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

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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 healthcare 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 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) cancer treatment regimens are provided only to supplement the latest treatment strategies.

These Cancer Treatment Guidelines are a work in progress that may be refined as often as new significant data becomes 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 National Comprehensive Cancer Network 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.

(Revised 11/2016)

© 2016 Haymarket Media, Inc.

CLL/SLL Without del(17p)/TP53 Mutation1

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

First-line therapy for frail patients with significant comorbidities

REGIMEN

DOSING

Obinutuzumab + chlorambucil (Category 1)2

Day 1: Obinutuzumab 100mg IV + chlorambucil 0.5mg/kg orally

Day 2: Obinutuzumab 900mg IV

Day 8: Obinutuzumab 1,000mg IV

Day 15: Obinutuzumab 1,000mg IV + chlorambucil 0.5mg/kg orally.

Repeat cycle every 28 days for 6 cycles with obinutuzumab given at a dose of 1,000mg IV on day 1 of subsequent cycles.

Ibrutinib (Category 1)3

Ibrutinib 420mg orally once daily until disease progression or unacceptable toxicity.

Ofatumumab + chlorambucil4

Cycle 1

Day 1: Ofatumumab 300mg IV

Days 1–7: Chlorambucil 10mg/m2 orally

Day 8: Ofatumumab 1,000mg IV

Subsequent Cycles

Day 1: Ofatumumab 1,000mg IV

Days 1–7: Chlorambucil 10mg/m2 orally.

Repeat cycle every 28 days for a maximum of 12 cycles.

Rituximab + chlorambucil5

Cycle 1

Days 1–7: Chlorambucil 8mg/m2/day orally

Cycle 3

Day 1: Rituximab 375mg/m2 IV

Days 1–7: Chlorambucil 8mg/m2/day orally

Cycle 4–8

Day 1: Rituximab 500mg/m2 IV

Days 1–7: Chlorambucil 8mg/m2/day orally.

Repeat cycle every 28 days; administer rituximab at dose of 375mg/m2 IV every 2 months for 2 years as maintenance therapy.

Obinutuzumab (Category 2B)6

Cycle 1

Day 1: Obinutuzumab 100mg IV

Day 2: Obinutuzumab 900mg IV

Day 3: Obinutuzumab 1,000mg IV

Days 8 and 15: Obinutuzumab 2,000mg IV

Cycles 2–8

Day 1: Obinutuzumab 2,000mg IV.

Repeat cycle every 21 days.

Rituximab (Category 3)7

Day 1, 8, 15, and 22: Rituximab 375mg/m2/day IV.

Chlorambucil (Category 3)8,9

Days 1–28: Chlorambucil 0.4mg/kg/day with an increase to 0.8mg/kg orally daily.

Repeat cycle every 28 days for 12 cycles.

First-line therapy for patients age ≥65 with significant comorbidities

Obinutuzumab + chlorambucil (Category 1)2

Day 1: Obinutuzumab 100mg IV + chlorambucil 0.5mg/kg orally

Day 2: Obinutuzumab 900mg IV

Day 8: Obinutuzumab 1,000mg IV

Day 15: Obinutuzumab 1,000mg IV + chlorambucil 0.5mg/kg orally.

Repeat cycle every 28 days for 6 cycles with obinutuzumab given at a dose of 1,000mg IV on day 1 of subsequent cycles.

Ibrutinib (Category 1)3

Ibrutinib 420mg orally once daily until disease progression or unacceptable toxicity.

Ofatumumab + chlorambucil4

Cycle 1

Day 1: Ofatumumab 300mg IV

Days 1–7: Chlorambucil 10mg/m2 orally

Day 8: Ofatumumab 1,000mg IV

Subsequent Cycles

Day 1: Ofatumumab 1,000mg IV

Days 1–7: Chlorambucil 10mg/m2 orally.

Repeat cycle every 28 days for a maximum of 12 cycles.

Rituximab + chlorambucil5

Cycle 1

Days 1–7: Chlorambucil 8mg/m2/day orally

Cycle 3

Day 1: Rituximab 375mg/m2 IV

Days 1–7: Chlorambucil 8mg/m2/day orally

Cycle 4–8

Day 1: Rituximab 500mg/m2 IV

Days 1–7: Chlorambucil 8mg/m2/day orally.

Repeat cycle every 28 days; administer rituximab at dose of 375mg/m2 IV every 2 months for 2 years as maintenance therapy.

Bendamustine ± rituximab10-12

Day 0: Rituximab 375mg/m2 IV

Days 1 and 2: Bendamustine 70mg/m2 IV.

Repeat cycle every 28 days for 6 cycles with rituximab given at a dose of 500mg/m2 on day 1 and bendamustine at a dose of 90mg/m2 of subsequent cycles.

Obinutuzumab (Category 2B)6

Cycle 1

Day 1: Obinutuzumab 100mg IV

Day 2: Obinutuzumab 900mg IV

Day 3: Obinutuzumab 1,000mg IV

Days 8 and 15: Obinutuzumab 2,000mg IV

Cycles 2–8

Day 1: Obinutuzumab 2,000mg IV.

Repeat cycle every 21 days.

Chlorambucil (Category 3)8,9

Days 1–28: Chlorambucil 0.4mg/kg/day with an increase to 0.8mg/kg orally daily.

Repeat cycle every 28 days for 12 cycles.

Rituximab (Category 3)7

Day 1, 8, 15, and 22: Rituximab 375mg/m2/day IV

First-line therapy for patients age <65 without significant comorbidities

Fludarabine + cyclophosphamide + rituximab (FCR)
(Category 1)
13-15a

Day 1: Rituximab 375mg/m2 IV

Days 1–3: Fludarabine 25mg/m2/day IV plus cyclophosphamide 250mg/m2/day IV.

Repeat cycle every 28 days for 6 cycles with rituximab given at a dose of 500mg/m2 on day 1 of subsequent cycles.

Fludarabine + rituximab (FR)16b

Days 1–5: Fludarabine 25mg/m2 IV

Day 1: Rituximab 50mg/m2 IV

Day 3: Rituximab 325mg/m2 IV

Day 5: Rituximab 375mg/m2 IV.

Repeat cycle every 28 days for 6 cycles with rituximab given at a dose of 375mg/m2 on day 1 of subsequent cycles.

Pentostatin + cyclophosphamide + rituximab (PCR)17

Day 1: Pentostatin 2mg/m2 IV plus cyclophosphamide 600mg/m2 IV, and rituximab 375mg/m2 IV.

Repeat cycle every 21 days for 6 cycles; administer rituximab thrice weekly at a dose of 100mg/m2 on day 1, followed by 375mg/m2 on days 3 and 5 of the first week only.

Bendamustine ± rituximab10-12

Day 1: Rituximab 375mg/m2 IV

Days 1 and 2: Bendamustine 90mg/m2 IV.

Repeat cycle every 28 days for 6 cycles with rituximab given at a dose of 500mg/m2 on day 1 of subsequent cycles.

Ibrutinib3

Ibrutinib 420mg orally once daily until disease progression or unacceptable toxicity.

CLL/SLL With del(17p)/TP53 Mutation1

First-line therapy

Alemtuzumab ± rituximab18a

Day 1: Alemtuzumab 3mg IV

Day 2: Alemtuzumab 10mg IV

Day 3, 10, 12, 17, 19, 24, and 26: Alemtuzumab 30mg IV

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

Repeat cycle once depending on response and toxicity.

High-dose methylprednisolone + rituximab19,20

Days 1–3: Methylprednisolone 1g/m2 IV

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

Repeat cycle every 28 days for 3 cycles.

Ibrutinib3

Ibrutinib 420mg orally once daily until disease progression or unacceptable toxicity.

Obinutuzumab + chlorambucil (Category 3)2

Day 1: Obinutuzumab 100mg IV and chlorambucil 0.5mg/kg orally

Day 2: Obinutuzumab 900mg IV

Day 8: Obinutuzumab 1,000mg IV

Day 15: Obinutuzumab 1,000mg IV and chlorambucil 0.5mg/kg orally.

Repeat cycle every 28 days for 6 cycles with obinutuzumab given at a dose of 1,000mg on day 1.

a Data from the CLL10 study confirm the superiority of FCR over bendamustine plus rituximab (BR) in younger patients. For patients older than 65 years, the outcome was similar for both regimens with less toxicity for BR. BR may be a reasonable alternative for older patients otherwise eligible for chemoimmunotherapy and is associated with fewer myelosuppressive toxicities.

b Not for del(11q).

c While alemtuzumab is no longer commercially available for CLL, it may be obtained for clinical use. It is less effective for bulky (>5cm) lymphadenopathy. Monitor for cytomegalovirus reactivation.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. V1.2017. Available at: http://www.nccn.org. Accessed September 29, 2016.

2. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (CIb) or rituximab plus CIb versus CIb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL (BO21004 phase III trial [abstract]. J Clin Oncol. 2013;31:Abstract 7004.

3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.

4. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): Results of the phase III study Complement 1 (OMB110911) [abstract]. Blood. 2013; 122:Abstract 528.

5. Foa R, Alietti A, Guarini A, et al. A phase II study of chlorambucil rituximab (CLB-R) followed by R maintenance vs observation in elderly patients with previously untreated chronic lymphocytic leukemia (CLL): induction phase results [abstract]. Haematologica. 2011;96:Abstract 532.

6. Flynn JM, Byrd JC, Kipps TJ, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in patients with chronic lymphocytic leukemia (CLL): results of the phase II GAGE (GAO4768g) trial [abstract]. J Clin Oncol. 2014;32(15_suppl):Abstract 7083.

7. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98(5):1326–1331.

8. 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;114:3382–3391.

9. Rai KR, Peterson BL, Applebaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–1757.

10. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30:3209–3216

11. Knauf WU, Lissitchkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378–4384.

12. Knauf WU, Lissitchkov T, Aldaoud A, et al. Bendamustine in the treatment of chronic lymphocytic leukemia–consistent superiority over chlorambucil in elderly patients and across clinically defined risk groups [abstract]. Blood. 2009;114: Abstract 2367.

13. Keating MJ O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079–4088.

14. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008; 112:975–980.

15. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomized, open-label, phase 3 trial. Lancet. 2010;376:1164–1174.

16. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101:6–14.

17. Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007;109:405–411.

18. Faderl S, Thomas DA, O'Brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003;101:3413–3415.

19. 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;23:1779–1789.

20. Thornton PD, Matutes E, Bosanquet AG, et al. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann Hematol. 2003;82:759–765.

21. Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil (R-Chlorambucil) as first-line treatment chronic lymphocytic leukemia (CLL): Final analysis of an open-label phase II study [abstract]. Ann Oncol. 2011;22:Abstract 120.

22. Raphael B, Andersen JW, Silber R, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991;9(5):770–776.

23. Foon KA, Boviadzis M, Land, SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(4):498–503.


Hematologic Cancer Drug Monographs

Leukemias, Lymphomas, And Other Hematologic Cancers

ADCETRIS ALKERAN ALKERAN FOR INJECTION
ARRANON ARZERRA BELEODAQ
BENDEKA BEXXAR BICNU
BLEOMYCIN BLINCYTO BOSULIF
BUSULFEX CAMPATH CERUBIDINE
CLADRIBINE CLOLAR CYCLOPHOSPHAMIDE
CYTARABINE CYTOXAN INJECTION DACOGEN
DARZALEX DEPOCYT DOXIL
DOXORUBICIN HCL DOXORUBICIN HCL SOLUTION DTIC-DOME
EMPLICITI ERWINAZE EVOMELA
FARYDAK FLUDARA FOLOTYN
GAZYVA GLEEVEC GLEOSTINE
HYDREA ICLUSIG IDAMYCIN
IDAMYCIN PFS IMBRUVICA INTRON A
INTRON A SOLN ISTODAX JAKAFI
KEYTRUDA KYPROLIS LEUKERAN
MARQIBO MATULANE METHOTREXATE FOR INJECTION
METHOTREXATE INJECTION MITOXANTRONE HCL MUSTARGEN
MYLERAN NINLARO ONCASPAR
ONTAK OPDIVO PAMIDRONATE DISODIUM INJECTION
PENTOSTATIN POMALYST PURINETHOL
PURIXAN REVLIMID RITUXAN
SPRYCEL SYNRIBO TABLOID
TARGRETIN TARGRETIN GEL TASIGNA
THALOMID TREANDA TREXALL
TRISENOX UVADEX VALCHLOR
VELCADE VENCLEXTA VESANOID
VIDAZA VINBLASTINE FOR INJECTION VINBLASTINE INJECTION
VINCASAR PFS VUMON ZEVALIN
ZOLINZA ZOMETA ZYDELIG

Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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