Long-Term Analysis of Anti-CD20mab + HDMP for the Treatment of Patients with Chronic Lymphocytic Leukemia

Background: The addition of an anti-CD20 monoclonal antibody (mAB) to high dose methylprednisolone (HDMP) has been demonstrated to be an effective, non-myelosuppressive treatment (Tx) regimen for patients (Pts) with chronic lymphocytic leukemia (CLL). (Castro et al., 2009) We performed a single institution retrospective analysis of Pts treated with an anti-CD20 mAB and HDMP evaluating long-term efficacy, safety, and immune reconstitution.

Methods: 102 Pts treated between the years of 2001 and 2015 were evaluated. Tx consisted of HDMP 1gm/m2 IV on days 1, 2, and 3 of each cycle. Rituximab (R) was administered as either 375 mg/m2 weekly; 750 mg/m2 daily on days 1, 2 and 3; or 750 mg/m2 weekly times during cycle one and daily times three for cycle two and three. Obinutuzumab (G) and ofatumumab (O) were administered per FDA standard dosing. Pts received 3-6 cycles of Tx. Some Pts who achieved a partial response (PR) to initial therapy underwent alemtuzumab (Alem) consolidation, 10mg, administered three times a week for a total of eight weeks. All Pts received anti-microbial prophylaxis consisting of fluconazole, bactrim and acyclovir. Response assessment was performed using iwCLL criteria.

Results: The Pts had a median age of 66 (range; 40-85). Rai stage at time of Tx initiation: I 6%; II 43%; III 17%; Stage IV 34%. 63% of Pts were previously treated. The median number of previous Txs was 2 (range; 1-5). 55% of Pts had been treated with immunotherapy alone, 67% with chemoimmunotherapy, and 13% of Pts with a BCL2 inhibitor. Pts harbored the following cytogenetic abnormalities: del(13q) 46%; trisomy 12 30%; del(11q) 22%; normal 13%; del(11q) 22%; del(17p) 19%; and complex in 26%. 58% of Pts harbored an unmutated immunoglobulin heavy chain (IGHV). 84% of Pts were treated with R, 11% with G, and 5% with O.

96 Pts (94%) had a response to Tx (OR). 18 Pts (18%) achieved a complete response (CR); 78 Pts (76%) achieved a PR; and six Pts (6%) had stable disease (SD). Seventeen Pts underwent Alem consolidation. Twelve Pts (71%) achieved a CR; four Pts (24%) achieved a PR; and one patient (6%) had SD after Alem consolidation. With a median follow-up of 114 months, the median progression free survival (PFS) for the entire cohort was 27.1 months. The median time to next treatment (TTNT) for the entire cohort was 30.0 months. For Pts who received Alem consolidation, the median PFS was 90.1 months, and the median TTNT was 97.8 months. (Figure 1A) Employing cox proportional hazards model, factors associated with improved PFS were IGHV mutated (HR 0.38; 95% CI 0.18 to 0.79); CR (HR 0.17; 95% CI 0.05 to 0.47); and Alem consolidation (HR 0.21; 95% CI 0.09 to 0.46). Factors associated with improved TTNT was presence of del13q (HR 0.41; 95% CI 0.18 to 0.93); IGHV mutated (HR 0.36; 95% CI 0.13 to 0.92); CR (HR 0.12; 95% CI 0.03 to 0.37); and Alem consolidation (HR 0.24; 95% CI 0.10 to 0.53).

9% Pts developed infection requiring hospitalization, and 5% Pts developed an opportunistic infection. Immediately after Tx, serum IgA, IgG and IgM levels decreased (mean IgA pre-Tx 69.4mg/dL vs post-Tx 43.0mg/dL; p <0.0001; mean IgG pre-Tx 738.0mg/dL vs post-Tx 494.3mg/dL; p <0.001; mean IgM pre-Tx 94.8mg/dL vs post-Tx 44.5mg/dL; p = 0.07). At approximately 36- and 48-months serum IgA and IgG levels returned to normal levels, respectively. (Figure 1B) 57% of Pts received supplemental intravenous immunoglobulin, thus we investigated factors associated with recovery of serum IgA levels at 36 months. We found that only disease status at 36 months impacted serum IgA levels. (Mean IgA without progression at 36 months 74.7mg/dL vs 44.9 mg/dL with progression at 36 months; p = 0.035).

Conclusions: In our analysis of Pts with CLL treated with an anti-CD20 mAB + HDMP we found a high OR of 94% and median PFS of 27.1 months. This compares favorably to traditional low intensity chemoimmunotherapy approaches for CLL. Pts who received Alem consolidation had durable remissions, with a median PFS of 90.1 months. The overall incidence of infectious complications was manageable, with normalization of serum IgA and IgG three and four years after completion of therapy. Patients without progression at 36 months were found to have higher serum IgA levels. While the Tx landscape for CLL has dramatically changed, the addition of HDMP to an anti-CD20 mAB can be a Tx option for patients desiring short course of Tx, requiring bridging to more definite therapy, or debulking strategy prior to venetoclax based Tx.

Heyman:Oncternal Therapeutics, INC: Research Funding; Epizyme, INC: Honoraria; Aztrazeneca: Research Funding; Beigene: Honoraria. Choi:Abbvie, TG Therapeutics, Geron, Merck, Oncternal, Pharmacyclics: Research Funding. Kipps:Abbvie: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Oncternal Therapeutics, Inc: Current holder of stock options in a privately-held company, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Dava Oncology: Honoraria.