ALBERT

Description: Background: The natural history of CLL/small lymphocytic lymphoma (SLL) treated with chemo-immunotherapy included enrichment for del(17p) with each progression and evolution to Richter transformation (RT) in some patients (pts) with refractory disease.In early phase clinical trials, the BCL2 inhibitor venetoclax achieves objective responses in ~80% of pts with heavily pre-treated relapsed/refractory CLL/SLL, irrespective of disease bulk, chemo-refractoriness or del(17p)/TP53 aberrations. However, the nature of progressions during ongoing therapy has not yet been well characterised. We report the clinicopathological features, outcomes and dominant predictors of progression on venetoclax for CLL/SLL. Methods: We retrospectively reviewed data from 67 pts treated with venetoclax for relapsed/refractory CLL/SLL at two institutions in Australia between June 2011 and March 2016. Pts were enrolled in 1 of 3 ongoing trials: Phase 1 venetoclax monotherapy (NCT01328626), Phase 1b venetoclax + rituximab (NCT01682616), or Phase 2 venetoclax monotherapy in del(17p) CLL (NCT01889186). Pts received 150Ð1200mg/day of venetoclax ± 6 doses of rituximab (n=16).Forty-nine received the approved dose of 400mg/day or higher.Pts were investigated for RT at progression with PET scans and biopsies. There was no mandated systematic screening for RT at trial entry. Univariate Kaplan Meier, Cox proportional hazards multivariate and Classification and Regression Tree (CART) analyses were used to identify risk factors for progression. Results: Median age was 68 (range 20Ð87) years; pts had received a median 3 (1Ð12) prior therapies. CLL/SLL was fludarabine refractory (F-refr; defined as no response or progression within 6 months) in 51%. With median follow up of 23 (2Ð46) months, 25 pts (37%) had progressed; 17 (68%) with RT (14 DLBCL, 3 Hodgkin-like) and 8 (32%) with CLL/SLL. Median time-to-progression (TTP) was 8 (1Ð23) months for RT and 23 (7Ð38) months for CLL/SLL (p = 0.0033). PET scans were performed in 12/17 cases of RT. High FDG-avidity disease (SUVmax 〉 10) was multifocal in 9 cases (median 4 sites (2 Ð 10)),unifocal in 2 and negative in 1pt with histologically confirmed DLBCL RT. All 13 cases of DLBCL RT tested for BCL2 protein expression by IHC were positive. TTP was closely related to best iwCLL response (median: not reached, 25 and 6 months for CR, PR and SD, respectively; p5 cm), presence of del(17p), presence of del(17p) and/or TP53 mutation, del(11q), and concurrent rituximab therapy. None were statistically significant (p〉0.1). F-refr disease and complex karyotype (defined as ³3 cytogenetic abnormalities on conventional karyotype) were associated with risk of progression by univariate analysis (HR 6.1, p=0.0052;and HR 6.6, p=0.0045, respectively; see Figure). A limited power multivariate and CART analysis supported independence between these variables. Median overall survival after progression was 11.4 months (32% at 2-years). Salvage chemotherapy was used in 16/17 pts with RT, followed byautograftsor allografts in 2 cases each. Seven pts with RT remain alive (response to salvage: 5 CR, 2 PR), including all 3 pts with Hodgkin-like RT (22, 23 and 43 months post progression). Three pts with DLBCL RT who responded to salvage (2 CR, 1 PR) subsequently progressed with CLL/SLL and remain alive on BTK inhibitors (BTKIs) at 30, 34 and 38 months. Six of 8 pts with progressive CLL/SLL onvenetoclaxwere treated withibrutinib(5 PR, 1 SD) and 3 remain alive on therapy at last follow up (6, 6 and 9 months). Conclusions: F-refractoriness and complex karyotype are the dominant risk factors for progression onvenetoclax, which may presentearly as RT, as might be expected in heavily pretreated patients with these risk factors, or later as CLL/SLL, with PET features being discriminatory. A minority of pts with RT progression can attain durable disease control with multimodality therapy and progressive CLL/SLL can respond to BTKIs, even if after RT. Patients with CLL/SLL that isF-refr or has complex karyotype should have clinically occult RTexcluded before treatment with venetoclax monotherapy. Disclosures Anderson: Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Tam:janssen: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huang:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment.

Description: Background: Venetoclax (Ven), an orally bioavailable BCL2 inhibitor, is approved as monotherapy (Ven-mono) and in combination with rituximab (R; VenR) for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and combined with obinutuzumab in 1L CLL. Herein, we present the long-term efficacy data, including durability of response of continuous and fixed-duration therapy, from the initial phase 1b study (Seymour, et al. Lancet Oncol. 2017) of VenR in R/R CLL with median follow-up on study of 4.9 yrs. Methods: Pts with relapsed CLL received Ven daily (200 - 600 mg) and 6 - 9 doses of R over 6 mo, then Ven-mono (NCT01682616). Minimal residual disease (MRD) was assessed in bone marrow (BM) using multicolor flow cytometry (1 pt were pneumonia (n=2) and osteoarthritis (n=2). Thirty-three pts (67%) achieved CR or BM uMRD by 12 mo and opted to remain on Ven-mono (n=15) or stopped therapy with Ven due to good response (n=18) and stayed on study; DOR and PFS estimates using Kaplan-Meier methodology are presented in the Table. Of the 16 pts not achieving CR or uMRD by 12 mo and continuing therapy, all subsequently discontinued the trial (withdrew consent [n = 2], AEs [n = 2], progressive disease [PD] with CLL [n = 7], or Richter transformation [n = 5]). One pt (1/16) had PD at 36.9 mo (best response on therapy was partial response [PR]) and received an additional round of R treatment starting at 51.9 mo, but the disease did not respond to intensified treatment and the pt came off Ven at 58.4 mo. Of the 15 pts (CR or BM uMRD by 12 mo) who remained on Ven-mono long-term, PD occurred in 5 pts and 1 pt died in ongoing response due to myocardial ischemia (unrelated) (Figure). Two pts received an additional round of R treatment after PD, one at 55.3 mo (achieved uMRD CR [DOR post-R, 11.3+ mo]) and the other at 70.5 mo (recently restarted R). At data cut-off, 10 pts were in remission: 6 in CR (including 1 pt retreated with R and 1 pt who recently stopped Ven after 4.3 yr due to being disease-free) and 4 in uMRD PR. Response for the last pt post-R retreatment is pending. Of the 18 pts who stopped Ven in deep response (14 uMRD CR, 2 MRD-positive CR, 2 uMRD PR [Figure]), the median time on Ven prior to cessation was 16 mo (5 - 40) and median time off Ven is 40.3 mo (1.1 - 70.0) to date. Four have discontinued study without progression (withdrew consent [n = 2], elected for stem cell transplant [n = 1], lost to follow-up [n = 1]). Four pts (2 MRD-positive CR and 2 uMRD CR) had PD after stopping Ven (all asymptomatic) at 25.5, 29.0, 33.3 and 42.0 mo off Ven and have been re-treated with VenR or Ven-mono, and 3 have been re-evaluated for response. All achieved at least PR (2 without BM assessment so unevaluable for CR), with 2 having ongoing response. One pt with PR but residual BM infiltrate had subsequent PD 18 mo later. The fourth pt was recently re-treated with Ven-mono; response is pending. Two additional pts had PD off Ven and had not been re-treated as of the data cutoff; both remain on study. Conclusions: In relapsed CLL, VenR induces deep responses within 12 mo in 67% of pts. These responses are highly durable whether on continuous or limited duration therapy, with treatment-free remissions of 〉4 yr now being observed. Re-treatment of pts with Ven or VenR re-exposure has resulted in response in some pts. In addition to long PFS, which represents time to first PD or death, pts who cease Ven in deep response have the opportunity for further disease control through reintroduction of Ven. Disclosures Brander: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding. Seymour:Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Kipps:Genentech, Inc.: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Ma:Abbvie: Research Funding; Beigene: Research Funding; Janssen: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Kite: Consultancy; Bioverativ: Consultancy; Incyte: Research Funding; Juno: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Xeme: Research Funding. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Masud:AbbVie: Employment, Other: Stock/stock options. Nandam:AbbVie: Employment, Other: Stock/stock options. Jacobson:AbbVie: Employment, Other: Stock or options. Roberts:Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; BeiGene: Research Funding.

Description: Background CBF abnormalities remain a robust prognostic indicator of relatively favorable outcome in AML. Several groups have demonstrated greater responsiveness to HiDAC and studies at MD Anderson established the feasibility of omitting anthracycline when using fludarabine to favourably modulate the intracellular accumulation of cytarabine (Borthakur Cancer 2008). This study further explored that approach by assessing the clinical outcome and molecular responses of patients (pts) treated with fludarabine and HiDAC in the absence of anthracycline. Patients and Methods 52 eligible pts with previously untreated newly diagnosed CBF AML were enrolled from 13 centres between 02/05 and 06/09 (protocol registration ANZCTRN012605000152628). One enrolled pt with non-CBF AML was excluded from analysis. Therapy consisted of induction with fludarabine 30 mg/m2/d followed by cytarabine 2 g/m2/d for 5 days (FA) and post-remission treatment with 3 cycles of HiDAC (2 g/m2 q 12 h Days 1, 3 and 5) followed by 3 cycles of FA for 4 days. No patient was transplanted in first complete remission (CR). Quantitative PCR (QPCR) for CBF-specific fusion transcripts was conducted at diagnosis, post induction, post consolidation cycles and 3 monthly during 2 years of post-treatment follow-up. The primary endpoints were failure free survival (FFS) at 2 and 4 years. Results Median age was 39 (17 – 62) years. 22 pts had t(8;21) and/or AML1-ETO and 30 had inv(16)/t(16;16) and/or CBFB-MYH11, of which 21 had Type A, 5 type D, 3 Type E and 1 Type G transcripts. CR was achieved in 48 of 52 pts (92%): 2 of 4 non-CR pts were responding (post-induction blast counts of 6 and 7%), 1 had residual extra-medullary disease and only 1 pt had refractory AML. 13 pts relapsed (3 AML1-ETO and 10 CBFB-MYH11 p=0.17; median time to relapse 12.4 (range 9.1 – 25.1) months) and 3 died in CR (sepsis). At a median follow-up of 4.6 (range 2.4 – 6.8) years, FFS was 62% (95% CI 50–77%) and 60% (47–75%) at 2 and 4 years respectively. Overall survival (OS) was 83% at 2 years (95% CI 73–94%) and 78% at 4 years (68–91%) reflecting the relative success of salvage (10 of 13 relapsed pts underwent allogeneic transplant). There was no statistical difference between the 2 molecular subtypes for either PFS (p=0.27) or OS (p=0.5). OS was similar to that achieved in our previous trial (Bradstock Blood 2005) utilizing ICE induction followed by either one further ICE or two IcE consolidation cycles (81% at 2 years). Time to neutrophil recovery (〉0.5 x 109/L on 2 consecutive measures) was longer for FA cycles compared to HiDAC (mean 10 vs 6 days; p = 0.001). The rate of grade 3,4 infection was high (88% of pts had at least 1 episode) with 17% coming off protocol for toxicity and only 29 pts (56%) completing all 6 cycles of post-remission therapy with no difference in cycles received between pts who relapsed and those who did not (median cycles delivered was 6 in both groups). Detectable QPCR levels in remission were significantly associated with risk of relapse (10 of 13 relapses were preceded by MRD positivity at a median of 13 weeks; p=0.001). All 10 patients with levels 〉250 copies in PB or BM at any post induction time point subsequently relapsed. LFS was significantly different for patients with MRD positivity (〉10 copies on 2 consecutive measurements or 〉250 at any time) during follow-up compared to those who remained negative (Fig 1). Multivariate analysis did not identify any significant associations between recognized clinical variables and either PFS or OS. LFS was not associated with c-kit mutational status for the subset of 33 pts with results available (p = 0.6). Conclusions The high CR rate and relatively favourable FFS and OS of pts with CBF AML treated with non-anthracycline containing fludarabine-modulated HiDAC based therapy, are similar to published results achieved with standard anthracycline combination treatments. Short-term infectious toxicity of this regimen, particularly during the prolonged post remission therapy, remained significant and the lack of association between relapse and number of cycles delivered suggests the duration may be shortened. QPCR monitoring was confirmed to be clinically useful in the prediction of relapse. Results will be updated after the planned final analysis. Disclosures: Off Label Use: Fludarabine in the treatment of AML.

Description: AIMS Computerised Tomography (CT) scanning is the primary modality for assessment of therapeutic response in DLBCL. We evaluated whether functional imaging utilising FDG-PET may provide additional prognostic information in response assessment prior to completion of chemotherapy for patients with DLBCL. METHODS We performed a retrospective, single-centre study of patients with DLBCL who received anthracycline-based chemotherapy +/− radiotherapy (RT) and had PET prior to completion of therapy. RESULTS From 1996–2004 there were 45 eligible patients. Median age was 59 years (range 26–82) with disease stage I–II (n=25) or III–IV (n=20). Median IPI was 2[IPI 0–2(n=27), IPI 3–4(n=13)] in 40 evaluable patients. Therapy included full-course CHOP/CHOP-like therapy (n=26); HyperCVAD (n=6) and limited (3–4 cycles) CHOP/CHOP-like chemotherapy with RT (n=13). Rituximab was used concurrently in 18 patients. Planned RT was administered in 23 patients. 13 (29%) patients were PET positive after a median of 3 chemotherapy cycles (range 1–5). Of these, 7 (54%) progressed a median of 7.2 months following completion of therapy. Of the 6 progression-free, 4 demonstrated residual low-grade activity at sites of prior bone involvement (median follow-up 50.8 months), while 2 patients (stage I and IV disease) had limited follow-up (

Description: The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Description: Imatinib-treated chronic myeloid leukemia (CML) patients with acquired resistance commonly have detectable BCR-ABL kinase domain mutations. It is unclear whether patients who remain sensitive to imatinib also have a significant incidence of mutations. We evaluated 144 patients treated with imatinib for BCR-ABL kinase domain mutations by direct sequencing of 40 accelerated phase (AP), 64 late chronic phase (≥ 12 months from diagnosis, late-CP), and 40 early-CP patients. Mutations were detected in 27 patients at 17 different residues, 13 (33%) of 40 in AP, 14 (22%) of 64 in late-CP, and 0 of 40 in early-CP. Acquired resistance was evident in 24 (89%) of 27 patients with mutations. Twelve (92%) of 13 patients with mutations in the adenosine triphosphate (ATP) binding loop (P-loop) died (median survival of 4.5 months after the mutation was detected). In contrast, only 3 (21%) of 14 patients with mutations outside the P-loop died (median follow-up of 11 months). As the detection of mutations was strongly associated with imatinib resistance, we analyzed features that predicted for their detection. Patients who commenced imatinib more than 4 years from diagnosis had a significantly higher incidence of mutations (18 [41%] of 44) compared with those treated within 4 years (9 [9%] of 100), P 〈 .0001. Lack of a major cytogenetic response (MCR) was also associated with a higher likelihood of detecting a mutation; 19 (38%) of 50 patients without a MCR had mutations compared with 8 (8.5%) of 94 with an MCR, P 〈 .0001. In conclusion, the detection of kinase domain mutations using a direct sequencing technique was almost always associated with imatinib resistance, and patients with mutations in the P-loop had a particularly poor prognosis. (Blood. 2003; 102:276-283)

Description: Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL–negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL–negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase–polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion–positive, BCR-ABL–negative CMPDs.