CLL/SLL

ASCO® 2016 Poster Discussion - Small Molecule Therapy in Chronic Lymphocytic Leukemia

The ‘Hematologic Malignancies-Lymphoma and Chronic Lymphocytic Leukemia’ poster discussion session took place on Monday June 6, 2016, between 13:15–14:45. The session was jointly chaired by Susan Mary O’Brien, MD, Associate Director for Clinical Science, at Chao Comprehensive Cancer Center in the University of Irvine, California, and John Leonard, MD, of Weill Cornell Medicine, New-York.

Pr Thorsten Zenz , MD, of the Department of Internal Medicine V, University of Heidelberg, Germany, presented a poster titled ‘Small molecule therapy in Chronic Lymphocytic Leukemia’. This poster presentation discussed abstracts 75197520 and 7521.

Abstract 7519: Venetoclax Activity in CLL Patients Who Have Relapsed After or Are Refractory to Ibrutinib or Idelalisib

CLL patients who experience relapse after or become refractory to BCR inhibitors have been found to have abysmal prognosis. One such BCR inhibitor is venetoclax (VEN), a selective, oral inhibitor of BCL2, which has been found to have robust activity in R/R CLL.

In this abstract, the results of an ongoing phase II study (NCT02141282) investigating venetoclax (20mg daily followed by a 5-week ramp up yo 400mg daily) in CLL patrients R/R to ibrutinib (IBR; Arm A) or idelalisib (IDE; Arm B). ORR by iwCLL criteria and safety were the primary endpoints of this study. 

  • In total, 54 pts enrolled: Arm A = 41; Arm B = 13
  • Refractory to IBR = 25, to IDE = 6; intolerant with CLL progression after stopping IBR = 12, IDE = 6
  • 3 pts in each arm had received IBR and IDE
  • Over half (54%) had >5 previous therapies; unmutated IGHV = 83%; del(17p) = 35%
  • Median time on VEN: Arm A = 31.9 weeks (0.6–52.9); Arm B = 23.7 weeks (5.4–52.9)
  • Discontinued VEN: Arm A = 8 (4 PD, and 1 respiratory failure, 1 multi-organ failure, 1 death of unknown cause, and 1 withdrawal of consent); Arm B = 2 (1 PD, 1 non-response) 
  • 14/22 Arm A and 3/5 Arm B refractory pts achieved response
  • At week 24, 8/27 pts were MRD-negative by flow cytometry of blood; all pts were on Arm A: 2 CRs, 1 nPR, 4 PR, and 1 SD
  • AEs in >20% pts: neutropenia (48%), diarrhea (37%), nausea (35%), anemia (32%), fatigue (24%), hyperphosphatemia (20%)
  • Grade 3–4 AEs >10%: neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%)
  • SAEs in ≥2 pts: pneumonia (9%), febrile neutropenia (7%), as well as increased potassium, multi-organ failure, and septic shock (4% each)
  • Laboratory TLS without clinical sequelae was reported in 2 pts 

 

Ibrutinib Arm (n=43)

Idelalisib Arm (n=21)

Best response, n(%)

Assessed by

Assessed by

Investigator

IRC

Investigator

IRC

ORR

26 (61)

30 (70)

7 (33)

10 (48)

CR/CRi

2 (5) / 0

0 / 1 (2)

1 (5) / 1 (5)

0 / 0

PR

22 (51)

29 (67)

5 (24)

10 (47)

SD

12 (28)

-

12 (57)

-

PD

1 (2)

-

1 (5)

-

Non-responder

-

13 (30)

-

11 (52)

It was concluded that treatment with single-agent VEN resulted in encouraging responses in CLL patients R/R to IBR or IDE. This included MRD-negativity at 24 weeks, as well as an acceptable safety profile. This is the first prospective study to demonstrate efficacy in this poor prognosis population. Follow-up will assess depth and duration of response.

Abstract 7520: Outcomes in Ibrutinib by Line of Therapy in Patients with CLL: Analyses From Phase III Data

IBR was the first-in-class Bruton's Tyrosine Kinase (BTK) inhibitor to be approved by the U.S. Food and Drug Administration (FDA) in CLL patients who had received one or more previous therapies. In this abstract, analysis was presented on outcomes with IBR based on prior lines of therapy and after discontinuation in CLL patients. Data from two phase III trials was analyzed: the RESONATE  (in patients aged 65 years or older with newly diagnosed CLL) and RESONATE-2 (in previously treated CLL patients, excluding those with del(17p) trials. 

  • In newly diagnosed vs. previously treated pts, median age = 73 vs. 66 years
  • Previously treated pts had a median of 3 prior therapies including CD20 antibody (93%), purine analog (87%), or alkylating agents (93%; bendamustine 41%)
  • Median PFS and OS were not reached (NR) for newly diagnosed and previously treated pts, with 89–92% progression free at 2 years for pts treated with IBR in first or second line
  • ORR was high regardless of line of therapy (91% in newly diagnosed, 92% in previously treated pts)
  • Most pts continue IBR
  • AE profile was similar for both groups
  • Pts receiving IBR in earlier line of therapy were less likely to discontinue due to progression
  • Median OS post IBR discontinuation was not reached for pts who received IBR in first or second line (n = 23) vs. 7–9 months in third line and beyond (n = 34) 
 

Subgroups by Prior LoT (N = 271)

0 (n = 136)

1 (n = 27)

2 (n = 41)

≥ 3 (n = 67)

Med age, yrs (range)

73 (65-89)

64 (30-85)

66 (46-86)

67 (44-83)

Med follow up, m (max)

22 (32+)

30 (36+)

31 (34+)

30 (37+)

Continuing study ibr, n (%)*

116 (85)

19 (70)

28 (68)

36 (54)

24-mo PFS, %

92

89

80

69

30-mo OS, %

97

93

83

82

ORR (w/PR-L), %

91

100

93

88

    CR/CRi

17

7

15

6

    PR-L

3

0

2

9

DC due to, n (%)*

    PD

4 (3)

2 (7)

5 (12)

11 (16)

    AEs

13 (10)

1 (4)

6 (15)

7 (10)

    Deaths

2 (2)

2 (7)

1 (2)

5 (7)

    Other

1 (1)

2 (7)

1 (2)

4 (6)

Med time post DC*, m

    Follow up

9

5

9

10

    OS

NR

NR

9

7

    OS: DC due to AE

NR

NR

16

NR

    OS: DC due to PD

NR

NR

8

6

Pts/w subsequent therapy, n

4

1

6

11

Common subsequent therapy

2 FCR, 1 BR, 
1 clb

1 EPOCH-R

3 R-CHOP

4 idela±R, 
3 ofa

*5 pts who discontinued study IBR to receive commercial IBR not included.

In conclucion, IBR resulted in favorable PFS and OS, and high ORR irrespective of line of therapy in CLL patients. Patients who recieved first or second line IBR were less likely to experience progressive disease and had superior post-IBR survival outcomes.

Abstract 7521Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)

BTK is involved in BCR signaling and is a key target for therapy for CLL. Acalabrutinib is an irreversible, selectibr BTK inhibitor. This abstract contained preliminary results of the ongoing phase I–II CLL-001 study (NCT02029443) of single-agent acalarutinib in newly diagnosed CLL patients. Patients were administered oral acalabrutinib at 100mg BID (n = 62) or 200mg QD (n = 37). CLL responses were assessed per modified iwCLL criteria; results of the first 74 treated patients, including 72 evaluable for response.

Primary endpoints of the study were safety and progressive disease (BTK occupancy) and secondary objectives were ORR, DoR, and PFS.

  • Median age = 64 years (range, 48–85)
  • Bulky lymph nodes ≥5 cm = 47%; unmutated IGHV = 57%, 38/67
  • Median time on study (N = 74) = 11 months (range, 1–15)
  • Acalabrutinib is being continued in 97% (72/74)
  • The majority of AEs were Grade ≤2; the most common Gr 1–2 AEs in ≥15% pts were headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%), and increased weight (18%)
  • Gr 3–4 AEs that occurred in ≥2 pts were syncope (n = 2, both Grade 3) and hypertension (n = 2, both Grade 3)
  • One Grade 5 event (pneumonia) was reported
  • One Grade 3 upper GI bleed due to a gastric ulcer and aspirin use was reported
  • No atrial fibrillation events were reported
  • Clinical activity was observed with both dose schedules; BTK occupancy was highest with BID dosing (98% vs 93% predose at Day 28)
  • All pts had a rapid reduction in lymphadenopathy
  • Treatment-related lymphocytosis occurred in 53% (39/74) of pts and resolved in 97% (38/39) of these pts
  • Generally, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 (range, 3–15) weeks
  • Best ORR = 96% (PR = 86%, PR+L = 10%, SD = 4%, PD = 0%)
  • Median time to response = 2 months (2–8)
  • No CLL progression or Richter’s transformation were reported

 

N = 72

Best response, n(%)

CR

0

PR

63 (87.5)

PRL

7 (10)

SD

2 (3)

ORR (CR+PR), n(%; 95% CI)

63 (87.5; 95% CI, 78–94)

ORR (CR+PR+PRL), n(%; 95% CI)

70 (97; 95% CI, 90–100)

It was concluded that acalabrutinib acheived high response rates and a favorable safety profile in patients with newly diagnosed CLL. Based on these results, a phase III trial has commenced (NCT02029443).

References
  1. Jones JA, et al. Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. J Clin Oncol 34, 2016 (suppl; abstr 7519).
  2. O’Brien SM, et al. Outcomes with ibrutinib by line of therapy in patients with CLL: analyses from phase III data. J Clin Oncol 34, 2016 (suppl; abstr 7520).
  3. Byrd JC, et al. Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL). J Clin Oncol 34, 2016 (suppl; abstr 7521).