Supplemental file

RESULTS

Historical Comparison of OFAR2 with OFAR1

Clinical outcomes of OFAR2 were compared with those of OFAR1. In patients with RS, the overall response rate was 39% (12/31) with OFAR2 and 56% (10/18) with OFAR1 (p = 0.37, Fisher’s exact test); the median survival with OFAR2 and OFAR1 was 6.6 months and 13.1 months, respectively (p = 0.20, log-rank test); and the respective median FFS was 3.0 months and 6.8 months (p = 0.051, log-rank test).

In patients with CLL, the overall response rate was 50.8% (33/65) with OFAR2 and 33.3% (10/30) with OFAR1 (p = 0.13, Fisher’s exact test); the median survival was 20.6 months with OFAR2 and 12.9 months with OFAR1 (p = 0.19, log-rank test), and the respective median FFS was 4.4 months and 3.9 months (p = 0.38, log-rank test). In OFAR1, all patients with CLL were fludarabine refractory, and in OFAR2, 48% (32/67) of patients with CLL were fludarabine refractory.

We also performed a multivariate analysis of survival in patients with RS treated with OFAR1 or OFAR2. The only factor associated with longer survival was absence of 17p deletion (relative risk [RR] = 0.41; p = 0.049). There was no significant difference in survival between treatment groups (OFAR1 vs. OFAR2; RR = 0.79; p = 0.68); refractoriness to fludarabine was not an independent factor predicting survival (RR = 1.47; p = 0.47).

When a multivariate analysis was performed for patients with relapsed/refractory CLL treated with OFAR1 or OFAR2, the only factor associated with superior survival was absence of 17p deletion (RR = 0.54; p = 0.03). There was a trend towards longer survival for patients who (a) were not refractory to fludarabine (RR = 0.51; p = 0.07); (b) had an absolute lymphocyte count ≤ 5 x 109/L (RR = 0.61; p=0.08), and (c) had a Zubrod performance score < 2 (RR = 0.55, p = 0.08). Survival was similar between treatment groups (OFAR2 vs. OFAR1; RR = 0.80; p = 0.45).

Historical Comparison of OFAR2 with FCR and CFAR

We also performed multivariate analyses of patients with relapsed/refractory CLL treated with OFAR2, FCR, or CFAR. Outcomes of both phase I and phase II patients in the current study were analyzed together. Patients treated with OFAR2 (n=67) had higher-risk pretreatment characteristics compared with those treated with FCR (n=284) and CFAR (n=80). The rates of refractoriness to fludarabine were 48%, 19%, and 39%, respectively. The proportions of patients with ≥3 prior therapies were 72%, 31%, and 56%, respectively. Deletion 17p was noted in 44%, 7%, and 18%, respectively.

Independent factors associated with response were absence of 17p deletion (p = 0.0004), no refractoriness to fludarabine (p = 0.001), and platelet count ≥ 100 x 109/L (p = 0.002). There was no statistically significant difference in response between OFAR2 and CFAR (p = 0.57) or between OFAR2 and FCR (p = 0.69).

Independent factors associated with superior survival were absence of 17p deletion (p < 0.0001), no refractoriness to fludarabine (p < 0.0001), and platelet count ≥ 100 x 109/L (p= 0.0001). When compared to CFAR, OFAR2 was an independent factor associated with longer survival (p = 0.005). There was no statistically significant difference in survival between OFAR2 and FCR (p = 0.50). There was a trend towards longer survival for patients with β2-microglobulin <4 mg/dL (p = 0.051).

Independent factors predicting longer FFS were absence of 17p deletion (p < 0.0001), no refractoriness to fludarabine (p < 0.0001), β2-microglobulin <4 mg/dL (p = 0.009), platelet count ≥ 100 x 109/L (p = 0.014), and lactate dehydrogenase levels < 1.5 x ULN (p = 0.027). There was no statistically significant difference in FFS between OFAR2 and CFAR (p = 0.21). When compared to OFAR2, FCR was an independent factor associated with longer FFS (p = 0.002).

Historical Comparison of OFAR1, OFAR2, Hyper-CVAD, and R-CHOP in Richter’s Syndrome

Patients with RS treated with OFAR2 or OFAR1 had high-risk pretreatment characteristics (i.e., older age, worse performance status, more prior therapies) overall and particularly compared to R-CHOP (Supplemental Table 3).

We performed multivariate analyses of patients treated with OFAR1, OFAR2, Hyper-CVAD, or R-CHOP. There were no independent factors predicting response. Performance status <1 was associated with a trend towards higher response rates (p = 0.06).

In multivariate analyses for survival, there was a trend towards longer survival with OFAR1 (compared to OFAR2; RR = 0.58, p = 0.14) or R-CHOP (compared to OFAR2; RR = 0.53, p = 0.17). No other factors had independent significance.

In multivariate analyses, independent factors associated with longer FFS were OFAR1 (compared to OFAR2; RR = 0.44, p = 0.03) or R-CHOP (compared to OFAR2; RR = 0.32, p = 0.01). No other factors had independent significance.

RESULTS

In patients with relapsed/refractory CLL, those treated with OFAR2 had more high-risk factors than those treated with CFAR or FCR. In multivariate analyses, OFAR2 was comparable to CFAR and FCR in terms of response. In multivariate analyses for survival, taking into consideration factors including genomic aberrations, refractoriness to fludarabine, platelet counts, and number of prior therapies, when compared to CFAR, OFAR2 was an independent factor predicting longer survival (p = 0.005). There was no significant difference in survival between OFAR2 and FCR. In multivariate analyses, treatment with FCR was associated with superior FFS, whereas FFS with CFAR was similar to that of OFAR2. Although these results were not derived from randomized trials, the differences noted in the multivariate analyses were perhaps associated with the intensity of the regimens and further support the need to adjust treatment to patients’ baseline characteristics.

In addition, patients with RS who were treated with OFAR1 were older overall, and a higher proportion of them had performance status >1 and >1 prior therapies than patients treated with HyperCVAD or R-CHOP. Results for OFAR2 and CHOP in patients with RS were similar, but the numbers of patients were too small to draw meaningful conclusions.

Supplemental Table 1. Interval in days between cycles of OFAR2 in patients with relapsed/refractory CLL and RS

Richter Syndrome
Cycle	Median duration of cycle	Median duration of Grade 3-4 thrombocytopenia	Median duration of Grade 3-4 neutropenia
1	31	7	5
2	37	7	3
3	45	0	0
4	34	4	0
5	40	7	15
6	49	7	9
Chronic lymphocytic leukemia
Cycle	Median duration of cycle	Median duration of Grade 3-4 thrombocytopenia	Median duration of Grade 3-4 neutropenia
1	31	8	1
2	36	4	0
3	49	3	1
4	48	0	0
5	49	0	7
6	49	0	0

Supplemental Table 2. Time to cycle 2 (days)

Treatment delays	RS	CLL
Number of patients started 2nd cycle 30 days after the 1st cycle started	7/35 (20%)	22/102 (22%)
Number of patients started 2nd cycle 45 days after the 1st cycle started	1/35 (3%)	2/102 (2%)

Supplemental Table 3. Therapeutic regimens in Richter’s syndrome. Historical comparison

Patient characteristics	OFAR1	OFAR2	Hyper CVAD+R	R-CHOP	p
No. of patients	18*	31**	35	12
Age ≥ 60 yrs, %	61	74	37	17	0.001
PS > 1, %	33	29	23	0	0.164
PLT >= 100 x 109/L, %	56	48	63	50	0.672
Prior therapies >1, %	72	71	71	33	0.076
Overall response, %	56	39	46	50	0.705
Median survival, months	13.1	6.6	9.08	14.92	0.132
Median FFS, months	6.77	3	6.49	9.18	0.001

*Patients treated with oxaliplatin dose 20-25 mg/m2; 2 patients with no response data are excluded.

**Patients treated with OFAR2, including 31 at the Phase II recommended dose

R = rituximab