Fludarabine, Cyclophosphamide And Rituximab Research Articles

Ibrutinib, Fludarabine, Cyclophosphamide and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without Del(17p)/ TP53 Mutation: Six-Year Follow-up Analyses

Background Patients (pts) with IGHV-mutated ( IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab). We designed an investigator-initiated, phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809), and we report here an updated analysis with a median follow-up of 72 months. Methods Inclusion criteria included diagnosis of previously untreated CLL/SLL needing treatment per iwCLL criteria, age ≥18, IGHV-M, absence of both del(17p) and TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (BM) (4-color flow-cytometry, sensitivity 10 -4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with U-MRD (CR/CRi or PR) at end of Cycle 12 stopped all therapy, including ibrutinib. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by clinical examination, blood counts and peripheral blood MRD every 6 months. Results Between March 2016 and August 2018, 45 pts initiated treatment. Data cutoff was July 15, 2023. Baseline characteristics are shown in Table 1. All pts per study inclusion criterion had IGHV-M; however, 1 enrolled pt was later reclassified as IGHV-unmutated. A total of 69% pts had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. Median follow-up duration is 72 months. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy. The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively. Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse. No pt had progression to Richter transformation. One pt developed therapy-related myelodysplastic syndrome; this pt is being monitored for 58+ months without any active therapy for MDS with normal blood counts. One pt died from congestive heart failure during month 9 of the study. Conclusions iFCG regimen with only three cycles of combination chemotherapy achieves U-MRD rates of 98% in bone marrow on an intent-to-treat analysis and a 6-year PFS of 92% in IGHV-M CLL. These results are favorable compared to the 5-year PFS of approximately 65% with FCR (CLL10 trial) for the same genomic subgroup. Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

Targeted Agents in Chronic Lymphocytic Leukemia (CLL): Advancements in Overall Survival Outcomes?

The impact of targeted agents (TAs) in fully mitigating the detrimental effects of CLL on overall survival (OS) remains uncertain. To address this, we compared the 5-year OS of treatment-naïve CLL pts who received targeted agents (TAs) in phase 3 clinical trials with the 5-year OS of age- and gender-matched general population (AGMGP) in Italy and the US. For this analysis, we included clinical trials that involved elderly or unfit pts (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW). We also considered trials enrolling fit pts eligible for FCR (Fludarabine, Cyclophosphamide, and Rituximab) treatment (ECOG1912, FLAIR, and CLL13). We used the method proposed by Liu et al. [BMC Med Res Methodol 2021;21(1):111] to reconstruct individual patient data (IPD) from published Kaplan-Meier survival curves. The expected OS rate for the control population was calculated using 2019 Italian data from the Istituto Nazionale di Statistica (ISTAT) and the 2019 US database. OS of CLL pts and AGMGP were compared for restricted mean overall survival time (RMOST). The treatment effect on OS was then measured as the difference of RMOST and expressed in months. The elderly CLL trial analysis group (2,222 pts) received TAs (58.1%) or chemo-(immunotherapy)(CT/CIT) (41.8%). TAs included Bruton Kinase inhibitors (BTKis) (i.e., ibrutinib [I] or acalabrutinib [A]) alone or with anti-CD20 (75%) or fixed-duration (FD) venetoclax [V] combos (25%). The control CT/CIT arm mainly consisted of CLB+Obinu (66%). The median age of pts was 70 years (range 47-93). The prevalence of del(17p)/mutated TP53, unmutated IGHV, or CIRS score>6 were 9.1% (0-16%), 62.4% (43-66.5%), and 48.6% (11.7-86.1%), respectively. In the aggregate analysis, the 5-year RMOST of elderly pts treated with CT/CIT (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW) was found to be inferior compared to the 5-year RMOST of Italian [Difference (D), -4.2 months; 95% CI: -5.3 to -3.0; P < 0.0001] and US [D, -3.6 months; 95% CI: -4.7 to -2.4; P < 0.001] AGMGP (Fig 1). The analysis of pts treated with TAs provided conflicting results. In the cross-matched comparison between Italian AGMGP and pts treated with BTKi single-agent or combined with anti-CD20, the 5-year RMOST difference indicates an OS advantage for the former (Fig 1). The same applied in the comparison between pts who received FD V-based therapies and Italian or US AGMGP. Notably, the 5-year RMOST of elderly CLL pts treated with BTKi single-agent (RESONATE2, ALLIANCE, ELEVATE-TN) or combined with anti-CD20 (ILLUMINATE, ALLIANCE, ELEVATE-TN) was similar to the 5-year RMOST of US AGMGP [D, -1.2 mo. (-2.5 to 0.1); P = 0.07 for both](Fig 1). OS comparisons between elderly CLL pts and control populations, although controlled for age and gender, do not account for the interaction between comorbidity burden and OS. The proportion of pts with CIRS score > 6 varied widely across trials: RESONATE2, 31%; ELEVATE-TN, 11.1% in the A-arm and 16.8% in the AO-arm; ILLUMINATE, 32.7%; CLL14, 86.1%; and GLOW, 69.0%. Since CLL pts eligible for FCR enrolled in the ECOG1912, FLAIR, and CLL13 trials typically have fewer comorbidities, they enable a clearer evaluation of the TA's impact on OS. Overall, 1,437 patients (64.5%) received TAs, and 789 (35.4%) received CIT. TAs consisted of I+R (51.5%) or FD V-based combinations (VO, VI, VO+Ibr) (48.5%). The median age of pts was 62 years (range 27-84). The prevalence of ECOG PS 0 and unmutated IGHV were 68% and 56%, respectively. The 5-year RMOST of younger/fit pts treated with FCR was inferior to the 5-year RMOST of Italian AGMGP [D, -1.1 mo; 95% CI: -1.8 to -0.3; P = 0.003] but similar to the 5-year RMOST of US AGMGP [D, -0.4 mo; 95% CI, -1.1 to 0.4; P = 0.28]. Interestingly, no significant difference could be observed between the 5-year RMOST of younger/fit pts treated with TAs (IR or Ven-based) and the 5-year RMOST of Italian or US AGMGP (Fig 2). In conclusion, our results suggest that in comparison to CIT, TAs mitigate but do not fully abrogate the detrimental impact of CLL on OS. The intricate interaction between CLL characteristics and the burden of comorbidities can potentially lead to misleading results in clinical trials of elderly pts. The extent of OS improvement obtained with TAs seems higher in younger/fit CLL pts who have fewer comorbidities. However, longer follow-up is needed to discern the ability of these treatments to mitigate the impact of CLL on OS over longer time intervals.

Ibrutinib and Rituximab Versus Fludarabine, Cyclophosphamide, and Rituximab for Patients in NCRI FLAIR Study with Previously Untreated CLL: Assessment of Mutational Landscape of Patients at Baseline and Prognostic Impact

Introduction: Recent studies using next generation sequencing have revealed recurrent mutated genes in CLL are associated with clinical outcome. We assessed the baseline mutational profile of 771 patients from FLAIR treated with either fludarabine, cyclophosphamide and rituximab (FCR) or ibrutinib and rituximab (IR). The prognostic impact of individual gene mutations on disease progression was investigated. Method: FLAIR is a phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to IWCLL criteria. Patients with >20% chromosome 17p deletion were excluded. Patients were randomised to FCR or IR. Somatic hypermutation (SHM) status was determined by PCR amplification of IGHV-IGHD-IGHJ gene rearrangements using IGHV leader/FR1 primers. Bidirectional Sanger sequencing was analysed using IMGT V-Quest and the ARResT/AssignSubsets tool. Extracted DNA was sequenced using an Illumina MiSeq and analysed using an in-house pipeline. Amplicon based targeted sequencing of 33 recurrently mutated genes in lymphoid malignancies were performed in parallel. Detected variants were reported down to minimum variant allele fractions of 3-5% and coverage of 100X. Low level variants were confirmed by repeat sequencing. Results: 771 patients were randomly assigned to receive FCR (385) or IR (386). IGHV gene SHM status was available for 728/771 (94.4%): 388 (53.3%) IGHV unmutated (>98% of nucleotide identity to germline), 294 (40.4%) IGHV mutated and 46 (6.3%) stereotyped subset #2 (n=28 IGHV mutated, n=18 IGHV unmutated). Gene mutations were assessed in 767/771 (99.5%) patients at baseline and mutations (>1) were detected in 480/767 (62.6%). Mutation frequencies ranged from 0.1-18.8% with mutations in SF3B1 (18.8%), ATM (14.5%), NOTCH1 (10.0%), MYD88 (6.1%), POT1 (5.7%), TP53 (5.0%), BRAF (4.4%) and RPS15 (4.0%) being the most frequent. No detectable mutations at baseline were found in 287/767 (37.4%) and there was no significant difference in PFS or OS compared to patients with >1 mutation. A significantly shorter PFS and OS was observed for TP53 mutated patients compared to wildtype (HR 2.23 [95% CI 1.31-3.79]; p=0.003 and HR 2.43 [95% CI 1.04-5.66]; p=0.039 respectively). When further subdivided by treatment, a trend for shorter PFS was observed in TP53 mutated patients in both arms compared to wildtype, but significance was only achieved for FCR (HR 2.48 [95% CI 1.25-4.91]; p=0.009) and not IR (HR 2.27 [95% CI 0.97-5.30]; p=0.059). A significantly shorter PFS was observed for FCR compared to IR in patients with ATM mutations at baseline (HR 0.35 [95% CI 0.16-0.80]; p=0.012) and RSP15 (HR 0.19 [95% CI 0.04-0.96]; p=0.044). A trend for shorter PFS was also observed in NOTCH1 mutated patients treated with FCR however, this was not found to be significant when compared to wildtype or NOTCH1 mutated IR patients. CREBBP mutation at baseline (n=19; 2.5%) was associated with shorter PFS (HR 2.63 [95% CI 1.29-5.35]; p=0.008) and OS (HR 4.37 [95% CI 1.75-10.94]; p=0.002) compared to wild type (Fig). When further subdivided by treatment arm, shorter PFS and OS was also observed for CREBBP mutated patients treated with FCR compared to wildtype (n=11; HR 4.37 [95% CI 1.75-10.94]; p=0.002 and HR 10.14 [95% CI 3.83-26.83]; p<0.001 respectively). A similar trend was not observed with IR (n=8; PFS HR 0.79 [CI 0.11-5.74]; p=0.819 and OS HR NE [95% CI NE-NE]; p=0.988). CREBBP mutated patients treated with FCR had a shorter PFS compared to IR (HR 0.1 [95% CI 0.01-0.86]; p=0.036). The PFS and OS for IGHV subset #2 was similar to IGHV mutated patients (Fig). In FCR treated patients there was no difference between mutated (n=13) and unmutated subset #2 (n=7) but with IR there was a trend that IGHV mutated subset #2 patients (n=15) had better PFS and OS than their IGHV unmutated counterparts. Conclusions: Our study confirms that TP53 mutations result in shorter PFS and OS in CLL. We demonstrate improved PFS when patients with ATM or RPS15 mutations are treated with IR compared to FCR. Mutations in the CREBBP gene have recently been described as a novel candidate driver in CLL. We report a significant improvement in disease progression in CREBBP mutated patients treated with IR when compared to FCR. In contrast to previous studies in frontline CLL IGHV subset #2 patients had a similar outcome to good risk IGHV mutated patients.

Using Peripheral Blood (PB) Measurable Residual Disease (MRD) Levels to Predict

CONCLUSIONS Time-limited treatments for CLL are under investigation but the optimal target for treatment cessation is not fully clear. Bone marrow (BM) measurable residual disease (MRD) is usually the most sensitive measure but would be too invasive to guide treatment in a routine setting. The iwCLL threshold of BM uMRD4 (<0.01%) has been demonstrated to be a powerful indicator of improved outcomes across multiple different trials and the aim of this analysis is to determine the feasibility of using PB MRD analysis to identify patients who have attained BM uMRD4. FLAIR (ISRCTN01844152) is an open-label, randomised, controlled, phase 3 trial comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR), subsequently amended to compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Paired PB & BM samples were scheduled at: (1) response assessment 9 months after randomization in all arms (n=1086); (2) end of treatment after 72 months in the ibrutinib-containing arms (n=137, most I/I+V participants have not reached this timepoint yet); and (3) confirmation of BM uMRD4 for initiation of planned stopping rules in participants with sustained PB uMRD4 defined as <0.01% PB MRD at 3 timepoints over 6 months (n=188 in the I+V arm). MRD analysis was performed using an ERIC-compliant 8-colour flow cytometry assay targeting acquisition of 2.2 million events (detection limit MRD5/0.001%). As the target could not always be met due to sample/laboratory limitations, stringent uMRD4 assessing 500 thousand leucocytes (detection limit 0.005%) was also evaluated. Table 1 shows the BM vs. PB MRD levels for different treatment arms and timepoints. The greatest discrepancy was observed in participants receiving FCR with a median 0.8log higher disease in the BM vs. PB. Participants receiving ibrutinib monotherapy had similar PB and BM MRD levels while the addition of either rituximab or venetoclax was associated with slightly higher (median <0.1 log) BM vs. PB MRD levels for both IR and I+V arms. The difference did not persist in the IR arm but remained during I+V treatment in some cases, with median >0.59 log higher BM vs. PB MRD levels in 29/182 participants achieving PB uMRD4 but with detectable BM MRD. Table 1 also shows the proportion of cases that attain BM uMRD4 according to different PB MRD thresholds. For participants with rituximab exposure in the past 3 months, BM uMRD4 was attained in 75-88% of participants with PB uMRD5, and only 43-76% of participants with stringent uMRD4. For participants with PB dMRD5 (0.001-0.01% MRD), only 14-52% achieved BM uMRD4. However, participants on I+V with either PB uMRD5 or stringent uMRD4 attained BM uMRD4 in 94-96% of cases. Planned cessation of treatment in the FLAIR trial was guided by sustained PB uMRD4, defined as 3 successive results with <0.01% PB disease over six months with confirmation of BM uMRD4 at the final time point. This strategy in the I+V arm is highly effective in achieving improved progression-free and overall survival compared to FCR [see related abstract]. Sustained PB uMRD4 led to BM assessments in 188 participants of which 173/188 (92%) attained BM uMRD4. High sensitivity PB MRD gave concordant results to BM MRD4 analysis in 91% of participants (172/188), while 9/188 (5%) had PB dMRD5 / BM uMRD4 (7/9 had detectable BM MRD in the range 0.002-0.007% and 2/9 had BM uMRD5/<0.001%) and 7/188 (4%) had PB uMRD5/stringent uMRD4 but with persistent BM dMRD4 (median 0.02% BM MRD, range 0.01-0.055%). PB MRD level correlates closely with BM MRD level but there is lower concordance at the 0.01%/MRD4 threshold after recent cessation of therapeutic antibody. PB uMRD4 is not a suitable target for treatment cessation as the majority of patients with 0.001%-0.01% PB MRD have >0.01% BM disease. For the identification of people attaining BM uMRD4 (<0.01%) on I+V treatment, sustained PB uMRD4 was >90% effective. For translation into MRD-guided treatment in future routine clinical practice, BM assessment may be replaced with PB MRD monitoring if the 0.001%/MRD5 threshold is applied.

Lenalidomide Consolidation Improves Measurable Residual Disease (MRD) Rates and Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - Final Analysis of CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Introduction Eradication of MRD after first line chemoimmunotherapy (CIT) correlates with longer progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients. Lenalidomide (LEN) has antiproliferative and immunomodulatory effects in CLL and may improve response following CIT (Buhler et al 2016; Fink et al 2017). Here we report the final analysis of the phase III, randomized, CLL6 RESIDUUM trial, that aimed to determine whether LEN improves immunophenotypic (IP) complete response (CR) rates and extends remission duration in patients with CLL who have MRD following induction CIT. Methods The CLL6 trial was a joint trial of the ALLG and the FILO. CLL patients with CIRS score <6 requiring treatment according to iwCLL received 4 to 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). After completion of treatment, patients with clinical, radiological and/or flow cytometry evidence of MRD in blood (PB) or bone marrow (BM) were randomized 1:1 to receive 2 years of 10 mg daily LEN consolidation or observation (OBS). High sensitivity (HS) MRD were scheduled at month 3, 6 and every 6 months until month 24 then every 12 months until month 72 in PB and at screening and on months 12 and 24 in BM. The primary endpoint was time to clinical disease progression, or death, from randomization. The study planned to randomize 192 patients to detect a hazard ratio of 1.94, i.e., an increase in the % of patients remaining progression free at 4 years to 70% in the LEN arm compared with 50% in the OBS arm (two-sided log rank test at alpha = 0.05, no competing risks or loss to follow up, power = 0.86). Results The study closed prematurely because of an acute lymphoblastic leukemia (ALL) warning (3 of 56 patients [5.4%]) in the CLLM1 trial (Fink et al., 2017; Fürstenau et al., 2021). Between May 2011 and January 2018, 143 patients were randomized (70 in Australia and 73 in France) to the LEN (n=71) or OBS (n=72) arms. Median age was 63 [range 41-78], and 60 [26-79] years in the LEN and OBS arms respectively, 113 patients were males. At randomization, 27 (38 %) and 23 (32%) patients were in CR, 9 (13%) and 10 (14%) in nPR, 35 (49%) and 39 (54%) in PR in LEN and OBS arms respectively. Forty-nine (69%) and 47 (65%) had PB and 56 (79%) and 58 (81%) had BM detectable MRD in LEN and OBS arm respectively. Median follow-up (FU) is 52.6 months (range 44.9-59.0; LEN 49.8 [41.9-57.1], OBS 55.59 [44.0-61.7]). Twenty-eight (39%) patients progressed in the LEN arm versus 40 (56%) in the OBS arm (χ² p=0.01), 8 died in each arm. Median PFS was 64.6 (95%CI 47.7-not reached [NR]) months in the LEN arm versus 42.4 (32.3-61.6) months in the OBS arm (p=0.039). Multivariate analysis did not identify any predictive factor of relapse. Median overall survival was not reached (NR) (77.58-NR) in the LEN arm and 107.7 (107.6-NR) months in the OBS arm. There were 118 adverse events (AE), 87 in the LEN and 31 in the OBS arms respectively, with more neutropenia (n=21 vs n=1), gastrointestinal (n=10 vs n=4), respiratory (n=9 vs n=0) nervous system (n=6 vs n=1) and musculoskeletal (n=4 vs n=1) in the LEN arm. Most of the excess of AEs in LEN arm occurred after the end of the treatment. Severe AEs were reported in 35 patients (24.5%), 24 in the LEN arm and 11 in OBS. Fifteen secondary malignancies occurred: 8 in the LEN arm; 7 in the OBS arm. Six were of hematological origin (2 Richter transformation in each arm, 1 marginal zone lymphoma in the OBS arm and 1 myelodysplastic syndrome in the LEN arm). No case of ALL occurred. HS MRD analyses were performed in 71/73 patients in the French cohort. A follow-up was available in 65/71 with a median number of 7 time-points per patients (range 3-10). Different MRD kinetics were observed. While MRD rates in OBS arm increased in 33/34 patients, LEN consolidation led to long-lasting and transient deep IP CR in 4/31 and 9/31 patients respectively, MRD rate stabilization in 10/31 patients, and MRD increase in the remaining 6/31 patients. Conclusion The CLL6 RESIDUUM study demonstrated a significant benefit of consolidation therapy with lenalidomide in CLL patients with residual disease after FCR treatment. LEN resulted in a significantly longer PFS, with no unacceptable toxicity including ALL. Although FCR is no longer considered gold standard initial CLL therapy, eradicating residual disease can remain challenging with newer targeted agents. Patients with CLL MRD following initial therapy may experience prolongation in progression free survival from LEN consolidation.

Fludarabine, Cyclophosphamide and Rituximab (FCR) As First Line Treatment in Patients with Chronic Lymphocytic Leukemia (CLL): A Long-Term Analysis of the German CLL Study Group (GCLLSG) Registry

Introduction: Large randomized trials investigating targeted agents have resulted in a markedly improved progression-free survival (PFS) when compared to standard chemoimmunotherapy. However, for small subgroups with a favorable risk profile, overall survival was not consistently superior for targeted agents. Long-term follow up on FCR suggested that favorable risk patients (pts) benefit significantly from this therapy and can expect an exceptionally long PFS. In addition, targeted first line (1L) therapies for favorable risk pts are reimbursed only in a minority of countries. Here, we report long-term efficacy data of FCR treatment obtained from pts documented within the GCLLSG registry. Methods: Documentation within the GCLLSG registry started in 2013 and included both pts from prospective trials (29.7%), most importantly of the CLL8 trial (22.6%) and CLL10 trial (62.1%) as well as retrospective data. Pts with confirmed diagnosis of CLL who received FCR as 1L treatment were included. Patient characteristics were reported in median, interquartile ranges or frequencies and percentages. Response was reported as response or non-response. Event-free survival (EFS), which was defined as the time from start of (first) FCR treatment to disease progression, initiation of subsequent treatment for CLL or death. EFS was chosen as an endpoint for this report due to concerns that PFS might give unrealistically good results due to lack of documentation. However, PFS and TTNT data will be presented at the meeting. Overall survival was calculated from initiation of 1L treatment for all pts who received 1L treatment after 2013. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards regression. Variables that were significantly associated with EFS in univariate analyses (significance level was set at 5%) were considered as candidates for the multivariate modelling to identify independent prognostic risk factors. Results: As of September 2021, a total of 5922 pts were enrolled in the registry of which 417 received FCR as 1L treatment between 2003 and 2021. 223 pts (53.5%) received treatment before 2013 and 194 (46.5%) after 2013. Median observation time from 1L treatment was 95.8 (interquartile range 58.7-126.8) months. Patient characteristics showed a median age of 58 (range 24-83) years. Unmutated IGHV (U-CLL) was present in 61.4% of the pts. Regarding genomic aberrations based on the hierarchical model, del(17p) was found in 1.9%, del(11q) in 15.2%, trisomy12 in 15.5%, mono-allelic del(13q) in 34.3% and none of these changes in 33.0% of the pts. 88.8% of the pts responded to first line therapy, 11.2% were documented as non-responder. Median EFS was 71.1 month, for 188 pts no event was documented at the time point of data cut-off. Age group (≤ 65 years, >65 years), del(11q), IGHV mutational status, TP53 status, and serum thymidine kinase (TK) were associated with EFS in univariate analyses. Overall, 116 pts with 67 events were included in the final multivariable model for EFS. U-CLL (HR 1.949 (95%CI: 1.170-3.247; p=0.010) and TK >10 U/l (HR 2.107 (95%CI: 1.153-3.849; p=0.015) were independent adverse prognostic risk factors for EFS. When low TK and M-CLL were combined, the median EFS was not reached, with a 5-year survival rate of 95.8%. In contrast, median EFS was 84.1 months for pts with U-CLL and high TK. In U-CLL pts, median EFS was 87.0 months for pts with TK ≤ 10 U/l, and 58.9 months for pts with TK > 10 U/l. Median overall survival was not reached with a 5-year survival rate of 92.7%. Conclusion: Within this cohort of pts with a long follow up in the GCLLSG registry, FCR treatment was associated with a long EFS especially in pts with a low risk profile exhibiting a mutated IGHV status und low TK. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 study)

Background: Fludarabine, cyclophosphamide and rituximab (FCR) regimen was previously recommended as standard chemoimmunotherapy for young fit patients (pts) with CLL prior to the advent of novel target drugs. Orelabrutinib, a highly selective BTK inhibitor, had approved for relapsed/refractory (RR) CLL treatment. Obinutuzumab, a glycoengineeredtype II CD20 mAb, had shown to be superior to rituximab in CLL treatment.Pts achieving minimal residual disease (MRD)-negative status in peripheral blood (PB) or bone marrow (BM) had a better progression free survival (PFS) and overall survival (OS) outcome irrespective of treatment received compared to those who could not achieve MRD negativity (CRISTALLO endorsed). Methods: This is an investigator-initiated phase II trial (NCT 05322733). Eligible pts had previously untreated CLL/SLL with ECOG PS 0-2, 18-65 years old, Cumulative disease score ≤ 6, and Creatinine clearance rate ≥ 70 ml / min (N=25). Patients with IGHV unmutated, del (17p) and/or TP53 Mutation are included. Enrolled patients will receive 7-day lead-in therapy of Orelabrutinib 150 mg once daily. Then all Pts receive three cycles of OFCG. After the 3 cycles, following evaluation by MRD in BM detected by multi-color flow cytometry (FCM) at 10-4 sensitivity according to ERIC methodology. Patients will continue to receive 3 cycles of OFCG regimen if the MRD is positive. Otherwise, the patients will continue to receive 3 cycles of OG regimen if the MRD is negative. At the 7th-12th cycles, Based on the achievement of uMRD in BM at the end of Cycle 6, patients would be decided to received O monotherapy (with uMRD) or OG regimen (without uMRD). Similarly, at the 13rd-24th cycles, patients would be decided whether to discontinue treatment based on the evaluation results of Cycle 12. (Figure 1) We set every 28 days as a dosing cycle. Obinutuzumab, 1000mg, D1/D8/D15 in C1, D1 in other cycles, (first dosing: 100 mg in D1 and 900 mg in D2). Orelabrutinib: 150 mg, QD. Fludarabine: 25 mg/m2, D1-3, per cycle. CTX: 250 mg/m2, D1-3, per cycle. The primary endpoint is the percentage of undetectable MRD in BM after 6 cycles of treatment. The percentage of MRD negativity by NGS is an exploratory endpoint (at 10-6 sensitivity). Results: By the end of July 2022, 13 patients were screened, of which 7 patients have begun treatment with the combination regimen, and 1 patient completed 2 cycles treatment and the first efficacy evaluation who with undetectable BM MRD after 3 cycles treatment. We will update the first efficacy evaluation reporting of 10 patients at this ASH. Conclusions: Enrollment, treatment and follow up continues. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P673: DEPLETION AND RECOVERY OF NORMAL B-CELLS DURING AND AFTER TREATMENT WITH CHEMOIMMUNOTHERAPY, IBRUTINIB OR VENETOCLAX.

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5–2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinib-containing regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Image:Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.

Examining Treatment Patterns and Real-World Outcomes in Chronic Lymphocytic Leukemia Using Administrative Data in Ontario

Information on the real-world experience of Canadians diagnosed with chronic lymphocytic leukemia (CLL) is limited. This study was conducted to report treatment patterns and outcomes of CLL using Ontario administrative data. A retrospective cohort study was conducted in patients diagnosed with CLL between 1 January 2010 and 31 December 2017 identified in the Ontario Cancer Registry (OCR). Data were accessed using the Institute of Clinical Evaluative Sciences (ICES), which collects various population-level health information. In the Ontario Cancer Registry, 2887 CLL patients receiving treatment and diagnosed between 2010–2017 were identified. Fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapy was most frequently used as a first line, but use declined since ibrutinib and obinutuzumab combinations were funded in 2015. In patients treated with frontline FCR, survival at year one was 89% pre-2015 and 96% post-2015; at year four, survival was 73% and 87%, respectively. Survival in patients treated with frontline chlorambucil was 76% pre-2015 and 75% post-2015 in year 1, and 45% and 56% in year 3. Our analysis shows that, as the treatment landscape for CLL has shifted, use of newer and novel agents as a first line or earlier in the relapsed/refractory setting has resulted in improved survival outcomes.

Small Lymphocytic Lymphoma Presenting as a Breast Lump: A Rare Presentation of Non-Hodgkin's Lymphoma

Approximately one-fourth of non-Hodgkin's lymphomas (NHLs) present with an extranodal origin. Primary and secondary involvements of the breast by lymphoma are rare because of the paucity of lymphoid tissue in the breast. Primary breast small lymphocytic lymphoma (SLL) typically presents as a manifestation of widespread chronic lymphocytic leukemia (CLL). A 58-year-old female presented to our clinic with a palpable breast mass. She had no cytopenias and her absolute peripheral B lymphocyte count was less than 5000/microL. The mass was biopsied and histology with immunohistochemistry showed neoplastic cells positive for CD23 and CD5 confirming the diagnosis of small B cell lymphocytic lymphoma of the breast. Further imaging revealed extensive mediastinal and retroperitoneal lymphadenopathy. Histopathology of bone marrow biopsy revealed diffuse infiltration with SLL. The patient was treated with six cycles of fludarabine, cyclophosphamide and rituximab (FCR) with excellent clinical response. To our knowledge, this is the first case of SLL infiltration of the breast without CLL treated successfully with FCR.

Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial

Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial

Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter “Real-World” Study

Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter “Real-World” Study

Quality of Life in Patients

Quality of Life in Patients <=70 Years of Age with Chronic Lymphocytic Leukemia Treated Frontline with Ibrutinib-Rituximab Versus Fludarabine Cyclophosphamide Rituximab: Analysis from ECOG-ACRIN E1912

Awareness, Knowledge, and Preferences of United States (US) Patients with Chronic Lymphocytic Leukemia (CLL) and Their Caregivers Related to Finite Duration (FD) Therapy and Minimal (Measurable) Residual Disease (MRD)

Awareness, Knowledge, and Preferences of United States (US) Patients with Chronic Lymphocytic Leukemia (CLL) and Their Caregivers Related to Finite Duration (FD) Therapy and Minimal (Measurable) Residual Disease (MRD)

Chronic Lymphocytic Leukemia with Deletion 13q: Prognostic Predictors and Outcome after Treatment with Fludarabine, Cyclophosphamide and Rituximab (FCR)

INTRODUCTIONChronic lymphocytic leukemia (CLL) with deletion 13q (del13q) has historically better outcome after chemotherapy. However a sizeable number of such patients do progress with a decreased progression free survival (PFS) and overall survival (OS). We analyzed this group of patients treated with FCR to characterize the relationship between clinico-biological parameters and outcome. METHODSWe retrospectively analyzed 134 CLL patients with del(13q) treated with FCR from March 2004 to August 2014 in our institution. The association between base line characteristics, 12 month minimal residual disease (MRD) status as detected by flow cytometry with PFS and OS was assessed using univariate Cox proportional hazards model on all patients. RESULTSOf 134 patients 63% (n=84) were male and 37% (n=50) female, and median age was 60 (range 35-83) yrs. Median follow up was 70.3 mths (5.9 yrs). Median WBC was 39.3 K/μL (3.2-666.5) and Hb 13.6 (g/dL) (7.1-16.4). Seventy three (54%) were IGVH mutated and 51(38%) unmutated. Eighty nine (66%) had beta-2 microglobulin (β2M) <4 and 44 (33%) > 4 μg/mL. Karyotype was diploid in 107 (80%) patients and abnormal in 16 (12%) patients. By fluorescence in situ hybridization (FISH), %age of cells having del(13q) ranged from 8-98% with median of 55.75%. One locus was involved in 110 (82%) and both loci in 20 (15%) patients. Splenomegaly was present in 55 (41%) and absent in 76 (57%). Ninety six percent (n=129) patients had non bulky disease and only 4 (3%) had bulky disease. After FCR therapy, 83 patients (62%) achieved complete response (CR), 26 (20%) nodular partial response (nPR), 21 (16%) partial response (PR) and 4 (3%) treatment failure. Overall 38% (n=51) patients experienced disease progression. Thirteen percent (n=17) patients died after FCR treatment, of which 8 had progressed and 9 had not progressed. There were 12 malignancies detected after diagnosis of CLL: 4 basal cell carcinomas, 4 squamous cell carcinomas, 1 breast carcinoma, 1 colon carcinoma, 1 small bowel carcinoma, 1 therapy related acute myeloid leukemia, 1 therapy related myelodysplastic syndrome, 1 B-acute lymphoblastic leukemia. Median PFS was 83.1 mths (6.9 years), OS at 5 years was 89.9%, and at 10 years was 79.1%. Median OS was not reached. Of 51 patients who experienced disease progression, there were 8 observed deaths. Due to small number of observed events, estimated survival rates could not be ascertained meaningfully. β2M >4 (HR 1.85, p=0.02), high WBC count (HR 1.55, p<0.01), Hb <10 gm/dL (p=0.01), unmated IGVH (HR 2.78, p=0.001), abnormal karyotype (HR 2.01, p=0.04), splenomegaly (HR 2.45, p=0.001), MRD positivity at 12 months (HR 2.87, p=0.01) had a significant negative impact on PFS. Platelet count <50,000/μl, bi-allelic del(13q) while showing a negative impact on PFS was not statistically significant. Percentage of del(13q) >50% had no impact on PFS. Except for Hb <10 gm/dl (p=0.001), none of other parameters had statistically significant impact on OS. This could be explained by the limited statistical power for detecting OS due to small number of observed patient deaths. CONCLUSIONIn CLL with del(13q), a subset of patients progress after FCR therapy and have poor PFS. β2M, WBC count, Hb, unmated IGVH, abnormal karyotype, splenomegaly, MRD positivity at 12 months have a significant impact on PFS. [Display omitted] DisclosuresKantarjian:Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Wierda:The University of Texas MD Anderson Cancer Center: Employment; Sanofi: Consultancy, Honoraria; Kite: Research Funding; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Merck: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Juno: Research Funding. Burger:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Real-World Testing and Treatment Patterns in Chronic Lymphocytic Leukemia (CLL) in the United States during the Modern Era: A SEER Patterns of Care Analysis

Introduction: The use of fluorescence in situ hybridization (FISH) and IgVH mutation analyses were initially used to help prognosticate CLL patients in clinical trials. In the modern era of Bruton tyrosine kinase inhibitors and improved response rates in patients with deletion 17p, and demonstrated long-term remissions among mutated IgVH patients treated with fludarabine, cyclophosphamide and rituximab (FCR), the use of testing prior to treatment is now considered standard of care to determine appropriate therapy. Several therapies were FDA approved for CLL since 2008 through 2014, including bendamustine and novel therapeutics (obinutuzumab, ibrutinib, and idelalisib). We aimed to look at patterns of real-world testing frequencies and treatment patterns by comparing two United States population based samples of untreated and treated CLL patients in 2008 and 2014.Methods: The National Cancer Institute sponsored Patterns of Care (POC) study was conducted in a population of CLL patients, randomly sampled from 13 Surveillance, Epidemiology, and End Results (SEER) program registries, diagnosed in 2008 and again in 2014. Trained abstractors collected data on demographics, diagnostics, testing, and treatments from patient medical records within 24 months post-diagnosis (along with a physician verification survey). Patient characteristics were described by age, sex, race, Charlson comorbidity index, area-based socioeconomic status, insurance status, receipt of systemic therapy, and type of treatments by diagnosis year. Patient characteristics and frequency of testing (FISH and IgVH mutation analyses) in 2008 and 2014 were compared using Rao-Scott chi-square tests. Logistic regression taking into account sampling weights was used to estimate odd ratios and 95% confidence intervals for receipt of FISH testing, both unadjusted and adjusted for age, sex, race, insurance status, and receipt of systemic treatment. Adjusted models were run overall and stratified by age at diagnosis (<65 and ≥65).Results: This study included 1,008 CLL patients diagnosed in 2008 and 1,367 CLL patients diagnosed in 2014. The mean age was 69.6 years in 2008, and 68.0 years in 2014. Among those with a known status for FISH testing, the proportion of patients who underwent testing was 51.3% in 2008, which increased to 59.6% in 2014 (p<0.01). Among those with a known status for IgVH mutation analyses, 8.5% underwent testing in 2008, which increased to 15.1% in 2014 (p<0.01). Older age was a strong predictor for not receiving FISH testing in both 2008 and 2014 (adjusted p-trend <0.01 for both years). In 2014, Hispanic patients were less likely to undergo testing (aOR 0.68, 95% CI: 0.48-0.96) compared to non-Hispanic whites, but no significant difference was found among non-Hispanic blacks. Among patients 65 or older, those with Medicare without private insurance were less likely to receive testing compared to Medicare patients with private insurance (aOR 0.49, CI: 0.32-0.74).Most CLL patients were untreated within the first two years from diagnosis (74.3% in 2008, and 70.6% in 2014). FISH testing occurred in a majority but not all patients who received therapy (64.5% of treated patients in 2008, increased to 74.7% in 2014). In 2008, the four most frequently used regimens for first treatment were 1) FCR, 2) rituximab monotherapy, 3) FR, and 4) chlorambucil based regimens. This is in contrast to 2014, where the regimens were 1) bendamustine and rituximab (BR), 2) rituximab monotherapy, 3) FCR, and 4) ibrutinib. When evaluating the use of novel therapies (obinutuzumab, ibrutinib, and idelalisib) for those diagnosed in 2014, there were no significant differences in distribution by age, race/ethnicity, comorbid conditions, SES, or insurance type.Conclusions: There has been an increase in frequency of FISH testing and IgVH mutation analyses from 2008 to 2014. FISH testing is more common compared to IgVH mutation analyses which was modest in both years. Patients of older age, Hispanic ethnicity, and Medicare with no private insurance were also less likely to receive FISH testing in 2014. There are significant differences in the treatment patterns of patients in 2008 compared to 2014, with the use of bendamustine being more common at the expense of FCR. These results highlight rapidly changing practices within CLL in the modern era. DisclosuresNo relevant conflicts of interest to declare.

Idelalisib-Rituximab Results in Considerable Toxicity but Induces Durable Clinical Remissions in Patients with TP53 Disrupted B Cell Prolymphocytic Leukemia

BackgroundB-cell prolymphocytic leukaemia (B-PLL) is a rare disorder representing 1% of lymphocytic leukemias. With a median age of 69 years, pts characteristically present with B symptoms, marked lymphocytosis, cytopenias, massive splenomegaly and minimal lymphadenopathy. The largest trial of B-PLL included only 14 patients (pts) (Döhner et al, 1993). There are no randomized trials published in B-PLL. The median overall survival is 3 years. 13q14, 11q23 and 17p deletions are common by fluorescence- in-situ hybridisation (FISH) (Lens et al, 1999). TP53 mutations are noted in >50%, conferring resistance to immunochemotherapy (Dearden 2012). In the absence of international guidelines or trial data, clinicians typically employ fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine-R (BR) in TP53- intact pts with allogeneic stem cell transplant (allo-SCT) consolidation in eligible, chemotherapy-sensitive pts (Castagna et al, 2005). For TP53 -disrupted B-PLL, alemtuzumab has efficacy but is associated with serious infectious toxicity.The B-cell-receptor signaling pathway plays a critical role in CLL pathogenesis, although little is known regarding its importance in B-PLL (Bernal et al, 2001). This pathway is partly mediated by the activation of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) which is highly expressed in lymphoid cells (Herishanu et al, 2011). Idelalisib is a first-in-class, potent, oral, selective PI3Kδ inhibitor. Initial results of the first 5 pts in the compassionate use programme describe clear efficacy of idelalisib-rituximab (I-R) in TP53- disrupted B-PLL (Eyre et al, 2016). We update this series with considerably longer follow up and additional pts.Methods8 pts received I-R in a UK-wide compassionate use programme supported by Gilead. Data was retrospectively collected for adverse events (AEs), clinical and radiological responses. Rituximab (375 mg/m2) was given 2-weekly (cycle (C) 1-2) and then 4-weekly (C3-6). Idelalisib 150 mg b.d. was given continuously with dose interruption and reduction as required for toxicity and was continued in pts with response after C6 as monotherapy. Response was ascertained radiologically and clinically according to institutional practice. AEs were reported prospectively to Gilead. FISH for p53 deletion was performed in all pts. Sanger sequencing was performed in 3 pts. Standard infectious prophylaxis was routinely added at the time that the safety signal was announced.ResultsThe median age was 64.5 years (range: 57-76 years). 7 were male and 1 was female. The median time from diagnosis to first treatment was 9.5 months (range: 2-60 months). 1 pt had a prior splenectomy, but all others had small volume lymphadenopathy and splenomegaly prior to I-R. TP53 deletions by FISH were found in 7 pts. No known additional mutations were noted. Standard cytogenetics were not performed. 4 pts were treatment naïve, 1 pt received prior methylprednisolone, 1 pt BR, gemcitabine-cisplatin and alemtuzumab, 1 pt alemtuzumab and 1 pt R-CVP and then BR. 5 pts completed 6C x 28-day I-R. 3 pts stopped early: 1 pt died of an unrelated lung cancer in C2, and 2 pts stopped due to idelalisib-related grade (G) 4 colitis at C4.All 8 pts responded to I-R. The single pt who died early of lung cancer obtained a partial response. All other 7 pts obtained complete remission (CR) when assessed by examination, FBC, radiological and FISH. Of those 7 pts, only 1 progression has occurred. This pt subsequently responded to ibrutinib. 1 pt (treatment naïve) died in CR of G5 pneumonitis at 10 months on therapy. There are 5 ongoing CRs at a median of 18 months (range 17-29 months). 2 of these 5 have stopped idelalisib due to toxicity (both G3-4 colitis), 2 remain on monotherapy, and 1 has undergoing consolidation with an allo-SCT having stopped idelalisib (G3 diarrhoea). The median follow up for all pts is 18 months (range 1-29 months).ConclusionsI-R displays rapid, deep and durable remissions in TP53 -disrupted B-PLL. The toxicity profile of idelalisib is well described and is clearly demonstrated in this cohort. Pneumonitis, colitis and CMV reactivation were particularly noteworthy. Of interest, remissions were durable in the 2 pts that stopped therapy following colitis for 13 and 14 months respectively. Our data supports importance of compassionate use programme to study novel agents in rare disorders. Updated response and toxicity data will be presented. [Display omitted] DisclosuresFox:Gilead: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau. Bloor:Roche: Honoraria; Gilead: Consultancy, Other: travel expenses; AbbVie: Honoraria, Other: travel expenses; Janssen: Other: travel expenses, Speakers Bureau. Dungawalla:Gilead: Honoraria. Shankara:Gilead: Honoraria, Other: Travel expenses, Speakers Bureau. Schuh:Abbvie: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients.

Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) can induce long-term remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to FCR in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable (IGHV) gene. In order to identify patients who specifically benefit from FCR, we developed integrative models including established prognostic parameters and gene expression profiling (GEP). GEP was conducted on n=337 CLL8 trial samples, “core” probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and IGHV gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and GEP variables performed equal to models including only established non-GEP variables. GEP variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the IGHV gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. GEP-based prognostic models can help to identify patients who specifically benefit from FCR treatment. The CLL8 trial is registered under EUDRACT-2004-004938-14 and clinicaltrials gov. Identifier: NCT00281918.