ALBERT

Description: Background: Tumor microenvironment (ME) plays an important role in MM. It is associated with disease progression, metastasis, and resistance to therapy. Therefore, targeting the ME and the tumor cell simultaneously may be an effective way to overcome resistance in pts with rel/ref MM. Aim: Orlowski et al reported improved anti-tumor responses when bortezomib (V) was combined with doxil (D) in pts with hematologic malignancies. We investigated clinically, this approach i.e., targeting the MM cell as well as its ME, using a combination of V, D and low-dose thalidomide (T) as salvage therapy for pts with rel/ref MM. Here we report the final results along with survival data of this phase II study. Methods: All pts with rel/ref disease were eligible for this study. V was given at 1.3mg/m2 (D1,4,15,18) and D at 20mg/m2 (D1,15) every 4 weeks with daily T (200 mg) for 4–6 cycles. SWOG criterion was used to assess response. Low-dose coumadin (1–2 mg po qd) was used for prevention of venous thromboembolism (VTE). Results: Twenty three pts (9M, 14F; median age −57 , range 43–79 yrs; 21MM, 2 WM) have been enrolled. All pts had Stage III disease, median b2M was 4.2 and median number of prior therapies were 5(range 1–6). Prior therapies included stem cell transplant(SCT) in (41%), T (41%), adriamycin(A) (65%) steroids (82%) and velcade (12%). 74% had refractory disease. Seventeen pts have completed at least 1 cyc and are available for toxicity and response evaluation. One pt died of sepsis prior to completing 1 cyc and 1 pt with PR was taken off study for non-compliance after 1 cyc. ORR was with 65%(CR+PR) with 23% CR all of whom were IFE negative. The Median Progression Free survival was 10.9 months with an median overall survival of 15.7 months. Toxicity: 2 pts developed Gr. II plantar-palmar erythrodysthesia (PPE) and 1 had Gr. III cellulitis. No VTE was noted. No significant non-hematologic Gr. III/IV toxicity were seen. Despite prior exposure to anthracycle, we did not noted any cardiotoxicity with D.No significant neuropathy was noted. Conclusions: Pt with rel/ref MM usually have aggressive disease with paucity of effective regimens. VDT is an effective salvage regimen. Final results show high response rates with 22% of the patients achieving complete (IFE−) remissions. Responses were noted regardless of type of prior therapy. VDT could be safely given in patients with renal failure/insufficiency. Venous Thromboembolism (VTE) does not appear to be a problem with low dose coumadin prophylaxis. Final results of this phase II study will be presented at the 48 th annual ASH meeting.

Description: Introduction: Pts with Chronic Lymphocytic Leukemia (CLL) are reported to have quantitative and qualitative T and NK cell dysfunction. While NK cells act through non-specific killing, T-cells are more specific. The 2 types of T-lymphocytes, CD4+ (Th; helper) and CD8+ (Ts; cytotolytic/suppressor) are subcategorized based on cytokine secretion profile upon activation. Release of different cytokines from these immune cells modulates the host response. T1 cells (Th1, Ts1) secrete IL-2 and interferon-g which initiate the Th1 response- mainly CD4+ activation along with B and T cells, leading to proliferation and differentiation of these cells. T2 (Th2, Ts2) cells initiate the Th2 response (release of TNF-a, IL-10) resulting in direct lysis of the target cell by production of cytokines such as IL-4, IL-5 and IL-10. Hypothesis: To decipher this antitumor mechanism of L in CLL pts we investigated its effect on the efferent arm of immune response by evaluating the T cell population and the afferent response by change in expression of co-stimulatory molecules on B-CLL cells and cytokine profile in these pts treated on a phase II clinical study. Methods: CLL pts treated with L were evaluated for absolute number of T (CD4+, CD8+) and NK (CD56+) cells by flow cytometry on day before (day0) start and on Day 8 of treatment with L. Peripheral blood was collected and ficolled to obtain enriched mononuclear cells. The serum was used to study the cytokines. Activation status was determined by co-expression of CD45+. Serum cytokine profile was measured by Flow cytometry using the Luminex system. B-CLL surface co-stimulatory molecules were detected by flow cytometry and analyzed by FACS. These responses were correlated with the tumor flare (TF) reaction that the patients developed during the first week of treatment with L. Results: Eighteen out of 45 pts have so far been evaluated for immunomodulatory activity of L. There were 2 complete responders (CRs) and 6 partial responders (PRs); while 4 had stable disease (SD), 4 were clinically unevaluable and 2 were too early for response in this group. Mean baseline (bl) NK cell count pretreatment was 251 (range 31–1510) vs. post treatment was 193 (range 6–13,482). Six out of 18 patients showed an increase, ranging from 20 −199% in the absolute NK (CD16+/CD56+/CD45+). While there was no appreciable change in CD4+ numbers there was a general trend in increase of CD8+ cells. No change in monocyte population was noted. Concurrent increase in the expression of co-stimulatory molecules such as CD95 and CD80 was noted. This response in co-stimulation was confirmed by in vitro experiments done on isolated B-CLL cells (n=4)treated with L. An increase in Th-2 cytokines such as IL-4, IL-5, IL-6 and IL-10 was noted in all eight responders, while VEGF levels were decreased in 6/18 patients. 99% of patients had a TF and the grade of TF correlated with the changes in T cells and cytokine profile. Conclusion: It appears that in vivo L is able to orchestrate an anti-tumor response in CLL by modulating the NK cells, changing the cytokine profile and up-regulating co-stimulatory molecules. This change in the immune effector cell repertoire and the Th2 skewing may explain the initial flare reaction noted in these L treated pts. Data from these correlative studies is being evaluated in the context of the phase II clinical trial to be reported at the 48th ASH annual meeting.