Phase II Study of Acalabrutinib and High-Frequency Low-Dose Subcutaneous Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Abstract Background: Continuous Bruton's tyrosine kinase (BTK) inhibition represents an effective and easily administered oral therapy for patients with CLL; however, it is not curative, can have serious side effects, and is expensive. Novel combinations may provide deep remissions allowing fixed duration therapy. The second generation BTK inhibitor acalabrutinib (ACALA) has demonstrated an improved safety profile compared to ibrutinib. Importantly, unlike ibrutinib, ACALA does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis (VanDerMeid et al, Cancer Immuno Res 2018). Using standard doses, rituximab (RTX) rapidly exhausts the finite innate immune system cytotoxic capacity (Pinney, et al Blood 2020) and also causes loss of cell membrane CD20 from CLL cells by trogocytosis. Previous studies have shown that high frequency low dose (HFLD) IV RTX (20mg/m 2 three times per week) was effective and limited loss of CD20 (Zent, et al Am J Hematol, 2014). Subcutaneous (SQ) RTX is FDA approved in CLL, has similar efficacy and pharmacokinetics, and can be self-administered. This phase II study tested the efficacy and tolerability of the combination of ACALA and HFLD RTX as initial treatment for patients with treatment-naïve CLL. Methods: Eligible patients were treated with 50mg RTX on day 1 and 3 of each week for six 28-day cycles. The first dose was administered IV over 2 hours. If tolerated, subsequent doses were SQ and could be self-administered at home by trained patients. ACALA 100mg BID therapy was initiated on cycle 1 day 8 for a minimum of 12 cycles. Treatment response was assessed during cycles 12 and 24. Patients achieving an iwCLL complete response (CR) with undetectable minimal residual disease (uMRD) by 6-color flow cytometry (£ 1:10 -4)at either time point could stop therapy. The primary objective was to determine the rate of iwCLL CR with a secondary endpoint of rate of uMRD. Results: 37 patients have been treated with a median follow-up of 14 months. Baseline demographics were male/female (22/15) and median age 67 years (range 40-78). High-risk genetic features included TP53 mutation (21.6%), del17p (13.5%), del 11q (16.2%), unmutated IGHV (62.2%), NOTCH1 mutation (21.6%) and SF3B1 mutation (10.8%). Grade 3/4 AEs occurring in ≥5% of patients were infections (13.5%), neutropenia (8.1%) and anemia (8.1%). No patients discontinued therapy due to AEs and there were no deaths on treatment. The most common (≥20%) AEs (all grades and all causality) were infusion-related reactions (62.1%), infections (56.8%) (upper respiratory infections in 29.7% of patients, urinary tract infections in 18.9%, COVID-19 pneumonia in 8.1%), fatigue (51.3%), anemia (51.3%), headache (43.2%), rash or other skin changes (32.4%), thrombocytopenia (29.7%), bruising (27.0%), and diarrhea (21.6%). Injection site reactions (8.1%) from SQ RTX were grade 1. Three patients contracted COVID-19 while on study during times of high community transmission prior to the availability of vaccines. Two required hospitalization, one contracted the virus following cycle 1 requiring a delay in RTX, and all patients remained on ACALA while COVID-19 positive. 27 patients have completed 12 cycles and been evaluated for response. All patients responded with 1 MRD+ CR, 20 partial responses (PR), and 6 PR with sustained lymphocytosis. 10 of these patients have completed 24 cycles and had a sustained PR. One patient with del17p and TP53 mutation had progressive disease after 25 cycles of therapy. All other patients remain on treatment per protocol. Conclusion: HFLD RTX and ACALA is a tolerable, effective and convenient therapy that could be the basis for regimens incorporating other novel agents. It is notable that three patients have contracted COVID-19 during the trial; however, none required intubation, and all remained on ACALA during their infection. This at-home combination markedly decreased patient infection risk during the COVID-19 pandemic. This regimen has the potential to enable RTX to be administered at facilities with limited medical IV infusion capacity which could be very useful in rural and economically disadvantaged areas. While all patients have responded to therapy, no patients to date have achieved an uMRD CR, suggesting that additional agents are required to allow for time-limited treatment. Disclosures Baran: AstraZeneca/Acerta: Research Funding. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC . Reagan: Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Seagen: Research Funding; Curis: Consultancy. Casulo: Verastem: Research Funding; Genentech: Research Funding; BMS: Research Funding; Gilead: Research Funding. Zent: TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding. Barr: Morphosys: Consultancy; Janssen: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Beigene: Consultancy; Seattle Genetics: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy.

Download Full-text

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 ◽

10.1182/blood.v122.21.1641.1641 ◽

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.

Download Full-text

Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Blood ◽

10.1182/blood.v124.21.3341.3341 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3341-3341 ◽

Cited By ~ 3

Author(s):

Sophie de Guibert ◽

Marie-Sarah Dilhuydy ◽

Loic Ysebaert ◽

Laurence Sanhès ◽

Sylvain Choquet ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Interim Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Risk Group ◽

High Dose ◽

Color Flow ◽

High Dose Methylprednisolone

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

Download Full-text

A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed By Ofatumumab-Alemtuzumab in 17p Deleted or TP53 Mutated CLL

Blood ◽

10.1182/blood.v126.23.4159.4159 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4159-4159 ◽

Cited By ~ 1

Author(s):

Matthew S. Davids ◽

Haesook T. Kim ◽

Stacey M. Fernandes ◽

Jeffrey Hellman ◽

Karen Francoeur ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Tp53 Mutation ◽

Phase Ii Study ◽

Infectious Complications ◽

High Dose ◽

Color Flow ◽

Part C ◽

High Dose Methylprednisolone ◽

Grade 3

Abstract BACKGROUND: Even in the age of kinase inhibitors, the prognosis for patients (pts) with CLL with del(17p) or TP53 mutations remains poor, with the median PFS only 28 mo. for pts with relapsed/refractory del(17p) CLL treated with ibrutinib. High dose methylprednisolone (HDMP) and alemtuzumab (alem) both have activity in 17p disease and work independently of TP53. Prior work has demonstrated that giving HDMP/alem simultaneously is efficacious, but toxic. We hypothesized that giving these agents sequentially with ofatumumab (ofa) would maintain efficacy while decreasing toxicity. METHODS: This phase II study of ofa/HDMP followed by ofa/alem in CLL pts with 17p deletion or TP53 mutation employed a parallel 2-arm design (treatment-naive (TN) and relapsed/refractory (R/R)). Therapy was the same in both arms and included ofa/HDMP for 2-4 cycles (part A) followed by ofa/alem for 4-24 weeks, up to maximum response (part B). Responders could proceed to alloHSCT or a maintenance phase with ofa given q2 mo and alem given q2 wks (part C). Antimicrobial prophylaxis for PCP, HSV/VZV, and fungal infections was mandatory, as was G-CSF support. The primary objective was to estimate the ORR at the conclusion of the two-part induction therapy in both cohorts. Secondary objectives were to estimate the rate of CR, objective response by compartment, rate of MRD negativity by 4 color flow cytometry, PFS, and OS, rate at which transplant-eligible pts were able to proceed to alloHSCT, and to assess safety. Toxicity was assessed by IW-CLL and CTCAE v4.0. Response assessments by IW-CLL criteria were performed mid-way and at the end of parts A and B, and q6 mo. on part C. RESULTS: A total of 30 patients were enrolled. Baseline pt characteristics were as follows: TN (n=15): median age 64 (range 45-86), median WBC 58K, Hct 31, Plts 134, B2M 4.3, IGHV unmutated 79%, median %bone marrow (BM) involvement 80%. R/R (n=15): median age 65 (range 58-80), median WBC 31, Hct 33, Plts 114, B2M 4.5, IGHV unmutated 73%, median %BM involvement 60%, median # prior therapies 2 (range 1-4) including 9 pts with prior FCR or FR and 7 pts with prior BR. One patient in each arm had TP53 mutation without 17p deletion, and 4 pts had mut NOTCH1. The median number of copy number changes by SNP array was high, at 12.4 in the TN and 14 in the R/R cohorts. In the TN arm, 14/15 pts moved from part A->B, 5 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the TN arm was 80% (67% PR, 13% CR), with 12/15 (80%) pts achieving BM MRD negativity. The TN 2-yr PFS and OS are 70% and 85%, respectively. In the R/R arm, 8/15 pts moved from part A->B, 4 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the R/R arm was 68% (all PRs), with 8/15 (54%) pts achieving BM MRD negativity. The R/R 2-yr PFS and OS are 53% and 67%, respectively. Responses in both arms were independent of TP53 and NOTCH1 mutation status. Studywide, a greater number of somatic mutations was associated with shorter PFS and OS (HR 1.13 per mutation, 95% CI 1.02-1.25, p=0.015 and HR 1.185, 95% CI 1.047-1.341, p=0.0073, respectively). The most common grade 3/4 toxicities were: neutropenia (33%), thrombocytopenia (20%), anemia (10%). Infectious complications included pneumonia (5 cases, 1 Gr2, 3 Gr3, 1 Gr4), febrile neutropenia (2 cases, both Gr3), and cellulitis (1 case, grade 3). Four pts had low-level CMV reactivation, but no CMV infections occurred. Venous thromboembolism occurred in 3 pts. With a median follow-up time among survivors of 25 mo., 21 of the total 30 pts are still alive, and causes of death included: progressive disease n=6, infection n=3. 12/18 (67%) pts who were transplant eligible were able to proceed to HSCT. Discontinuations were due to: progressive/refractory disease (n=10, including 3 Richter's transformations (R/R n=2, TN n=1)), physician decision (n=2), and unacceptable toxicity (n=1). CONCLUSION: Ofa/HDMP followed by Ofa/alem is highly active for both TN and R/R CLL pts with del(17p) and/or TP53 mutation. In addition to a robust ORR, we observed a high rate of MRD-negativity in the bone marrow, which allowed most of the transplant-eligible pts to proceed to alloHSCT. Sequential dosing appears to reduce infectious complications compared to concurrent dosing. This regimen is a feasible option for pts with ultra-high risk CLL to facilitate maximal cytoreduction prior to alloHSCT. <> Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Download Full-text

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 ◽

10.1182/blood-2018-99-111681 ◽

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.

Download Full-text

Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life

Blood ◽

10.1182/blood.v122.21.2877.2877 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2877-2877 ◽

Cited By ~ 1

Author(s):

Michael Doubek ◽

Yvona Brychtova ◽

Anna Panovska ◽

Jakub Trizuljak ◽

Ludmila Sebejova ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Lymphocytic Leukemia ◽

High Dose ◽

In Vitro Testing ◽

Grade 3

Abstract The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population. The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles. Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts. The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached. During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.). The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359). In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy. Conclusions The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen. The study was registered at www.clinicaltrials.gov (NCT01310101). Disclosures: Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.

Download Full-text

Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study

Blood ◽

10.1182/blood.v116.21.697.697 ◽

2010 ◽

Vol 116 (21) ◽

pp. 697-697 ◽

Cited By ~ 15

Author(s):

Peter Hillmen ◽

John G. Gribben ◽

George A. Follows ◽

Donald Milligan ◽

Hazem A. Sayala ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Lymphocytic Leukemia ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Off Label

Abstract Abstract 697 Introduction: Despite the increasing use of combination therapy with rituximab, fludarabine and cyclophosphamide (R-FC) for chronic lymphocytic leukemia (CLL), a significant proportion of patients (pts) are not suitable or eligible for such intensive chemotherapy due to co-morbidity and/or age. In those pts considered unfit for R-FC, chlorambucil (Chl) remains a widely used first-line therapy. However, overall responses rates with Chl are relatively modest with very few complete remissions and therefore more effective treatment options are required for this patient group. In this multi-centre Phase II study we evaluate the feasibility of adding R to Chl and assess response rate compared to single agent Chl. Methods: One hundred previously untreated CLL pts requiring therapy according to iwCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1–7; 10mg/m2/day p.o.) every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in pts with continuing clinical response at 6 cycles. Efficacy data were compared to matched historic data from the UK LRF CLL4 trial, which treated pts between 1999 and 2004 with Chl-monotherapy at the same dose as used in this study. Each patient of this study was matched to 2 pts treated with Chl in the LRF CLL4 study according to Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. It should be noted that the CLL4 data was from 1999–2005, while the Chl-R responses were from 2008. Over this time, any improvements in patient response may be due to better care, improved knowledge, different concomitant medications, etc, rather than treatment used. In addition the median age of patients in LRF CLL4 was significantly lower than those treated with Chl-R (66.5 compared with 70 yrs). Results: A total of 100 pts from 12 centres, who had completed the treatment were included in this analysis; median age was 70 years (range 43–86) and 65% were male. To date, 88 pts remain alive and 12 pts have died. Ninety-two pts (92%) had reported an AE by the end of treatment. The most common AEs were: nausea (47 pts), neutropenia (39 pts), lymphopenia (38 pts), fatigue (26 pts), pyrexia (26 pts), leukopenia (21 pts), diarrhoea (20 pts), vomiting (19 pts), anaemia (18 pts) and thrombocytopenia (18 pts). Most AEs reported were Grade 1–2; Grade 3–4 neutropenia occurred in 39% of pts. Infusion-related reactions occurred in 7 pts. Overall, 37% of pts reported a total of 53 serious AEs (SAEs). The most common SAEs were febrile neutropenia (5 pts) and neutropenic sepsis (4 pts). Overall response rate (ORR) on an intent-to-treat analysis was 82% (95% CI, 73.1–89.0), with 9 pts achieving a complete response (CR), 58 pts showing partial response (PR), 15 pts showing nodular PR (nPR) and 11 pts with stable disease (SD). Median PFS to date is 23.5 months. ORR in this study was 16% higher than in the matched subset of Chl pts from the CLL4 study (95% CI, 6.0–26.0%), suggesting improved responses for Chl-R compared with Chl-alone. Conclusions: With a median age of 70 years, the population in this study was noticeably older than that of pts in CLL4 and other large trials in CLL. This study represents a more typical CLL patient population, as often seen in the clinic. These data confirm that in previously untreated CLL pts who are unable to tolerate a more intensive chemotherapy regimen, the combination of R and Chl is an efficacious therapy with an acceptable tolerability profile resulting in a better ORR than Chl monotherapy. Further evaluation of R-Chl in a randomized Phase III study is warranted. Disclosures: Hillmen: F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is used broadly in this indication at some specific lines of therapy/chemotherapy combinations may be off label in some countries. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kennedy:Roche Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pettitt:Glaxo Smith Kline: Research Funding. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Pocock:F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text