Table 2: Trials using lenalidomide in combination in CLL patients.

ReferencesRegimenNo.TLS %TFR %AE 3-4 (%)Response

Chanan Khan [31]
2006-7
Phase II
Relapsed or refractory
Lenalidomide 10 mg per day escalated up to 5 mg each 1-2 week (max 25 mg) 21 days each 28
Rituximab 375 mg/m2 days 1, 8, and 15 (cycle 1) and days 1 and 15 (cycles 2–6)
3058Neutropenia 70%
Thrombocytopenia 45%
Anemia 18%
ORR 57.7%
RC 18%
TFS 19.4 months
ORR 38% (high risk cytogenetic)

James 2011 [30]
Phase II frontline
CLL Research Consortium CRC-014
Lenalidomide cycle 1: 2.5 mg; cycles 2–7: 5 mg escalated up to 10 mg (days 1–21 each 28)
Rituximab: 50 mg/m2 day 29; 325 mg/m2 day 31; 375 mg/m2 day 33 (cycle 1), 375 mg/m2 weekly (cycle 2) and 375 mg/m2 day 1 (cycles 3–7)
691.4Neutropenia 49%
Thrombocytopenia 6%
Anemia 11%
ORR 95% (<65 y)
ORR 78% (>65 y)
RC 20% (<65 y)
RC 8% (>65 y)
TFS 19-20 m

Badoux [29, 43]
Phase II relapsed or refractory
Lenalidomide was started on day 9 at cycle 1 and on day 1 of the cycles 3–12: 10 mg continuously
Rituximab 375 mg/m2 weekly during cycle 1 and on day 1 cycles 3 to 12
591.727Neutropenia 73%
Thrombocytopenia 34%
Anemia 15%
Infection 15%
ORR 66%
RC 12%
OS: 71% at 36 months
TFS: 17.4 m

Veliz 2009 [32]
Phase II
Relapsed or progression after rituximab
Heavily treated
Lenalidomide cycle 1: 2.5 mg (days 1–7), 5 mg (days 8–15), 10 mg (15–21 days) followed by 7 days of rest and then 20 mg 21 each 28 days
Rituximab 375 mg/m2 weakly each 4 weeks (day 15)
10(RF) 1212Neutropenia 41%ORR 30%
RC 0

Chen 2012 [39]
Phase II
frontline
Lenalidomide: 5 mg per day escalated 5 mg each 28 days (max 25 mg)
Dexamethasone: 12 mg days 1–4; 14, 21, and 28
Maximum 18 cycles
1805Neutropenia 53%
Neutropenia febrile 24%
Thrombocytopenia 12%
0R 59%
RC 1%
RP 53%

Badoux [33]
Phase II
Relapsed or refractory
Lenalidomide 10 mg per day
Ofatumumab weekly
16NR13Neutropenia 50%
Anemia 13%
ORR 63%
RC: 13%
OS: NR
TFS: NR

Ferrajoli [44]
2012
Phase II
Relapsed or refractory
Lenalidomide 10 mg day 9 continued for 24 months
Ofatumumab weekly for 3 weeks (300 mg week; 1000 mg week 2 and thereafter) monthly (months 2–6); every other month (months 7–24)
3600Neutropenia 47%
Thrombocytopenia 9%
Anemia 6%
ORR 68%
RC 24%

Blum [38]
2011
Phase I
Relapsed or refractory very adverse
Lenalidomide 2.5 mg escalating up to 25 mg days 1–21
Flavopiridol 30 mg/m2 in bolus followed of 30–50 mg/m2 days 1, 8, and 15 (cycle 1) and then days 3, 10 and 17
3037Neutropenia 47%
Thrombocytopenia 60%
Anemia 33%
ORR 57%
RC: 0%
OS 7 m
TFS 23 m

GIMEMA [34]
LLC 606
Phase I
Relapsed or refractory
Lenalidomide 2.5 mg escalating up to 15 mg Cyclophosphamide Fludarabine9011Neutropenia transitory 3-4 in the majority of the patientsORR 67%
RC 33%
NR
NR

Egle [36]
2011
Phase I/II
Frontline
Lenalidomide 2.5 mg/day (days 7–21) escalating up to 25 mg (day 1–21)
Fludarabine 40 mg/m2 1–3
Rituximab 375 m/m2 day 3 cycle 1; 500 mg/m2 day 1 cycles 2–6
Maintenance:
R: 375 mg/m2 cycles 2, 4, and 6 Lenalidomide (maximum tolerated dose)
4500Neutropenia 88%ORR 87%
RC 49%
NR
NR

Flinn [45]
2012
Phase I-II
Frontline
Rituximab 375 mg/m2 (cycle 1); 500 mg/m2 (cycle 2–6)
Fludarabine 25 mg/m2 (days 1–3)
Lenalidomide 2.5–5 mg (days 8–28)
6 cycles
5160Neutropenia 47%
Anemia 14%
Thrombocytopenia 6
Rash 14%
ORR: 78%
RC 19%
PFS 71%
OS 88%
(median FU 21 months)

Brown [35]
Phase I
Frontline
Fludarabine: 25 mg/m2 (days 3–5)
Rituximab: 50 mg/m2 day 1 and 325 mg/m2 day 3
Lenalidomide: 2.5 mg to alternate days (21 each 28 days)
Followed by two cycles of consolidation with lenalidomide
9 1/92/9Neutropenia 66%
Thrombocytopenia 2/9
Allergy
Syndrome hand-foot
ORR 56%
RC 1/9

TLS: tumor lysis syndrome; TFR: tumor flare reaction; AE: adverse effects; NR: not reported; ORR: overall response; CR: complete remission; OS: overall survival; TFS: treatment-free survival; y: year; m: month; RF: renal failure.