Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)

Abstract BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body. METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm. All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79). Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%). Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR. Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm. Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented. CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

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Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽

10.1182/blood.v118.21.2860.2860 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2860-2860

Author(s):

Petra Jenke ◽

Barbara Eichhorst ◽

Raymonde Busch ◽

Nadine Anheier ◽

Ulrich Duehrsen ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Research Funding ◽

Progression Free Survival ◽

Response Rates ◽

Median Number ◽

Response Evaluation ◽

Free Survival ◽

Richter's Transformation ◽

Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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Subcutaneous Alemtuzumab Combined with Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT In CLL with 17p- or Refractory to Fludarabine – Interim Analysis of the CLL2O Trial of the GCLLSG and FCGCLL/MW

Blood ◽

10.1182/blood.v116.21.920.920 ◽

2010 ◽

Vol 116 (21) ◽

pp. 920-920 ◽

Cited By ~ 12

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Thorsten Zenz ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Remission Rate ◽

High Dose ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Oral Dexamethasone ◽

Label Use

Abstract Abstract 920 CLL refractory to purine analogues (e.g. fludarabine, F) or with 17p- is associated with very poor prognosis. Alemtuzumab is active in F-refractory CLL, and has proven efficacy in patients (pts) with 17p-. However, outcome of F-refractory CLL is still poor in terms of remission rate and duration of remission. The multinational, multicenter CLL2O trial aims at achieving a higher remission rate by adding high-dose dexamethasone to alemtuzumab, and prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (allo-SCT). Pts with CLL refractory (no PR/CR or PR/CR < 6 months) to F-based (e.g. FR, FC, FCR) or similar chemotherapy (i.e. pentostatin, cladribine, bendamustine), or exhibiting 17p- (untreated or at relapse) were eligible if they had “active disease”. Treatment was with subcutaneous alemtuzumab 30 mg weekly × 3 for 28 days, combined with oral dexamethasone 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or alemtuzumab maintenance with 30mg weekly every 14 days for up to 2 years (yrs). Decision for one of the two consolidation options was at discretion of patient and physician. From January 2008 to July 2010, 80 pts were enrolled at 22 centers and 79 were eligible; F-refractory (n=31), 17p- without prior therapy (n=31), and 17p- in relapse (n=17). Median age was 65 yrs in the F-refractory (range 38–76) and 17p- 1st-line group (36-76), and 60 yrs for the 17p- relapse group (54-73) with male predominance (F-refractory 74%, 17p- 1st-line 71%, 17p- relapse 82%). In the 17p- 1st-line and relapse groups, 52% and 50% were stage Binet C and exhibit reduced performance status (ECOG 1–2), compared to 81% Binet C and 60% ECOG 1–2 for the F-refractory cohort. Pretreated pts had received a median of 2 prior lines (F-refractory 1–6; 17p- relapse 1–5), and 5 pts had received prior SCT. In the F-refractory group, 16% of pts had 11q- and 52% had 17p-. IGHV was unmutated in 64% of 17p- groups and 72% in the F-refractory group. The median levels of ß2-MG / TK were 4.35 / 35.40 in the 17p- groups and 4.12 / 22.65 in the F-refractory group. Treatment data are currently available for 50 pts who completed induction therapy; F-refractory (n=19),17p- 1st-line (n=22), 17p- relapse (n=9). Full treatment duration (12 weeks) could be achieved in 47% F-refractory, 67% 17p- relapsed and 82% 17p- 1st-line pts. In the latter cohort, early stop of therapy was mainly correlated with CR, while in the F-refractory cohort with disease progression (n=2) and infections (n=5, 4 with no documented response). Response rates (ORR / CR) were 47% / 0% in the F-refractory cohort, 78% / 0% in the 17p- relapsed, and 100% / 23% in the 17p- 1st-line cohorts (as compared to this, ORR / CR was 71.4% / 4.8% with FCR in the 17p- 1st-line group of CLL8). Adverse events during treatment were mostly grade 1/2 apart from hematotoxicity. Grade 3/4 non-CMV infection occurred in 35% of F-refractory, 12% of 17p- relapsed, and 16% of 17p- 1st-line pts. CMV reactivation was observed in 32 % of the 17p- 1st-line pts, and less for the pretreated groups (F-refractory 16%, 17p- relapsed 18%). All CMV episodes were successfully treated, and there was no CMV-related death. Among 18 pts documented to receive alemtuzumab maintenance treatment, so far 3 SAEs have been reported: ITP (n=1, twice in the same pt), and fever / diarrhea / thyroiditis (n=1). At a median follow-up of 41.9 weeks (maintenance 54.7 weeks, allo-SCT 29 weeks), there were 7 (37%) deaths in the in the F-refractory cohort, 2 due to disease progression, and 5 due to infection. For the 17p- relapsed group, 3 progressions and 3 deaths were reported, with one case in each treatment option (SCT/maintenance), and one pt in salvage therapy. In the 17p- 1st-line cohort, 4 progressions occurred, 2 pts died, both in maintenance therapy. At 12 months, estimated overall survival was 54%, 66% and 100% in the F-refractory, 17p- relapse, and 17p- 1st-line cohorts, respectively. Accrual is currently ongoing with a target enrolment of 122 pts and updated results will be presented at the meeting. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Off Label Use: off-label use of diagnostic tests and therapeutic agents. Leblond:ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Choquet:ROCHE : Consultancy. Hallek:Roche: Honoraria, Research Funding. Döhner:Pfizer: Research Funding.

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Final Report of a Randomized Study of Decitabine Versus Conventional Care (CC) for Maintenance Therapy in Patients with Intermediate and High Risk Acute Myeloid Leukemia (AML) in First or Subsequent Complete Remission (CR)

Blood ◽

10.1182/blood.v118.21.1530.1530 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1530-1530

Author(s):

Yanis Boumber ◽

Jean-Pierre Issa ◽

Jeffrey L. Jorgensen ◽

Stefan Faderl ◽

Ryan J Castoro ◽

...

Keyword(s):

Maintenance Therapy ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Conventional Care ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Poor Risk ◽

Grade 3

Abstract Abstract 1530 Background: Maintenance therapy in acute myeloid leukemia (AML) is not standard of care. It has been reported that continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). Methylation status of tumor suppressor genes in clinical remission may predict the relapse in AML, with earlier relapse in patients with methylated genes. Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival. Methods: We have conducted a clinical trial comparing decitabine to conventional care (CC, low dose subcutaneous cytarabine, prolonged intensive therapy, or observation) in patients (pts) with AML in their first or subsequent complete remission (CR). Pts with non-favorable risk AML (including intermediate and poor risk) received induction therapy followed by appropriate consolidation. They were then stratified by age (£ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or CC. Pts in second or subsequent CR were randomized after completion of salvage therapy. Primary endpoint was considered to be no relapse at 1 year. We also monitored minimal residual disease (MRD) by multicolor flow cytometry (MFC) using custom staining panels based on the leukemic phenotypes. Aberrant myeloid blasts were identified by comparison to normal bone marrow CD34+ cells. Serial samples for DNA methylation studies were also collected and methylation analysis was performed. Results: 50 patients have been enrolled. Of those, 45 (19 M, 26 F) pts (including 35 in first CR and 10 in subsequent CR) were evaluable for the primary endpoint. Median age was 57 years (range, 24–77). 27 pts were £ 60 years and 18 > 60. Cytogenetics at diagnosis was intermediate in 34 pts, poor-risk in 10 pts, and favorable [inv(16)] in one patient in second CR. 20 evaluable pts were randomized to decitabine and have received a median of 4.5 cycles (range 1–12). 25 evaluable pts were randomized to CC. With a median duration of follow up for the entire group of 36.3 months (range 6.3–55), 11 pts on the decitabine arm and 10 pts on the CC arm have remained in remission; 9 of 20 (45%) on DAC versus 15 of 25 (60%) on CC have relapsed (p = 0.7). 45 pts including 20 receiving decitabine and 25 receiving CC have been followed for at least 1 year; 9 of 20 (45%) on decitabine versus 9 of 25 (36%) on CC are alive in CR (p=0.9). Toxicity in the decitabine treated pts was limited to 19 episodes of grade 3/4, neutropenia, 14 episodes of grade 3/4 thrombocytopenia, and 1 episode of grade 2 anemia. All were short in duration and reversed without any associated adverse events. Non-hematological grade 3 and 4 adverse events on the decitabine arm include 3 infections, 1 episode each of hypertension and fatigue. There have been no deaths on the study. MFC identified MRD (<5% blasts on smears) in 9 of 19 (47%) patients with subsequent relapse, at levels from 0.04% to 1% of total cells. In 18 pts remaining in CR, no MRD was identified. Relapse occurred from 1.5 to 10 months after the first positive MFC. There was a statistically significant higher LINE methylation at baseline between the pts who relapsed and those who remained in CR (78% vs 73%, P=0.02), whereas no differences were observed for methylation of CDH13 and Mir124a-1 genes. Conclusions: We conclude that administration of decitabine in CR at the above schedule/dose is well tolerated. The study has been terminated early by the data monitoring safety board due to the higher incidence of relapse at 1 year in the decitabine arm. Interestingly, at a median of 36.3 months, decitabine treated patients had lower relapse and higher survival rates than conventionally treated patients, although these differences were not significant. These data suggest the need for larger randomized studies of hypomethylating agents in maintenance therapy in AML. Disclosures: Off Label Use: Off label use of decitabine in maintenance therapy in AML. Issa:GSK: Consultancy; SYNDAX: Consultancy; Merck: Research Funding; Eisai: Research Funding; Celgene: Research Funding; Celgene: Honoraria; Novartis: Honoraria; J&J: Honoraria. Faderl:Eisai: Research Funding. Borthakur:Eisai: Research Funding. Cortes:Eisai: Research Funding. Kantarjian:Celgene: Research Funding. Ravandi:Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Induction Treatment with Alemtuzumab Combined with Polychemotherapy Containing Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) Followed By Alemtuzumab Maintenance in Patients with T-Cell Prolymphocytic Leukaemia (T-PLL): First Analysis of a Prospective Multicenter Phase-II-Trial (T-PLL2) Conducted By the German CLL Study Group (GCLLSG)

Blood ◽

10.1182/blood.v124.21.1999.1999 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1999-1999

Author(s):

Natali Pflug ◽

Georg Hopfinger ◽

Paula Cramer ◽

Alexandra Schrader ◽

Nicole Weit ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Maintenance Treatment ◽

Induction Treatment ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Travel Grant ◽

Grade 3

Abstract Introduction: T-cell prolymphocytic leukemia (T-PLL) is a very rare & aggressive disease. Therapeutic advances during recent years have been very limited. Even after initial response, the vast majority of T-PLL patients (pts) relapse quickly and the median overall survival remains below 2 years (ys). This also holds true for induction therapies with the anti-CD52 antibody Alemtuzumab (A). Furthermore, life-threatening viral infections are a severe problem in pts treated with this antibody. In a precursor trial (Hopfinger et al, Cancer 2013), we evaluated a consolidation therapy with A after polychemotherapy induction. In the T-PLL2 trial, we evaluated feasibility, safety and efficacy of the addition of A s.c. to an induction treatment with Fludarabine, Mitoxantrone & Cyclophosphamide (A-FMC), followed by an A s.c. maintenance therapy. Patients and Methods: 16 pts (12 untreated and 4 with pretreatments) with T-PLL were enrolled between 06/2010-09/2013. Pts received an induction treatment with A 10mg s.c. on day (d) 1-3 combined with 20mg/m2 Fludarabine i.v. d 1-3, 6mg/m2 Mitoxantrone i.v. d1 & 200mg/m2 Cyclophosphamide d1-3. After 2 cycles the A dose was increased to 30 mg s.c., if a stable disease (SD) or a partial remission (PR) was achieved. A-FMC treatment was administered every 28 days for up to 4 cycles, followed by a maintenance treatment with 30mg A s.c. starting 1 month (mo) after final staging. During the first 6 mo, A s.c. was administered monthly and in addition once in mo 10 and 13. For younger and fit pts, the option of allogeneic transplantation (tx) was explicitly recommended after induction therapy. Peripheral blood (PB) samples were taken at diagnosis & at the time of relapse/progression. Valganciclovir was recommended for prophylaxis. Results: 16 pts with a median age of 68 ys (range 32-78) and a median score on the cumulative illness rating scale of 3 (range 0-6) were enrolled. The diagnosis of T-PLL was established based on clinico-pathologic characteristics, with the lead finding of a monoclonal mature T-cell population in PB. All leukaemias (100%) were CD52 positive, 15/16 cases (93.75%) expressed TCL1 & the most frequent abnormalities by FISH/classical karyotyping were aberrations involving 14q32.1 in 14/14 cases (100%), gains of chromosome 8q in 10/14 cases (71%), & deletion 11q23 in 8/14 cases (57%). A median number of 4 courses (range 2-4) were administered for induction treatment. Six pts (37.5%) proceeded with maintenance treatment with a median of 4 (range 1-6) A applications. In total, 94 non-infectious CTC grade 3-4 adverse events (AE) & 28 episodes of CTC grade 1-4 infections were documented. Non-infectious grade 3/4 AEs were most frequently due to myelosuppression: neutropenia/leukopenia occurred in 14/16 pts (87.5%), anaemia in 7/16 pts (43.75%) & thrombocytopenia in 10/16 pts (62.5%). Two cases of cytomegalovirus (CMV) & 1 case of varicella zoster infection were documented. Most AEs could be successfully managed, however 2 (12.6%), possibly treatment related deaths occurred, both from fatal bleeding in thrombocytopenia. In all pts response data after induction treatment was available. The overall response rate was 68.75% (11/16pts) with complete remissions (CR) in 4 pts (25%), CR with insufficient bone marrow recovery in 1 pt (6.25%) & a PR in 6 pts (37.5%). Progressive disease (PD) was documented in 4 pts (25%), a SD in 1 pt (6.25%). The trial was terminated in May 2014. Until today, 11 deaths (68.75%) were reported & 1 pt (6.25%) was lost to follow-up. Prophylaxis with Valgancyclovir was administered in 12/16 pts (75%), 2 pts (12.5%) received prophylactic Valaciclovir & 2 pts (12.5%) received no viral prophylaxis at all. Seven pts (43.75%) received an allogeneic tx after the study treatment: 3 pts after the induction phase, 1 pt after 5 maintenance applications & 3 pts after bridging/salvage therapy. Tx outcomes were documented with 5 CRs & 2 PDs. Conclusion: A s.c. combined with FMC & A maintenance therapy is a relatively safe and feasible regimen in pts with T-PLL. However, safety seems to come at the cost of response quality. Therefore, the authors currently recommend using A i.v. as part of the initial therapy for T-PLL pts. Prophylaxis with Valganciclovir was effective in preventing CMV infection, one of the major threats to pts treated with A. Most importantly, the study emphasizes the need for new therapies and intensified clinical research for pts with T-PLL. Disclosures Off Label Use: Therapeutic off-label use of Alemtuzumab, Fludarabine, Cyclophophamide and Mitoxantron in T-PLL. Hopfinger:Genzyme: Research Funding. Weit:Beckman Coulter GmbH, Krefeld, Germany: Employment. Stilgenbauer:Genzyme : Consultancy, Honoraria, Research Funding. Eichhorst:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Hallek:Genzyme, Bayer: Research Funding.

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Updated Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Blood ◽

10.1182/blood.v126.23.4246.4246 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4246-4246 ◽

Cited By ~ 2

Author(s):

Ajay K. Nooka ◽

Michael Wang ◽

Andrew J. Yee ◽

Sheeba K. Thomas ◽

Elizabeth K. O'Donnell ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Response ◽

Board Of Directors ◽

Research Funding ◽

Post Treatment ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Label Use

Methods: As reported previously, PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM and were HLA-A2-positive were eligible. The primary objective of this study was to determine the tolerability of PVX-410, initially as monotherapy. Immune response and change in M protein and free light chain ratio (FLC) were also assessed. PVX-410 alone was safe and immunogenic in the initial 12 patients treated, with all 12 having positive immune response to at least 1peptide, as determined by interferon-gamma enzyme-linked immunosorbent spot (Elispot) and tetramer assays. Given its immunomodulatory properties, it was hypothesized that co-administration of lenalidomide (len; Celgene Corporation) would enhance the T cell-mediated immune response induced by PVX-410. Accordingly, the tolerability, immunogenicity, and anti-MM activity of PVX-410+len was then investigated. Results in the PVX-410 alone cohort were previously reported. In the PVX-410+len cohort, patients received a dose of PVX-410, 0.8mg (0.2mg/peptide / 0.8mg total dose) subcutaneously plus 0.5 mL (1mg) Hiltonol® (poly-ICLC; Oncovir, Inc.) intramuscularly every 2 weeks for a total of 6 doses with 3 standard cycles of len (25 mg orally) on Days 1-21 every 28 days, without dexamethasone. Patients are followed for 12months post-treatment. Blood samples for immune response evaluation are collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response is assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria. Results: Overall, 22 patients have been enrolled, with ages ranging from 39 to 82 years. Ten patients were enrolled in the PVX-410+len cohort, with 9 evaluable for response. All 10 patients received at least 1 cycle of len; 8 received all 3 cycles; 1 received 1 cycle before discontinuing due to a deviation; and 1 completed 2 cycles as of the cutoff date. One patient had 7 of 21 planned doses held due to neutropenia related to lenalidomide, but resumed the next cycle at a reduced dose (from 25 mg to 20 mg). Immunogenicity data with PVX-410+len and PVX-410 alone, as determined via intracellular cytokine staining and tetramer analysis, will be presented. With PVX-410 alone, 5 patients, 2 of 3 with the low-dose of 0.4 mg (0.1mg/peptide) and 3 of 9 at the target-dose (0.2 mg/peptide), experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at the last follow up visit in the 12 month follow up period. With PVX-410+len, 5 patients have experienced partial or minimal responses and 3 have experienced SD. Durability of response is assessed through the 12-month study period; 1 patient has progressed to active myeloma during this time. PVX-410 was well-tolerated alone and with len. Most adverse events (AEs) have been ≤Grade 2 and non-serious. AEs seen more frequently with PVX-410+len versus PVX-410 alone are expected with len and include hematologic abnormalities (neutropenia, anemia, thrombocytopenia), gastrointestinal disorders (nausea, diarrhea, constipation), skin and cutaneous disorders (rash, pruritus), and myalgia. There was 1serious AE in the combination cohort (pneumonia), considered possibly related to len and unrelated to PVX-410. Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with SMM. Additional AEs seen with PVX-410+len versus PVX-410 alone were expected with the addition of len to the treatment regimen. An immune response to the vaccine was seen in all patients treated with PVX-410 alone and is expected to be enhanced with PVX-410+len; these data will be presented. Based on the promising findings to date, an evaluation of PVX-410 in combination with an antibody to the programmed cell-death-1-ligand complex (PD1/PDL1) is planned to begin in 2015. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Off Label Use: Off label use of lenalidomide. Wang:Janssen: Honoraria; Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. O'Donnell:Millennium: Consultancy. Shah:Millenium: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Kaufman:Milleniumm, Celgene, Novartis, Onyx, Spectrum: Consultancy. Lonial:Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Raje:Takeda: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Amgen: Consultancy; Onyx: Consultancy; AstraZeneca: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding.

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Variation In Health-Related Quality of Life (HRQOL) by ISS Stage and ECOG Status Among Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v116.21.3828.3828 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3828-3828

Author(s):

Chris L Pashos ◽

Brian G. M. Durie ◽

Robert M. Rifkin ◽

Jatin J Shah ◽

Thomas K. Street ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Self Care ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Hrqol Data ◽

Label Use

Abstract Abstract 3828 Introduction: Attention is being paid to HRQOL when monitoring hematologic disorders or the impact of treatments on those disorders. Minimal HRQOL data have been published on multiple myeloma (MM) patients (pts) in the United States (US). This analysis characterizes variation in the HRQOL of pts with active, symptomatic MM by International Staging System (ISS) stage and ECOG status. Methods: Data were collected as part of Connect MM®, a prospective observational registry initiated in September 2009 involving centers in the US. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was reported by pts in the clinic at enrollment, within two months of diagnosis. Pts completed 3 psychometrically validated instruments: EQ-5D, Brief Pain Inventory (BPI), and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by ISS and ECOG status. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results: HRQOL data were reported by 328 pts, enrolled from 135 centers. Pts were predominantly male (60%) and white (79%) with mean age at 67.3 (standard deviation [SD] 11.6) yrs. HRQOL scores by evaluable ISS stage (n=236) and ECOG status (n=258) are presented. BPI data (on a scale of 0 [no pain] to 10 [worst pain]) indicate that average reported pain worsens by ISS and ECOG severity. Mean EQ-5D scores (on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity]) indicate that pain/discomfort, and usual activities are most compromised, and with self care increase in severity as ISS and ECOG worsen. Anxiety/depression level is associated with ECOG, but not with ISS. FACT-MM results indicate that ISS and ECOG severity is associated with greater decrement in physical and functional domains. The associations of HRQOL with ECOG status were stronger than with ISS stage. Specifically, scores on the BPI, all EQ-5D domains, and all FACT-MM domains (except the social/family domain) were statistically significantly associated with more severe ECOG status. Conclusions: Initial results from the Connect MM® Registry indicate that HRQOL worsens with worsening ISS stage and ECOG status, especially in physical and functioning domains, pain/discomfort, and ability to conduct usual activities and to provide self care. These areas should receive attention at diagnosis. Future analyses should be conducted on: (1) more newly diagnosed patients; (2) how HRQOL may be affected over time with changes in disease; and, (3) how HRQOL may be influenced by alternative therapies. Results reported here should serve as useful baseline reference. Disclosures: Pashos: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: CONNECT is a disease registry and includes data on off-label use of anti-myeloma agents. Durie:Celgene & Millennium: Consultancy. Rifkin:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Street:Celgene: Employment. Sullivan:Celgene: Employment, Equity Ownership. Khan:Celgene Corporation: Employment.

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A Phase II Multi-Center Trial Of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) In Older Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽

10.1182/blood.v122.21.4177.4177 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4177-4177 ◽

Cited By ~ 2

Author(s):

Marco Montillo ◽

Davide Rossi ◽

Marina Motta ◽

Giulia Quaresmini ◽

Marianna Rossi ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Clinical Activity ◽

Advisory Committees ◽

Free Survival ◽

Grade 3 ◽

Anti Cd20

Abstract Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

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Ofatumumab Based Chemoimmunotherapy (CIT) for Patients with Previously Untreated CLL,

Blood ◽

10.1182/blood.v118.21.3898.3898 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3898-3898

Author(s):

Tait D. Shanafelt ◽

Mark C Lanasa ◽

Clive S. Zent ◽

Jose F. Leis ◽

Timothy G Call ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Previous Experience ◽

Stage Iii ◽

Hematologic Toxicity ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Grade 3

Abstract Abstract 3898 Background: Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 4050 of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a humanized anti-CD20 monoclonal antibody that is approved for patients with relapsed CLL refractory to fludarabine and alemtuzumab. The single agent activity of ofatumumab in patients with refractory CLL suggests it may have greater efficacy than rituximab in patients with CLL. To explore the efficacy of ofatumumab based CIT, we initiated a clinical trial studying the effect of ofatumumab in combination with pentostatin and cyclophosphamide (PCO) for patients with previously untreated CLL. METHODS: Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). The treatment schema included 6 cycles of ofatumuamb (300 mg on day 1 of cycle 1;1000 mg on day 2 of cycle 1 and day 1 of cycles 26) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) administered every 21 days. All patients underwent complete response evaluation including evaluation for MRD using sensitive flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 33 patients were enrolled at Mayo Clinic and Duke University between 3/2010 and 9/2010. All patients were eligible for treatment and have completed active treatment. Clinical characteristics included: 76 male, median age 63 (range: 5083); intermediate Rai risk 27; and high Rai risk 73. On prognostic testing 33 were CD38, 48 Zap-70 , 58 IGHV unmutated, and 6 had high risk FISH (del 17p13; del 11q22). 26 of 33 eligible patients (79) completed all 6 cycles of PCO induction. Seven patients went off treatment early (toxicity: n5; refusal: n1; progression: n1). Adverse events deemed at least possibly related to PCO induction included 8 (24) patients with grade 3 hematologic toxicity and 5 (15) with grade 3 non-hematologic toxicity. The overall response rate to PCO induction was 94 (31/33) with 15 (45) CR/CRi, 5 (15) CCR, 9 (27) nPR, and 2 (6) PR. 2/10 (20) patients with CR's tested for MRD were also MRD negative by 6 color flow cytometry analysis. Finally, we compared this cohort of patients treated with ofatumuamb-based CIT to our prior 108 patient cohort of patients treated with rituximab-based CIT both of which used an identical chemotherapy backbone (pentostatin and cyclophosphamide). Although the age, gender, ALC, and prognostic profile (CD38, ZAP-70, and IGHV mutation status) of treated patients were similar (all p0.3), the ofatumumab cohort included more advanced stage patients (Rai stage III/IV: 73 vs. 41 p0.002). Ofatumumab-based CIT appeared to be better tolerated than our previous experience with rituximab-based CIT (grade 3 hematologic toxicity ofatumumab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{8$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT51 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{55$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.009; grade 3 non-hematologic toxicity ofatumumab-CIT 15 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{5$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{26$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.34). Despite a higher proportion of Rai Stage III/IV patients in the ofatumumab cohort, the efficacy of ofatumumab-based CIT also compared favorably to our previous experience with rituximab based CIT (Table). CONCLUSION: Front-line ofatumumab-based CIT appears to be well-tolerated in patients with CLL. Compared to our historic experience with rituximab based CIT, ofatumumab-based CIT appeared to have less hematologic toxicity and improved efficacy. This trial has been expanded to provide a larger experience with ofatumumab-based CIT. Disclosures: Shanafelt: Hospira: Research Funding; Glaxo-Smith-Kine: Research Funding; Genentech: Research Funding. Off Label Use: Off label use of pentostatin and Ofatumumab. Lanasa:GlaxoSmithKline: Consultancy, Speakers Bureau. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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