELA), A PHOSPHOINOTISIDE-3 KINASE-DELTA INHIBITOR, IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Conclusion: Pts with no or minimal comorbidities have favorable outcomes when treated with IDELA and anti-CD20 therapy. While presence of severe comorbidities negatively impacts overall survival regardless of therapy, such patients still benefit from the addition of IDELA to anti-CD20 therapy. Interestingly, unlike ibrutinib (Gordon et al, 2018), comorbidities do not impact IDELA dose interruption/reduction or therapy discontinuation, indicating that the mechanism(s) by which comorbidities lead to inferior outcomes may differ between treatment types. Pts with CLL who have comorbidities continue to represent an unmet medical need.
Paolo Ghia, Ian Flinn, Nicole Lamanna, Marco Montillo, et al.
EFFECT OF DOSE MODIFICATIONS ON RESPONSE TO DUVELISIB IN PATIENTS WITH RELAPSED/REFRACTORY CLL/SLL IN THE DUO TRIAL
Conclusion: DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1-2 weeks or more do not appear to significantly impact response to DUV or PFS.
Jacqueline Barrientos, Ian Flinn, Matthew Davids, Amanda Cashen, et al.
PATTERNS OF DUVELISIB-INDUCED LYMPHOCYTOSIS IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA INCLUDING THOSE WITH HIGH-RISK FACTORS TREATED IN THE DUO TRIAL
Conclusion: DUV monotherapy induces rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in patients with R/R CLL/SLL. Notably, DUV resulted in a deep and prolonged resolution of lymphocytosis to >50% below BL. The pattern of lymphocytosis in high-risk patients was similar to that in the general patient population.