Final Restaging Research Articles

MRD-Guided Zanubrutinib, Venetoclax and Obinutuzumab after an Optional Debulking with Bendamustine in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Primary Endpoint Analysis of the Phase 2 CLL2-Bzag Study

Background In chronic lymphocytic leukemia (CLL) triple combinations of BTK inhibitors (BTKi), venetoclax (ven) and CD20 antibodies have been tested mostly as first-line treatments and so far sparse data is available on their efficacy in the relapsed/refractory (r/r) setting. In this phase 2 trial, we evaluate the combination of zanubrutinib (zanu), ven and obinutuzumab (obi) in r/r CLL. In order to tailor therapy to the different needs of differently pretreated patients (pts), treatment duration was based on detection of measurable residual disease (MRD). Furthermore, a ctDNA-based MRD monitoring and a ctDNA-based real-time screen of resistance and driver mutations were performed throughout the study. Methods The CLL2-BZAG study evaluated a combination of obi, zanu and ven after an optional debulking with bendamustine in r/r CLL. In the induction, obi was administered 3 times in cycle 1 (days 1/2, 8 & 15) and monthly in cycles 2-6. Zanu was added in cycle 2 and ven in cycle 3 with a dose ramp-up over 5 weeks. Maintenance with continuous zanu and ven and 3-monthly obi was administered either until achievement of a deep remission with undetectable MRD <10 -4 (uMRD) in peripheral blood (PB) or for up to 24 months. The primary endpoint was the uMRD rate by flow cytometry (FCM) in PB at the final restaging (RE, after 6 months of triple therapy). MRD was measured by FCM from PB and by digital droplet PCR (ddPCR) of patient-specific VDJ rearrangements from blood plasma. uMRD was defined as <1 CLL cell/10,000 leukocytes (<10 -4) and no detectable patient-specific VDJ ctDNA. Results Between 11/2020 and 10/2022, 42 pts were enrolled, 2 pts with ≤2 induction cycles were excluded from the analysis population as predefined by the protocol. Median age was 64 years (range 40-82), 32.5% of pts were female. All 40 pts had r/r CLL with a median of 1 prior therapy (range 1-5), 18 pts (45%) had already received a BTKi, 7 pts ven (17.5%), of these 5 pts (12.5%) had received both. Fifteen pts (37.5%) had a del(17p)/ TP53 mutation, 31 (77.5%) had unmutated IGHV and 19 of 38 pts with available information (50%) a complex karyotype. Nineteen pts (47.5%) received bendamustine debulking, 37 pts (92.5%) completed 6 induction cycles and 19 pts (47.5%) have already stopped MRD-guided maintenance treatment with 2 pts who discontinued maintenance early due to adverse events (AEs). With a median observation time of 21.5 months (range 8.0-35.3), 445 AEs were reported, including 90 AEs of CTC grades 3-4. Two pts had fatal AEs (COVID-19, fungal pneumonia secondary to COVID-19). The most common AEs were COVID-19 (n=26 pts), diarrhea (n=15), infusion-related reactions (n=15), thrombocytopenia (n=14), nausea (n=12), fatigue (n=12) and neutropenia (n=12). The most frequent grade ≥3 AEs were neutropenia (n=10 pts), COVID-19 (n=9), thrombocytopenia (n=7) and pneumonia (n=5, Table 1). Two pts had grade ≥3 cardiac AEs (1 pt with grade 3 non-ST-elevation myocardial infarction, 1 pt with 2 AEs of grade 3 atrial fibrillation and a history of atrial fibrillation). At RE all pts responded and 21 (52.5%) showed uMRD in PB ( Figure 1A). In many pts remissions deepened over time, with 34 (85%) achieving uMRD in PB in the course of the study. The proportion of pts with uMRD was similar in pts with TP53 aberrations (80%) and in pts previously exposed to venetoclax and/or BTKi (80%). The estimated PFS and OS rates at 18 months were 96% and 96.8% ( Figure 1B). PFS rates at 18 months were similar for pts with TP53 aberrations (100%) and pts pretreated with BTKi/ven (90%). Two pts had a disease progression per iwCLL criteria, however no pt has yet required a subsequent treatment. Of 22 pts who achieved uMRD and are now off-treatment, only 1 had MRD recurrence (≥10 -4) during follow-up. Serial MRD (FCM) and ctDNA (ddPCR) assessments were done on 281 paired blood/plasma samples throughout the study. At RE, 8 pts who achieved uMRD by FCM still had detectable VDJ ctDNA in blood plasma. Four pts without ctDNA were still MRD positive by FCM at RE. Apart from one PLCG2_S707F mutation that occurred 11 months after the end of treatment, no acquisition of known resistance mutations - in particular in BTK, BCL2 - was observed using ddPCR. Conclusions The time-limited MRD-guided triple combination of zanu, ven and obi induced deep remissions in a r/r CLL population enriched for pts previously treated with BTKi and/or ven. Apart from COVID-19, low rates of infectious AEs were observed and cardiac toxicities were rare.

Long-Term Remissions with MRD-Guided Acalabrutinib, Venetoclax and Obinutuzumab in Relapsed/Refractory CLL: Follow-up Efficacy and Circulating Tumor DNA Analysis of the CLL2-Baag Trial

Background The phase 2 CLL2-BAAG trial tested a triple combination of acalabrutinib (acala), venetoclax (ven) and obinutuzumab (obi) after an optional debulking with bendamustine in patients (pts) with relapsed/refractory (r/r) CLL. In its primary endpoint analysis, 75.6% of pts achieved undetectable MRD (uMRD) in peripheral blood (PB) at final restaging (RE) after approximately 6 months of the triplet (Cramer, Lancet Haematol. 2022). We now report efficacy data and circulating tumor DNA (ctDNA) analyses with additional follow-up. Methods In the induction phase, obi was started in cycle 1 (days 1, 8, 15) and given 4-weekly in cycles 2-6. Acala was added in cycle 2 and ven in cycle 3. Maintenance treatment with continuous acala and ven and 3-monthly obi was administered until achievement of a deep remission with uMRD <10 -4 in PB or for up to 24 months (mo). MRD was measured centrally by flow cytometry (FCM) in PB and by digital droplet PCR (ddPCR) of patient-specific VDJ rearrangements and CLL-related mutations in blood plasma. uMRD was defined as <1 CLL cell/10,000 leukocytes (<10 -4) and no detected ctDNA. Results In total, 46 pts were included in the trial, 1 pt had to be excluded from the analysis due to a retrospectively noted violation of exclusion criteria. The median number of previous treatments was 1 (range 1-4) and 18 pts (40%) had received a BTK inhibitor (BTKi) and/or ven (BTKi: 8, ven: 7, both: 3) prior to inclusion, 14/44 pts (31.8%) had del(17p) and/or TP53 mutations, 34 (75.6%) had unmutated IGHV. With a median observation time of 34.4 mo (range 12.0-39.2), all 45 pts are off study treatment. The median treatment duration was 14.7 mo (range 6.1-32.9), 2 pts (4.4%) discontinued treatment during the first 6 induction cycles, both due to adverse events (AEs). Following the MRD- and response-guided approach, 25 pts (55.6%) discontinued therapy according to confirmed uMRD and 9 pts (20.0%) completed the maximum of 8 maintenance cycles due to persisting MRD and/or lack of a complete response. As reported, the uMRD rate in PB at RE was 75.6% with 10 pts showing detectable MRD ≥10 -4. In the course of maintenance, 7 of these 10 pts (70%) achieved uMRD, 1 pt had a Richter's transformation (RT) and 2 pts still had detectable MRD after 8 cycles of maintenance ( Figure 1A). With all pts off-treatment, uMRD <10 -4 in PB was achieved in 42 of 45 pts (93.3%) at any time point,including 17 of 18 pts (94.4%) previously exposed to ven and/or a BTKi and 13 of 14 pts (92.9%) with TP53 aberrations. The median time to uMRD in PB was 5.4 months from the start of study treatment. Median progression-free survival (PFS) was not reached, the estimated 30-mo PFS rate for the whole analysis population was 88.2% ( Figure 1B). A similar PFS was shown for pts with TP53 aberrations (30-mo PFS 85.7%) and pts previously exposed to BTKi and/or ven (30-mo PFS 93.3%). The estimated overall survival at 30 mo was 100%. One patient died of COVID-19 18 mo after the end of study treatment. In total, 564 paired FCM/ctDNA samples were available. Overall, 17 MRD recurrences (after uMRD by both methods) occurred. Of these, 11 were first detected by ctDNA, and 3 by FCM (+3 with concordant detection, Figure 1C). Among those with earlier ctDNA detection, more pts appeared to have high-risk genetics (unmutated IGHV in 10/11 pts, complex karyotype in 4/8 evaluated pts), del(11q) and prior exposure to ven/BTKi compared to those with earlier detection by FCM, and MRD recurrences seemed to occur earlier (mean, 7.1 mo after end of treatment). Notably, in 2 of 3 CLL-type progressions (PD, both nodal with normal lymphocyte counts), ctDNA was detected 6 mo/14 mo before MRD by FCM and 7 mo/17 mo before clinical PD, in the third pt ctDNA and FCM MRD recurred at the same time. In a pt with RT (DLBCL), patient-specific VDJ ctDNA was detected at diagnosis while FCM MRD remained negative. At the time of the data cut (02/2023) 50 serious AEs (SAEs) were reported, 33 were of CTC G3, 6 of CTC G4 and 1 CTC G5. The most common SAEs were COVID-19 (n=8), other pneumonias (n=5), infusion-related reactions (n=5) and neutropenias (n=3). Conclusions Time-limited MRD-guided acala, ven and obi led to an estimated 30-mo PFS rate of 88.2% in pts with r/r CLL. Remissions deepen with ongoing maintenance and almost all pts achieve uMRD in PB including pts with TP53 aberrations and those treated with BTKi and/or ven in prior lines. The addition of ctDNA-based analyses to conventional MRD assessment by FCM seems to improve early detection of relapses.

Final Analysis of the Prospective Multicenter CLL2-Give Trial of Obinutuzumab (GA101, G), Ibrutinib (I), and Venetoclax (Ve) in Untreated Patients with CLL with 17p Deletion/TP53 Mutation

Background There is still need for improvement in outcome of high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. The CLL2-GIVe trial tested time limited, response-adapted, fixed duration combination treatment of obinutuzumab, ibrutinib and venetoclax ("GIVe" regimen) in high-risk CLL patients (pts) with a combination of three different agents with distinct mechanisms of action. Here we present the final analysis at the end of the study. Methods CLL2-GIVe is an open-label, multicenter phase 2 trial including pts with previously untreated CLL with del(17p) and/or TP53 mutation. Induction therapy contained 6 cycles (C) of obinutuzumab (GA-101), ibrutinib, and venetoclax, venetoclax and ibrutinib were continued up to C12 as consolidation. Ibrutinib monotherapy was given for C13 to C36 in pts not achieving a complete response (CR) and undetectable minimal residual disease (uMRD) at cycles 9 and 12. The primary endpoint was CR rate at C15 (final restaging) with a null-hypothesis of 25%. Secondary endpoints included MRD, survival, and safety. Results Between September 2016 and August 2018, 41 pts were enrolled. The last pt reached end of study in January 2022. Median age was 62 (range 35-85) years, del(17p) was present in 26 pts, TP53mut in 39 pts and 32 pts had an unmutated IGHV status. With a CR rate of 58.5% (24 pts) at final restaging (C15), the primary endpoint was met (95% CI: 42.1-73.7, p<0.001), rate of partial remission (PR) was 41.5% (17 pts). Peripheral blood uMRD at C15 was achieved in 32 pts (78%). After a median observation time of 38.4 (3.7 - 44.9) months, 9 progression-free survival (PFS) events and 3 overall survival (OS) events had occurred. The 36-month OS is 92.6 % (Figure 1a) and median OS is not reached. Three pts died (1 pt at C3 due to retrospectively pre-existing ovarian cancer, 1 pt at C9 due to cardiac failure unrelated to study treatment, 1 pt due to respiratory tract infection after Richter transformation (RT) under subsequent treatment). The PFS rate at 36 months is 79.9% and median PFS is not reached (Figure 1b). Progressive disease (PD) was observed in 7 pts between C27 and C42. PD was nodal (n=3) or lymphocytosis (n=3), and 1 case of RT occurred. Subsequent treatments were administered in 4 pts (1 pt with 3 therapies: venetoclax, idelalisib/rituximab, ibrutinib; obinutuzumab (n=1); acalabrutinib/venetoclax/obinutuzumab (n=2)). Six pts received complete ibrutinib maintenance treatment after C15 due to PR at final restaging, 3 of these had also detectable MRD. None of these pts progressed. 6 pts with PR and uMRD discontinued treatment at C15 not according to protocol: 2 pts stopped due to adverse event (AE); 4 pts due to other reasons. 5 pts with PR who discontinued treatment at C15 not according to protocol had no uMRD: 2 pts stopped due to AE, 1 pt due to death, 1 pt due to other reasons, 1 pt refused ibrutinib maintenance. At C36, 18 (43.9%) of pts had uMRD in peripheral blood, while 12 pts (29.3%) had detectable MRD at C36: 8 pts were MRD intermediate (≥ 10-4 and < 10-2) (19.5%), 4 pts positive (≥10-2) (9.8%). In 11 pts (26.8%) analysis was not performed due death (n=2), beginning of a new CLL therapy (n=2), 1 withdrawal of informed consent, missed visits during Covid19 pandemic (n=3), 3 pts were lost to follow-up. The most frequent grade 3-5 AEs up to the end of study were blood and lymphatic system disorders (58.5%), with neutropenia (48.8%) and thrombocytopenia (17.1%), and infections (19.5%). Most frequent AEs of any grade were gastrointestinal disorders in 85.4% of pts, most of them were low grade. Most common cardiac disorder of any grade was atrial fibrillation in 14.6% of pts. Conclusion The CLL2-GIVe regimen is a potent and promising fixed-duration, first-line treatment for pts with high-risk CLL with a manageable safety profile worthy of further exploration in phase 3 studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial

Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine. This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6 and every 12 weeks in the maintenance phase), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day). Eligible patients were aged 18 years or older with an ECOG performance score 0-2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary endpoint was uMRD (<10-4) in peripheral blood at the end of induction treatment assessed centrally at the final restaging, 12 weeks after the start of the last induction cycle. As per protocol, all patients with more than two induction cycles were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing. Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients). With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended. Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie.

Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia

AbstractDespite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL.

High Resolution Assessment of Minimal Residual Disease (MRD) By Next-Generation Sequencing (NGS) and High-Sensitivity Flow Cytometry (hsFCM) in the Phase 3 GAIA (CLL13) Trial

High Resolution Assessment of Minimal Residual Disease (MRD) By Next-Generation Sequencing (NGS) and High-Sensitivity Flow Cytometry (hsFCM) in the Phase 3 GAIA (CLL13) Trial

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

Bendamustine Followed By Ofatumumab and Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BIO Trial of the German CLL Study Group (GCLLSG)

Bendamustine Followed By Ofatumumab and Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BIO Trial of the German CLL Study Group (GCLLSG)

Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

Nivolumab and AVD for Early-Stage Unfavorable Hodgkin Lymphoma (NIVAHL)

Background The anti-PD1 antibody nivolumab is approved for relapsed or refractory classical Hodgkin lymphoma (cHL) showing high overall response rates (ORR) and a favorable safety profile. However, complete response (CR) is rare in this setting, and most patients develop progressive disease. To evaluate the efficacy of combined nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) as 1st-line treatment for early-stage unfavorable cHL, we conducted the GHSG NIVAHL trial. Methods NIVAHL is a prospective, randomized, investigator-sponsored single-stage phase II trial that enrolled treatment-naïve early-stage unfavorable cHL patients between 18 and 60 years at 35 German centers (NCT03004833). In arm A, patients received 240mg nivolumab and AVD at standard doses on day 1 and 15 of each 28-day cycle for a total of four cycles (4xNivoAVD). In arm B, the same treatment was administered sequentially, starting with 4x nivolumab in 2-weekly intervals, followed by 2xNivoAVD and 2xAVD. Both groups received 30Gy involved-site radiotherapy (IS-RT). Primary endpoint is the centrally reviewed PET/CT-based CR rate after completion of protocol therapy including IS-RT. 55 patients per group were enrolled in order to exclude a CR rate ≤80% with a power of 90% on a one-sided alpha level of 2.5% each. Secondary endpoints will be analyzed descriptively and include treatment-related morbidity (TRMorbidity), progression-free (PFS), overall survival (OS), response at interim and final restaging as well as patient-reported outcomes. Sequential biopsies, blood and microbiome samples were collected for correlative studies. Results Between 04/2017 and 10/2018, a total of 110 patients were enrolled with one patient disqualified due to alteration of HL diagnosis by central pathology review (N=109, group A n=55, group B n=54). The median age of the predominantly female patients (60%) was 27 years. Stage II was present in 95% of cases with ≥3 involved areas as most common risk factor (69%), followed by elevated ESR (48%), large mediastinal mass (20%) and extranodal disease (13%). Mean duration of chemoimmunotherapy was 15 (standard deviation (SD) 3) weeks and 22 (SD 6) weeks with a mean relative dose intensity of 87.4 (SD 15.9)% and 85.8 (SD 24.2)% in groups A and B, respectively. Severe protocol deviations occurred in 4 patients in group A and 5 in group B. Reasons were toxicity (n=5), patient's wish (n=2), incorrect allocation to early-stage unfavorable risk group (n=1) and progressive disease (n=1). Another 2 patients refused to receive IS-RT. Any adverse events (AEs) were reported for 98% of patients. AEs ≥°3 were observed in 73% and 78%, respectively, and serious AEs occurred in 38% and 28% of patients in groups A and B, respectively. TRMorbidity defined as organ toxicity ≥°3 or anemia, thrombocytopenia or infection °4 was documented in 16% and 22% of patients; all of these were organ toxicities predominantly of liver and gastrointestinal tract, with 19/21 events occurring during the first 2 treatment cycles. Data on ongoing or late toxicities is limited by short follow-up. Until 07/2019, 4 cases of persistent hypothyroidism have been reported. At the 1st interim restaging after 2xNivoAVD and 4x nivolumab, the ORR was 100% (54/54) and 96% (49/51), with a CR rate of 85% and 53% in groups A and B, respectively. Interim remission status was not assessed in 1 and 3 patients, respectively, due to treatment discontinuation after incorrect allocation to early-stage unfavorable risk group (n=1) or toxicity (n=3). After completion of systemic therapy, ORR was 100% (54/54) and 98% (50/51) with a CR rate of 81% and 86%, respectively. One patient in group B developed histologically proven primary progressive HL during nivolumab monotherapy while no other case of progressive or relapsed disease or death has been documented so far. The centrally reviewed CR rate at the end of treatment will be reported at the meeting. Additionally, initial data from currently ongoing histopathologic and immunologic studies will also be presented. Conclusion Concomitant and sequential therapy with nivolumab and AVD is feasible with acceptable toxicity. In early-stage unfavorable cHL, concomitant Nivo-AVD induces a high early CR rate. The interim CR rate observed with 4x nivolumab monotherapy is higher than previously reported in relapsed or advanced-stage disease. The primary endpoint and initial PFS data will be reported at the meeting. Disclosures Bröckelmann: Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe &amp; Dohme: Research Funding. Kerkhoff:EUSA: Honoraria; Hexal: Honoraria; Celgene: Honoraria, Other: Travel Support; Roche: Honoraria; Novartis: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses. von Tresckow:MSD Sharpe &amp; Dohme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria; Amgen: Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. OffLabel Disclosure: Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Residual Abdominal Lymphadenopathy after Intensive Frontline Chemoimmunotherapy Is Associated with Inferior Outcome Regardless of MRD Status in Advanced Chronic Lymphocytic Leukemia (CLL)

Residual Abdominal Lymphadenopathy after Intensive Frontline Chemoimmunotherapy Is Associated with Inferior Outcome Regardless of MRD Status in Advanced Chronic Lymphocytic Leukemia (CLL)

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Preliminary Results of a Phase Ib Study of Duvelisib in Combination with FCR (dFCR) in Previously Untreated, Younger Patients with CLL

Abstract Background: FCR remains the gold standard for the initial treatment of younger patients with CLL, yet only about 20% of patients will achieve complete response (CR) with minimal residual disease (MRD) negativity in the bone marrow (BM), which is likely a prerequisite for cure. Duvelisib (formerly IPI-145) is a delta/gamma PI3K inhibitor with promising efficacy in relapsed/refractory CLL. We report on the preliminary results of an investigator-initiated, phase Ib study of duvelisib plus FCR (dFCR) as upfront treatment for younger patients with CLL. Methods: A standard 3 + 3 phase I design included 2 dose levels of duvelisib (25 mg daily (starting level) and 25 mg bid). The primary objectives were to determine the RP2D and toxicities. Secondary objectives included efficacy by IW-CLL criteria, including the rate of CR with BM MRD-negativity at final re-staging. Duvelisib monotherapy was given for 1 week, with FCR started on day 8. Up to 6 cycles of FCR were given with continuous duvelisib, and responders could then continue on duvelisib monotherapy for up to 2 years of maintenance. Eligibility criteria included: age ≤ 65, requiring treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. Toxicity evaluations were performed by CTCAE v4.03/IW-CLL, and response evaluations occurred after 3 cycles, 2 months after final FCR, and q6 months thereafter. MRD was assessed by four-color flow cytometry (sensitivity of 10-4). Results: As of July 27, 2015, 12 patients were accrued, with 6 patients each at duvelisib 25 mg daily and 25 mg bid. The median age at enrollment was 57 (range 46-65). Unmutated IGHV was present in 8/12 (66.7%), ZAP-70 was positive in 6/12 (50%), 2 patients had del(11q), and 1 patient had del(17p). The only DLT was gr3 febrile neutropenia at 25 mg qd (n=1). Hematologic toxicity included neutropenia (67%; 50% gr 3-4), thrombocytopenia (25%; 17% gr 3-4), and anemia (17%, no gr 3-4). All grade non-hematologic toxicities included nausea (83%), fever (50%), diarrhea, anorexia, and fatigue (42% each), transaminitis, pruritus, and vomiting (25% each). SAEs included pneumonia (n=4, including 2 cases of PCP), Gr 3 transaminitis (n=2), and Gr 3 febrile neutropenia, diarrhea, pruritus, and CMV infection (n=1 each). The ORR was 100% (n=9 evaluable at final re-staging 2 months post FCR), with 33% achieving CR (n=2) or CRi (n=1), and 67% achieving PR. Five of the 7 patients with PR had residual lymph nodes &lt; 2.5 cm in long axis by CT imaging. The rate of MRD-negativity in the BM was 8/9 (89%). The median follow-up is 8.7 months, and all 9 patients who completed chemotherapy are now on duvelisib maintenance. A phase II expansion cohort at 25 mg bid of duvelisib recently opened, and updated results will be presented on all patients. Discussion: The RP2D of duvelisib given with FCR is 25 mg bid. The toxicities with dFCR are manageable and comparable to historical toxicities observed with duvelisib and FCR individually. Although the ORR and CR rates are also similar to FCR alone, the 89% rate of BM MRD negativity with dFCR is substantially higher. Most patients who achieved PR with MRD-negativity have small residual nodes and will be monitored for conversion to CR while on duvelisib maintenance. dFCR is a feasible regimen for the initial therapy of younger, fit patients with CLL, and the promising preliminary efficacy data warrant further exploration in a phase II expansion cohort (NCT02158091), which is now ongoing. Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Phase II Study of Ofatumumab in Relapsed Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report from the German Hodgkin Study Group

Background:Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma (HL) cases. One hallmark of NLPHL is the consistent expression of CD20 on the malignant lymphocyte predominant (LP) cells. To shed more light on the role of anti-CD20 antibody treatment in relapsed NLPHL, we conducted a phase II study evaluating the fully humanized anti-CD20 antibody ofatumumab in 28 patients. Treatment consisted of 8 weekly doses (week 1: 300 mg, week 2-8: 1000 mg) of the antibody.Results:The median age of study patients was 45 years (range: 22-68) and the majority were male (64%). A median of 1 line of therapy (range: 1-5) had been applied prior to study treatment and 7/28 patients (25%) already had rituximab-containing treatment. At the final restaging 3 months after the end of treatment, response was documented in 27/28 patients (96%; 95%-CI: 84%-100%). After a median follow-up of 26 months, 1-year and 2-year progression-free survival (PFS) estimates were 93% and 80%, respectively. No patient died. Transformation into aggressive non-Hodgkin lymphoma (NHL) occurred in 2/28 patients (7.1%). No grade III/IV toxic events were observed.Conclusion:In summary, the anti-CD20 antibody ofatumumab represents a highly active and well tolerated treatment option in relapsed NLPHL. Longer follow-up is required for final conclusions. DisclosuresOff Label Use: Ofatumumab in lymphocyte-predominant Hodgkin lymphoma. von Tresckow:Takeda: Consultancy; Celgene: Other: honoraria for preparation of scientific educational events; Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events. Borchmann:Millennium: Research Funding. Engert:Takeda: Consultancy, Research Funding.

Primary Progressive Disease in Hodgkin Lymphoma Patients: A Retrospective Analysis from the German Hodgkin Study Group

Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients.Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp).Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years.3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months.After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p<0.001). OS was significantly worse in patients with primary progressive disease when compared to the complementary study cohort in both treatment groups (each p<0.001). When comparing patients with primary progressive disease with those patients with a relapse of HL (n=272), there were significant advantages of the latter regarding OS and OSp within the BEACOPP-pre-treated subgroup (each p<0.001). In patients pre-treated with ABVD variants, there was also a significant difference in OS (p=0.007), but no detectable difference regarding OSp (5-year OSp 74% vs. 78%, p=0.3).Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients. Disclosuresvon Tresckow:Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.

Targeted Beacopp Variants in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Final Analysis of a Randomized Phase II Study

Rationale: The intensified BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has substantially improved the survival of advanced stage Hodgkin Lymphoma (HL) patients. However, the efficacy of this regimen comes along with severe acute toxicities. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in relapsed/refractory HL. We introduced BV into the BEACOPP regimen in order to improve its toxicity profile while maintaining its efficacy.Methods: Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), vincristine was replaced by BV and bleomycin omitted. A more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) was designed to reduce procarbazine induced gonadal toxicity. Both regimens are administered q21d for 6 cycles. This is a randomized phase II study with the combined primary endpoint being the PET-based complete response rate (CRR) after chemotherapy and the complete remission rate (CR/CRu rate) at final restaging including early follow-up for each of the regimens. Safety and feasibility are secondary trial objectives.Results: From October 2012 to May 2014, 104 patients have been enrolled and are evaluable for this analysis (52 patients in each treatment arm). Median age is 29 years (range 18-60 years), 61% are male, and 83% have Ann-Arbor stage III or IV disease. Overall, risk factors were well balanced between the treatment arms and in line with the previous GHSG studies besides a higher number of patients presenting with large mediastinal mass (40% in each treatment arm). 102 patients qualify for the safety analysis (BrECADD n=52, BrECAPP n=50) with two patients not having commenced treatment in the latter group. All 52 patients with BrECADD received the planned number of cycles, 2/50 terminated BrECAPP after 2 and 3 cycles due to toxicity and revision of initial staging by expert panel, respectively. 70% and 60% with complete cycles of BrECADD and BrECAPP received the last treatment cycle at full dose level. The majority of patients did not have treatment delays.101 patients qualify for the efficacy analysis (BrECADD n=52, BrECAPP n=49). CRR is 88% (95%-CI: 77% - 96%) for the BrECADD regimen and 86% (95%-CI: 73% - 94%) for BrECAPP with both groups achieving the required number of 42 patients with CRR demanded by the protocol. Regarding the co-primary endpoint CR/CRu, the corresponding rates were 88% for BrECADD (95%-CI: 77% - 96%), and 94% (95%-CI: 83% to 99%) for BrECAPP. Survival analyses for the BrECADD regimen revealed a progression free survival (PFS) of 94% (95%-CI: 87% - 100%) at 12 months, and 89% (95%-CI: 77% - 100%) at 18 months. Corresponding numbers for BrECAPP were 98% (95%-CI: 94% - 100%), and 93% (95%-CI: 83% - 100%). Overall survival (OS) after a median follow-up time of 18 months for BrECADD was 100%. In the BrECAPP group the median follow-up was 16 months and one patient died. This patient had never received the study treatment. However, this event led to a 1-year OS of 98% (95%-CI: 94% - 100%) in the BrECAPP group.Hematological toxicity grade 3 or 4 occurred in 42/52 (88%) of BrECADD treated patients, and in 47/50 (96%) with BrECAPP. Main hematotoxicity was leukopenia resulting in 15% (BrECADD) and 8% (BrECAPP) grade 3 or 4 infections. Organ toxicity grade 3 or 4 occurred in 4% of BrECADD treated patients (all events grade 3), and in 17% in the BrECAPP group (5% grade 4). Severe neurotoxicity (i.e. grade 3 or 4) was not observed in the BrECADD group and in one patient (2%) in the BrECAPP group (grade 3 sensory neuropathy). Grade 1 or 2 sensory neuropathy occurred in 35% and 30%, respectively.Conclusion: This is the largest study of BV in combination with chemotherapy in the first line treatment of HL reported so far. Both targeted BEACOPP variants are active and well feasible. Based on its superior organ toxicity profile, we have chosen the BrECADD regimen to challenge the GHSG standard of care escalated BEACOPP for advanced stage HL patients in an international, randomized phase III study. DisclosuresBorchmann:Millennium: Research Funding. Engert:Milennium: Research Funding.

Value of Minimal Residual Disease (MRD) Negative Status at Response Evaluation in Chronic Lymphocytic Leukemia (CLL): Combined Analysis of Two Phase III Studies of the German CLL Study Group (GCLLSG)

Value of Minimal Residual Disease (MRD) Negative Status at Response Evaluation in Chronic Lymphocytic Leukemia (CLL): Combined Analysis of Two Phase III Studies of the German CLL Study Group (GCLLSG)

Targeted Beacopp Variants In Patients With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Interim Results Of a Randomized Phase II Study

RationaleBEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has substantially improved the outcome for patients with advanced stage Hodgkin Lymphoma (HL) achieving an overall survival of 95% at five years. Although this certainly is the most important endpoint for these mainly young patients, there still is concern about the toxicities of this intensified chemotherapy regimen. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in HL. We aimed at improving the toxicity profile of BEACOPPescalated while maintaining its efficacy by introducing BV (targeted BEACOPP). MethodsTwo modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), we replaced vincristine by BV and omitted bleomycin. In the more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) we additionally replaced procarbazine by dacarbazine to reduce gonadal toxicity, reduced the dose of etoposide to decrease risk of second acute myeloid leukemia while slightly increasing the dose of doxorubicin to maintain efficacy, and introduced dexamethasone (day 1-4) substituting for prednisone (day 1-14) to avoid immunosuppressive steroid treatment during neutropenia (please see table 1). Both regimens are administered q21d for 6 cycles. This is an ongoing randomized phase II study with the combined primary endpoint being the PET-based complete response rate after chemotherapy and the complete remission rate at final restaging including early follow-up. Here we report on the first 48 patients (planned n=100). ResultsThe study started in October 2012. 48 patients have been enrolled by June 2013 and are included in this analysis. Median age is 29 years (range 19-60 years), 60% are male, and 83% have Ann-Arbor stage III or IV disease. 14 patients have been staged after 6 cycles of chemotherapy, 6 in the BrECAPP and 8 in the BrECADD arm. Four of these patients have not reached a complete response. The 95% confidence interval for the number of treatment successes is 42% to 92% and contains both the margin for failure (65%) as well as the margin for success (85%). Regarding feasibility, 6 of 15 patients (60%) with 6 cycles of chemotherapy required no dose reductions of etoposide, cyclophosphamide or doxorubicin during the entire treatment period (corresponding number for 6 cycles of BEACOPPescalated in the HD15 study: 50%). Hematological toxicity grade 3 or 4 of the targeted BEACOPP variants was documented in 26 of 32 patients (81%) with at least 1 cycle of chemotherapy documented (corresponding number for 4-6 cycles of BEACOPPescalated in the GHSG HD15 study: 91.7%), and grade 3 or 4 organ toxicity in 1 patient (3%, GHSG HD15 study: 14.1%). Four patients reported symptoms of peripheral sensory neuropathy so far (grade 1 n=2; grade 2 n=2). BV was not given in the 6th cycle in two of these patients. ConclusionThese ongoing phase II trial results indicate that anti-CD30 targeted BEACOPP variants may be well feasible without compromising the efficacy associated with BEACOPPescalated. Enrollment is ongoing and updated results will be presented. Disclosures:Borchmann:Takeda: Honoraria, Research Funding. Off Label Use: Brentuximab vedotin first line Treatment of Hodgkin´s Lymphoma. Diehl:Takeda: Membership on an entity's Board of Directors or advisory committees. Engert:Takeda: Consultancy.

Prognostic Impact of the MRD Status After Induction Treatment with Rituximab Plus Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) in Patients with Chronic Lymphocytic Leukemia Receiving Rituximab Maintenance Therapy

AbstractAbstract 3930Chemoimmunotherapy combination regimens achieve high rates of negative minimal residual disease responses in CLL, which has been correlated with prolonged PFS and OS. In the present study, we addressed the prognostic value of MRD levels obtained after rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) induction treatment in the response duration of patients with CLL included in the GELLC-1 trial and receiving maintenance rituximab treatment (Bosch et al. J Clin Oncol 27:4578–4584, 2009). Patients achieving CR or PR after R-FCM induction received rituximab maintenance consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). MRD was evaluated by four-color flow cytometry assays giving a sensitivity < 10−4 in paired peripheral blood (PB) and bone marrow (BM) samples three months after R-FCM induction therapy, every 6 months during rituximab maintenance, and at the final restaging 3 months after conclusion of treatment. Sixty-seven patients (median age 60 years, 70% male) received a median of 8 cycles of rituximab maintenance (range, 1 to 8), 76% of them completing the entire planned treatment. After R-FCM induction, MRD was considered negative in 45/59 patients (76%) in PB and in 35/63 patients (55%) in BM. Of note, these patients with negative MRD in PB had longer PFS in comparison to those with detectable MRD (at 4 years, 88%, [95%IC 98%-78%] vs 27%, [95%IC 51%-3%] respectively; p<0.01) (Figure 1). MRD negativity in BM showed a trend for a prolonged PFS (p=0.056). When MRD levels in BM after R-FCM induction where categorized, we observed that PFS was similar between the MRD negative (<10−4; n=35) and intermediate (>10−4 to <10−2; n=20) subgroups, whereas it was significantly shorter in patients showing high (>10−2, n=8) MRD levels (PFS at 4 years, 84%, 74%, and 25%, respectively, p<0.01). MRD levels after RFCM induction were compared between PB and BM paired samples. Whereas 12/57 patients (21%) that were MRD negative in PB resulted positive in BM, all patients with negative MRD in BM also had negative MRD in PB. Patients with discrepancies (negative in PB but positive in BM) in their MRD status presented a similar PFS than those with negative MRD in BM (4 year PFS, 85% vs. 90%, P=NS). The impact of MRD levels in PB achieved after R-FCM induction on PFS was also analyzed. MRD status proved to be a superior predictor for PFS than clinical response (Figure 2). In addition, when different prognostic variables (lymphocyte doubling time [LDT, cutoff 12 months], ZAP-70, serum ß2microglobulin and LDH, cytogenetic abnormalities, and MRD levels) were analyzed as predictors for PFS, only MRD status in PB along with LDT remained significantly predictive. After rituximab maintenance, 40.6% of patients achieved a MRD-negative CR, 40.6% a MRD+ CR, 5% a PR, and 14% failed to treatment. Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155–161,2008). Moreover, 3 patients that achieved MRD negative in PB but remained MRD positive in BM after the initial R-FCM treatment, became MRD-negative in BM upon rituximab maintenance. Patients that remained MRD negative in PB at the end of rituximab maintenance treatment had an excellent outcome with a PFS of 93% at 4 years in comparison to 68% in patients with MRD positive status (p=0.016). In conclusion, in patients receiving rituximab maintenance MRD levels obtained after R-FCM induction correlated with PFS duration, this correlation being independent of the clinical response attained. The sensitivity of the detection of MRD in these patients was higher in BM than in PB. Finally, maintenance treatment with rituximab seems to prolong the PFS of patients with MRD positive status, minimizing the negative impact of low levels of MRD after induction therapy. [Display omitted] [Display omitted] Disclosures:Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. Bosch:Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG)

Abstract 977 Introduction:For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ≥ 24 months. 15% of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis. Methods:In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10−4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors. Results:This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-β2m. A combination of MRD levels of >10−2 or of MRD levels of >10−4 to <10−2plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970–10.347; p<0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799–11.844, p<0.0001). Conclusion:The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation. Disclosures:Fink:Hoffmann La Roche: Travel Grants. Pflug:Hoffmann La Roche: Travel Grants. Boettcher:Hoffmann La Roche: Honoraria, Travel Grants. Winkler:Hoffmann La Roche: Travel Grants. Ritgen:Hoffmann La Roche: Travel Grants. Fischer:Hoffmann La Roche: Travel Grants. Eichhorst:Hoffmann La Roche: Honoraria, Travel Grants. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Mendila:Hoffmann La Roche: Employment. Wenger:Hoffmann La Roche: Employment. Doehner:Hoffmann La Roche: Honoraria. Kneba:Hoffmann La Roche: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Hallek:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. [Display omitted] [Display omitted]