An Effective and Tolerable Chemoimmunotherapy Regimen For Relapsed/Refractory and Very-High Risk Chronic Lymphocytic Leukemia Combining Alemtuzumab With Pentostatin and Low Dose Rituximab

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1641-1641
Author(s):  
Clive S. Zent ◽  
Betsy R LaPlant ◽  
Wenting Wu ◽  
Timothy G. Call ◽  
Deborah Bowen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Lymphocytic Leukemia ◽  
Bulky Disease ◽  
Purine Analogue ◽  
Very High

Abstract Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. Methods This two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. Results Forty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%). Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications. The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. Discussion PAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures: Zent: Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.

scholarly journals A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
N Rates

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Eradication of Minimal Residual Disease Using Alemtuzumab Consolidation After High-Dose Methyl-Prednisolone Plus Rituximab (HDMP-R) Is Safe, Effective and Induces Long Term Remission in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2866-2866
Author(s):  
Januario E. Castro ◽  
Lina M. Ariza-Serrano ◽  
Juan S. Barajas-Gamboa ◽  
Julio A. Diaz-Perez ◽  
Danelle F. James ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Bulky Disease ◽  
Minimal Residual

Abstract Abstract 2866 Despite advances in the treatment of patients with chronic lymphocytic leukemia (CLL), the disease still remains incurable and eradication of minimal residual disease (MRD) being one of the most challenging goals of treatment. Alemtuzumab (Campath-H1™) has been shown to effectivily eradicate MRD from the bone marrow and induce long-term remissions, however its use is limited to patients without bulky disease. Futhermore, combination of alemtuzumab with chemotherapy has resulted in serious adverse events. In this study, we evaluate the toxicity and efficacy of alemtuzumab as consolidation therapy for CLL patients following induction with high-dose methylprednisolone in combination with rituximab (HDMP-R). Twenty-one patients with evidence of residual disease after treatment with HDMP-R received additional treatment with alemtuzumab. This antibody was administered three times a week for a total of 8 weeks. Patients received antibiotic prophylaxis with trimethoprim-sulfamethoxazole 160/800 mg twice a day × 3 per week, fluconazole 100 mg / day and valganciclovir 900 mg / day. The median age was 60 years (range, 49–73), with Rai stage III-IV in 81% of the patients. Twelve patients (57%) had evidence of unmutated IgVH gene and thirteen (62%) had high level of ZAP-70 expression. Cytogenetic and FISH analysis showed eight patients with deleletion 13q, three patients with trisomy 12, one patient with deletion 11q, five patients with no chromosomal abnomalities and in six patients data was not available. The median number of previous treatments was 1.3 (range, 0–5) and the median time from the end of HDMP-R treatment to initiation of alemtuzumab was 5 months (range, 1–14). After HDMP-R, nine patients (43%) achieved CR and twelve (57%) were in PR; all of them had evidence of residual disease in the bone marrow by 4-color flow cytometry analysis. Eight additional patients achieved CR after consolidation with alemtuzumab for a total of 17 patients (81%) in CR at the end of the study. We found no evidence of MRD (MRDneg) in 12 of those patients (57% of the total and 71% of CR patients). Of the remaining patients, one had PR and three patients had progressive disease for an overall response rate of 86%. The median progression-free survival (PFS) was 63 months (range, 6–84) for all patients. The median PFS in CR MRDneg patients has not been reached at a median follow-up of 46 months (range, 18–84), with 8/12 patients that have not progressed after a time at risk of 3.8 years. CR MRDpos patients have a median PFS of 48 months (range, 6–48). The treatment was well tolerated and there were no deaths attributed to therapy. Adverse events were classified following the NCI common terminology criteria for adverse events (CTCAE) Version 4.0. Two patients (9.5%) developed infections. The first event occurred during the administration of alemtuzumab and required hospitalization of the patient for management of pneumonia galactomannan positive suspicious for invasive aspergillosis (Grade 3), the second event was in a patient with aspegillus sp. infection of the skin that occurred four months after completion of alemtuzumab (Grade 2). Both patients recovered completely. We observed no CMV or other opportunistic infections. Three patients (14%) developed cytopenias; two patients with (Grade 4) thrombocytopenia and three patients with (Grade 4) neutropenia. In conclusion, alemtuzumab consolidation for residual disease after treatment with HDMP-R was well tolerated and effective in patients with CLL. We observed a near two-fold increase in the number of patients that achieved CR and the majority of these (71%) had no evidence of MRD. Moreover, patients with CR MRDneg have an exceptionally long PFS. The low rate of infection and lack of treatment related mortality compares very favorably with previous studies using alemtuzumab consolidation after chemotherapy treatment in which toxicities including treatment related death were found to be prohibitive. These encouraging results provide the rationale for additional studies using this combination therapy. Disclosures: James: Celgene: Research Funding.

scholarly journals Clinical Characteristics and Treatment Allocations in Patients with Myelodysplastic Syndromes and Monosomy 7: Results from an International Multicenter Study Suggest That Hypomethylating Agents Significantly Improve Overall- and AML-Free Survival in Patients Classified As Very High Risk By IPSS-R

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4656-4656 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Ghulam J. Mufti ◽  
Elena Crisà ◽  
Austin Kulasekararaj ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Study Cohort ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction: Total (-7) or partial (7q-) monosomy 7 is the second frequent abnormality in MDS, occurring in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with -7 or del(7q) in a multicentric, retrospective cohort study. Patients and Methods: 471 patients with MDS/AML following MDS and monosomy 7 were registered and retrospectively analyzed. The median observation time was 3.6 years. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, bone marrow blast count <=30% and presence of -7 or 7q- proved by chromosome banding analysis (CBA) or fluorescence in situ-hybridization (FISH). The data was coalesced from 8 centers in London (n=140; 29.7%), Duesseldorf, (n=120; 25.5%%), Goettingen (n=118; 25.1%), Cologne (n=38; 8.1%), Freiburg (n=29; 6.2%), Munich (n=13; 2.8%), Dresden (n=10; 2.1%) and Mannheim (n=3; 0.6%). The median age in the study cohort was 66 years, 63% of patients were males. MDS/AML was therapy-associated in 53 (11%). According to IPSS-R, 9 (1.9%) were assigned to the low risk group, 39 (8.3%) to the intermediate group, 81 (17.2%) to the high-risk group and 133 (28.2%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), hypomethylating agents (HMA; either 5-azacytidine or decitabine), and others (e.g. valproic acid, steroids, lenalidomide or thalidomide). Survival analyses were performed regarding overall- (OS) as well as AML-free survival (AFS) using the Kaplan-Meier method. Results: 147 patients (31.2%) showed 7q-, 313 (66.5%) -7 and 11 (2.3) patients showed both abnormalities at the first cytogenetic examination. The abnormality was detected by CBA±FISH in 440 (93.4%) and by FISH only in 31 (6.6%). In the latter cases, the CBA was either unsuccessful or showed a normal karyotype. In 182 (38.6%) patients, -7/del7q was detected as a single abnormality, 77 (16.3%) showed two abnormalities and 184 (39.1%) showed a complex karyotype involving -7/7q-. As previously described (Schanz et al., 2012), untreated patients with an isolated 7q- as compared to an isolated -7 show a better prognosis regarding OS (median: 4.0 vs. 0.7 years; p<0.01) as well as AFS (median not reached vs. 2.3 years; p=0.062). Median hemoglobin level in the study cohort was 9.3 g/dl, ANC 0.98*103/μl, platelet count 73*103/μl and the median number of bone marrow blasts was 8%. Regarding the treatment, a best supportive care regimen was chosen in 195 (41%) patients. The remaining 276 (58.6) patients received 1-5 sequential therapies (one therapy: 31.6%; more than 1 therapy: 27.0%). 81 patients received an allogeneic bone marrow transplantation (ATX). Within the group of patients treated with HMA at any time of their disease (n=167), 147 (31.2%) received 5-Azacytidine, 8 (1.7%) Decitabine and 12 (2.5%) patients were treated with both drugs. As the first line therapy, 122 patients (25.9%) received HMA, 50 (10.6%) HDC, 28 (5.9%) ATX, 28 (5.9%) 11 (2.3%) LDC, and 28 (5.9%) were treated with other therapies. Patients eligible for ATX showed a significantly better prognosis as compared to any other therapy strategy: The median OS in was 2.1 years as compared to 1.1 years in non-transplanted patients (p<0.01). In patients not eligible for ATX, treatment with HMA at any course of their disease as compared to a BSC strategy was associated with a better OS (1.4 vs. 0.8 years, p=0.014). By comparing HMA to any other therapy, the OS did not differ significantly (1.4 years in HMA vs. 1.1 years in any other, p n.s.). In patients classified as very high risk according to IPSS-R, the median OS was significantly prolonged in patients receiving HMA as compared to BSC (1.1 vs. 0.6 years, p<0.01). This was also observed for the risk of AML-transformation in this subgroup of patients: The median time to AML was 1.8 years in HMA-treated patients versus 0.6 years in BSC (p=0.012). Conclusions: To our knowledge, the study describes the largest patient cohort with MDS/AML and monosomy 7 published to date. Further data regarding the clinical characteristics of this subgroup of patients and the treatment regimes applied will be presented in detail. The study was supported by research funding from Celgene Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schanz: Celgene: Honoraria, Research Funding, Travel grants: Celgene, Novartis, Lilly Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Nolte:Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

scholarly journals A Multicenter Study of Ibrutinib Resistance Development and Intervention with Venetoclax in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3049-3049
Author(s):  
Kerry A Rogers ◽  
Lai Wei ◽  
Seema A. Bhat ◽  
Dan Jones ◽  
Erlene K. Seymour ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Response Assessment ◽  
Ohio State University ◽  
Lymphocytic Leukemia ◽  
State University ◽  
Phase 2 ◽  
University Patents ◽  
Secondary Endpoints

Background: Ibrutinib (ibr) for the treatment of chronic lymphocytic leukemia (CLL) has improved progression-free survival (PFS) compared to other treatments, especially in high-risk patients (pts). However, resistance occurs and is associated with mutations in the drug binding target (BTK) and its immediate downstream target (PLCg2). These ibr resistance mutations (IRmut) are detectable months prior to developing progressive disease (PD) and predict clinical relapse. Prospectively determining the time from starting ibr to development of IRmut and from IRmut detection to PD will improve our understanding of how to manage these patients. Venetoclax (ven) is highly effective after ibr and decreases IRmut. Adding ven to ibr for ibr resistance is a rational choice as this combination is safe and effective in CLL. Adding an agent rather than stopping ibr avoids disease flare associated with ibr discontinuation. This phase 2 study was designed to follow CLL pts taking ibr and at high risk for resistance (observation cohort) and to test ven in combination with ibr for those who develop PD (intervention cohort). This will determine: the incidence of IRmut and PD in this population, the ORR with ibr/ven, and the ability of this combination to eliminate IRmut. Trial Design and Methods: This multisite study will open at 4 centers initially. Eligible pts are adults with CLL taking ibr for ≥12 months and at high risk for ibr resistance defined as having ≥2 prior treatments and del(17p)(p13.1) on FISH panel and/or a complex karyotype. Pts with known IRmut or who cannot continue ibr for any reason are excluded. Enrolled pts enter the observation cohort and are followed every 3 months with a clinic visit, blood counts, and testing for IRmut. Pts who develop IRmut will also have CT scans at their visits to detect PD. Those with IRmut who develop PD by iwCLL 2018 criteria will enter the intervention cohort. Pts in the intervention cohort will start ven in addition to ibr. Ven will be ramped-up over 5 weeks to a target dose of 400mg. Pts will take combination ibr/ven for 12 cycles of 28 days in length. After 12 cycles they will undergo response assessment and those achieving a complete remission (CR) with no detectable leukemia (uMRD) in both the blood and bone marrow will stop ven and continue ibr alone. Those who do not achieve CR with uMRD will continue ibr/ven until cycle 24 and undergo a second response assessment. If in a CR with uMRD after 24 cycles they continue on ibr alone. If a CR with uMRD is not achieved after 24 cycles patients continue ibr/ven until PD, intolerance, death, or end of study which is 30 months after the last patient enters the intervention cohort (Figure). In the intervention cohort all pts will be tested for IRmut in the blood every 3 months with bone marrow testing at response assessments. The study has co-primary endpoints of ORR to combination ibr/ven after 12 cycles and the rate of IRmut negative status at that time in the intervention cohort. ORR will be tested first using a single-stage phase 2 design with a null hypothesis that the rate is ≤50% versus the alternative hypothesis that it is ≥75%. Only if the combination is effective in ORR will the rate of IRmut negative status be formally tested. Constraining overall Type I and II errors to 0.10 using this sequential testing strategy, 26 evaluable pts are required and 28 will be accrued. Secondary endpoints for the intervention cohort are the PFS and overall survival since starting the combination ibr/ven and the incidence and type of adverse events with ibr/ven. Secondary endpoints in the observation cohort are the incidence of IRmut during ibr treatment and the PFS after developing an IRmut. We estimate that 180 pt-years of follow up for the observation cohort will be needed. The yearly rate of mutation development in this population is approximately 20%, therefore this will identify 36 pts with IRmut. Of those with IRmut, approximately 80% will remain eligible to enter the intervention cohort. Accrual to the observation cohort will stop once 28 pts enter the intervention cohort. Conclusion: This multicenter phase 2 trial examines the development of IRmut and clinical resistance to ibr in a cohort of high-risk CLL pts and will determine the efficacy of adding ven to ibr in those who develop PD. We expect to determine the natural course of molecular and clinical ibr resistance in CLL and if adding ven is an effective treatment strategy. Figure Disclosures Rogers: Acerta: Consultancy; Genentech: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Ye:Janssen: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Sanofi: Research Funding. Byrd:Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. OffLabel Disclosure: This abstract discussion the use of combination ibrutinib and venetoclax in CLL.

scholarly journals A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2749-2749
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Kelsey Tague ◽  
Veronica Romines ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Induction Phase ◽  
Advisory Committees ◽  
Study Therapy

Abstract Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of &gt;90% and deep remission in &gt;40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Retrospective, Single-Institution Analysis Based on Risk Features and Debulking Strategy with Anti-CD20 Monoclonal Antibody

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5484-5484 ◽  
Author(s):  
Ariel F Grajales-Cruz ◽  
Julio Chavez ◽  
Virginia Olivia Volpe ◽  
Jose Sandoval-Sus ◽  
Bijal Shah ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
Very High

Background: The treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) has continued to evolve in recent years, offering the patients different therapeutic options. Venetoclax (ven) is a selective, small molecule inhibitor of B-cell receptor-2 (BCL-2) approved by the FDA for patients with newly diagnosed and relapsed/refractory CLL. Stratification based on tumor lysis syndrome (TLS) risk is recommended and may guide debulking strategies. Methods: We retrospectively analyzed 36 patients with relapsed/refractory (RR) CLL who received treatment with ven at the Moffitt Cancer Center between January 2016 and July 2019. Objective response to therapy was determined based on iwCLL. Progression free survival (PFS) and overall survival (OS) were evaluated via Kaplan-Meier method; overall response rate (ORR) and complete response (CR) via Fisher's exact test. Adverse events (AEs) were graded by CTCAEv5. Results: The median age was 58.5 years (28-82). Median follow up was 12.97 months. The vast majority of patients had high risk disease; Chromosomal analysis by Fluorescence In Situ Hybridization (FISH) reported Del17p and Del11q (+/- others, except Del17p) in 18 (50%) patients and 6 (16.7%) patients respectively. Twenty one (58.3%) patients had a TP53 mutation by next generation sequencing. Twenty five (80.6%) patients had unmutated IGHV status, and 24 (79.9%) patients had high or very high CLL-International prognostic Index (CLL-IPI) score. Twenty-four patients (66.7%) had been previously treated with Ibrutinib, 11 of those progressing on it. Further characteristics are described in table 1. Median OS was not reached. Median PFS was 23.93 months, figure 1a. Median duration of response was 25.97 months. The ORR (PR+CR) at the time of analysis was 63.9%, with CR rate of 33.3%, and PR rate of 30.6%. Nine patients (25%) had stable disease (SD), while four patients (11.1%) progressed on treatment. Minimal residual disease (MRD) was evaluated as part of the response assessment in 7 patients (19.4%) by flow cytometry (1 patient) and by clonoSEQ (6 patients), and 4 (11.1%) had achieved undetectable disease. Response rates were also based on risk stratification; OS and PFS were not affected by the presence of TP53 mutation (p=0.1145) as described in figure 1b, IGHV unmutated status, or NOTCH1 mutation. PFS was inferior in patients with high-very high CLL-IPI score (p=0.0414), figure 1c. The presence of bulky lymphadenopathy (≥5 cm) did not affect outcomes (p=0.5772), figure 1d. Reasons for treatment discontinuation were: progressive disease (PD) in 6 (16.7%), MD/patient preference in 5 (13.9%), Richter's transformation in 2 (5.6%), AEs in 1 (2.8%), allogeneic transplant in 1 (2.8%), and death while on treatment in 1 (2.8%) case. Twenty patients (55.6%) were considered to be at intermediate/high risk of developing TLS, of whom 15 (75%) received debulking therapy with rituximab (1), ofatumumab (11), or obinutuzumab (3) prior to ven. Based on the absolute lymphocyte count (ALC), the risk of TLS became low in 12 patients. The use of a debulking monoclonal antibody (MoAb) improved lymphocytosis, but did not impact PFS. Treatment was well tolerated, and was not dependent on the use of debulking MoAb; however, out of the 18 patients (50%) who underwent debulking therapy, 9 (25%) had grade 3/4 toxicities. Neutropenia was the most common grade 3/4 toxicity in all patients, which was seen in 7 (19.4%) patients, and diarrhea was the most common grade 3/4 non-hematologic toxicity, seen in 4 (11.1%) patients; grade 3/4 neutropenia was seen in 4 (57.1%) of those patients who received debulking therapy, while diarrhea was only seen in 1 (25%). No cases of TLS were observed. Ten patients (27.8%) were admitted for ramp up of ven as per physician preference, independent of TLS risk and comorbidities. Conclusion: Venetoclax is a very active agent for R/R CLL with an acceptable toxicity profile. Debulking strategy is a tolerable option for patients with high burden disease and may reduce the incidence of TLS and/or hospitalization. Nonetheless, based on this retrospective study, it does not seem to have a significant impact in outcomes, and it carries a higher risk for potential cumulative toxicity. Disclosures Chavez: Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau.

scholarly journals Subcutaneous Low Dose Alemtuzumab: Role As a Salvage Therapy in Immune -Mediated Marrow Failure Conditions

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1505-1505 ◽  
Author(s):  
Swapna Thota ◽  
Srinivasa Reddy Sanikommu ◽  
Bhumika Patel ◽  
Meena Sadaps ◽  
Cassandra M. Hirsch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Salvage Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Immune Mediated ◽  
Heavily Pretreated

Abstract Aplastic anemia (AA), pure red cell aplasia (PRCA), pure white cell aplasia (PWCA), idiopathic neutropenia (IN) and T cell large granular lymphocytic leukemia (LGL) are bone marrow failure (BMF) conditions unified by immune-mediated pathogenesis leading to cytopenias. Intravenous alemtuzumab, a CD52 monoclonal antibody approved for the treatment of chronic lymphocytic leukemia (CLL) and used for relapsed AA, has a response rate in AA of 37-58%. However, dosing and route was likely based on those used in CLL regimens and resulted in significant immunosuppressive complications. Here we summarize our experience with sc alemtuzumab given at the maximum dose of total 100 mg as etiologic treatment (either salvage therapy or preferred therapy) to patients with various BMF. We investigated the therapies administered to patients seen at the Cleveland Clinic or at the University of Naples (NCT00895739) between years 2002-2015. Of 484 patients with BMF conditions (Cleveland: AA: 204, LGL: 174, PRCA: 56; Naples: AA: 24, LGL: 2, PRCA: 14), 65 patients with AA (N=22), PRCA (N=22), LGL (N=18) and 3 cases of IN/PWCA were treated sc alemtuzumab, given according 2 distinct schedules: i. initial dose of 3 mg sc followed by 10 mg once or twice weekly for at least 8 consecutive weeks; ii. 4-5 day dose escalation (3-10-30-30-30 mg) regimen. In both schedules, some patients received a much longer course with maintenance treatment or occasional boosts to prevent or treat relapse. Patients received bactrim and acyclovir prophylaxis, IVIG for hypoglobulinemia and underwent CMV monitoring. The median age of patients was 57.5 years (range: 31-84 years). Alemtuzumab was used as salvage therapy in Cleveland (except for 3 AA cases with contraindication to anti-thymocyte globulin or cyclosporine), whereas in Naples untreated patients were allowed per protocol. As a result, patients had a median of 2 lines of therapy (range: 0-6), had either untreated (35%), relapsed (22%) or refractory (43%) BMF condition. Among the 22 AA patients 12 were untreated, or had relapsed (N=4), or refractory disease (N=6), with concomitant PNH clone in 8/22 patients. LGL patients (N=18) treated with alemtuzumab were younger, had a median of 2 prior therapies, 50% were STAT3 mutants, with comparable degree of cytopenias but excess splenomegaly (60% vs. 38%, p=.012) at presentation, compared to the remainder LGL cohort. Amongst these patients, 18% had relapsed LGL while the rest had refractory disease. PRCA cases treated were either idiopathic (N=18, of whom 3 associated with thymoma) or LGL-associated (N=4); this group was very heterogeneous, including 9 untreated patients (in Naples) and a subgroup of heavily pretreated patients (5 with refractory disease) with a median of 5 prior therapies, with mean hemoglobin of 7.5 g/dL. Among the group of PWCA/IN, one case of PWCA was LGL-associated. The treatment was well tolerated in 92% of the patients, except in four patients who did not complete treatment course due to adverse events. The main adverse events include infectious complications with 7/65 developing CMV reactivation, 4/65 HSV reactivation, and more rarely other viral reactivation (VZV and HBV, 1/65 each). Two fatal infections were recorded: 1 fungemia (heavily pretreated with other therapies) and 1 JCV-related PML (in a patients also receiving chemotherapy for refractory thymoma). The overall response rate was 55%; by disease subtype 54% of AA, 44% of LGL, 59% of PRCA and all three cases of PWCA/IN responded. The median time to response in AA was 12 weeks (range: 6-24 weeks), and responses lasted a median of 6 months (range: 2-72 months). In AA, we observed responses in 72% of the cases treated with almetuzumab upfront and 45% of the relapsed/refractory disease. Similarly in PRCA cases, 77% of the alemtuzumab upfront and 46% of the relapsed/refractory disease responded. With a median follow up >4 years, no late treatment-related complication emerged; treatment failures were mostly due to relapses (sometimes refractory to further immunosuppressive treatment), with clonal evolution around 15% (mostly in non-responders). In summary, low-dose sc alemtuzumab is a reasonable alternative option for patients with BMF conditions, especially in relapsed/refractory cases; patients need to be monitored with a heightened vigilance for infectious complications, as well as for possible recurrence of their underlying disease. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Alnylam: Research Funding; Rapharma: Research Funding; Novartis: Research Funding.

Lenalidomide in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia with Chromosome 5 Abnormalities.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 115-115 ◽  
Author(s):  
Lars Möllgård ◽  
Lars Nilsson ◽  
Lars Kjeldsen ◽  
Ingunn Dybedal ◽  
Inge Hogh Dufva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Underlying Disease ◽  
Low Risk ◽  
Induction Treatment ◽  
Complex Karyotype ◽  
A Minor

Abstract Abstract 115 Background: Treatment with lenalidomide in patients with low risk MDS with deletion del(5q) has resulted in a high proportion of transfusion independence and also cytogenetic responses. The aim of this study was to evaluate the effect of lenalidomide in high risk MDS and AML patients with del(5q) or monosomy 5 not eligible for induction treatment, primary cases as well as patients relapsing/refractory to intensive treatment. Methods: This investigator-initiated prospective phase II study assessed the effects of continuous lenalidomide treatment during 16 weeks, in increasing doses from 10 to 30 mg, with 8 weeks on the highest level. Dose modifications due to hematologic toxicity were performed according to the clinical judgment of the treating physician. The primary objective was cytogenetic response, assessed by FISH on bone marrow (BM) smears at inclusion and after 8 and 16 weeks. Clinical and morphological BM response was evaluated every 4 weeks. Results: 25 patients were included from October 2007 to July 2009, 22 of which are so far evaluable. Overall, the patient cohort included several patients with very advanced disease and two patients died before treatment was started. Fourteen MDS patients and 11 AML patients have been included. Twenty-two of the patients had 5q- (9 of these had a complex karyotype and 5 had del(5q)+1) and 3 patients had monosomy 5 (all complex karyotype). The median time of treatment was 13 weeks (range 0–16 weeks). The reason for early termination in the patients who started lenalidomide treatment was progressive disease (3) and adverse events (10). Six of 7 patients who completed the study (16 weeks of treatment) had a response: Two MDS patients with del(5q-)+1, and del(5q)+2, respectively, achieved a major cytogenetic response (≥50 % reduction), in one of these patients the blast count decreased from 9.5% to <5%. Two MDS patients with 5q- and complex karyotype had a minor cytogenetic response (≥25% reduction) and a reduction to <5% blasts, respectively. One AML with 5q- and a complex karyotype had a minor cytogenetic response and a complete BM response. Another AML patient with isolated 5q- showed a complete BM, but no cytogenetic response. In total, 6 of the 20 patients (30%) who started treatment had a cytogenetic and/or morphological BM response. Four of 6 responders also experienced hematologic response. Twenty-one serious adverse events (SAE) have been reported in 15 of the patients. The main SAE criterion has been inpatient hospitalization. Fourteen of the SAE:s were infection or febrile neutropenia. In 6 patients the outcome of the SAE has been death. For these patients the causality/relationship to lenalidomide has been judged as not suspected or not related. The cause of death has been the underlying disease or complications to the underlying disease like infections. Conclusion: Lenalidomide as a single agent, but in higher doses than those applied to low-risk MDS patients resulted in cytogenetic and/or morphological bone marrow response in 30% of patients with high-risk MDS or AML with del(5q) or monosomy 5. We considered this a promising response rate, considering the high frequency of very advanced patients, and complex karyotypes. The main serious adverse event was infections. Future combinations with cytostatic or hypometylating agents may further improve these results. Disclosures: Möllgård: Celgene: Research Funding. Hellström-Lindberg:Celgene: Research Funding.

scholarly journals A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4306-4306 ◽  
Author(s):  
Sameer A. Parikh ◽  
Eli Muchtar ◽  
Betsy Laplant ◽  
Wei Ding ◽  
Sikander Ailawadhi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Early Stage ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Study ◽  
Very High

Background: The 2018 iwCLL guidelines recommend close observation of early stage CLL pts who do not meet indications for therapy ("watch and wait" strategy). Prior attempts at early therapeutic intervention in unselected early-stage CLL pts using alkylating agents such as chlorambucil and chemoimmunotherapy failed to show a significant benefit; and these therapies were associated with substantial toxicities. The introduction of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the treatment landscape of CLL. The German CLL Study group recently presented results of the CLL12 study which demonstrated a significant improvement in event-free survival (EFS) among untreated early stage high risk CLL pts who received ibrutinib compared to placebo (median EFS not reached vs. 47.8 months, respectively; Langerbeins, EHA, 2019). Acalabrutinib is a more selective second-generation BTK inhibitor that has fewer adverse events in pts with CLL, and has shown equally impressive clinical activity for CLL pts. We are conducting an investigator initiated randomized phase 2 study to compare acalabrutinib with or without obinutuzumab (a glycoengineered anti-CD20 monoclonal antibody approved in the treatment of CLL) among high risk early stage CLL pts. Study Design: All pts with newly diagnosed (<2 years from registration) previously untreated early stage CLL who do not meet the 2018 iwCLL guidelines for initiation of therapy are eligible for enrollment in this study. Pts undergo risk stratification according to the CLL-International prognostic index (CLL-IPI) which consists of the following 5 variables: age >65 years (1 point), Rai stage I-IV (1 point), del17p and/or TP53 mutation (4 points), unmutated immunoglobulin heavy chain (IGHV) genes (2 points), and serum β2-microglobulin >3.5 g/dL (2 points). Pts with high (4-6) and very high (7-10) risk CLL-IPI are randomly (1:1) assigned to acalabrutinib 100 mg orally twice daily (Arm A) or acalabrutinib with obinutuzumab at a standard approved schedule (Arm B). Treatment with acalabrutinib is continued for a minimum of 2 years unless the patient has unacceptable side effects or withdraws consent. Pts with low (0-1) and intermediate (2-3) risk CLL-IPI score are assigned to an observation arm with follow-up once every 6 months for 2 years, and then according to routine clinical practice (Arm C). Endpoints: The primary endpoint of the intervention arms (Arms A and B) is the achievement of minimal residual disease (MRD)-negative complete remission in the bone marrow after 2 years of therapy. MRD is assessed using an 8-color flow cytometry with a detection limit of 0.01%. The primary endpoint of the observation arm (Arm C) is time to first therapy. Secondary endpoints for all arms are: progression-free survival, overall survival, and safety. Statistical design: A randomized trial comparing the experimental arm (acalabrutinib plus obinutuzumab) against the control arm (acalabrutinib alone) will be conducted as described by Rubinstein. A sample size of 36 pts per arm provides 80% power to detect an improvement in MRD-negative complete response rate from 10% to 30%, using a one-sided test at a significance level of 0.10 (EAST 6.4). We anticipate accruing an additional 8 high/very high risk pts (4 in each arm) to account for ineligibility, cancellation, or major treatment violation. The total enrollment for Arms A and B will be 80 pts. We will enroll 40 pts to Arm C; for a total enrollment of 120 pts. Key correlatives: Comprehensive profiling to assess the innate and adaptive immune system in paired peripheral blood and bone marrow will be conducted in all pts registered to Arms A and B at baseline, 12 and 24 months after enrollment. In addition, bone marrow hematopoietic function will be assessed in all pts at these time points. We will employ a CLL focused custom 61-gene panel to estimate tumor mutational burden as well as mutational profiles for each patient at baseline, 12, and 24 month time points, as well at the time of disease progression. Preliminary results: The trial is registered at clinicaltrials.gov NCT03516617. The trial opened to accrual at all three Mayo Clinic sites (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ) in September 2018. Twenty-eight pts have been registered; the baseline characteristics are shown in Table 1. The trial is expected to complete enrollment in September 2020; and the primary analysis will be available in September 2022. Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria. Ding:DTRM Biopharma: Research Funding; Merck: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Chanan-Khan:Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Jansen: Research Funding; AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding. Kay:Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board. OffLabel Disclosure: Drug: Acalabrutinib Purpose: treatment of CLL

scholarly journals Results of a Phase II of Low-Dose Fludarabine and Cyclophosphamide Combined with Standard Dose Rituximab (FCR-LITE) in Elderly, Untreated Patients with Chronic Lymphocytic Leukemia (CLL): The Israeli CLL Study Group Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5566-5566
Author(s):  
Tamar Tadmor ◽  
Yair Herishanu ◽  
Andrei Braester ◽  
Osnat Bairey ◽  
Ariel Aviv ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
Categorical Variables ◽  
Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission. When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy. Patients and Methods We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m2/day together with IV cyclophosphamide 150 mg/m2/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m2, and at 500 mg/m2 on day 1 of cycles 2-6. Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up. All statistical tests were two sided. P<0.05 was considered as statistically significant. Results Forty patients treated with FCR-LITE were included in the efficacy analysis. The median age of the entire cohort was 72.7 years (range, 65.0 to 85.0), and 69% were male. The mean number of treatment cycles was 5.1 (range 1-6). The overall response rate was 67.5% (95% CI, 50.9%-81.4%); 17 patients (42.5%) achieved CR and 10 (25.0%) PR. Median PFS was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Reduced cumulative doses of FCR and fewer courses of treatment were both associated with lower CR rate. Hematological toxicities were the most common side effects encountered; grade-3/4 neutropenia occurred in twenty (47.6%) patients, only six (14.3%) developed neutropenic fever. Positive direct antiglobulin test (DAT), was seen in 11 patients but none of them developed autoimmune hemolytic anemia (AIHA) during treatment; two patients (4.8%) progressed to Richter's transformation and two (4.8%) had second malignancies (lung and metastatic colon carcinoma). Conclusion FCR-LITE is effective and safe for treating elderly patients with therapy-naïve CLL. It has the advantage of being both time and cost effective. In an era of novel agents, it can still be considered as suitable frontline treatment for fit elderly patients with CLL. This research was supported by roche pharmaceuticals Table. Table. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; NOVARTIS: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy. Herishanu:JNJ: Consultancy; ABBVIE: Consultancy; ROCHE: Research Funding. Bairey:ROCHE: Research Funding; AbbVie: Consultancy; Jansen: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Rahimi-Levene:ABBVIE: Consultancy. Fineman:ABBVIE: Consultancy; JNJ: Consultancy. Ruchlemer:JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:JNJ: Consultancy; ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

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