International Workshop On Chronic Lymphocytic Leukemia Research Articles

Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial

The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT. This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed. The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT. Roche.

Outcomes of Conservative Indication Criteria for First-Line Treatment in Chronic Lymphocytic Leukemia: Insights from the Brazilian Registry of CLL

Introduction: Chronic lymphocytic leukemia (CLL) exhibits diverse treatment requirements, with some patients receiving immediate treatment while others remain under observation. In 2008, the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) established criteria for treatment indications, widely adopted in clinical practice and trials. The Brazilian Group of CLL (BGCLL) has been evaluating a more conservative approach to treatment indication performed in multiple centers, which avoids predefined cutoff levels for cytopenias and refrains from considering progressive lymphocytosis, extranodal involvement, or disease-related symptoms as isolated criteria. However, the safety and potential different outcomes of this conservative approach compared to the strict IWCLL criteria remain uncertain. Objective: This study aims to compare the outcomes of CLL patients without indication for treatment according to the BGCLL criteria, who were either treated or not based on the center's decision. Methods: We conducted a retrospective analysis of CLL patients enrolled in the Brazilian Registry of CLL, observed between January 2009 and March 2023, meeting the minimum data availability criteria for analysis and following IWCLL inclusion guidelines. Results: A total of 2396 patients from 41 centers were included. Among them, 1313 patients (55%) met the IWCLL criteria for treatment indication, while only 558 patients (23%) fulfilled the more conservative BGCLL indication. Of the 1240 untreated patients, 247 (20%) had a treatment indication based on IWCLL guidelines. Common indications for treatment initiation included cytopenias in 159 patients (64%), disease-related constitutional symptoms in 41 patients (17%), and symptomatic lymphadenopathy in 22 patients (9%). Non-treatment despite having an indication was attributed to BGCLL's more conservative criteria in 67% of cases, severe comorbidities in 6%, and death during follow-up in 27%. Among the 1156 treated patients, 90 patients (8%) received treatment despite lacking a treatment indication according to the IWCLL criteria. According to BGCLL's conservative criteria, 600 (48%) treated patients did not have a treatment indication. After a median follow-up of 58 months (range: 3-506), the overall survival (OS) was 70% at 8 years. Among patients without an indication for treatment according to BGCLL's conservative criteria, OS was significantly worse in treated patients (79%) compared to untreated patients (64%, P<0.0001, figure 1). Conclusion: These real-world data demonstrate that a conservative approach in indicating first-line treatment for CLL is safe and associated with improved survival, possibly by mitigating toxicities and treatment-related complications such as clonal selection. Furthermore, this strategy may conserve resources, enhancing drug accessibility for a larger number of patients in clear need of treatment, particularly in low-income countries.

Real-World Outcomes of Second-Line Chronic Lymphocytic Leukemia Treatments: Retrospective Analysis of the Brazilian Registry of CLL

Introduction: Major advances in the treatment of relapsed-refractory (RR) chronic lymphocytic leukemia (CLL) patients were observed in the last decade with the adoption of targeted agents. While a shift away from chemotherapy is expected, the impact of delayed or unequal access to targeted agents in low- and middle-income countries needs to be uncovered through real-world data. Objective: To assess the clinical outcomes of second-line treatment in RR CLL patients included in the Brazilian Registry of CLL (BRCLL). Patients and Methods: This is an observational study of second-line CLL treatments started between January 2006 and December 2021. BRCLL is a prospective non-interventional data collection tool. All participant centers registered their CLL patients online, after study approval at each center's ethical review board. Diagnosis and staging of included CLL patients were performed in accordance with recommendations from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL). Results: Four hundred and forty-four CLL patients in second-line were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). At CLL diagnosis, Binet staging was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). High beta-2-microglobulin levels at diagnosis were found in 58%, and unmutated IGHV was observed in 61% of patients. At diagnosis, FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed second-line treatments were: FC (+/- R) in 160 patients (36%); chlorambucil (+/- R) in 109 (25%); ibrutinib in 63 (14%); CHOP/CVP (+/- R) in 62 (14%); monoclonal antibodies (+/- steroids) in 33 (7%); allogeneic stem cell transplantation in 9 (2%) and venetoclax in 8 (2%). Forty patients (9%) were treated in clinical trials. Median follow-up after second-line treatment was 34 months (range: 3-176). Median time-to-next treatment (TTNT) was 28 months. TTNT was statistically longer in patients who received second-line with ibrutinib or venetoclax in comparison with FC or chlorambucil +/- anti-CD20 (not reached versus 29 months, p<0.0001) or those who received other regimens (CHOP or CVP +/- anti-CD20, monoclonal antibodies +/- steroids - 12 months, p<0.0001). Higher 3-year treatment-free survival (TFS) was also observed with ibrutinib or venetoclax (69% versus 41% and 23%, respectively, p<0.0001). Among patients included in clinical trials, 3-year TFS was also higher (70% versus 38%, p<0.0001). TFS for patients receiving allogeneic stem cell transplantation was 86% at 3 years. Overall survival (OS) probability at 3 years was 71%. OS was significantly shorter in those who received other regimens (CHOP/CVP-like or monoclonal antibodies +/- steroids - 53%), in comparison with those who received ibrutinib or venetoclax (80%, p<0.0001), or FC/chlorambucil-based chemotherapy (69%, p=0.01). Conclusion: Over the reported period, second-line CLL treatments in Brazil were mostly chemotherapy- or chemoimmunotherapy-based, with unfavorable outcomes associated with CHOP/CVP-like regimens or monoclonal antibodies +/- steroids. While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in the public setting.

Clinico-Hematologic Profile of Chronic Lymphocytic Leukemia inEgypt: A Three-Center Experience

AbstractBackground: Chronic lymphocytic leukemia is a malig-nancy of CD5+ B cells that is characterized by the accumulationof small, mature-appearing neoplastic lymphocytes in theblood, bone marrow and secondary lymphoid tissues, resultingin lymphocytosis, leukemic cell infiltration of the bone marrow,lymphadenopathy and splenomegaly.Aim of Study: Our objective was to analyse clinical,haematological, immunophenotypic and cytogenetic profilesof Chronic Lymhocytic Leukemia (CLL) in Egypt.Patients and Methods: This retrospective study involvedone hundred and twenty adult CLL patients diagnosed accord-ing to International Workshop on Chronic LymphocyticLeukemia (IW-CLL) from January 2011 to December 2019.Data were collected and statistically analysed.Results: Chronic lymphocytic leukemia is a disease ofelderly and may have an association hepatitis C virus. Thestudy showed that mean of age of CLL patients was 61.03 (±9.9), 42 (35%) of patients were positive for hepatitis Cantibody.Conclusion: Chronic lymphocytic leukemia is adiseaseof elderly, there may be an association between hepatitis Cvirus and development of chronic lymphocytic leukemia.

Favorable Outcome in CLL Patients Not Treated Despite Presenting Iwcll Criteria: A Retrospective Analysis of the Brazilian CLL Group

Introduction: Some patients with CLL will require treatment at diagnosis, but many other will remain untreated under observation for several years. In 2008, the International Workshop on Chronic Lymphocytic Leukemia(IWCLL) defined the criteria for treatment indications, which have been widely used in daily practice and in clinical trials. We have observed that many patients tolerate several of these clinical manifestations without treatment need, especially in public hospitals were resources and treatment options are scarce. We identified 5 reference centers for CLL that share the same profile of being more conservative in indicating treatment for CLL patients. We decided to analyze if more conservative local criteria for treatment indication impacts on patients' outcomes. Objective: To describe the outcomes of a series of CLL patients treated according to locally defined more conservative criteria for initiating treatment. Methods: The Brazilian Registry of CLL was started in 2004 as a prospective observational data collection tool. Inclusion criteria for enrollment followed the IWCLL guidelines. We retrospectively evaluated all patients with CLL in the Brazilian Registry of CLL who were followed between January 2013 and April 2020 at the 5 reference centers (3 public and 2 private). The following local criteria were used for treatment indications to all patients included: 1) persistent and progressive symptomatic cytopenias (no predefined minimum levels), 2) Massive or symptomatic lymphadenopathy, 3) Massive or symptomatic splenomegaly, 4) Disease-related symptoms, only if persistent and if other causes were excluded, and 5) Autoimmune complications including anemia or thrombocytopenia non-responsive to steroids. Progressive lymphocytosis and extranodal manifestations were not considered for treatment indication. Results: A total of 581 patients were followed during the observation period of 7 years (median follow-up was 40 months (range: 3-86). Median age was 65 years (range: 32-98) and most patients were male (57%). Binet stage was A in 67%, B in 14% and C in 19% of cases. FISH, performed in only 199 patients (34%), was normal in 47%, and showed del13q in 22%, trisomy 12 in 17%, del11q in 8% and del17p in 7%. According to IWCLL criteria, 257 (44%) presented indication for treatment over the time: 140 (55%) at diagnosis and 117 (45%) during follow-up. Based on the local criteria, 148 (25%) patients met criteria for indication of treatment. Therefore, 109 patients with IWCLL indication were not treated to date according to the local criteria. The IWCLL indications for these untreated patients were: cytopenias in 50 patients (48%), constitutional symptoms in 37 patients (35%), progressive lymphocytosis in 9 (9%), and lymphadenopathy or splenomegaly in 8 (8%). The median observation time for these untreated patients from the time of indication of treatment by IWCLL until the analysis was closed was 39 months, ranging from 3 to 86 months. Of the 109 untreated patients, 12 (13%) died during follow-up: 4 from infections probably unrelated to CLL (all patients were elderly, Binet A, non-neutropenic and non-hypoglobulinemic), 2 from cardiac causes, 1 from a car accident and 5 of unknown causes (lost follow-up after at least 2 years). No deaths were attributable to LLC. Overall survival at 4 years was 90% for the patients who were treated versus 89% for the patients who were not treated (P=0.85). Conclusion: Our data suggest that it is feasible and safe to adopt more conservative criteria to indicate treatment in a CLL patient. A more restrict approach may not only reflect in a significant financial impact to the health care system but also avoid premature exposition to prolonged and/or potentially toxic treatments. This finding might be of special interest to low-income countries. Disclosures No relevant conflicts of interest to declare.

Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: A systematic review and meta-analysis.

e19003 Background: Chronic lymphocytic leukemia (CLL) patients with undetectable minimal residual disease (U-MRD) (i.e., &lt; 10-4) after upfront chemotherapy (CT) or chemo-immunotherapy (CIT) have better outcomes than those with detectable MRD (D-MRD). To validate the importance of achieving U-MRD and to assess the magnitude of improvement in progression free survival (PFS) and overall survival (OS) we conducted a systematic review and meta-analysis. Methods: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. Results: Eleven studies comprising 2457 CLL patients treated upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Four studies (n = 924) analyzed the impact of U-MRD on both PFS and OS while 8 studies (n = 1984) provided data only on PFS and 6 (n = 1074) exclusively on OS. U-MRD status was associated with significantly longer PFS overall (P &lt; .001) and in patients who achieved complete remission (CR) according to the International Workshop on CLL (IWCLL) guidelines (P = 0.01). Tests of heterogeneity revealed significant differences across studies evaluating PFS in both patients with U-MRD (Q = 49.27; P = 0.00; I2= 80%) and D-MRD (Q = 199.15; P = 0.00; I2= 95%). OS was also longer in patients with U-MRD overall (P &lt; .001). Test of heterogeneity revealed no significant differences across studies evaluating OS in patients with U-MRD (Q = 9.16; P = 0.06; I2= 56%). Of note, U-MRD did not predict for a longer OS in patients who achieved IWCLL CR. (P = 0.82). This contrasts with data from single series and needs prospective assessment. Conclusions: This study validates the importance of achieving U-MRD in newly diagnosed patients with CLL treated with CT or CIT and provides quantitative evidence of the improvement regarding PFS and OS. MRD status should be incorporated as endpoint into prospective clinical trials and in the evaluation of new agents for CLL therapy as already accepted by the European Medicines Agency (EMA). The clinical significance of MRD in patients treated with BCR or BCL2 inhibitors is largely unknown and warrants study.

Acalabrutinib in Patients with Relapsed/Refractory (R/R) and High-Risk, Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL)

Background: Bruton tyrosine kinase (BTK) is a critical component of B-cell receptor signaling and a validated target for CLL. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor, which has shown promising efficacy and safety in patients with CLL, including high-risk patients. We present preliminary efficacy, safety, and pharmacodynamic results from an ongoing single-center, open-label, phase 2 study of acalabrutinib monotherapy in patients with R/R and high-risk, TN CLL.Methods: Patients with R/R or high-risk (chromosome 17p deletion [del17p] or mutation in TP53 or NOTCH1) TN CLL/small lymphocytic lymphoma (SLL) who met International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for treatment and had an Eastern Cooperative Oncology Group performance status ≤2 were eligible. Patients who had prior BTK inhibitor therapy were excluded. Patients were randomized to receive oral acalabrutinib 100 mg twice daily (BID) or 200 mg daily (QD) until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR) by IWCLL 2008 criteria with modification for lymphocytosis. Secondary endpoints included safety and BTK occupancy. BTK occupancy was measured with a biotin-tagged analogue probe in peripheral blood cells at drug trough time points after 3 days of dosing and after 1, 6, and 12 mo of treatment. BTK occupancy in lymph node samples was measured at drug trough time points after 3 days of dosing.Results: Forty-six patients were enrolled and treated (100 mg BID, n=22; 200 mg QD, n=24). The median age was 64 years (range, 45-83), and 35% (16/46) were TN. Approximately 39% of patients (25% of TN) had bulky lymph nodes ≥5 cm, 37% (50% of TN) had Rai stage III-IV disease at baseline, 76% (88% of TN) had unmutatedIGHV, 21% (40% of TN) had del(17p), 21% (23% of TN) had TP53 mutation, and 47% (54% of TN) had NOTCH1 mutation. As of April 13, 2018, the median time on study for all treated patients was 20 mo (range 1-39), with 89% (41/46) remaining on acalabrutinib. Two patients (9%) in the BID group and 3 patients (13%) in the QD group discontinued treatment due to an adverse event (AE; n=1), progressive disease (n=1), and other reasons (n=3). The patient who discontinued due to progressive disease (BID group) achieved partial response at 2 mo and developed Richter transformation at 6 mo.The ORR was 90% (95% CI: 76, 97) for efficacy evaluable patients (N=39), defined per protocol as patients who had ≥ 6 mo of acalabrutinib (Table). ORR was 95% (75, 100) and 84% (60, 97) for the BID and QD group, respectively. For the intent-to-treat population (N=46), ORR was 80% (66, 91). Most AEs were grade 1/2 and did not require dose delays or modifications. The most common AEs (all grades; >25%) were headache (63%), contusion (50%), diarrhea (43%), upper respiratory tract infection (43%), arthralgia (33%), influenza-like illness (28%), maculo-papular rash (28%), myalgia (26%), and nausea (26%). Grade 3/4 AEs occurred in 33% (15/46) of patients (BID, 27% [6/22]; QD, 38% [9/24]), most commonly (>10%) infections (13%; urinary tract infection, lung infection, hepatitis B reactivation, which led to treatment discontinuation and fatal hepatic failure after 10 mo of treatment, and an invasive pulmonary aspergillosis at 2 mo in the setting of prolonged neutropenia and recent systemic corticosteroid use that led to treatment discontinuation) and neutropenia (11%). Approximately 33% (15/46) of patients (BID, 23% [5/22]; QD, 42% [10/24]) reported serious AEs (all grades), most commonly (>5%) lung infection (7%). No atrial fibrillation was reported, and one grade 1 atrial flutter occurred (BID).On day 4 of cycle 1, median trough BTK occupancy was significantly higher for the BID group versus the QD group in the peripheral blood (95% vs 87%; P<0.001) and in the lymph node (98% vs 90%, P<0.001). Median trough BTK occupancy in the peripheral blood was also higher for the BID group at 1, 6, and 12 mo (range, 98%-99% for BID vs 95%-97% for QD; P<0.05 at all time points).Conclusion: Acalabrutinib monotherapy produced high ORR in R/R and high-risk TN CLL, with an acceptable safety profile. The study was not designed to detect a statistically significant difference in clinical outcomes between the dosing groups. Near complete target coverage (>95%) was more rapidly achieved with 100 mg BID than 200 mg QD dosing in the lymph node and peripheral blood. [Display omitted] DisclosuresNierman:National Institutes of Health: Employment. Covey:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: various patents for ACP-196. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Liu:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Wiestner:Pharmacyclics LLC, an AbbVie Company: Research Funding.

Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study

Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study

Chronic Lymphocytic Leukemia: Clinical Stages Maintain Their Prognostic Significance Over the Course of the Disease and Are Surrogates for Response to Therapy

BackgroundTo determine whether in patients with chronic lymphocytic leukemia (CLL), the clinical stage maintains prognostic significance over time and can be considered as a surrogate for the response to therapy. Patients and MethodsThe data from 229 CLL patients were retrospectively evaluated. The main aims of the study were to describe the changes in clinical stage during the course of CLL as a result of the response to treatment and to determine the time to next therapy (TTNT) and overall survival (OS) according to those changes, in particular, among the heterogeneous International Workshop on CLL (IWCLL) partial response (PR) category. ResultsAmong the patients in the IWCLL PR category, differences were found in TTNT and OS according to the clinical stage at the response evaluation. With a median follow-up period of 91 months (range, 2-390 months), patients with a PR- Binet A at the response evaluation had significantly longer TTNT and OS compared with those with PR-Binet B/C (median TTNT, 26 vs. 11 months; P = .00; median OS, 63 vs. 43 months; P = .047). ConclusionThe results of the present study have shown that for patients with CLL, the Binet clinical stages are good outcome predictors throughout the disease course and also suggest that changes in Binet clinical stage could be useful as response surrogates and to divide the IWCLL PR category into different prognostic subgroups.

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial

Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. AbbVie, Genentech.

Plasma B-Cell Maturation Antigen Levels Are Elevated and Correlate with Disease Activity in Patients with Chronic Lymphocytic Leukemia

Background: B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that promote survival of B-cells, including neoplastic B cells from chronic lymphocytic leukemia (CLL) patients (pts). We have found that BCMA is increased in plasma or serum from patients with multiple myeloma (MM). The level of serum BCMA found among MM pts associates with clinical status and predicts overall survival (OS). However, it is not known whether plasma (p) BCMA levels are elevated in pts with other B-cell malignancies, such as CLL. We examined plasma from healthy adults and pts with CLL for pBCMA and associated the observed levels in CLL pts with disease characteristics and/or known prognostic markers, such as white blood cell counts (WBC), serum β2-M, CLL-cell expression of mutated (M) or unmutated (U) immunoglobulin heavy-chain variable region (IGHV) or ZAP-70, or CLL-cytogenetic markers. We also examined the relationship between pBCMA and time from diagnosis (DX) or sample collection (SC) to initial treatment (treatment-free survival (TFS)) or OS.Methods: We examined the archived, plasma samples of 171 pts with CLL that were collected upon initial presentation to UCSD for studies on factors that could associate with disease outcome. Pts received therapy if they satisfied International Workshop on CLL (IWCLL) criteria for treatment. We examined serial plasma samples from a subset of these pts (n = 21) collected soon after DX, prior to first treatment, after treatment, and at relapse after therapy. We also assessed plasma samples of 76 healthy adults. We determined the pBCMA levels using a polyclonal anti-BCMA antibody in an ELISA available from R&D Systems (Minneapolis, MN). We used Mann-Whitney analysis to assess for associations between the relative pBCMA levels and disease characteristics assessed at the time of SC and Kaplan-Meier analysis to assess the relationship between measured pBCMA and TFS (median 4.1 years) and OS (median follow-up 7.8 years).Results: The median level of pBCMA in pts with CLL obtained from pts that were untreated at the time of first determination of pBCMA levels, regardless of whether they subsequently received therapy (n = 166; 58.54 ng/mL), was higher than that of healthy adults (n = 76; 6.32 ng/mL, P < 0.0001). The median pBCMA levels of samples from pts with CLL-cells that used M-IGHV (n = 87; median 42.13 ng/mL), or that lacked expression of ZAP-70 (n = 88; median 42.59 ng/mL), was lower than that of pts with CLL-cells that used U-IGHV (n = 84; 87.46 ng/mL, P < 0.0001), or that expressed ZAP-70 (n = 83; median 87.38 ng/mL, P < 0.0001). The median pBCMA level of pts with CLL cells that had del(13q) (n = 83; 46.57 ng/mL) was lower than that of pts with CLL cells that did not have detectable del(13q) (n = 77; 73.8 ng/mL; P = 0.0002). The median pBCMA of pts with CLL cells with del(17p) (n = 16; 77.23 ng/mL) appeared lower than that of pts without detectable del(17p) (n = 144; 51.77 ng/mL), but did not reach significance (P = 0.09). The TFS was longer (overall median time from SC to treatment: 2.36 years) among pts with pBCMA levels in the lowest three quartiles (median 3.72 years; range of pBCMA 13.21 - 104.69 ng/mL) when compared to patients with pBCMA in the highest quartile (median 0.67 years; range of pBCMA 110.1 - 782.97 ng/mL; P < 0.0001). Serial pBCMA levels consistently correlated with changes in clinical status among pts (n = 21) who had a pBCMA sample taken within three months of the determination of their clinical status. CLL pts with a pBCMA in the highest quartile had a significantly shorter OS when compared to pts with pBCMA levels in the lower three quartiles (P = 0.023).Conclusions: This is the first study to show that BCMA levels are increased in the plasma of CLL pts. We also demonstrate that the pBCMA levels correlate with other known prognostic indicators of CLL, such as IGHV mutational status, ZAP-70 expression and chromosomal abnormalities. CLL pts with higher pBCMA levels have a shorter TFS and OS. Furthermore, changes in pBCMA levels show consistent correlation with changes in the pts' clinical status during treatment. In summary, pBCMA appears to be a new plasma biomarker to monitor the disease course of CLL patients and determine their outcome. DisclosuresKipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Changes in the incidence, pattern of presentation and clinical outcome of early chronic lymphocytic leukemia patients using the 2008 International Workshop on CLL guidelines

Objectives: Before 2008, diagnosis of chronic lymphocytic leukemia (CLL) relied on 1996 National Cancer Institute Working Group criteria which required an absolute lymphocyte count of 5.0 × 109/l or higher. The up-dated 2008 International Workshop on CLL (IWCLL) guidelines recommend using the B-cell count as a basis for the diagnosis of CLL and indicate a B-cell threshold of 5.0 × 109/l. The objective of this study was to assess the effects of these changes on the pattern of presentation and clinical outcome of early CLL. Methods: For this purpose we analysed 414 patients with previously untreated, Binet stage A CLL diagnosed between January 2006 and December 2010 and registered prospectively at a national database. Results: After patients were reclassified according to updated 2008 IWCLL guidelines, 130 Rai stage 0 CLL patients were reclassifed as clinical monoclonal B-cell lymphocytosis, resulting in a 31.4% decrease (from 414 to 284) in the diagnosis of early stage CLL. Moreover, a shift towards a more advanced Rai clinical stage under 2008 IWCLL criteria was observed. Finally, the estimated 3-year time to first treatment decreased from 77.2 to 69.9% according to whether 1996 National Cancer Institute Working Group criteria or 2008 IWCLL criteria were used. Conclusion: In conclusion, the 2008 IWCLL guidelines modify the distribution of Rai stage at diagnosis and shorten the time to first treatment in early CLL patients. We expect that these changes might be considered in the interpretation of epidemiologic studies in CLL and in designing clinical trials of early therapeutic intervention in patients with asymptomatic CLL.

Update On The Safety and Efficacy Of The Pan Class I PI3K Inhibitor SAR245408 (XL147) In Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients

BackgroundConstitutive activation of phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway by various mechanisms has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). There is mounting evidence suggesting that along with PI3Kγ, PI3Kα may be involved in CLL/NHL. SAR245408 is a potent and selective inhibitor of all α, γ and δ class I PI3K isoforms. It has been shown to inhibit PI3K signaling and impact tumor growth in preclinical tumor models. The impact of SAR245408 on safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor effect was evaluated in patients with relapsed/refractory CLL and NHL from the Sanofi sponsored phase 1 single-agent study (NCT00486135) [Brown et al. ASH Annual Meeting Abstracts 2011. 118 (21): 2683]. MethodsSAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 25 patients were enrolled at the maximum tolerated dose identified in solid tumor patients as part of the expansion cohort in relapsed/refractory lymphoproliferative malignancies. Plasma cytokines and chemokines were evaluated using the Myriad RBM Human Discovery MAP250+ panel (> 250 analytes) and ELISA assays. ResultsAmong the 25 patients (pts), 40% (n=10) had refractory CLL and 60% (n=15) had various relapsed/refractory lymphomas (R/RL), including follicular lymphoma (FL) (n=5), diffuse large B-cell lymphoma (DLBCL) (n=4), Waldenstrom's macroglobulinemia (WM) (n=3), Hodgkin lymphoma (n=2) and B-cell prolymphocytic leukemia (n=1). The median age was 65 years (range 28–83), and 56% were female. Eighty percent of pts had stage III-IV disease and 48% had bulky disease. Five pts were categorized as having refractory disease and the median number of prior regimens was 1 (range 1-7) for CLL pts and 3 (range 0-9) for R/RL pts. For all 25 patients, the median starting absolute lymphocyte count was 1.15 x 103/μL (range 0.3–37.2), the median starting hemoglobin was 11.4 g/dL (range 9.1–15) and the median platelet count was 162 x 103/μL (range 60–431). The median number of cycles administered in CLL pts was 10 (range 5-24) and 5 (range 1-26) in R/RL pts. Six CLL pts experienced an increase in absolute lymphocyte counts within 2-4 weeks of treatment, as has been seen with other PI3K inhibitors. According to modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria, 4 CLL pts had partial response (PR), 1 had nodal PR with increased lymphocytosis, and 5 had stable disease (SD); the progression free survival (PFS) in the responding pts was 22, 21.2, 15.6 and 15.4 months while in the SD pts was 12.5, 9.2, 7.4, 5.6, 4.6 and 3.6 months. According to the modified International Working Group response criteria, 3 PRs were reported in R/RL pts [1 WM, 1 DLBCL (transformed) and one FL with PFS of 23.7, 18.4 and PFS 4.8 months respectively]. One hundred percent of CLL and 80% of R/RL pts reported grade 3 or higher AEs, with the most common (≥ 10% of patients) including neutropenia, diarrhea, anemia and hypotension. SAR245408 induced a reduction in levels of chemokines involved in lymphocyte trafficking in CLL subjects (n=8), including CXCL13, CCL3, CCL22 and CCL19 (64, 58, 52 and 54% reduction, respectively, p<0.05) similar to what was reported with PI3K δ specific inhibitors. In addition, a reduction of tumor necrosis factor receptor 2 (TNFR2) and interleukin-2 receptor alpha (IL-2Rα) levels was observed (63% reduction each, p<0.01). ConclusionsThe recommended phase 2 dose of SAR245408 in solid tumor patients was confirmed as safe and tolerable in patients with CLL and R/RL. Single agent SAR245408 demonstrates clinical activity in patients with relapsed or refractory CLL and promising pharmacodynamic effects on chemokine levels involved in lymphocyte trafficking. Disclosures:Brown:Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding; Avila: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy. Off Label Use: The abstract shows scientific information on SAR245408 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Egile:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau.

Phase I Study of Novel Prodrug Dual PI3K/mTOR Inhibitor SF1126 In B-Cell Malignancies.

AbstractAbstract 1783 Background:The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents. Objectives:The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL. Methods:Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial. Results:At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned. Disclosures:Garlich:Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.

The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)–like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring

AbstractIn the revised National Cancer Institute Working Group (NCI-WG)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for CLL, CLL-like monoclonal B lymphocytosis (MBL) is defined as the presence of less than 5 × 109/L B lymphocytes in the peripheral blood. However, the concentration of MBL in the blood is extremely variable. MBL in subjects with lymphocytosis require treatment at a rate of 1.1% per year and present immunoglobulin (IG) gene features and similar to good prognosis CLL. Little is known about low-count MBL cases, accidentally found in the general population. We analyzed IGHV-D-J rearrangements in 51 CLL-like MBL cases from healthy individuals, characterized by few clonal B cells. Seventy percent of the IGHV genes were mutated. The most frequent IGHV gene was IGHV4-59/61, rarely used in CLL, whereas the IGHV1–69 gene was lacking and the IGHV4-34 gene was infrequent. Only 2 of 51 (3.9%) MBL cases expressed a CLL-specific stereotyped HCDR3. Therefore, the IG gene repertoire in low-count MBL differs from both mutated and unmutated CLL, suggesting that the detection of MBL in an otherwise healthy subject is not always equivalent to a preleukemic state. Detailed IG analysis of individual MBL may help to identify cases that necessitate continuous clinical monitoring to anticipate disease progression.

Prognostic factors in chronic lymphocytic leukemia

There has been tremendous progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with chronic lymphocytic leukemia (CLL) or detect minimal residual disease after therapy. These developments have created some uncertainty for clinicians with regard to the optimal incorporation of these novel markers into the daily management of CLL patients. Therefore, this article will attempt to summarize the current evidence with regard to novel biological markers in CLL. The recommendations of the recently revised National Cancer Institute guidelines for the diagnosis and treatment of CLL as reported by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) [1] will be incorporated.

Detection of minimal residual disease in B chronic lymphocytic leukemia (CLL).

In the absence of specific chromosomal translocations the best method for detecting minimal residual disease (MRD) in B cell malignancies is based on the uniqueness of immunoglobulin (Ig) genes rearrangement. We here report a very sensitive method for assessing MRD in complete hematological remission (CHR) chronic lymphocytic leukemia (CLL) patients as defined by the international workshop on CLL (IWCLL). Twelve CLL patients in CHR and complete phenotypic remission (CPR) were included in the study. Eight of them received Fludarabine (FDR), one was treated by Chop regimen, and the remaining 3 were rescued by polychemotherapy followed by autologous bone marrow transplantation (ABMT). DNA extracted from peripheral blood lymphocytes (PBL) of each patient was amplified with VH family specific and framework 3 primers in 5' and a consensus JH primer in 3', before treatment and sequentially after the CPR completion. When no clonal rearrangement could be detected by this assay, the CDR3 sequence specific probe of the clone was used as the 3' primer, associated to the VH family specific primer in 5'. PCR products were analyzed by classical procedures in agarose and/or acrylamide gels. Mixtures of leukemic cells and normal PBL showed detection of a single leukemic cell among more than 10(5) normal cells. Four out of the 12 patients achieved molecular remission (MR) when employing CDR3 amplification. All 3 autografted patients were in MR, whereas only one out of the 9 patients treated by chemotherapy alone achieved MR. When using a clone specific probe, a clonal signal was observed in all cases but one (ABMT). Results presented here confirm that MR may be achieved in a few cases of B-CLL. Further studies are needed to determine the exact relationship between MRD and clinical outcome.

Prognosis of chronic lymphocytic leukemia: analysis of one hundred cases.

One hundred patients with chronic lymphocytic leukemia (CLL) followed in our department between November 1969 and December 1982 were reviewed and classified according to the staging system proposed by the International Workshop on CLL (IWCLL). Analysis of actuarial survival curves revealed a significant chi-square value for heterogeneity and trend. In addition, thrombocytopenia and anemia appeared to be the most important risk factors. A large variability in the course of disease, not well explained by the staging system of the IWCLL, was found among the nonanemic and nonthrombopenic patients. Analysis of A and B stage patients according to absolute peripheral blood lymphocytosis (less or more than 50 X 10(9)/liter) showed two separate patterns of survival.