5.17 Chemoimmunotherapy Improves Survival of Patients with Chronic Lymphocytic Leukemia

Abstracts action remains ill defined but may involve immune stimulation. Myelosuppression, especially neutropenia, is a concerning side effect. We therefore reasoned that pulsed dosing of lenalidomide could reduce myelosuppression while maintaining the immune stimulatory effect. Methods: We initiated a single center, phase II trial of lenalidomide given in cycles of 3 weeks on, 3 weeks off drug (42-day cycles) (ClinicalTrials.gov Identifier: NCT00465127). Patients with relapsed CLL or small lymphocytic lymphoma with an absolute neutrophil count greater than 500/␮L and platelet count greater than 20,000/␮L were eligible. The primary end point was defined as response after 4 cycles. Patients with partial response or complete response were allowed to receive up to 4 additional cycles. The starting dose for the first 10 patients was 20 mg/d; the starting dose for patient 11 onward was decreased to 10 mg/d because of toxicities observed in other lenalidomide trials in CLL. Allopurinol was given as tumor lysis syndrome prophylaxis during cycle 1-3. Ibuprofen and corticosteroids were allowed to treat symptoms of a tumor flare syndrome. Responses were assessed by International Workshop on CLL criteria and included computed tomography. Thirty-three patients were included. The median age was 64 years (range 36-78 years), and the median number of prior therapies was 3 (range 1-7). Fifty-two percent had Rai stage III-IV disease, 70% had bulky disease, and 30% were fludarabine refractory; 56% (of 27 patients) were ZAP70positive; 64% (of 25 patients) had unmutated IgVH, 43% had del 17p, and 15% had del 11q. To investigate the effects of lenalidomide on costimulatory molecules and apoptosis markers, we performed flow cytometry analysis on peripheral blood mononuclear cells obtained before and during lenalidomide therapy (day 8). T-cell subsets were analyzed before and during therapy in peripheral blood and in lymph node biopsy samples. Results: 31 patients received at least 2 cycles of therapy (range 2-8 cycles) and were evaluable for response; 5 patients (16%) had a partial response, 18 (58%) had stable disease, and 8 (26%) had progressive disease. Progression-free survival was 16 versus 7 months (p ⬍ 0.001) and time to next therapy was 17 versus 6 months (p ⬍ 0.01) (n ⫽ 5, partial responders) versus nonresponders (n ⫽ 26, stable disease and progressive disease), respectively. Once treatment was stopped, duration of response was short (median 6 months [range 2-18 months]). Four of 5 responders had del 17p and bulky disease. Responders and nonresponders differed significantly in terms of glomerular filtration rate, age, and lenalidomide dose (all p ⬍ 0.05). Grade 3/4 tumor flare reactions (TFRs) were observed in 40% of responders and 15% of nonresponders. In 41% of cycles, dose adjustments were needed before or during cycles. Nine patients (27%) did not complete 4 cycles of lenalidomide owing to side effects. Toxicity: Myelosuppression was the most commonly observed grade 3/4 toxicity. Grade 3/4 neutropenia was observed in 56% of cycles and thrombocytopenia in 30%. Grade 3/4 infections were encountered in 11% of the cycles. Grade 1/2 and 3/4 TFRs were observed in 43% and 10% of cycles, respectively. Other common side effects were fatigue (62%), rash (39%) and muscle cramps (27%), all grade 1/2. No case of tumor lysis syndrome was seen. Correlative studies: On day 8 of therapy, cell surface markers CD40, 54, 86, 95, and DR5 on CLL cells were upregulated (n ⫽ 11, p ⬍ 0.01 or ⬍ 0.05), whereas CD5 and 20 were downregulated (all p ⬍ 0.001). CD54 upregulation (p ⫽ 0.02) and CD5 downregulation (p ⬍ 0.05) was more significant in responders than nonre-

sponders. T cell and natural killer cell counts decreased during lenalidomide therapy (p ⬍ 0.05), with no difference between responders vs nonresponders. In contrast, CD3 cell counts in lymph nodes increased in responders but not in nonresponders (p ⬍ 0.05). Conclusion: Immune activation (TFR and CD3 cell count in lymph nodes) and a higher starting dose correlated with better responses. The low response rate suggests that pulsed dosing with a 3-week off-drug period is not desirable and did not lead to less toxicities.

5.17 Chemoimmunotherapy Improves Survival of Patients with Chronic Lymphocytic Leukemia Gabriela Ghita, Julio Delgado, Tycho Baumann, Ivan Dlouhy, Marta Aymerich, Dolors Colomer, Maria Rozman, Neus Villamor, Natalia Creus, Arturo Pereira, Emili Montserrat Institute of Hematology and Oncology, Department of Hematology, Hospital Clínic, Barcelona, Spain

Introduction: Studies have shown a higher response rate and longer progression–free survival in patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, namely fludarabine, cyclophosphamide, and rituximab (FCR). In addition, evidence indicates that chemoimmunotherapy prolongs survival. This concept mainly derives from a large randomized study in which a small, albeit significant, survival difference was observed in patients treated with FCR compared with those receiving fludarabine and cyclophosphamide1 and a historical comparison.2 Additional data supporting this observation comes from a recent epidemiologic study that showed a 25% lower risk of mortality in patients treated with chemoimmunotherapy3 and from observational studies.4,5 Study Purpose: We sought to ascertain whether chemoimmunotherapy given at any time during the course of the disease, independent of treatment phase, prolonged survival in a group of unselected patients with CLL managed at a single institution. Patients and Methods: Of 1042 consecutive patients diagnosed with CLL and followed at Hospital Clínic from 1980 to December 2010, we selected 340 patients who received 1) alkylating agents and no purine analogues (PAs) or rituximab (R) (no PA no R); 2) PAs at some point in their disease evolution, but no R (PA); or 3) PAs plus rituximab (PA⫹R). Information on clinical (age, sex, and Binet stage) and laboratory characteristics (␤2-microglobulin, CD38, ZAP-70, genomic alterations, and IGHV mutational status) at disease presentation, treatment, and follow-up was obtained from a database that has been prospectively managed at our institution from the 1970s onward. All treated patients were included in the analysis regardless of the number of cycles of therapy given and independent of whether they had been included in clinical trials. Patients who received allogeneic stem cell transplantation (n ⫽ 29) were censored at the time of transplant. Results: The median age of the overall series (n ⫽ 340 [222 men and 118 women]) was 56 years (range 24-84 years); 38% of patients were older than 60 years. Pretreatment characteristics are shown in Table 1. After a median follow-up of 9.4 years (range 0.3-21 years), 148 (44%) patients remain alive. At 10 years, overall survival in the

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Abstracts Abstract 5.17: Table 1: Patient Characteristics Variable Median Age at Diagnosis (range), y Men, n (%)

No PA No R (n ⴝ 67)

PA (n ⴝ 159)

PAⴙR (n ⴝ 114)

P

59 (29–65)

56 (27–84)

55 (24–78)

0.150

49 (73%)

96 (60%)

77 (68%)

0.152

Binet Stage at Treatment (nⴝ307), n (%) Stage A

0.584 16 (28.1%)

31 (21.2%)

24 (23.1%)

Stage B or C

41 (72%)

115 (79%)

80 (77%)

␤2-Microglobulin Level > 2.4 mg/L (nⴝ233), n (%)

16 (55%)

54 (49%)

42 (45%)

0.633

Positive CD38 Expression (nⴝ175), n (%)

2 (13%)

31 (46%)

51 (55%)

0.006

Positive ZAP-70 Expression (nⴝ220), n (%)

6 (27%)

54 (55%)

54 (54%)

0.052

Genomic Aberrations by FISH (nⴝ207), n (%) Normal, del13q, ⴙ12

0.026 17 (94%)

65 (73%)

64 (64%)

Del11q, del17p

1 (6%)

24 (27%)

36 (36%)

Unmutated IGHV gene (nⴝ146), n (%)

2 (25%)

35 (61%)

62 (77%)

0.005

20.8 (3.8–20.8)

12.3 (0.3–17.6)

8.1 (0.6–12.9)

⬍0.001

Median Follow-up (range), y

FISH ⫽ fluorescence in situ hybridization; no PA no R ⫽ alkylating agents and no purine analogues or rituximab; PA ⫽ purine analogues, but no rituximab; PA⫹R ⫽ purine analogues plus rituximab.

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Abstract 5.17: Overall Survival

THERAPY No PA no R PA PA+R No PA no R-censored PA-censored PA+R-censored

1.0

0.8 OVERALL SURVIVAL

PA⫹R group was 65% (95% CI 53%-77%), compared with 43% (35%-51%) and 43% (31-54%) for the no PA no R and PA groups, respectively (p ⬍ 0.001) (Figure). Discussion: Several aspects of this study deserve comment. First, patients older than 65 years were excluded from the no PA no R group in order to have 3 comparable groups in terms of age and to avoid bias in the results due to the worse prognosis of older patients. Nevertheless, when all patients who did not receive Pas or R were included in the study (n ⫽ 211), the statistically significant difference was maintained (data not shown). Second, the majority of patients from the no PA no R group were generally treated before 2000; because of this, such markers as CD38, ZAP-70, IGHV, and cytogenetics were not as frequently available as in those treated more recently. Of note, however, patients in both the PA group and the PA⫹R group had poorer prognostic features (Table 1), which is in keeping with a more conservative therapeutic approach in patients with low-risk disease and poorer risk in patients treated with PAs with or without R. Finally, patients were included in their respective treatment groups independent of whether therapy was given front-line or as a subsequent treatment (Table 2). When the survival of patients treated with PA⫹R was analyzed according to the time at which this treatment was administered (first-line vs second-line or greater), no differences were observed (p ⫽ 0.8). With all necessary caveats, it is tempting to speculate that the beneficial effect of chemoimmunotherapy might be independent of the phase of the disease at which treatment is given, an issue that can be only appropriately answered in a clinical trial. Conclusion: Chemoimmunotherapy prolongs survival of patients with CLL requiring therapy. This effect may be independent of the phase of the disease at which chemoimmunotherapy is given.

0.6

0.4

0.2 P < 0.001

0.0 0

5

10

15

20

25

YEARS

no PA no R ⫽ alkylating agents and no purine analogues or rituximab; PA ⫽ purine analogues, but no rituximab; PA⫹R ⫽ purine analogues plus rituximab.

References 1. 2. 3. 4. 5.

Hallek et al. Lancet 2010;376:1164. Tam et al. Blood. 2008;112:975. Danese et al. Blood. 2011;117:3505. Abrisqueta et al. Blood. 2009;114:2044. Kristinsson et al. Haematologica. 2009;94:1259.

Abstracts Abstract 5.17: Table 2: Treatment Modalities No PA No R (n ⴝ 67)

PA (n ⴝ 159)

PAⴙR (n ⴝ 114)

P

Median Age at Front-Line Treatment (range), y

61 (30.6–74.7)

59 (27.3–86.8)

57 (24–82.6)

0.118

Median Time from Diagnosis to Treatment (range), mo

12.3 (0–232.9)

12.3 (0–195.4)

16.5 (0–144.1)

0.426

54 (80.6%)

83 (52.2%)

15 (13.2%)

Treatment

First-Line Treatment, n (%) Alkylating agents PA

0

72 (45.3%)

38 (33.3%)

PA⫹R

0

0

51 (44.7%)

Other

13 (19.4%)

4 (2.5%)

10 (8.8%)

Second-line Treatment, n (%) Alkylating agents

19 (61.3%)

29 (23.6%)

14 (18.2%)

0

82 (66.7%)

17 (22.1%)

PA PA⫹R

0

0

21 (27.3%)

Other

12 (38.7%)

12 (9.8%)

25 (32.5%)

Median number of treatment lines (range)

1 (1–6)

3 (1–7)

2 (1–7)

⬍0.001

Hematopoietic stem cell transplantation, n (%)

5 (7.4%)

31 (19.4%)

21 (18.4%)

0.466

Autologous (n ⫽ 28)

2 (3%)

15 (9.4%)

11 (9.6%)

Allogeneic (n ⫽ 18)

3 (4.5%)

10 (6.3%)

5 (4.4%)

0

6 (3.8%)

5 (4.4%)

ALO-RIC (n ⫽ 11)

ALO-RIC ⫽ reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation; no PA no R ⫽ alkylating agents and no purine analogues or rituximab; PA ⫽ purine analogues, but no rituximab; PA⫹R ⫽ purine analogues plus rituximab.

5.18 Milatuzumab as a Single Agent in Refractory Chronic Lymphocytic Leukemia: Interim Results of a Phase 1–2 Study and Future Plans Michal Haran, Alain Berrebi

suggest that this agent is safe and improves quality of life and functional abilityofamongfrailelderlypatientswithadvanced-stageCLL.Thefindings also suggests that milatuzumab should be given continuously; in most patients, the effects decreased after a short period of discontinuation of therapy, in terms of both in clinical and laboratory variables. One patient received milatuzumab for more than 1 year with no significant adverse effects.

Kaplan Medical Center, The Israeli CLL Study Group, and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

References

Our previous work showed that the major histocompatibility complex class II–related protein CD74 is overexpressed from the very early stages of chronic lymphocytic leukemia (CLL). Activation of CD74 with its ligand MIF leads to survival signals in all stages.1 Furthermore, it leads to increased VLA-4 expression, with resultant homing to the bone marrow in advanced stages of the disease. We also showed that blocking CD74 with the humanized monoclonal antibody milatuzumab leads to increased apoptosis and decreased migration to the bone marrow.2 We therefore decided to translate our results to a clinical trial using milatuzumab. So far, 6 patients with advanced refractory CLL have been recruited. Three of the 6 patients showed significant improvement in cytopenia, with no need for blood transfusions in 2 patients who were transfusion-dependent before enrolment. Five of 6 patients had significant improvement in B symptoms and functional level. No patient died or had significant treatment-related toxicity during the study period. Patient samples showed a decrease in bcl-2 , mcl-1 and VLA-4 mirroring those that we observed in the xenograft mouse model. Our results thus far, combined with data from other studies of milatuzumab in the United States,

5.19

1. Binsky et al. Proc Natl Acad Sci U S A 2007;104:13408. 2. Binsky et al. J Immunol 2010;184:4761.

AMD3100 Disrupts Cross-talk Between Chronic Lymphocytic Leukemia Cells and Their Microenvironment: Preclinical Evidence for Its Association with CLL Treatments Basile Stamatopoulos,1 Nathalie Meuleman,1 Cécile De Bruyn,1 Karlien Pieters,1 Philippe Mineur,2 Christine Le Roy,3 Dominique Ledoux,3 Nadine Varin-Blank,3 Florence Cymbalista,3,4 Dominique Bron,1 Laurence Lagneaux1 1

Laboratory of Clinical Cell Therapy, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 2 Department of Hemato-Oncology, Grand Hôpital de Charleroi, Gilly, Belgium; 3UMR U978 INSERM (Adaptateurs de Signalisation en Hématologie), Université Paris Nord, PRES Sorbonne Paris Cité, Bobigny, France; 4Department of Hematology, Hôpital Avicenne, Bobigny, France

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