Relapsed Chronic Lymphocytic Leukemia Research Articles

Transforming CLL Management with Immunotherapy: Investigating the Potential of CAR T-Cells and Bispecific Antibodies

Immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies or T-cell engagers, have revolutionized the treatment landscape for various B-cell malignancies, including B-acute lymphoblastic leukemia and many non-Hodgkin lymphomas. Despite their significant impact on these malignancies, their application in chronic lymphocytic leukemia (CLL) management is still largely under investigation. Although the initial success of CD19-directed CAR T-cell therapy was observed in three multiply relapsed CLL patients, with two of them surviving over 10 years without relapse, recent CAR T-cell therapy trials in CLL have shown reduced response rates compared to their efficacy in other B-cell malignancies. One of the challenges with using immunotherapy in CLL is the compromised T-cell fitness from persistent CLL-related antigenic stimulation, and an immunosuppressive tumor microenvironment (TME). These challenges underscore a critical gap in therapeutic options for CLL patients intolerant or resistant to current therapies, emphasizing the imperative role of effective immunotherapy. Encouragingly, innovative strategies are emerging to overcome these challenges. These include integrating synergistic agents like ibrutinib to enhance CAR T-cell function and persistence, and engineering newer CAR T-cell constructs targeting diverse antigens or employing dual-targeting approaches. Bispecific antibodies are an exciting "off-the-shelf" prospect for these patients, with their investigation in CLL currently entering the realm of clinical trials. Additionally, the development of allogeneic CAR T-cells and natural killer (NK) cells from healthy donors presents a promising solution to address the diminished T-cell fitness observed in CLL patients. This comprehensive review delves into the latest insights regarding the role of immunotherapy in CLL, the complex landscape of resistance mechanisms, and a spectrum of innovative approaches to surmount therapeutic challenges.

Absence of BTK, BCL2, and PLCG2 Mutations in Chronic Lymphocytic Leukemia Relapsing after First-Line Treatment with Fixed-Duration Ibrutinib plus Venetoclax.

Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study. A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax). Genomic risk features [del(11q), del(13q), del(17p), trisomy 12, complex karyotype, unmutated IGHV, TP53 mutated] and mutations in genes recurrently mutated in CLL (ATM, BIRC3, BRAF, CHD2, EZH2, FBXW7, MYD88, NOTCH1, POT1, RPS15, SF3B1, XPO1) were assessed at baseline in patients with and without PD at data cutoff; gene variants and resistance-associated mutations in BTK, PLCG2, or BCL2 were evaluated at PD. Of 191 patients completing fixed-duration ibrutinib plus venetoclax, with median follow-up of 38.9 months, 29 (15%) developed PD. No baseline risk feature or gene mutation was significantly associated with development of PD. No previously reported resistance-associated mutations in BTK, PLCG2, or BCL2 were detected at PD in 25 patients with available samples. Of the 29 patients with PD, 19 have required retreatment (single-agent ibrutinib, n = 16, or ibrutinib plus venetoclax, n = 3); 17 achieved partial response or better, 1 achieved stable disease, and 1 is pending response assessment. First-line fixed-duration combination treatment with ibrutinib plus venetoclax may mitigate development of resistance mechanisms associated with continuous single-agent targeted therapies, allowing for effective retreatment. See related commentary by Al-Sawaf and Davids, p. 471.

Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting. Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

Time to relapse in chronic lymphocytic leukemia and DNA-methylation-based biological age

Chronic lymphocytic leukemia (CLL) is a mature B cell neoplasm with a predilection for older individuals. While previous studies have identified epigenetic signatures associated with CLL, whether age-related DNA methylation changes modulate CLL relapse remains elusive. In this study, we examined the association between epigenetic age acceleration and time to CLL relapse in a publicly available dataset. DNA methylation profiling of 35 CLL patients prior to initiating chemoimmunotherapy was performed using the Infinium HumanMethylation450 BeadChip. Four epigenetic age acceleration metrics (intrinsic epigenetic age acceleration [IEAA], extrinsic epigenetic age acceleration [EEAA], PhenoAge acceleration [PhenoAA], and GrimAge acceleration [GrimAA]) were estimated from blood DNA methylation levels. Linear, quantile, and logistic regression and receiver operating characteristic curve analyses were conducted to assess the association between each epigenetic age metric and time to CLL relapse. EEAA (p = 0.011) and PhenoAA (p = 0.046) were negatively and GrimAA (p = 0.040) was positively associated with time to CLL relapse. Simultaneous assessment of EEAA and GrimAA in male patients distinguished patients who relapsed early from patients who relapsed later (p = 0.039). No associations were observed with IEAA. These findings suggest epigenetic age acceleration prior to chemoimmunotherapy initiation is associated with time to CLL relapse. Our results provide novel insight into the association between age-related DNA methylation changes and CLL relapse and may serve has biomarkers for treatment relapse, and potentially, treatment selection.

Mycobacterial Spindle Cell Pseudotumor of the Nasal Cavity.

Mycobacterial spindle cell pseudotumor (MSCP) represents an uncommon tumor-like proliferation associated with nontuberculous mycobacterial infection, i.e., M. avium intracellulare, affecting primarily the lymph nodes of immunocompromised men in their 5th decade. Involvement of the nasal cavity by MSCP is exceedingly rare with only 3 well-documented examples in the literature. A 74-year-old, HIV-negative, man presented with a 0.5-cm nodule of the left nasal cavity clinically presenting as a "nasal polyp." His medical history was significant for colonic adenocarcinoma, cutaneous basal cell carcinoma, and chronic lymphocytic leukemia (CLL) transforming to B-cell prolymphocytic leukemia, responsive to chemotherapy. The patient was diagnosed with prostatic adenocarcinoma treated with radiotherapy two months before the nasal lesion was detected. No lymph node enlargement, pulmonary involvement or hepatosplenomegaly were noticed. The nasal nodule was surgically excised and histopathologically examined to rule out metastatic disease or CLL relapse. Microscopically, the lesion comprised a well-circumscribed, monotonous, spindle cell population in a vaguely storiform arrangement mixed with a heavy infiltrate of neutrophils and sparse lymphocytes. The spindle cells featured finely granular rich eosinophilic cytoplasm with rounded, oval to epithelioid, or elongated nuclei with vesicular chromatin and one or two distinct nucleoli. The lesional cells lacked overt cytologic atypia and showed occasional regular mitoses. The surface epithelium was intact or focally ulcerated. By immunohistochemistry, the spindle cell population stained strongly and diffusely for CD68 and was negative for AE1/AE3, SMA, CD34, and PSA. CD3 highlighted scattered lymphocytes. Ziehl-Neelsen stain disclosed numerous intracytoplasmic acid-fast bacilli. A diagnosis of MSCP was rendered. No recurrences were observed during a 24-month follow-up period. Although exceptionally rare, MSCP should be considered in the differential diagnosis of nodular lesions of the nasal cavity that are characterized microscopically by marked spindle cell proliferation in a vague storiform pattern, admixed with a lymphocytic or mixed inflammatory infiltrate. A negative medical history for HIV infection and medication-induced immunosuppression should not preclude a diagnosis of MSCP, particularly in extranodal sites. Once the diagnosis is established, prognosis appears to be excellent for nasal MSCP following conservative surgical excision.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

THE COURSE OF CHRONIC LYMPHOCYTIC LEUKEMIA AFTER SARS-COV-2 VIRUS INFECTION.

Objective - to investigate the course of B-cell chronic lymphocytic leukemia (CLL) in patients after SARS-CoV-2 virus infection taking into account anamnestic exposure to the ionizing radiation (IR).Methods. The study was performed in a group of 51 CLL patients who were admitted to the Department of Radiation hematology of the National Research Center for Radiation Medicine of NAMS of Ukraine, Kyiv, from January 2020 (the beginning of SARS-CoV-2 epidemic) to August 2023. The group included 19 (37.3 %) clean-up workers of the Chornobyl NPP accident, 15 (29.4 %) inhabitants of radionuclide contaminated areas and 17 (33.3 %) IR non-exposed patients. The diagnosis of CLL was based on clinical history, lymphocyte morphology, and immunophenotypic criteria. Statistical studies were performed using the SPSS software package, version 20.0.Results. The diagnosis of CLL was established for the first time in 14 patients, in seven of them, CLL was diagnosed after 2-17 months after SARS-CoV-2 infection. In contrast to patients who did not suffer from a coronavirus infection, they had pronounced lymphadenopathy, which in some cases was accompanied by hyperleukocytosis, and needed early treatment. Thirteen patients with a previously established CLL were diagnosed with COVID-19 by PCR test. In seven of them (53.8 %) starting treatment was needed, or CLL has progressed. Seven of 51 patients (13.5 %) were vaccinated against SARS-CoV-2. Then, four of them were diagnosed with SARS-CoV-2 infection, confirmed by a positive PCR test, and two patients had a relapse of CLL within 1-2 months after vaccination. Most of patients with signs of the influence of SARS-CoV-2 infection on CLL belonged to sufferers of the Chornobyl NPP accident Conclusions. The clinical features of CLL that developed after SARS-CoV-2 were characterized firstly. The negative impact of SARS-CoV-2 infection on previously established CLL was established. The question about vaccination of CLL patients remains debatable.

68Ga-DOTATATE PET/CT Incidentally Detects Relapsed Chronic Lymphocytic Leukemia in Patient With Metastatic Neuroendocrine Tumor.

A 54-year-old man with metastatic well-differentiated neuroendocrine tumor of the pancreas underwent 68Ga-DOTATATE PET/CT scan to evaluate treatment response. Patient was known for remote history of chronic lymphocytic leukemia (CLL), previously treated. Scan revealed diffusely increased abnormal tracer uptake throughout the marrow of the axial and proximal appendicular skeleton. Bone marrow biopsy revealed relapsed CLL. We present a rare case of relapsed CLL incidentally detected on 68Ga-DOTATATE PET/CT.

Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy

AbstractVenetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

The therapy for early relapsed chronic lymphocytic leukemia: the development of the problem
 The results of the project with the discussion concerning the possibility of optimization approaches for the therapy

The Russian Oncohematology Society with the support of AbbVie completed the project that allows Russian hematologists to discuss the possibilities of optimization approaches for the therapy for early relapsed chronic lymphocytic leukemia, during 2021. The consolidated opinion of the specialists for several clinical situations was formulated at the final meeting.

A Clue to Better Select Chronic Lymphocytic Leukemia Patients with Optimal Response to BNT162b2 mRNA COVID-19 Vaccine

Given the immunosuppression of chronic lymphocytic leukemia (CLL), this disease represents a challenging model for assessing the extent of serologic response to mRNA vaccination against severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).In this perspective, we assessed the efficacy of the BNT162b2 mRNA COVID-19 vaccine in 70 CLL pts followed up at single hematological institution. The study was approved by the Institutional Review Board. Serologic testing for SARS Cov2 IgG was performed using the LIAISON® SARS-CoV-2 S1/S2 IgG test (DiaSorin; Saluggia, Italy), a chemiluminescence immunoassay for the quantitative determination of anti-S1 and anti-S2 specific IgG antibodies to SARS-CoV-2. Clinical sensitivity and specificity of assay were 98.7% and 99.5% respectively. Samples were considered negative for antibody titers below 13 AU/ml. Results were compared with those of an age-matched group of subjects with no hematological malignancy (n=57). Patient samples for serology testing were obtained after median time of 14 days (range, 14-28) from the second vaccine dose.Median age of CLL pts was 72 years (range, 63-88) and 71.4% were males. The median time from CLL diagnosis to vaccination was 82.5 mo. (range, 1-280). Twenty-three pts (32.9%) were treatment naïve (TN), 36 (51.4%) on active therapy (i.e., BTKi, 22; anti-BCL2 12; PI3Ki,1; cyclophosphamide,1) and 11 (15.7%) off-therapy (i.e., 8 in complete [CR] or partial remission [PR], and 3 in CLL relapse). Of note, 9 (25.7%) of 35 pts on therapy with a pathway inhibitor (PI) at the time of vaccination had been given an anti-CD20 antibody.The vaccine elicited an antibody-mediated response in 41 (58.5%) of the 70 CLL pts. An inferior response rate [RR] (58.5% vs 100%, OR, 0.012 [0.0007-0.206];P=0.02) and a lower antibody titers (median, 58 AU/ml; range, 1.8-800 vs. 284 AU/ml; range, 14-800; P< 0.0001) were observed in CLL pts in comparison to age-matched subjects with no hematological malignancy. The RR was higher in TN (87%) or off-therapy pts with sustained clinical response (87.5%) in comparison to pts on therapy at the time of vaccination (41.7%)(<0.0001). Similar results were observed when comparison was performed in terms of antibody titers (P=0.02;Kruskall-Wallis test; Fig 1). In comparison to pts treated with a PI as monotherapy, those who received an anti-CD20 antibody in association to PI had a lower antibody response to SARS-CoV-2 vaccine (11.1% vs 53.8%; OR,0.107 [0.011-0.984];P=0.04).In univariate analysis, the following variables were significantly associated with serological response to SARS-CoV-2 vaccination: early Rai stage (i.e.,0-I) (OR, 0.36 [0.13-0.97];P=0.04), mutated IGHV status (OR,0.30 [0.10-0.88]; P=0.02), lack of active therapy - which comprised TN and off-therapy pts with sustained response - (OR,0.09 [0.03-0.32];P<0.0001), and no anti-CD20 antibody exposure preceding vaccination (OR, 013 [0.01-1.23];P=0.04). Levels of immunoglobulins or absolute values of CD3,CD4,CD8, and CD16/CD56 cells measured before the first COVID-19 vaccination were not associated to vaccine response. Of note, in pts who experienced a serological response a concomitant increase of the absolute of CD16/CD56 positive cells was observed (P=0.02). Finally, Rai stage (OR, 0.19 [0.05-0.79]; P=0.02) and treatment status (OR, 0.06 [0.02-0.27]; P<0.0001) were independent predictors of response in multivariate analysis. We used these factors to build a score that identified pts with different pattern of response to vaccine. Serologic response to SARS-CoV-2 vaccination was 100% in pts with no factor (n=21), 45% in pts. with one factor (n=38) and 36% in pts with two factors (n=11) (P<0.0001).In agreement with results of recent studies (Herishanu et al, Blood 2021; Roeker et al, Leukemia 2021;Perry et al, Blood Cancer J. 2021; Benjamini O et al, Haematologica 2021 ) our findings suggest that antibody-mediated response to COVID-19 vaccination is significantly reduced in CLL and influenced by disease activity and treatment status. The serological response to SARS-CoV-2 vaccination observed in pts. with early disease with no need of therapy may help to identify CLL pts who are expected to achieve an optimal response to COVID-19 vaccine similarly to age- and sex-matched controls. [Display omitted] DisclosuresMolica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Combination Venetoclax and Rituximab: A Novel Approach to Gastrointestinal Hemorrhage from Acquired Von Willebrand Syndrome in the Setting of Relapsed Chronic Lymphocytic Leukemia

Congenital Von Willebrand Disease (VWD) is the most common bleeding diathesis in humans with a prevalence of one percent in the general population. However, acquired Von Willebrand Syndrome (aVWS) is a rare coagulopathy that has been reported to be associated with numerous conditions and occurs through a variety of mechanisms. In addition to causing bleeding diathesis due to coagulopathy, there is evidence that demonstrates Von Willebrand’s Factor (VWF) deficiency leads to aberrant blood vessel formation. Treatment for this disease is directed at stabilization of associated hemorrhage and correction of underlying etiology. We present the case of a patient with aVWS disease due to relapse of Chronic Lymphocytic Leukemia (CLL) complicated by gastrointestinal hemorrhage from gastric and small bowel angiodysplasia treated with rituximab and venetoclax, previously unreported in the medical literature.

Case Presentation – Relapse After Frontline BTKi Therapy in Patients with CLL: Options and Consideration

AbstractThe advent of small molecule inhibitors of B-cell receptor (BCRi) signaling has revolutionized the therapy for patients with chronic lymphocytic leukemia (CLL). These therapies have largely supplanted cytotoxic chemotherapy for both untreated and relapsed disease.1,2 The Bruton’s tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib, have demonstrated high rates of durable responses and prolonged progression free survival (PFS) and are approved for the treatment of previously untreated or relapsed CLL.3–11 Zanubrutinib, which is already approved for mantle cell lymphoma,12 is likely to gain approval for CLL in the near future, and there are other BTKi inhibitors including noncovalent BTKis that are currently in development.

Successful ibrutinib treatment for central nervous system relapse of chronic lymphocytic leukemia after allogeneic hematopoietic stem cell transplantation

Successful ibrutinib treatment for central nervous system relapse of chronic lymphocytic leukemia after allogeneic hematopoietic stem cell transplantation

Drug Screening Reveals That Ibrutinib (PCI-32765) Exhibits Synergy With BCL-2 and Proteasome Inhibitors In Models Of Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL)

BackgroundIbrutinib, a Bruton's Tyrosine Kinase inhibitor, is clinically effective in relapsed MCL and CLL, but responses are often partial and resistance eventually develops. To identify agents that synergize with ibrutinib, we performed an in vitro combinatorial drug screen and evaluated the most promising combinations in additional models. MethodsDrug screens were performed in JVM2 and Z138 MCL cell lines, combining ibrutinib with a diverse panel of secondary agents inhibiting targets within the B-cell receptor (BCR) pathway (SC514, PD325901, enzastaurin, R788, temsirolimus, dasatinib, idelalisib) and agents inhibiting targets outside the BCR pathway (ABT-199, bendamustine, carfilzomib, bortezomib, geldanamycin, panobinostat, PD0332991). Three doses (IC10, IC20, IC 30) for each drug were chosen and combined in a 3x3 format. Bliss Model of Additivity was used to quantitate synergistic cytotoxicity. Levels of cleaved PARP or Annexin V/PI staining were assessed for cell lines exposed to ibrutinib and synergistic agents, including bortezomib, carfilzomib, and ABT-199. The Ibrutinib + carfilzomib combination was further tested in MCL cell lines Rec1 and Jeko, in primary MCL and CLL patient (pt) samples, and in a MCL-SCID-hu mouse. Molecular analysis of the mechanistic interactions of the agents has been initiated using forward-phase antibody arrays (R and D Systems). ResultsInhibitors of targets within the BCR pathway were ineffective at potentiating the effects of ibrutinib (magnitude of synergy ranging -12%-9% in Z138, -25%-8% in JVM2). However, substantial synergistic cytotoxicity was seen with some agents that target outside the BCR pathway (magnitude of synergy ranging -5%-37% in Z138, -17%-48% in JVM2). Notably, we observed robust and reproducible synergistic cytotoxicity by combining ibrutinib with proteasome inhibitors carfilzomib and bortezomib as well as BCL-2 inhibitor ABT-199.The degree of synergyof ibrutinib + ABT-199 in MCL cell lines was durable across all 9 dosing combinations, (23-32% in Z-138, 10-26% in JVM-2). In CLL pt samples, ibrutinib + ABT-199 conferred modest synergy (10-20%) and near-complete cytotoxicity (61-70%). Flow cytometry for cleaved PARP demonstrated a high degree of apoptosis when combining ibrutinib with ABT-199 (94.5% in Z-138, 82.1% in Z-138).At optimal dosing, bortezomib conferred 19% synergy with ibrutinib in Z138 and 27% in JVM2. The best synergistic effect of carfilzomib and ibrutinib was 50% in Z138 and 65% in JVM2. The synergistic effect between carfilzomib and ibrutinib was maintained in Rec1 and Jeko MCL cell lines and in primary MCL pt samples. In CLL pt samples, ibrutinib + proteasome inhibition also conferred high degrees of total cytotoxicity (58-71% for carfilzomib, 42-62% for bortezomib). Flow cytometry for cleaved PARP or Annexin V/PI demonstrated increased apoptosis for ibrutinib +carfilzomib (92.3% in Z138, 61.2% in JVM2, 95% in Rec1, 90% in Jeko). The combination treatment increased the percent survival of MCL-SCID-hu mice in three-fold over single agent treatment in a 125-day trial.Preliminary analysis of proteomic changes induced by ibrutinib+ carfilzomib indicates synergistic alterations in cell cycle proteins and in apoptosis-regulating proteins, although the specific alterations differ between Z138 and JVM2 cell lines. DiscussionWhile agents within the BCR pathway did not display synergistic cytotoxicity with ibrutinib in our drug screen, several agents outside the BCR pathway did synergize with ibrutinib, notably ABT-199, bortezomib, and carfilzomib in two MCL cell lines. For all three drug combinations, this effect appeared to be mediated via apoptosis. The synergistic effect of ibrutinib + carfilzomib was further studied in 2 additional MCL cell lines, 3 MCL pt samples, and CLL pt samples. MCL-SCID-hu mice demonstrated three-fold increased survival when treated in combination over animals treated with either agent alone. The identification of unexpected synergistic cytotoxic interactions between inhibitors of apparently unrelated pathways is a benefit of our combinatorial screening approach, although the molecular mechanisms remain to be elucidated. The combination of ibrutinib with either proteasome or BCL-2 inhibition is proposed as promising novel treatments for MCL and CLL. A phase I/II clinical trial has been designed to test ibrutinib + carfilzomib in relapsed or refractory MCL and CLL. Disclosures:Williams:Celgene: Consultancy, Independent Data Safety Committee member Other, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Research Funding; Millennium: Consultancy, Independent Data Safety Committee member, Independent Data Safety Committee member Other, Research Funding; Pharmacyclics: Consultancy, Research Funding; Onyx: Research Funding; Gilead: Research Funding. Wang:Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

Exposure-Response of Idelalisib Administered in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Chronic Lymphocytic Leukemi

Background: Idelalisib (IDELA) is a potent and selective PI3Kδ inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) (in combination with rituximab) and relapsed indolent non-Hodgkin lymphoma (iNHL) subtypes, follicular lymphoma, and small-cell lymphocytic lymphoma. The relationship between plasma exposures of IDELA and clinical efficacy and safety were evaluated in relapsed/refractory CLL subjects following administration of IDELA 150 mg twice daily (BID) in combination with bendamustine (B) and rituximab (R; Study GS-US-312-0115).Methods: IDELA peak and trough plasma samples were collected every 4 weeks (up to 24 weeks) starting at baseline. Data for safety and efficacy endpoints were collected every 2 and 12 weeks, respectively. IDELA plasma exposures (Cmax, AUCtau, and Ctau) were generated using a previously developed population pharmacokinetic (PK) model (Jin F, et al. CCP . 77: 89-98, 2016). Efficacy and safety data from the phase 3, randomized, double-blind, placebo-controlled study (GS-US-312-0115) were included in the PK/pharmacodynamics (PD) analyses. Efficacy endpoints, including best overall response rate (BOR), duration of response (DOR), progression-free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR), were evaluated against IDELA exposures (AUCtau and Ctau). Safety endpoints, including Grade 3 or 4 adverse events of neutropenia, skin rash, infection, pneumonia, pneumonitis, diarrhea, colitis, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, were evaluated versus IDELA exposures (AUCtau and Cmax). The relationship between average daily dose of IDELA versus exposures (AUCtau and Cmax) was also evaluated. Statistical analysis (such as Kaplan-Meier survival analysis, Cox proportional hazard model, or logistic regression) was conducted for selected efficacy and safety endpoints.Results: Median IDELA exposures were similar in subjects who achieved an objective response (complete response or partial response) and subjects who did not respond (stable disease or progressive disease) and across the 4 response categories (p=0.68; Table 1). As IDELA exposure increased over quartiles, there was no clear trend of prolonged DOR (p=0.50), PFS (p=0.69), or change in SPD. No relationship between LNR (responder versus non-responder) and IDELA exposure was observed. No association was observed between IDELA exposure vs incidence of neutropenia (p=0.35), diarrhea (p=0.78), pneumonia (p³0.12), colitis (p=0.62), AST or ALT elevation (p=0.45), skin rash, and pneumonitis. An increase in the incidence of Grade 3 or 4 infections with higher IDELA exposures was observed (p=0.021). Overall, IDELA in combination with BR was well tolerated, as indicated by the comparable average daily doses (~300 mg) administered across quartiles of IDELA exposure.Conclusions: No exposure-response relationships were observed for efficacy or safety (except infections) endpoints at IDELA 150 mg BID. These results are consistent with the previously observed IDELA exposure-response relationship in subjects with CLL (in combination with rituximab or ofatumumab) and iNHL. Overall, this analysis supports IDELA 150 mg BID in combination with BR for the treatment of relapsed CLL in patients who are fit for immunochemotherapy. [Display omitted] DisclosuresDaryani:Gilead Sciences, Inc.: Employment, Equity Ownership. Sharma:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead: Employment, Equity Ownership. Silverman:Gilead Sciences, Inc.: Employment, Equity Ownership. Adewoye:Gilead Sciences, Inc.: Employment, Equity Ownership. Mathias:Gilead Sciences, Inc.: Employment, Equity Ownership.

Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib in Routine Clinical Practice at an Academic Medical Center

INTRODUCTIONThe effects of ibrutinib treatment on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukemia (CLL) patients (pts) treated on clinical trials suggests: i) a low rate of treatment-emergent (TE) AIC (~2%, Rogers, Leukemia 2016; Montillo, BCJ 2017) and ii) improved control of pre-existing AIC at the time ibrutinib is initiated with the ability to discontinue immunosuppressive therapies (~69%, Vitale, Haematologica 2016). Confirmation of these findings in CLL pts treated in routine clinical practice requires further investigation. METHODSBetween 4/2012 and 1/2017, 286 CLL pts treated with ibrutinib outside the context of a clinical trial were seen in the Division of Hematology at Mayo Clinic. The CLL Database and medical records of these pts were reviewed for details of past history of AIC and TE AIC; the diagnosis of AIC was determined by the treating physician. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the association of history of TE AIC with progression-free (PFS) and overall (OS) survival. Time-dependent Cox regression models were used to look at the association of TE AIC with PFS and OS. Fisher's Exact test was used to test for the association of clinical variables with TE. RESULTSAmong the 286 pts, 242 (85%) pts were treated for relapsed CLL and 44 (15%) pts for previously untreated CLL. The median age at ibrutinib start was 68 years, and 72% were males. Twenty-two percent had TP53 disruption (either del17p or TP53 mutation) and 78% had unmutated IGHV genes. We identified 37/286 (13%) pts with a history of AIC prior to ibrutinib start, including 15 pts with autoimmune hemolytic anemia (AIHA), 11 pts with immune thrombocytopenia (ITP), 5 pts with Evans syndrome, 3 pts with pure red cell aplasia (PRCA), 2 pts with autoimmune neutropenia, and 1 pt with aplastic anemia.Eleven (4%) pts developed TE AIC (including two pts with past history of AIC who developed a different AIC after ibrutinib therapy) including: AIHA (n=4), ITP (n=4), PRCA (n=1), aplastic anemia (n=1), and autoimmune neutropenia (n=1). This occurred after a median of 30 days following the initiation of ibrutinib (range, 8-325 days). Eight pts were able to continue ibrutinib after either temporarily holding ibrutinib (n=6), ibrutinib dose reduction (n=1), or no modification to ibrutinib therapy (n=1). Three of the 11 pts (ITP n=2, aplastic anemia n=1) permanently discontinued ibrutinib as a result of the AIC.Twenty-two of the 37 pts with a prior history of AIC had a remote history of AIC and were not on any AIC treatment and 15/37 pts were receiving AIC directed therapy at ibrutinib start. Among the 15 pts who were on AIC directed therapy at the time of ibrutinib initiation, 6 pts had uncontrolled disease, for which they were receiving ≥20 mg prednisone daily, and 9 pts had controlled AIC on therapy consisting of <20 mg of prednisone daily or equivalent. Five (33%) of the 15 pts on therapy were able to discontinue AIC therapy at a median of 2 months (range, 0-25), an additional 5 (33%) pts were able to reduce the dose and schedule of AIC therapy, and 3 (20%) pts continued AIC therapy with no changes. Two (14%) pts not previously on rituximab were started on the therapy due to continued steroid dependence and inability to taper off steroids. None of these 15 pts had worsening of their underlying AIC as a consequence of initiating ibrutinib therapy. See Figure 1 for temporal relationship of ibrutinib treatment.The median OS and PFS from time of ibrutinib start was not significantly different between pts with a history of AIC and those with no history of AIC (Figures 2 and 3). There was no statistically significant association between age, gender, TP53 disruption, IGHV mutation status, and history of AIC with development of TE or recurrent AIC (p-values all > 0.05). The PFS and OS were not significantly different among pts with TE AIC compared to those pts who did not develop TE AIC. CONCLUSIONIn this large retrospective cohort of ibrutinib treated CLL pts outside the context of clinical trials, we found that 1 out of every 25 pts developed TE AIC. Nonetheless, ~75% pts were still able to continue ibrutinib treatment. Improved control of AIC with discontinuation or de-escalation of AIC treatments in ~67% of pts on AIC directed therapy at ibrutinib start supports previous findings. We did not identify any risk factors for the development of TE AIC in our study. [Display omitted] DisclosuresDing:Merck: Research Funding. Kay:Gilead: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Tolero Corporation: Research Funding. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Hospira: Research Funding; Jannsen: Research Funding; Pharmacyclics: Research Funding. Parikh:AstraZeneca: Honoraria; Pharmacyclics: Honoraria; Pharmacyclics: Research Funding.

Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy

AbstractWe report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10−4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Updates in the Management of CLL/SLL: Management of Relapsed/Refractory Disease and the Role of Minimal Residual Disease

In relapsed chronic lymphocytic leukemia (CLL), the choice of therapy depends on the risk profile, prior therapy, and patient comorbidities. The first novel agent for patients who had previously received chemoimmunotherapy is typically a BTK inhibitor or combination venetoclax + rituximab. For patients with problematic comorbidities, however, a PI3K inhibitor can be used, but generally this is reserved for later lines of therapy. For those who stop ibrutinib due to adverse events, there are broad options but data are still limited. For those whose disease progresses on a BTK inhibitor, the only prospective data are for use of venetoclax. For patients who have been treated with venetoclax + rituximab and experience relapse, retreatment is a possibility if they have had a durable remission. Finally, undetectable minimal residual disease is strongly predictive of durability of response for time-limited regimens but not for continuous BTK inhibition, and is generally not indicated for monitoring patients.