Table 4.
Targeted therapy combination trials with a strategy for treatment cessation
| Study | Patient group | Fixed regimen | Cessation/continuation strategy | Preliminary data | Latest follow up |
|---|---|---|---|---|---|
| Tam et al.[228]
CAPTIVATE NCT02910583 (ibrutinib-venetoclax) |
TN, < 70 years
(n = 164) |
IBR for cycle 1-3
IBR + VEN for cycle 4-15 |
BM uMRD or -pos after cycle 15 randomized to placebo or IBR* | After 12 combination cycles:
PB uMRD 75% BM uMRD 72% 1 case laboratory TLS AEs leading to discontinuation in 7% |
Median 15 (< 1-20) months |
| Lampson et al.[229]
NCT03580928 (acalabrutinib-venetoclax-obinutuzumab) |
TN
(n = 37) |
ACAL for cycle 1-24 + G cycles 2-7 + VEN cycle 4-24 | Patient may cease therapy at cycle 15 or cycle 24 if BM uMRD CR | After cycle 8
PB uMRD 65% BM uMRD 50% Grade ≥ III neutropenia 32% Infusion reactions 22% |
Median 8 (2-11) months |
| Jain et al.[69,230]
NCT02756897 (ibrutinib-venetoclax) |
TN
Del(17p), mutated TP53, del(11q), unmutated IGHV or ≥ 65 years (n = 80) |
IBR for cycle 1-3
IBR + VEN for cycle 4-27 |
BM MRD-pos patients after cycle 27 can continue IBR* | After cycle 27:
79% BM uMRD 12 patients (15%) off trial 3 cases laboratory TLS Grade ≥ III neutropenia 48% |
Median 23 months |
| Jain et al.[231]
NCT02756897 (ibrutinib-venetoclax) |
R/R
(n = 80) |
IBR for cycle 1-3
IBR + VEN for cycle 4-27 |
BM MRD-pos patients after cycle 27 can continue IBR* | After cycle 27:
67% BM uMRD 19% off trial, mostly due to toxicity |
Median 22 months |
| Hillmen et al.[68]
CLARITY ISCRTN13751862 (ibrutinib-venetoclax) |
R/R
(n = 53) |
IBR for 2 cycles
IBR+VEN after cycle 2 |
PB/BM uMRD at cycle 8: cease therapy after cycle 14; PB/BM uMRD between cycle 14-26: cease therapy after cycle 26
MRD-pos at cycle 26: continue IBR monotherapy* |
After 12 months combination:
PB uMRD 53% BM uMRD 36% 34 episodes grade ≥ III neutropenia 1 case laboratory TLS |
Median 21 months |
| Rogers et al.[232]
NCT02427451 (ibrutinib-venetoclax-obinutuzumab) |
R/R
(n = 12) |
G cycle 1-8 + IBR cycles 2-14 + VEN cycle 3-14 | After cycle 14, can continue IBR monotherapy* | After cycle 14:
PB uMRD 100% BM uMRD 50% Grade ≥ III neutropenia 33% Infusion reaction 83% |
Median 24 months |
| Rogers et al.[233]
(ibrutinib-venetoclax-obinutuzumab) |
R/R (n = 25)
TN (n = 25) |
G cycle 1-8 + IBR cycles 2-14 + VEN cycle 3-14 | After cycle 14, can continue IBR monotherapy* | Mid therapy, 16/23 (70%) BM uMRD
Grade ≥ 3 neutropenia 56%, Grade ≥ 3 HTN in 32% 1 fatal neutropenic colitis |
Median 18 (0-25) months |
| Niemann et al.[234]
VISION/HOVON 141 NCT03226301 (ibrutinib-venetoclax) |
R/R
(n = 230) |
IBR for cycle 1-2
IBR + VEN for cycle 3-15 |
> PR and BM uMRD after cycle 15 randomized to observation or IBR monotherapy*
MRD recrudescence retreated with combination |
After 15 cycles:
PB uMRD 55% BM uMRD 39% AEs leading to discontinuation in 4% |
51 patients treated for duration of 15 cycles |
| Thompson et al.[235]
(ibrutinib-venetoclax) |
≥ 1 year of prior IBR treatment, not uMRD
High risk feature: TP53 mutation, del(17p), del(11q), CK, elevated B2MG (n = 35) |
Add VEN to IBR therapy for up to 2 years | uMRD CR on two assessments: discontinue all therapy or continue IBR monotherapy*
Patients MRD-pos or < CR: continue IBR monotherapy* |
BM uMRD 10/15 (67%) at 12 months | 15 patients evaluable at 12 months of combination therapy |
| Barr et al.[219]
NCT03801525 (umbralisib-venetoclax-ublituximab) |
R/R
(n = 21) |
UMBRA cycle 1-12 + UBLI cycle 1-3 + VEN cycle 4-12 | BM uMRD at cycle 12, discontinue all therapy
BM MRD-pos at cycle 12, continue UMBRA monotherapy |
4 patients with BM uMRD (19%) | Median 4 (< 1-14) months |
| Crombie et al.[236]
(duvelisib-venetoclax) |
R/R
(n = 12) |
DUV D1-7, then DUV+VEN for 12 cycles | uMRD on two assessments, discontinue all therapy
Resume VEN monotherapy at MRD recrudescence MRD-pos, continue VEN monotherapy |
1 patient with BM uMRD CR
Grade ≥ III neutropenia 83% |
Median number of cycles 6 (range 1-9) |
Cycles are 28 days unless otherwise stated. *Continued monotherapy until death. R/R: relapsed and refractory. TN: treatment naïve; R: rituximab; CIRS: cumulative illness rating scale; CrCl: creatinine clearance; PR: partial response; PB uMRD: peripheral blood measurable residual disease less than 10-4; BM uMRD: bone marrow measurable residual disease less than 10-4; IBR: ibrutinib 420 mg daily; ACAL: acalabrutinib 100 mg BD; VEN: venetoclax 400 mg daily after dose escalation; G: obinutuzumab (100 mg on Day 1, 900 mg on Day 2, 1000 mg on Days 8 and 15, then 1000 mg Day 1, 28 day cycles); UBLI: ublituximab 900 mg weekly for Cycle 1, then once for Cycles 2 and 3; UMBRA: umbralisib, 600 or 800 mg daily; DUV: duvelisib 25 mg BD; progression or unacceptable toxicity; CK: complex karyotype; B2MG: beta-2-microglobulin