Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treatment Regimens

Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma (CLL/SLL) Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶First-Line Therapy Without del (17p)/TP53 Mutation1

REGIMEN

DOSING

Patients age ≥65 years OR <65 years with significant comorbidities (creatinine clearance [CrCl] <70mL/min)

Preferred Regimens

Acalabrutinib
(Category 1)2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Acalabrutinib + Obinutuzumab
(Category 1)2,4,6,a,b

Obinutuzumab requires premedication.

Days 1-28: Acalabrutinib 100mg orally twice daily

Administer for one 4-week cycle, followed by:

Day 1 (Cycle 2): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 2): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 2): Obinutuzumab 1,000mg, followed by:

Day 1 (Cycle 3-7): Obinutuzumab 1,000mg IV

Days 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Ibrutinib
(Category 1)7-10,c

Day 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Obinutuzumab
(Category 1)6, 11-13, b,d,e

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for 6 cycles, with:

Days 22-28 (Cycle 1): Venetoclax 20mg orally once daily, followed by:

Days 1-7 (Cycle 2): Venetoclax 50mg orally once daily, followed by:

Days 8-14 (Cycle 2): Venetoclax 100mg orally once daily, followed by:

Days 15-21 (Cycle 2): Venetoclax 200mg orally once daily, followed by:

Days 22-28 (Cycle 2): Venetoclax 400mg orally once daily, followed by:

Days 1-28 (Cycle 3 and beyond): Venteoclax 400mg orally once daily.

Repeat cycle every 4 weeks for 12 cycles

Other Recommended Regimens

Bendamustine + Obinutuzumab (not recommended for frail patients)6,14.15,b,f

Obinutuzumab requires premedication.

Days 1-2 (Cycle 1): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily, followed by (if tolerated):

Days 1-2 (Cycles 2-6): Bendamustine 90mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

OR

Days 1-2 (Cycles 1-6): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

Bendamustine + Ofatumumab (not recommended for frail patients)14,16,17.f,g,h

Ofatumumab requires premedication.

Days 1-2 (Cycle 1): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily, followed by (if tolerated):

Days 1-2 (Cycles 2-6): Bendamustine 90mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Ofatumumab 300mg IV, followed by:

Day 8 (Cycle 1): Ofatumumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Ofatumumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

OR

Days 1-2 (Cycles 1-6): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Ofatumumab 300mg IV, followed by:

Day 8 (Cycle 1): Ofatumumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Ofatumumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

Bendamustine + Rituximab (not recommended for frail patients)14,18-21,f,i,j

Rituximab requires premedication.

Days 1-2 (Cycle 1): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily, followed by (if tolerated):

Days 1-2 (Cycles 2-6): Bendamustine 90mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Chlorambucil
(Category 3)22-24,k

Day 1: Chlorambucil 40mg/m2 orally

Repeat cycle every 4 weeks.

OR

Day 1: Chlorambucil 0.4-0.8mg/kg orally.

Repeat cycle every 2 weeks.

Chlorambucil + Obinutuzumab6,13,22,25,26,b,k

Obinutuzumab requires premedication.

Days 1,15: Chlorambucil 0.5mg/kg orally

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat every 4 weeks for 6 cycles

High-dose Methylprednisolone (HDMP) + Obinutzumab
(Category 2B)6,27,b

Obinutuzumab requires premedication.

Days 1-3 (Cycles 1-4): HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisolone (HDMP) + Rituximab
(Category 2B)18,28,29,i,j

Rituximab requires premedication.

Days 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Days 8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Days 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles

Ibrutinib + Obinutuzumab
(Category 2B)6,7,26,b,c

Obinutuzumab requires premedication.

Days 1-28: Ibrutinib 420mg orally once daily

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Obinutuzumab6,30,31,b

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV.

Administer for one 3-week cycle, followed by:

Days 1 (Cycle 2-8): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 7 cycles.

Rituximab
(Category 3)18,32,i,j

Rituximab requires premedication.

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

Patients Age <65 Years Without Significant Comorbidities

Preferred Regimens

Acalabrutinib
(Category 1)2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Acalabrutinib + Obinutuzumab
(Category 1)2,4,6,a,b

Obinutuzumab requires premedication.

Days 1-28: Acalabrutinib 100mg orally twice daily

Administer for one 4-week cycle, followed by:

Day 1 (Cycle 2): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 2): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 2): Obinutuzumab 1,000mg, followed by:

Day 1 (Cycle 3-7): Obinutuzumab 1,000mg IV

Days 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Day 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Ibrutinib
(Category 1)7-10, c

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Obinutuzumab6,11-13,b,d,e

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles, with:

Days 22-28 (Cycle 1): Venetoclax 20mg orally once daily, followed by:

Days 1-7 (Cycle 2): Venetoclax 50mg orally once daily, followed by:

Days 8-14 (Cycle 2): Venetoclax 100mg orally once daily, followed by:

Days 15-21 (Cycle 2): Venetoclax 200mg orally once daily, followed by:

Days 22-28 (Cycle 2): Venteoclax 400mg orally once daily, followed by:

Days 1-28 (Cycle 3 and beyond): Venteoclax 400mg orally once daily.

Repeat cycle every 4 weeks for 12 cycles.

Other Recommended Regimenso

Bendamustine + Obinutuzumab6,14,15,b,f

Obinutuzumab requires premedication.

Days 1-2 (Cycles 1-6): Bendamustine 90mg/m2 IV over 10-30 minutes

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for up to 6 cycles.

Bendamustine + Ofatumumab14,16,17,f-h

Ofatumumab requires premedication.

Days 1-2 (Cycles 1-6): Bendamustine 90mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Ofatumumab 300mg IV, followed by:

Day 8 (Cycle 1): Ofatumumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Ofatumumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

Bendamustine + Rituximab18-21,f,i,j

Rituximab requires premedication.

Days 1-2 (Cycles 1-6): Bendamustine 90mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

FCR (Fludarabine, Cyclophosphamide, Rituximab) (preferred for patients with IGHV-mutated CLL)18,21,33-35,i,j,l

Rituximab requires premedication.

Days 1-3: Fludarabine 25mg/m2 IV over 30 minutes daily

Days 1-3: Cyclophosphamide 250mg/m2 IV over 30 minutes daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

FR (Fludarabine + Rituximab)
(Category 3)18,33,36,37,i,j,l

Rituximab requires premedication.

Days 1-5: Fludarabine 25mg/m2 IV over 30 minutes

Day 1 (Cycle 1): Rituximab 50mg/m2 IV over 4 hours, followed by:

Day 3 (Cycle 1): Rituximab 325mg/m2 IV, followed by:

Day 5 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-6): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisolone (HDMP) + Obinutzumab
(Category 3)6,27,b

Obinutuzumab requires premedication.

Days 1-3 (Cycles 1-4): HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisone (HDMP) + Rituximab
(Category 3)18,28,29,i,j

Rituximab requires premedication.

Days 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Days 8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Days 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles.

Ibrutinib + Rituximab
(Category 2B)7,18,38,39,c,i,j

Rituximab requires premedication.

Days 1-28 (Cycles 1-6): Ibrutinib 420mg orally once daily

Days 1,8,15,22 (Cycle 2): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 3-6): Rituximab 375mg/m2 IV

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

▶Second/Subsequent-Line Therapy Without del (17p)/TP53 Mutation1

Patients Age ≥65 Years OR Patients Age <65 Years With Significant Comorbidities (Creatinine Clearance [CrCl] <70 mL/min)

Preferred Regimens

Acalabrutinib
(Category 1)2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Ibrutinib
(Category 1)7-10, c

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Rituximab
(Category 1)11,18,40,41,d,e,i,j

Rituximab requires premedication.

Days 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venteoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and beyond): Venetoclax 400mg orally once daily

Repeat cycle every 4 weeks for a maximum of 2 years, with:

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2 and beyond): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Other Recommended Regimens

Bendamustine + Rituximab
(Category 2B)18-21,f,i,j

Rituximab requires premedication.

Days 1-2 (Cycles 1-6): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Chlorambucil + Rituximab18,22,42,i-k

Rituximab requires premedication.

Days 1-7: Chlorambucil 10mg/m2 orally daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Duvelisib43-46,m

Days 1-28: Duvelisib 25mg orally twice daily

Repeat cycle every 4 weeks.

High-dose Methylprednisolone (HDMP) + Obinutuzumab
(Category 2B)6,27,b

Obinutuzumab requires premedication.

Days 1-3 (Cycles 1-4): HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisolone (HDMP) + Rituximab
(Category 2B)18,28,29,i,j

Rituximab requires premedication.

Days 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Days 8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Days 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles.

Idelalisib47,48,n

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Idelalisib+ Rituximab18,47-49,g,i,j,n

Rituximab requires premedication.

Days 1-28 (Cycles 1-6): Idelalisib 150mg orally twice daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 15 (Cycle 1): Rituximab 500mg/m2 IV, followed by:

Days 1,15 (Cycle 2): Rituximab 500mg/m2 IV, followed by:

Day 1 (Cycle 3-6): Rituximab 500mg/m2 IV

Repeat every 4 weeks for 6 cycles, followed by:

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Lenalidomide50-52,o

Days 1-28: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks for 4 cycles.

OR

Days 1-21: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks.

Lenalidomide + Rituximab18,50,53,i,j,o

Rituximab requires premedication.

Days 9-28 (Cycle 1): Lenalidomide 10mg orally once daily, followed by:

Days 1-28 (Cycle 2-12): Lenalidomide 10mg orally once daily

Days 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-12): Rituximab 375mg/m2 IV

Repeat cycle every 4 weeks for 12 cycles, followed by:

Days 1-28: Lenalidomide 10mg orally once daily.

Repeat cycle every 4 weeks.

Obinutuzumab6,30,31,b

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV.

Administer for one 3-week cycle, followed by:

Day 1 (Cycle 2-8): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 7 cycles.

Ofatumumab16,54-56,g,h

Ofatumumab requires premedication.

Day 1 (Week 1): Ofatumumab 300mg IV, followed by:

Day 1 (Beginning with Week 2): Ofatumumab 2,000mg IV

Repeat cycle weekly for 7 doses, followed by:

Day 1 (Beginning with Week 12): Ofatumumab 2,000mg IV

Repeat cycle every 4 weeks for 4 doses.

Rituximab (Dose-dense)
(Category 3)18,57,i,j

Rituximab requires premedication.

Day 1: Rituximab 100mg/m2 IV over 4 hours (do not titrate infusion rate), followed by:

Day 3,5,8,10,12,15,17,19,22,24,26: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

Venetoclax11,58,59,d,e

Days 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venetoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and Beyond): Venetoclax 400mg orally once daily.

Repeat cycle every 4 weeks.

Zanubrutinib (for patients with intolerance or contraindication to other BTK inhibitor)60-63,p

Days 1-28: Zanubrutinib 160mg orally twice daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Zanubrutinib 320mg orally twice daily.

Repeat cycle every 4 weeks.

Patients Age <65 Tears Without Significant Comorbidities

Preferred Regimens

Acalabrutinib
(Category 1)2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Ibrutinib
(Category 1)7-10,c

Day 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Rituximab
(Category 1)11,18,30,41, d,e,i,j

Rituximab requires premedication.

Days 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venteoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and beyond): Venetoclax 400mg orally once daily

Repeat cycle every 4 weeks for a maximum of 2 years, with:

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2 and beyond): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Other Recommended Regimenso

Alemtuzumab
(Category 3)64-67,q,r

Alemtuzumab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous.

Dose titration followed by three times weekly administration of Alemtuzumab (on alternate days) for a maximum of 12 weeks (including dose-escalation phase).

Alemtuzumab + Rituximab
(Category 3)18,64,68,69,i,j,q,r

Alemtuzumab requires premedication.

Rituximab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Days 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC <50,000/mcL), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC <50,000/mcL).

OR

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutanous, if tolerated followed by:

Day 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Day 1 (Week 1): Rituximab 100mg/m2 IV, followed by:

Day 2 (Week 1): Rituximab 275mg/m2 IV, followed by:

Days 8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC ≥50,000), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC ≥50,000).

Bendamustine + Rituximab14,18-21,f,i,j

Rituximab requires premedication.

Days 1-2 (Cycles 1-6): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection) daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Bendamustine + Rituximab + Ibrutinib
(Category 3)7,14,18,70,c,f,i,j

Rituximab requires premedication.

Days 1-28: Ibrutinib 420mg orally once daily

Days 2-3 (Cycle 1): Bendamustine 70mg/m2 IV over 10-30 minutes (based on product selection), followed by:

Days 1-2 (Cycles 2-6): Bendamustine 70mg/m2 IV over 30 minutes (based on product selection)

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 500mg/m2 IV

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Duvelisib43-46,n

Day 1-28: Duvelisib 25mg orally twice daily

Repeat cycle every 4 weeks.

FC (Fludarabine + Cyclophosphamide) + Ofatumumab
(Category 3)6,33,71,g,h,l

Ofatumumab required premedication.

Days 1-3: Fludarabine 25mg/m2 IV over 30 minutes

Days 1-3: Cyclophosphamide 250mg/m2 IV over 30 minutes

Day 1 (Cycle 1): Ofatumumab 300mg IV, followed by:

Day 8 (Cycle 1): Ofatumumab 1,000mg, followed by:

Day 1 (Cycle 2-6): Ofatumumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

FCR (Fludarabine + Cyclophosphamide + Rituximab)18,21,34,35,i,j,l

Rituximab requires premedication.

Days 1-3: Fludarabine 25mg/m2 IV over 30 minutes daily

Days 1-3: Cyclophosphamide 250mg/m2 IV over 30 minutes daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-6): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisolone (HDMP) + Obinutuzumab
(Category 2B)6,27,b

Obinutuzumab requires premedication.

Days 1-3 (Cycles 1-4): HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles.

High-dose Methylprednisolone (HDMP) + Rituximab
(Category 2B)18,28,29,i,j

Rituximab requires premedication.

Day 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Day 8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles.

Idelalisib47,48,n

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Idelalisib + Rituximab18,47-49,i,j,n

Rituximab requires premedication.

Days 1-28 (Cycles 1-6): Idelalisib 150mg orally twice daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 15 (Cycle 1): Rituximab 500mg/m2 IV, followed by:

Days 1,15 (Cycle 2): Rituximab 500mg/m2 IV, followed by:

Day 1 (Cycle 3-6): Rituximab 500mg/m2 IV

Repeat every 4 weeks for 6 cycles, followed by:

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Lenalidomide50-52,o

Days 1-28: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks for 4 cycles.

OR

Days 1-21: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks.

Lenalidomide + Rituximab18,50,53,i,j,o

Rituximab requires premedication.

Days 9-28 (Cycle 1): Lenalidomide 10mg orally once daily, followed by:

Days 1-28 (Cycle 2-12): Lenalidomide 10mg orally once daily

Days 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-12): Rituximab 375mg/m2 IV

Repeat cycle every 4 weeks for 12 cycles, followed by:

Days 1-28: Lenalidomide 10mg orally once daily.

Repeat cycle every 4 weeks.

Obinutuzumab6,30,31,b

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV.

Administer for one 3-week cycle, followed by:

Day 1 (Cycle 2-8): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 7 cycles.

Ofatumumab16,54-56,g,h

Ofatumumab requires premedication.

Day 1 (Week 1): Ofatumumab 300mg IV, followed by:

Day 1 (Beginning with Week 2): Ofatumumab 2,000mg IV

Repeat cycle weekly for 7 doses, followed by:

Day 1 (Beginning with Week 12): Ofatumumab 2,000mg IV

Repeat cycle every 4 weeks for 4 doses.

Venetoclax11,58,59,d,e

Day 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venetoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and Beyond): Venetoclax 400mg orally once daily.

Repeat cycle every 4 weeks.

Zanubrutinib (for patients with intolerance or contraindications to other BTK inhibitor)60-63,p

Days 1-28: Zanubrutinib 160mg orally twice daily.

Repeat cycle every 4 weeks.

oR

Days 1-28: Zanubrutinib 320mg orally twice daily.

Repeat cycle every 4 weeks.

▶First-Line Therapy With del(17p)/TP53 mutation1

Preferred Regimens

Acalabrutinib2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Acalabrutinib + Obinutuzumab2,4,6,a,b

Obinutuzumab requires premedication.

Days 1-28: Acalabrutinib 100mg orally twice daily

Administer for one 4-week cycle, followed by:

Day 1 (Cycle 2): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 2): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 2): Obinutuzumab 1,000mg, followed by:

Day 1 (Cycle 3-7): Obinutuzumab 1,000mg IV

Days 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-28: Acalabrutinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Ibrutinib7-10, c

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Obinutuzumab6,11-13,,b,d,e

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycle 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 4 weeks for 6 cycles, with:

Days 22-28 (Cycle 1): Venetoclax 20mg orally once daily, followed by:

Days 1-7 (Cycle 2): Venetoclax 50mg orally once daily, followed by:

Day 8-14 (Cycle 2): Venetoclax 100mg orally once daily, followed by:

Day 15-21 (Cycle 2): Venetoclax 200mg orally once daily, followed by:

Day 22-28 (Cycle 2): Venteoclax 400mg orally once daily, followed by:

Day 1-28 (Cycle 3 and beyond): Venteoclax 400mg orally once daily.

Repeat cycle every 4 weeks for 12 cycles

Other Recommended Regimens

Alemtuzumab64-67,q,r

Alemtuzumab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous.

Dose titration followed by three times weekly administration of Alemtuzumab (on alternate days) for a maximum of 12 weeks (including dose-escalation phase).

Alemtuzumab + Rituximab18,64,68,69,i,j,q,r

Alemtuzumab requires premedication.

Rituximab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Days 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC <50,000/mcL), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC <50,000/mcL).

OR

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutanous, if tolerated followed by:

Day 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Day 1 (Week 1): Rituximab 100mg/m2 IV, followed by:

Day 2 (Week 1): Rituximab 275mg/m2 IV, followed by:

Days 8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC ≥50,000), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC ≥50,000).

High-dose Methylprednisolone (HDMP) + Rituximab18,28,29,i,j

Rituximab requires premedication.

Day 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Days 8,15,22 (Cycle 1): Rituximab 375mg/m2 followed by:

Days 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles

Obinutuzumab6,30,31,b

Obinutuzumab requires premedication.

Day 1 (Cycle 1): Obinutuzumab 100mg IV, followed by:

Day 2 (Cycle 1): Obinutuzumab 900mg IV, followed by:

Days 8,15 (Cycle 1): Obinutuzumab 1,000mg IV.

Administer for one 3-week cycle, followed by:

Day 1 (Cycle 2-8): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 7 cycles.

Zanubrutinib (for patients with intolerance or contraindication to other BTK inhibitors)60-63,p

Days 1-28: Zanubrutinib 160mg orally twice daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Zanubrutinib 320mg orally twice daily.

Repeat cycle every 4 weeks.

▶Second/Subsequent-Line Therapy With del(17p)/TP53 mutation1

Preferred Regimens

Acalabrutinib
(Category 1)2-5,a

Days 1-28: Acalabrutinib 100mg orally every 12 hours.

Repeat cycle every 4 weeks.

Ibrutinib
(Category 1)7-10, c

Days 1-28: Ibrutinib 420mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax11,58,59,d,e

Days 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venetoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and Beyond): Venetoclax 400mg orally once daily.

Repeat cycle every 4 weeks.

Venetoclax + Rituximab
(Category 1)11,18,40,41,d,e,i,j

Rituximab requires premedication.

Days 1-7: Venetoclax 20mg orally once daily, followed by:

Days 8-14: Venetoclax 50mg orally once daily, followed by:

Days 15-21: Venetoclax 100mg orally once daily, followed by:

Days 22-28: Venetoclax 200mg orally once daily, followed by:

Days 29-35: Venteoclax 400mg orally once daily.

Administer for one 5-week cycle, followed by:

Days 1-28 (Cycle 2 and beyond): Venetoclax 400mg orally once daily

Repeat cycle every 4 weeks for a maximum of 2 years, with:

Days 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Days 1 (Cycle 2 and beyond): Rituximab 500mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

Other Recommended Regimens

Alemtuzumab64-67.q.r

Alemtuzumab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous.

Dose titration followed by three times weekly administration of Alemtuzumab (on alternate days) for a maximum of 12 weeks (including dose-escalation phase).

Alemtuzumab + Rituximab18,64,68,69,i,j,q,r

Alemtuzumab requires premedication.

Rituximab requires premedication.

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Days 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC <50,000/mcL), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC <50,000/mcL).

OR

Day 1 (Week 1): Alemtuzumab 3mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 2 (Week 1): Alemtuzumab 10mg IV over 2 hours OR subcutaneous, if tolerated followed by:

Day 3 (Week 1): Alemtuzumab 30mg IV over 2 hours OR subcutanous, if tolerated followed by:

Day 3,5 (Weeks 2-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Day 1 (Week 1): Rituximab 100mg/m2 IV, followed by:

Day 2 (Week 1): Rituximab 275mg/m2 IV, followed by:

Days 8,15,22: Rituximab 375mg/m2 IV

Administer for one 4-week cycle (if WBC ≥50,000), followed by:

Days 3,5 (Weeks 1-4): Alemtuzumab 30mg IV over 2 hours OR subcutaneous twice weekly

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle (if WBC ≥50,000).

Duvelisib43-46,m

Days 1-28: Duvelisib 25mg orally twice daily

Repeat cycle every 4 weeks.

High-dose Methylprednisolone (HDMP) + Rituximab18,28,29,i,j

Rituximab requires premedication.

Days 1-3: HDMP 1,000mg/m2 IV over 90 minutes

Day 1 (Cycle 1): Rituximab 100mg IV, followed by:

Day 2 (Cycle 1): Rituximab 375mg/m2 minus 100mg IV, followed by:

Days 8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Days 1,8,15,22 (Cycles 2-3): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 3 cycles.

Idelalisib47,48,n

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Idelalisib + Rituximab18,47-49,i,j,n

Rituximab requires premedication.

Days 1-28 (Cycles 1-6): Idelalisib 150mg orally twice daily

Day 1 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 15 (Cycle 1): Rituximab 500mg/m2 IV, followed by:

Days 1,15 (Cycle 2): Rituximab 500mg/m2 IV, followed by:

Day 1 (Cycle 3-6): Rituximab 500mg/m2 IV

Repeat every 4 weeks for 6 cycles, followed by:

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Lenalidomide50-52,o

Days 1-28: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks for 4 cycles.

OR

Days 1-21: Lenalidomide 10mg orally once daily (escalate dose every 14-28 days as tolerated up to a maximum dose of 25mg daily).

Repeat cycle every 4 weeks.

Lenalidomide + Rituximab18,50,53,i,j,o

Rituximab requires premedication.

Days 9-28 (Cycle 1): Lenalidomide 10mg orally once daily, followed by:

Days 1-28 (Cycle 2-12): Lenalidomide 10mg orally once daily

Days 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycle 2-12): Rituximab 375mg/m2 IV

Repeat cycle every 4 weeks for 12 cycles, followed by:

Days 1-28: Lenalidomide 10mg orally once daily.

Repeat cycle every 4 weeks.

Ofatumumab16,54-56.g,h

Ofatumumab requires premedication.

Day 1 (Week 1): Ofatumumab 300mg IV, followed by:

Day 1 (Beginning with Week 2): Ofatumumab 2,000mg IV

Repeat cycle weekly for 7 doses, followed by:

Day 1 (Beginning with Week 12): Ofatumumab 2,000mg IV

Repeat cycle every 4 weeks for 4 doses.

Zanubrutinib (for patients with intolerance or contraindication to other BTK inhibitors)60-63,p

Days 1-28: Zanubrutinib 160mg orally twice daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Zanubrutinib 320mg orally twice daily.

Repeat cycle every 4 weeks.

a  Acalabrutinib has multiple drug-drug interactions and/or drug-food interactions.

b  For Obinutuzumab, premedication for hypersensitivity is required. The recommended dosing is: diphenhydramine 50mg IV or orally at least 30 minutes pre-Obinutuzumab for doses 1 and 2. For subsequent doses, diphenhydramine should be administered to patients with grade ≥1 infusion-related reactions with the previous infusion AND acetaminophen 650-1,000mg orally at least 30 minutes pre-Obinutuzumab AND dexamethasone 20mg or methylprednisolone 80mg IV at least 60 minutes pre-Obinutzumab for doses 1 and 2. Hydrocortisone is not recommended. For subsequent doses, corticosteroid should be administered to patients with grade 3 infusion-related reactions with the previous infusion or with a lymphocyte count >2.5 x 109/L prior to next treatment.

c  Ibrutinib has multiple drug-drug interactions and/or drug-food interactions.

d  Venetoclax has multiple drug- drug interactions and/or drug-food interactions.

e  Venetoclax should be taken with food.

f  Bendamustine has multiple drug-drug interactions and/or drug-food interactions.

g  While Ofatuzumab is no longer commercially available for CLL, it may be obtained for clinical use.

h  For Ofatumumab: Premedication for hypersensitivity and/or infusion reaction is required. The recommended dosing is: diphenhydramine 50mg IV or orally 30-120 minutes pre-Ofatuzumab AND acetaminophen 1,000mg orally 30-120 minutes pre-Ofatuzumab AND prednisolone 50-100mg (or equivalent) 30-120 minutes pre-Ofatuzumab.

i   For Rituximab: Premedication is required. The recommended dosing is: diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-Rituximab AND acetaminophen 650mg orally 30-60 minutes pre-Rituximab.

j   Rituximab and Hyaluronidase Human (Rituxan Hycela) for subcutaneous injection may be substituted for Rituximab in patients who have received one dose of Rituximab product by IV route without experiencing severe adverse reactions.72 A biosimilar agent may be substituted for Rituximab if clinically appropriate.

k  Chlorambucil should be taken on an empty stomach.

l   Autoimmune hemolytic anemia (AIHA) should not preclude the use of combination therapy containing Flurdarabine; however, patients should be observed carefully and fludarabine should be avoided in those where a history of Fludarabine-associated AIHA is suspected.

m  Duvelisib has multiple drug-drug interactions and/or drug-food interactions.

n  Idelalisib is indicated for patients for whom rituximab monotherapy would be considered appropriate due to the presence of other comorbidities/reduced renal function as measured by CrCl <60ml/min or NCI CTCAE grade ≥3 neutropenia or grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents.

o  Lenalidomide can be given as continuous or interim dosing for patients with CLL. Growth factors and/or dose adjustment may be needed to address cytopenias, without necessitating holding treatment. See Andritsos L, et al. J Clin Oncol. 2008;26:2518-2525; Wendtner C, et al. Leuk Lymphoma. 2016;57:1291-1299.

p  Zanubrutinib has multiple drug-drug interactions and/or drug-food interactions.

q  While Alemtuzumab is no longer commercially available for CLL, it may be obtained for clinical use.

r   For Alemtuzumab: Premedication for infusion reactions is required prior to initial dose and dose escalations, then as clinically indicated. The recommended dosing is: diphenhydramine 50mg orally or IV 30 minutes pre-Alemtuzumab AND acetaminophen 500-1,000mg orally 30 minutes pre-Alemtuzumab.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V1.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdff. Accessed December 6, 2021.

2. Acalabrutinib (Calquence). [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2019.

3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.

4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020; 395(10232):1278-1291.

5.Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019; 3(9):1553-1562.

6. Obinutuzumab (Gazyva). [package insert]. South San Francisco, CA: Genentech, Inc.; January 2021.

7. Ibrutinib (Imbruvica). [package insert]. Horsham, PA: Janssen Biotech, Inc.; December 2020.

8. Burger JA, Tedeschi A, Bar PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.

9. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open=label, multicenter study. Lancet Oncol. 2016;17(10):1409-1418.

10. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363.

11. Venetoclax (Venclexta). [package insert]. North Chicago, IL: AbbVie Inc.; October 2021.

12. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236

13. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus ­chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.

14. Bendamustine (Bendeka). [package insert]. Parsippany, NJ: Teva Pharmaceuticals; October 2021.

15. Stilgenbauer S, Leblond V, Foa R, et al. Obinutuzumab plus bendamustine in ­previously untreated patients with CLL: a subgroup analysis of the GREEN study. Leukemia. 2018;32(8):1778-1786.

16. Ofatumumab (Kesimpta). [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2020.

17. Flinn IW, Panayiotidis P, Afanasyev B, et al. A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. Am J Hematol. 2016;91(9):900-906.

18. Rituximab (Rituxan). [package insert]. South San Francisco, CA: Genentech, Inc.; December 2021.

19. Michallet AS, Aktan M, Hiddemann W, et al. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018;103(4):698-706.

20. Fischer K, Cramer P, Bush R, et al. Bendamustine combined with rituximab in ­patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29(26):3559-3566.

21. Eichhorst B, Fink AM, Bhalo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942.

22. Chlorambucil (Leukeran) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; November 2006.

23.Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009 114(16):3382-3391.

24. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24): 1750-1757.

25. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29(7):1602-1604.

26. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56.

27. Castro JE, Amaya-Chanaga CI, Lujan JV, et al. Obinutuzumab (Gazyva) and high-dose methylprednisone (HDMP) combination for patients with chronic lymphocytic ­leukemia (CLL) – a phase Ib/II study. [abstract]. Blood. 2017;130(Suppl_1):1730.

28. Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23(10):1779-1789.

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(Revised 12/2021; NCCN CLL/SLL Guidelines V1.2022) © 2021 by Haymarket Media, Inc.

Topics:

Chronic Lymphocytic Leukemia Hematologic Cancers Leukemia Treatment Regimens