scholarly journals High Surface IgM Levels Associate with Shorter Response Duration and Bypass of the BTK Blockade during Ibrutinib Therapy in CLL Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1752-1752 ◽  
Author(s):  
Giorgia Chiodin ◽  
David Dutton ◽  
Enrica Antonia Martino ◽  
Samantha Drennan ◽  
Ian Tracy ◽  
...  
Keyword(s):  
Research Funding ◽  
High Surface ◽  
Single Agent ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Educational Support ◽  
Time Points ◽  
Board Membership ◽  
Duration Of Response ◽  
The University

The circulating tumor cells of chronic lymphocytic leukemia (CLL) are characterized by variably low surface IgM (sIgM) levels and signaling capacity, consequent to stimulation by tissue-based antigen. The variability is evident in both CLL subsets with unmutated and mutated immunoglobulin genes and affects tumor cell survival and proliferation. This appears clinically important because CLL with relatively higher sIgM levels/signaling capacity progress more rapidly than those with lower sIgM levels/signaling capacity (D'Avola, Blood 2016), likely due to a larger proliferative component at tissue sites. B-cell receptor (BCR)-signaling inhibitor ibrutinib exerts its therapeutic activity in CLL by irreversibly binding the Bruton's tyrosine kinase (BTK) at Cys481 in the active site. This leads to redistribution of CLL cells from tissue sites into peripheral blood and to a selective recovery of sIgM levels and function, consequent to release from antigen drive at tissue sites (Drennan, Clin Cancer Res 2019). We have now investigated the hypothesis that sIgM levels on the CLL cells affect duration of response to ibrutinib therapy possibly consequent to circumvention of the pharmacological BTK inhibition. Seventy CLL patients participating in the "real-world" observational study at the University of Southampton (NIHR/UKCRN ID: 31076) were investigated for phenotypic, molecular and functional characteristics associated with response to single-agent ibrutinib. Time to progression requiring a new treatment from ibrutinib start (TTNT) was used as primary endpoint to measure duration of response. The levels of sIgM were measured by flow cytometry. Anti-IgM induced signaling was determined by immunoblotting or iCa2+ mobilization. BTK and PLCγ2 mutations were determined using the Illumina NexteraXT kit and a MiSeq at the University of Southampton and validated independently at Karolinska Institutet. Our previous cut-offs of 50 (MFI) or 5 (iCa2+ % mobilization) were used to distinguish patients with high/low sIgM levels or signaling capacity, respectively. Median follow-up from ibrutinib start was 42 months (range 12-70). Pre-ibrutinib sIgM levels (range 7-618, median 65; high sIgM MFI 46/70, 66%) and sIgM signaling capacity (range 1-98; median 45; high sIgM signalers 56/70, 80%) were broadly heterogeneous. However, median values were significantly higher than the general CLL population at diagnosis, as expected in progressive CLL. By univariate analyses of clinical, phenotypic, FISH and immunogenetic characteristics for TTNT, high sIgM was the only parameter predicting shorter duration of response to ibrutinib (p=0.02). Only 2/24 CLL with low sIgM levels (CLLIgM_lo) had progressed (median TTNT not reached) compared to 15/46 CLL with high sIgM (CLLIgM_hi, 14% at 12 months, 18% at 24 months, 34% at 36 months, 44% at 42 months) during therapy. The levels of sIgM correlated significantly with sIgM signaling capacity prior to treatment (r= 0.68; p<0.0001) and were selectively maintained during ibrutinib therapy. From in vitro analysis of 13 therapy-naive CLL samples, the degree of inhibition by ibrutinib of anti-IgM induced signals downstream to BTK correlated negatively with sIgM levels (r=-0.68,p=0.01) and signaling (r=-0.71,p=0.009). Anti-IgM induced signals were then measured in 12 patients (7 CLLIgM_hi, 5 CLLIgM_lo) after 1, 4 and 12 weeks of ibrutinib therapy. These patients had not acquired BTK or PLCγ2 mutations and BTK phosphorylation appeared completely inhibited at all time-points. Mean anti-IgM induced iCa2+ mobilization and ERK1/2 phosphorylation were significantly reduced but not abolished during therapy and degree of inhibition was variable between individuals. Remarkably, degree of inhibition of anti-IgM-induced iCa2+ mobilization and pERK1/2 was significantly lower in CLLIgM_hi than in CLLIgM_lo (p<0.05 at all time-points). These results confirm that sIgM signaling is dependent on sIgM levels and that it can circumvent BTK blockade when sIgM levels are high. They suggest that high sIgM signaling can drive ibrutinib resistance despite ability of ibrutinib to fully occupy the BTK phosphorylation pocket. A possibility is that those CLL cells with high sIgM represent a potentially dangerous subpopulation equipped to migrate to tissue and to receive proliferative stimuli. These cells might be targeted by a combinatorial therapeutic approach with ibrutinib. Disclosures Johnson: Takeda: Honoraria; Kite: Honoraria; Bristol-Myers Squibb: Honoraria; Genmab: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Epizyme: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria. Duncombe:Abbvie: Other: Advisory Board membership;Educational support; Gilead: Other: Advisory Board membership; Janssen: Other: Advisory Board membership;Educational support; Novartis: Other: Advisory Board membership. Scarfo:Janssen: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria. Sutton:Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Ghia:Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; Novartis: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding. Forconi:Roche: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Menarini: Consultancy; Novartis: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead Sciences: Research Funding.

scholarly journals TP53 Clonal and Subclonal Architecture in Chronic Lymphocytic Leukemia Patients Under Ibrutinib Treatment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3119-3119
Author(s):  
Ilaria Del Giudice ◽  
Luciana Cafforio ◽  
Luca Vincenzo Cappelli ◽  
Caterina Ilari ◽  
Sara Raponi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Member ◽  
Clonal Evolution ◽  
Single Agent ◽  
Variant Calling ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Bioinformatics Pipeline ◽  
Time Points ◽  
Over Time

Abstract Introduction. Ibrunitib (IBR) is active in chronic lymphocytic leukemia (CLL) patients (pts) with TP53 aberrations. Few data describing the dynamics of TP53 mutated clones under IBR are available. We analyzed a cohort of 40 treatment-naïve and relapsed CLL pts treated with IBR to investigate the dynamics of clonal and subclonal TP53 mutations (TP53-mut). Methods. Forty pts (Table) underwent a longitudinal TP53 monitoring (117 samples) by ultra-deep sequencing (UDS): 26 received IBR + rituximab (IBR+RTX) in first line as part of the GIMEMA LLC 1114 protocol (IBR exposition: 8 months in 7 pts and 14 months in 19 pts) (cohort 1), while 14 received IBR single agent after a median of 1.5 (range: 1-4) chemo-immunotherapy lines (IBR exposition: 2.1 to 4 years in 12 pts) (cohort 2). Samples were analyzed by UDS on a MiSeq sequencer (Illumina, Inc.) to obtain a 5000X coverage/base. For variant calling, the MiSeq Reporter software and an in-house bioinformatics pipeline were applied. All mutations were checked on the IARC TP53 database and those with a variant allele frequency (VAF) <10% (i.e. subclonal) were confirmed in an independent UDS run. VAF was corrected to cancer cell fraction (CCF) by the proportion of CD19+/CD5+ cells. Results. In cohort 1, 12/26 pts were evaluated at 3 time-points: baseline (T0), +8 (T8) and +14 (T14) months from IBR+RTX, and 14 at T0 and either T8 or T14. At T0, 19/26 pts showed a mean number of 1.5 (range: 1-5) clonal/subclonal TP53-mut/pt, for a total of 28 mutations. Of those, 20/28 (71.4%) were clonal (mean VAF: 57.8%; range: 18-94.8%) and 8/28 (27.6%) were subclonal (mean VAF: 4.4%; range: 1.2-9.2%; VAF≤5% in 6). Seven/26 pts resulted wild-type (WT). Under IBR+RTX, of the 28 TP53-mut corrected to CCF (21 clonal and 7 subclonal), 12 (9 clonal + 3 subclonal) (42.8%) persisted stable, 9 (32.1%) clonal mutations decreased, 6 (21.4%) were lost, one evolved to clonal. No novel clonal or subclonal TP53-mut arose during IBR+RTX. According to CCF, the pts followed 5 patterns: 1) clonal TP53-mut present from T0 and persisting clonal with a stable (n=6) or decreasing CCF (n=7); 2) clonal TP53-mut disappearing during treatment (n=1); 3) subclonal TP53-mut evolving to clonal (n=1, CCF 8% at T0 and 17.5% at T14); 4) subclonal TP53-mut persisting subclonal (n=1); 5) absence of any detectable TP53-mut in all time-points (n=7). In addition, 3 cases showed coexisting clonal and subclonal TP53-mut at T0: in one case 3 TP53-mut remained stable; in another one, 4 TP53-mut, including one clonal, were lost, and one clonal decreased in CCF; in the last case, 1 TP53-mut decreased, 1 remained stable and 1 subclonal disappeared. In cohort 2, before IBR, 10/14 pts showed a mean of 3.1 (range: 1-11) clonal/subclonal TP53-mut/pt, for a total of 31 mutations. Of those, 11/31 (35.5%) were clonal (mean VAF: 31.9%; range: 10.5-78.8%) and 20/31 (64.5%) were subclonal (mean VAF: 2.9%; range: 0.9-6.8%). Four/14 pts were WT. Under IBR, 16/31 (6 clonal+10 subclonal) (51.5%) TP53-mut persisted stable, 2 (6.5%) clonal decreased, 11 (2 clonal+9 subclonal) (35.5%) were lost, 2 (6.5%) subclonal evolved to clonal; 2 novel subclonal mutations emerged. No mutation was identified in the 4 WT pts over time. In both cohorts, most of TP53-mut remained stable (42.8% vs 51.5% in cohort 1 and 2, respectively) or decreased (32.1% vs 6.5%) and 17 (5 clonal and 12 subclonal) were lost (21.4% vs 35.5%) (p=NS). Although the lymphocyte count significantly decreased during IBR+RTX/IBR exposure (cohort 1: 47.1 x 109/L vs 7.5 x 109/L, p<0.0001; cohort 2: 48.5 x 109/L vs 15.3 x 109/L, p=0.015), the mean CCF of the existing mutations remained stable on treatment (cohort 1: 48.1% vs 40.1%, p=0.42; cohort 2: 16.9 % vs 13.02%; p=0.5). Conclusions. Both when used front-line or as a subsequent line of therapy, IBR appears to decrease the TP53 clonal and subclonal numerosity and complexity. Clonal evolution and the occurrence of novel mutations are rare and occur mostly in pre-treated pts. The significant decrease of lymphocytosis with stable CCF, prove the IBR effectiveness both on TP53 mutated and WT CLL cells, regardless of previous therapies. A longer follow-up will better clarify the dynamics of clonal and subclonal TP53-mut and whether the persistent clones may survive over time and give rise to subsequent relapses. Figure. Figure. Disclosures Mauro: abbvie: Other: board member; janssen: Other: board member. Foà:GILEAD: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau.

scholarly journals Ruxolitinib and Lenalidomide As a Combination Therapy for Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1831-1831 ◽  
Author(s):  
Daver Naval ◽  
Jorge E. Cortes ◽  
Elias Jabbour ◽  
Naveen Pemmaraju ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Dose Adjustment ◽  
Financial Constraints ◽  
Single Agent ◽  
Advisory Board ◽  
Dose Increase ◽  
Median Response ◽  
Board Membership ◽  
Grade 3

Abstract Background: Ruxolitinib (RUX) is a potent and selective inhibitor of the JAK/STAT pathway that significantly abrogates splenomegaly and constitutional symptoms in patients (pts) with myelofibrosis (MF). Lenalidomide (LEN) is a second-generation immunomodulatory agent that may improve MF-associated anemia and thrombocytopenia. RUX and LEN possess complimentary efficacy profiles. Aim:Our single-center phase II open-labeled study was conducted to determine the efficacy and safety of the combination of RUX with LEN in pts with MF. Objective improvements were defined using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria. We were cognizant of an overlapping toxicity of the two medications, namely myelosuppression. Methods:Pts received 15 mg RUX orally twice daily in continuous 28-day cycles with 5 mg LEN orally once daily on days 1-21. Dosage was reduced, increased or delayed based on the assessment of efficacy and toxicity. Results: Thirty-one pts were enrolled between October 2011 and August 2013. Twenty-one (68%) had received prior treatment, including 2 with thalidomide. After a med follow-up of 21.6 mo (1.9-27.7), 28 pts remain alive. The median time on study was 14.7 mo (1.8-26.6) and the median number of cycles administered was 15 (1-29). Simultaneous administration of RUX and LEN was difficult. Only 2 (6%) pts have not required a dose interruption/dose adjustment. The median time to first dose interruption/dose adjustment was 56 days (4-360). Among the 29 pts who needed a dose interruption/adjustment, 23 (79%) needed it within 3 months of starting therapy. The first change in 23 (74%) pts was a dose interruption: median time to first dose interruption was 56 days (4-360), with 20 (87%) of the dose interruptions occurring within 3 months of therapy. LEN was held in all 23 pts and 14 (61%) never restarted LEN. RUX was concurrently held in 7 (30%), reduced in 9 (40%), and continued at same dose in 7 (30%). Reasons for the first dose interruption were low platelets (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1). The first change in 6 (19%) pts was a dose increase (all in RUX): median time to dose increase was 83 days, with 3 (50%) of the increases occurring within 3 months of starting therapy. The reasons for dose increase were leukocytosis (n=2), suboptimal response (n=2), increased spleen size (n=1), and thrombocytosis (n=1). At the time of submission, 18 pts remain on study: 7 on RUX alone and 11 on both medications. IWG-MRT defined clinical improvement (CI) in splenomegaly was noted in 11 (36%) pts. Of note, CI in splenomegaly was seen in 6 of 11 (55%) pts who did not require a dose interruption in the first 3 months. Median time to response was 1.0 mo (0.4-9.1) and median response duration was 19.3 mo (9.4-25.6+). An additional 18 (58%) pts had IWG-MRT defined stable disease. Reasons for discontinuation in 13 pts were lack of response (n=2), infection (n=2), progression (n=1), neuropathy (n=1), renal failure (n=1), diarrhea (n=1), myelosuppression (n=2), concurrent lymphoma (n=1), and financial constraints (n=2). Grade 3/4 myelosuppression was noted in 13 pts. Five pts experienced grade 3/4 non-hematological toxicity (related and unrelated): G3 diarrhea (n=1), G3 edema (n=1), G4 acute kidney injury (n=1), and G3 liver enzyme (n=2). Conclusion: Concomitant administration of RUX with LEN resulted in early dose interruption in a majority of pts. Most pts were unable to restart LEN after dose interruption. Starting the two drugs simultaneously compromised the expected efficacy of RUX alone. A sequential approach with single-agent RUX for the first 3-6 months followed by the addition of the second agent once a steady dose of RUX has been achieved and optimal benefit reached may be a more viable approach for future RUX combination strategies. Table 1: Pt characteristics (N = 31) Characteristic N (%) / [range] Median age, years 66 [37-82] Male 18 (58%) Diagnosis Post-essential thrombocytosis MF Post-polycythemia MF Primary MF 4 (13%) 12 (39%) 15 (48%) Splenomegaly 28 (90%) Median WBC x 109/L 19.0 [4.3-124.9] Median hemoglobin g/dL 11.0 [8.9-17.5] Median platelets x 109/L 250 [27-1898] Peripheral blood blasts ³ 1% 15.0 (48%) JAK2 + 26 (84%) Cytogenetics Diploid 18 (58%) Abnormal 12 (39%) Insufficient metaphases 1 (3%) Disclosures Naval: Incyte: Advisory board membership Other, Research Funding. Pemmaraju:Incyte: Advisory board membership Other. Verstovsek:Incyte: Research Funding.

Evaluation of Ofatumumab, a Novel Human CD20 Monoclonal Antibody, as Single Agent Therapy in Rituximab-Refractory Follicular Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 935-935 ◽  
Author(s):  
Anton Hagenbeek ◽  
Luis Fayad ◽  
Vincent Delwail ◽  
Jean Francois Rossi ◽  
Eric Jacobsen ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 935 Introduction: Patients with follicular lymphoma (FL) who are refractory to rituximab-based therapy have a need for new non-cytotoxic treatment options. Ofatumumab targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro cell lysis via complement-dependent cytotoxicity, even in rituximab-resistant B cells that express high levels of complement inhibitory proteins. Ofatumumab as single agent showed activity in relapsed/refractory FL, including in some patients previously exposed to rituximab (Hagenbeek et al, Blood 2008). Here we report preliminary results from an international, single-arm trial assessing ofatumumab monotherapy in patients with rituximab-refractory FL. Methods: Eligible patients (aged ≥18 years), with Grade 1 or 2 CD20+ FL considered refractory to rituximab alone or in combination with chemotherapy, were enrolled between Sept 2006 and Sept 2008 (N=116). Refractoriness to rituximab (at least 4 doses) was defined as failure to achieve at least a partial response, disease progression during rituximab treatment, or disease progression following a response within 6 months of last treatment with rituximab-containing regimens. Patients received 8 weekly infusions of ofatumumab (Dose 1, 300 mg; Doses 2–8, 500 or 1000 mg); glucocorticoid premedication was required before infusions 1 and 2, and acetaminophen and antihistamine were administered before every infusion. The primary endpoint was objective response (International Working Group criteria) in the 1000 mg dose group over 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee. Secondary endpoints included duration of response, progression-free survival (PFS) and adverse events (AEs). Results: Table 1 summarizes the baseline characteristics; 90% of patients received all 8 ofatumumab doses. The median follow-up time on the study was 4.7 months overall and 5.5 months for the 1000 mg group. The overall response rate (ORR) in the 1000 mg group was 10% (95% CI: 4, 17%), including 1 complete response. Stable disease was observed in 50% of patients. In the 1000 mg group, the median duration of response was 6.0 months (95% CI: 2.8, upper limit not estimable) and median PFS was 6.0 months (95% CI: 4.9, 9.1). The ORR in the total population was 11% (95% CI: 5, 17%). Among patients who were refractory to prior rituximab monotherapy (n=27), the ORR was 22% (95% CI: 7, 38%). The ORR among patients who were refractory to rituximab maintenance therapy (n=44) and rituximab combined with chemotherapy (n=45) was 9% (95% CI: 1, 18%) and 7% (95% CI: 0, 14%), respectively. During treatment and up to 30 days following the last dose, the most common AEs (>10% of patients) included rash (15%), urticaria (14%), fatigue (14%), pruritis (13%), nausea (12%), pyrexia (11%) and cough (11%); grade 3–4 infusion-related reactions occurred in only 3 patients (all grade 3 events), none of which were considered serious events; grade 3–4 hematologic AEs included neutropenia in 5% of patients, anemia in 3% and thrombocytopenia in 1%; grade 3 infections (sepsis, febrile neutropenia) occurred in 2 patients. Conclusions: The majority of patients with rituximab-refractory FL in this study were heavily pretreated, were also refractory to chemotherapy and had high-risk FLIPI scores. Although response rates were low with single-agent ofatumumab in patients refractory to rituximab-chemotherapy, a higher response rate was observed in patients who were refractory to rituximab monotherapy, indicating activity despite being refractory to single-agent rituximab. Ofatumumab was well tolerated in this heavily-pretreated population. Infusion reactions were manageable and no unexpected toxicities were observed. Further investigations with ofatumumab are warranted, including in combination with other therapies in patients with FL. Disclosures: Hagenbeek: Roche, Bayer Schering Pharma, Genmab: Advisory roles. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis).. Fayad:GlaxoSmithKline, Genmab: Research Funding. Rossi:GlaxoSmithKline: Investigator on trial funded by GSK. Kuliczkowski:GlaxoSmithKline: Investigator on trial funded by GSK. Link:Genentech: Advisory Board, Research Funding; Genmab, GlaxoSmithKline: Research Funding. Radford:GlaxoSmithKline: Equity Ownership. Hellmann:Novartis, BMS: Consultancy, Honoraria. Gupta:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Begtrup:Genmab: Employment, Equity Ownership. Schultz:Genmab: Employment. Bang:Genmab: Employment. Russell:Genmab: Employment, Equity Ownership. Czuczman:GlaxoSmithKline: Advisory Board, Honoraria, Research Funding; Genmab: Advisory Board, Research Funding.

Southwest Oncology Group Study S0530: A Phase 2 Trial of Clofarabine/ Cytarabine for Relapsed/ Refractory Acute Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3094-3094
Author(s):  
Anjali Advani ◽  
Holly Gundacker ◽  
Olga Sala-Torra ◽  
Jerald Radich ◽  
Raymond Lai ◽  
...  
Keyword(s):  
Research Funding ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Tissue Growth ◽  
Lymphocytic Leukemia ◽  
Nucleoside Transporters ◽  
Synergistic Activity ◽  
Consolidation Therapy ◽  
Number Of Patients

Abstract Abstract 3094 Poster Board III-31 Clofarabine (Clo) has demonstrated single agent activity in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia. Therefore, efforts have been undertaken to combine Clo with other antileukemic agents. Clo and cytarabine (Cy) target two different sites in DNA, have synergistic activity in vivo, and have non-overlapping toxicities, making this combination potentially promising for the treatment of relapsed/ refractory ALL. The maximum tolerated dose of this combination has been previously determined. The goals of this study were to: (1) evaluate the complete remission rate with and without complete count recovery (CR and CRi) of patients with relapsed/ refractory ALL treated with Clo/Cy; (2) to assess expression of connective tissue growth factor (CTGF) and nucleoside transporters in patients. Methods Patients were treated at SWOG institutions from February 2007 through July 2008. Clo was supplied by Genzyme. This protocol was reviewed and approved through each institution's review board. Eligibility criteria included: age ≥ 16 years, relapsed or refractory ALL (excluding Burkitts or mixed lineage leukemia), Zubrod performance status 0-2. CTGF expression was analyzed by triplicate RT-PCR on pre-treatment samples. Expression of the nucleoside transporters (hENT1, hCNT3, dCK) was analyzed by immunohistochemistry. All patients received treatment with Clo 40 mg/m2/d and Cy 1 g/m2/d on Days 1-5. Response was assessed between Days 28-35. Patients with a partial remission (a 50% decrease in marrow blast percentage) could receive re-induction therapy. CR was defined as < 5% marrow blasts, neutrophils > 1,000/μL, platelets ≥ 100,000/μL, and no evidence of extramedullary disease. CRi was defined the same as CR but the platelet count could be < 100,000/μL. Patients with a CR could receive one cycle of consolidation therapy. Patients were to be accrued in 2 stages. In the first stage, 20 patients were to be registered. If at least 2 CR/ CRis were observed, an additional 15 patients were to be accrued (87% power to conclude that an agent with a response rate of 30% warrants further study). Results The study met criteria to proceed to the second stage. Thirty-seven patients were enrolled. One patient is excluded from the analysis because treatment was not started due to high liver function tests after registration. Of the 36 evaluable patients, the median age was 41 years (range: 20-68), median WBC 5200/μL (range 900-93,700), and 23 patients (64%) were male. The median time from initial diagnosis to registration was 14 months (range 1-52 months). Nineteen patients (53%) were in first relapse, 7 (19%) in subsequent relapse, 1 (3%) with an unknown number of relapses, and 9 (25%) refractory. Two patients had received prior allogeneic BMT. Thirty-two patients have died, with 10 deaths occurring during protocol treatment and 7 of these deaths attributable to treatment [infection (3), pleural effusion (1) DIC (1), hypotension/ renal failure/ cardiac arrhythmia (1), multiorgan failure (1)]. Three patients received re-induction, and 1 patient received consolidation therapy. The CR/CRi rate was 17% (95% CI 6-33%), and median overall survival 3 months. At least 8 patients proceeded to BMT after completing protocol therapy. The number of patients accrued to this study was relatively small and the CR rate was low. Therefore, it is unlikely that any statistical differences in CR rate would be found, with respect to expression of various biologic correlates. However, there was a trend for patients with higher expression of CTGF having an inferior OS (p=0.13). In addition, although 70% of patients had high levels of hENT1 expression, only 33% and 44% of patients respectively had high levels of hCNT3 and dCK, which could serve as a mechanism of resistance to nucleoside analog therapy. Conclusion The CR/CRi rate in this study was modest. This regimen does not exhibit sufficient activity to warrant further testing unless it was significantly altered. However, this was a heavily pre-treated, poor risk population of patients. Of interest, low expression of nucleoside transporters and high expression of CTGF may predict response and OS. Larger prospective studies will be needed to confirm this. Therapies directly targeting these latter pathways or working independently of these pathways may help improve the prognosis of patients if these results are confirmed. Disclosures Advani: Genzyme: Honoraria, Research Funding. Off Label Use: The combination of clofarabine/ cytarabine is investigational. Radich:Novartis: Research Funding. Lancet:Genzyme: Consultancy. Stuart:Genzyme: Research Funding.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Combination of Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 720-720 ◽  
Author(s):  
Alessandra Ferrajoli ◽  
Lorenzo Falchi ◽  
Susan O'Brien ◽  
William Wierda ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Prior Treatment ◽  
Combination Regimen ◽  
Advisory Committees ◽  
Purine Analogs

Abstract Abstract 720 Based on the demonstrated activity of ofatumumab and lenalidomide as monotherapy in patients (pts) with CLL and on the activity of rituximab in combination with lenalidomide in pts with relapsed CLL, we conducted a phase II study to investigate efficacy and tolerability of a combination regimen of ofatumumab and lenalidomide in patients with relapsed CLL who had received prior treatment with purine analogs. Thirty-six pts entered this study between January 2010 and January 2011. All pts had an indication for therapy. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2 and adequate organ function (creatinine clearance > 30ml/min, total bilirubin < to 2 mg/dl, ALT < 2 X ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Treatment consisted of ofatumumab IV given weekly for 4 weeks (300 mg week 1; 1,000 mg weeks 2 and thereafter), monthly during months 2–6 and every other month during months 7–24, and lenalidomide 10 mg PO/day started on day 9 and continued for 24 months. Allopurinol 300 mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at months 3 and 6 and every 6 months thereafter. Thirty-four pts are evaluable (one pt withdrew consent prior to treatment with lenalidomide, and one was excluded because of concomitant MDS at study entry). Median age was 64 yrs (34–82). Twenty-two pts (65%) had Rai stage III-IV disease. Median β-2M level was 4.1 mg/dL (1.7–16). Twenty-two pts (65%) had unmutated IgHV and 23 pts (68%) expressed ZAP-70. Nine pts (26%) had del(17p), and 4 pts (12%) had del(11q). Median number of prior treatments was 2 (1–8). All pts had been previously treated with FCR and 13 pts (38%) were fludarabine-refractory. Three pts (9%) had relapse following SCT.Twenty-three pts achieved a response, for an overall response (OR) rate of 68%. Eight pts (24%) achieved a complete response (CR), including 3 MRD-negative CR, and 15 pts (44%) achieved a partial response (PR). Median duration of response is 22 months (4–30), with a median follow up of 24 months. Among the 9 pts with del17p, 5 (55%) achieved a PR. The average daily dose of lenalidomide was 10 mg in 9 pts (26%), 7.5 mg in 4 pts (12%), 5 mg in13 pts (38%) and 5 mg in 8 pts (23%). Seventy-six % of the pts are alive. No pt deaths occurred while on therapy. Eight deaths occurred after discontinuation of therapy: progression of CLL despite subsequent therapy (5 pts), complications of HSCT (1 pt), CLL/lung cancer (1 pt) and causes unrelated to CLL(1 pt). Seven pts are still on therapy and 10 pts have an ongoing response. Six pts discontinued therapy despite an ongoing response due to transition to HSCT (3 pts), toxicity (2 pts) and physician choice (1 pts), and 7 pts discontinued therapy because of loss of response [after 12 (1 pt), 16 (2 pts), 19 (2 pts), 22 (1 pt) and 29 (1 pt) months].The most common grade 3–4 treatment-related hematological adverse events consisted of neutropenia in 16 pts (47%), thrombocytopenia in 3 pts (9%) and anemia in 2 pts (6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 infectious episodes occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), cellulitis (2), HZV (1) and CNS toxoplasmosis (1). No G3-4 tumor lysis syndrome or tumor flare reaction (TFR) was observed. G1-2 TFR was observed in 8 pts (24%), In conclusion, the combination of ofatumumab and lenalidomide induced responses in 68% of pts with relapsed CLL, including pts with del17p, all of whom had received prior chemoimmunotherapy. This treatment was well tolerated and neutropenia was the most common toxicity. The severity of TFR with this combination was less than with single agent lenalidomide, possibly due to attenuation by the addition of treatment with ofatumumab. Several studies are currently investigating the combination of anti-CD20 mAb and lenalidomide used both as initial and salvage therapy of CLL. Disclosures: Ferrajoli: Celgene Corporation: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene Corporation: Consultancy. Wierda:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Keating:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 675-675 ◽  
Author(s):  
Jan A. Burger ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
Julia Hoellenriegel ◽  
Ghayathri Jeyakumar ◽  
...  
Keyword(s):  
High Risk ◽  
Subdural Hematoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Single Agent ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Bertrand Coiffier ◽  
John Radford ◽  
Dolores Caballero ◽  
Paul Fields ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Median Number ◽  
Advisory Board ◽  
Japanese Study ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3091-3091 ◽  
Author(s):  
Sonali M. Smith ◽  
Brandelyn Pitcher ◽  
Sin-Ho Jung ◽  
Nancy L. Bartlett ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Clin Oncol ◽  
Research Funding ◽  
Treatment Initiation ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Cell Transplant

Abstract Background: A number of targeted and orally available agents show promising activity in lymphoid malignancies, and a rational strategy is to evaluate combinations for safety and efficacy. Idelalisib (idela) is a highly specific and potent inhibitor of the delta isoform of PI3K, downstream of B-cell receptor signaling and upstream of other survival pathways in lymphoma. Idela has single agent activity in both follicular lymphoma (FL) and mantle cell lymphoma (MCL), with response rates over 50% (N Engl J Med. 2014;370:1008). Idela and rituximab (ritux) have been safely combined in chronic lymphocytic leukemia (N Engl J Med. 2014;370:997) and other indolent lymphomas. Two previous Cancer and Leukemia Group B and Alliance studies demonstrated high levels of clinical activity of lenalidomide (len) and ritux in combination without significant toxicity. In relapsed/refractory FL, len plus ritux had higher overall (ORR) and complete response (CR) rates (75% ORR, 32% CR) versus len alone (49% ORR, 13% CR)(J Clin Oncol. 2012;30(suppl; abstr 8000). In frontline FL, len plus ritux achieved 93% ORR and 72% CR rates (J Clin Oncol 32:5s, 2014 (suppl; abstr 8521). A051201 and A051202 were designed to evaluate the safety and activity of len and ritux, in combination with idela, in pts with relapsed MCL or FL, respectively. Methods: Both A051201 and A051202 are phase I trials with 3+3 designs and pre-specified dose-limiting toxicities (DLT). Treatment in the two trials was similar but not identical. A051201 started with len 15mg po day (d) 1-21 q28d idela 150mg bid with continuous 28-d cycles, and ritux weekly during cycle 1. A051202 started with len 10mg po d1-21 q28d and idela 150mg po bid with continuous 28-d cycles, and ritux on C1d8, C1d15, C1d22 and C2d1. Both studies included a maintenance component (data not presented). Biweekly conference calls for safety were established. After 3 patients (pts) from A051202 and 1 pt from A051201 developed severe and unexpected DLT, both trials were suspended and modified. Results: At the time of study suspension, 7 FL pts and 1 MCL pt had been enrolled. Pt characteristics include median age 58.5 years (y) (range, 47-77), 5 male/3 female, and median 1 (range, 1-7) prior treatment; all pts had prior ritux. The MCL pt had an autologous stem cell transplant 3 y prior to enrollment. This pt had a DLT consisting of grade (gr) 4 AST/ALT elevation in the setting of fevers, chills, hypotension at 22 d after treatment initiation. 3 FL pts had DLT consisting of gr 3 lung infection, gr 3 hypotension and rash, and gr 4 sepsis syndrome (culture-negative), respectively. Each of the 3 FL pts with DLT developed fevers and hypotension with or without a rash 11-17 d after treatment initiation and within 24-120 hours of last ritux exposure; 2 pts had pulmonary infiltrates. 3 DLT pts required ICU level support. Other notable toxicities in all 8 pts include gr 1/2 AST/ALT elevation (n=5), gr 3 lymphopenia (n=5), gr 1/2 thrombocytopenia (n=4), grade1/2/3 neutropenia (n=4). Conclusion: Whereas doublet therapy with len/ritux and idela/ritux has been safely combined in other trials and disease settings, we observed 4 DLTs among the first 8 pts, all concerning for high-level immune activation. Although the mechanism of these toxicities is unknown, the combination of rash, fevers, and hypotension is suggestive of cytokine release syndrome (CRS), which is a known but uncommon IL-6-mediated event seen with ritux, rarely reported after single agent len, and, to date, not observed with idela. Our observation of 4 potential CRS-like reactions among 8 pts suggests an additive and previously undescribed risk of this combination. Based on the severe toxicities noted, both trials have been amended to remove ritux and pursue a phase I safety assessment of idela and len without ritux in pts with relapsed FL or MCL. Disclosures Smith: Celgene: Consultancy, Research Funding; Gilead: Consultancy; Genentech: Consultancy, DSMB for another compound, DSMB for another compound Other. Off Label Use: Phase I results of combined idela/len and rituximab. Bartlett:Gilead: Consultancy, Research Funding; Celgene: Research Funding. Wagner-Johnston:Gilead: Consultancy; Celgene: Research Funding. Richards:Genentech: Consultancy; Celgene: Honoraria. Cashen:Celgene: Speakers Bureau. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Leonard:Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy.

Phase II Study of the Salvage Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin (INO) for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1606-1606 ◽  
Author(s):  
Koji Sasaki ◽  
Elias J. Jabbour ◽  
Susan M. O'Brien ◽  
Farhad Ravandi ◽  
Deborah A Thomas ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Conditioning Regimen ◽  
Advisory Board ◽  
Historical Cohort ◽  
Platelet Recovery ◽  
Low Intensity

Abstract Background: Outcome of patients with R/R ALL is poor. INO is a CD22 monoclonal antibody bound to a calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted therapy to effective low-intensity chemotherapy might further improve clinical outcome. The aims of this study are to evaluate response rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. INO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), the dose of INO was modified to 1.3 mg/m2 for Cycle 1 followed by 1.0 mg/m2 for subsequent cycles starting at the Patient #48. Results: Fifty-seven patients (29 men, 28 women) have been enrolled. Patient characteristics and outcome are summarized in Table 1. Median age is 34 years (range 9-87). Median follow-up is 15 months (range, 2-34). The overall response rate was 45 (79%): 31 (53%) CR, 13 (23%) CR without platelet recovery (CRp), and 1 (2%) CR with incomplete count recovery (CRi). Grade 3/4 toxicities included infections during induction (52%), infections during consolidation (73%), prolonged thrombocytopenia (79%), hyperglycemia (50%), hypokalemia (35%), hyperbilirubinemia (24%), elevated AST/ALT (21%), hemorrhage (18%), and VOD (11%; n=6). Of 6 patients who developed VOD, all 6 had allogeneic stem cell transplantation (allo-SCT) prior to or post INO therapy; three had prior allo-SCT (conditioning regimen; 2 fludarabine/clofarabine; 1 cyclophosphamide/total body irradiation); 4 had allo-SCT after INO therapy (conditioning regimen; 2 fludarabine/busulfan/clofarabine; 1 fludarabine/melphalan; 1 fludarabine/busulfan); 1 had chimeric antigen receptor T-cell therapy. Twenty-seven (47%) patients proceeded to receive allo-SCT. At the last follow-up, 25 (44%) patients are alive. Thirty-two (56%) patients died: 7 early death; 5 refractory disease; 7 post relapse after subsequent salvage, 3 in CR/CRp (1 sepsis; 2 unknown), 10 post allo-SCT (1 VOD; 3 transplant complications; 5 relapse; and 1 unknown). The 2-year PFS and OS rates were 52% and 34%, respectively (Figure 1). Median OS for patients with S1 was not reached with 2-year OS of 53%; patients with S2, 6 months with 2-year OS of 0%; patients with ≥S3, 5.6 months with 2-year OS of 0% (p=0.005). Patients who were treated with mini-hyper-CVD plus INO plus/minus rituximab had a tendency of higher PFS rates, and improved OS compared to a historical cohort with single-agent INO in R/R ALL (2-year PFS; 52% vs. 36%; p=0.20: 2-year OS; 44% vs. 25%; p=0.01). Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Burger:Pharmacyclics: Research Funding. Jain:Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; Infinity: Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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