Chronic Lymphocytic Leukemia Treatment Protocols 

Updated: Jun 01, 2019
  • Author: Sandy D Kotiah, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Treatment Protocols

Treatment protocols for chronic lymphocytic leukemia (CLL) are provided below, including the following:

  • Treatment for symptomatic disease
  • Various single-agent and combination regimens
  • Special considerations for treatment
  • Response assessment

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, for images and information on CLL identification and treatment.

Treatment recommendations for symptomatic CLL

With low-risk (formerly Rai stage 0) and intermediate-risk (formerly Rai stages I and II) CLL, patients with no treatment indications should be observed. With high-risk (formerly Rai stages III and IV) CLL, the overall survival rates for all of the recommended treatments are similar, so therapies should be chosen based on the individual patient characteristics and a review of toxicities. Fludarabine-based therapy is preferred.

Fludarabine-based therapy

Fludarabine-containing regimens include FCR (fludarabine, cyclophosphamide, and rituximab) and FR (fludarabine and rituximab). Both regimens are given every 28 d, along with infectious disease (ID) prophylaxis.

FCR

Cycle 1 of FCR consists of the following [1, 2, 3, 4] :

  • Rituximab 375 mg/m 2 IV at 50 mg/h (increase by 50 mg/h every 30 min until target rate of 400 mg/h is reached) on day 1 plus
  • Cyclophosphamide 250 mg/m 2 IV over 10-30 min on days 1-3 plus
  • Fludarabine 25 mg/m 2 IV over 20-30 min on days 1-3

FCR cycles 2-6 differ from cycle 1 only in that the rituximab dose is increased from 375 mg/m2 to 500 mg/m2; thus, the regimen is as follows [1, 2, 3, 4] :

  • Rituximab 500 mg/m 2 IV at 50 mg/h (increase by 50 mg/h every 30 min until target rate of 400 mg/h is reached) on day 1 plus
  • Cyclophosphamide 250 mg/m 2 IV over 10-30 min on days 1-3 plus
  • Fludarabine 25 mg/m 2 IV over 20-30 min on days 1-3 [5]

Responses to FCR are as follows:

  • Overall response - 95%
  • Complete response - 70%
  • Near-partial response - 10%
  • Partial response - 15%
  • Response duration - 69% at 4 y

Considerations for treatment modification include the following:

  • If the absolute neutrophil count (ANC) is < 1000/mm3 (see the Absolute Neutrophil Count calculator) and/or the platelet levels are < 80,000/mm3 after cycle 1, delay dose by 1 wk

  • If the parameters remain below the threshold or a major infection develops, reduce fludarabine to 20 mg/m2 and cyclophosphamide to 200 mg/m2

  • If further dose reduction is required, fludarabine can be reduced to 15 mg/m2 and cyclophosphamide can be reduced to 150 mg/m2

FR

Cycle 1 of FR consists of the following:

  • Rituximab 375 mg/m 2 on days 1 and 4 plus
  • Fludarabine 25 mg/m 2 IV over 20-30 min on days 1-5

Cycles 2-6 of FR consist of the following::

  • Rituximab 375 mg/m 2 on day 1 plus
  • Fludarabine 25 mg/m 2 IV over 20-30 min on days 1-5

Pentostatin-based therapy

The PCR (pentostatin, cyclophosphamide, and rituximab) regimen is given every 21 d with growth factor support and ID prophylaxis. Cycles 1-6 consist of the following:

  • Rituximab 375 mg/m 2 IV on day 1 plus
  • Cyclophosphamide 600 mg/m 2 IV over 15-60 min on day 1 plus
  • Pentostatin 4 mg/m 2 IV over 20-30 min on day 1

Responses to PCR are as follows:

  • Overall response - 95%
  • Complete response - 42%
  • Near-partial response - 27%
  • Partial response - 27%
  • Response duration - 50% at 32 mo

Indications for holding treatment with PCR are as follows:

  • Creatinine level is > 2 mg/dL or has risen 20% over baseline
  • Any grade 2-4 toxicity develops

Bendamustine-based therapy

The BR (bendamustine and rituximab) regimen is given every 28 d. Cycle 1 consists of the following:

  • Rituximab 375 mg/m 2 IV on day 1 plus
  • Bendamustine 70 mg/m 2 IV on days 1-2

Cycles 2-6 consist of the following:

  • Rituximab 500 mg/m 2 IV on day 1 plus
  • Bendamustine 70 mg/m 2 IV on days 1-2

Alemtuzumab therapy

Alemtuzumab (Campath) has been approved for use in CLL and has shown superior response rates compared with chlorambucil. However, Campath is no longer commercially available. It can only be obtained, for certain patients with CLL, through a limited-distribution access program.

Premedicate with acetaminophen and diphenhydramine; 8 d after first treatment, start ID prophylaxis with trimethoprim/sulfamethoxazole and valacyclovir [6] The alemtuzumab regimen is as follows:

  • Day 1 - Alemtuzumab 3 mg IV in 100 mL of 0.9% NaCl infused over 2 h
  • Day 2 - Alemtuzumab 10 mg IV in 100 mL of 0.9% NaCl infused over 2 h (maximum dose that can be given SC if IV access is lost)
  • Day 3 or 5 - Alemtuzumab 30 mg IV in 100 mL of 0.9% NaCl infused over 2h
  • Maintenance - MWF (Monday/Wednesday/Friday) schedule as tolerated for up to 12 wk

Chlorambucil therapy

Chlorambucil regimens are as follows:

  • 40 mg/m 2 PO on day 1; every 28 d for a maximum of 12 cycles [6]   or
  • 0.3 mg/kg for days 1-5; every 28 d or
  • 0.1 mg/kg PO daily; every 28 d until disease progression

Chlorambucil with obinutuzumab [7] is indicated for previously untreated CLL. Administer for six treatment cycles (28-d cycles).

Cycle 1 consists of the following:

  • Day 1 - Obinutuzumab 100 mg IV plus chlorambucil 0.5 mg/kg PO
  • Day 2 - Obinutuzumab 900 mg IV
  • Day 8 - Obinutuzumab 1000 mg IV
  • Day 15 - Obinutuzumab 1000 mg IV plus chlorambucil 0.5 mg/kg PO

Cycles 2-6 consist of the following:

  • Day 1 - Obinutuzumab 1000 mg IV plus chlorambucil 0.5 mg/kg PO
  • Day 15 - Chlorambucil 0.5 mg/kg PO

Ofatumumab therapy

Ofatumumab is indicated for use in combination with chlorambucil for the treatment of previously untreated CLL, in patients for whom fludarabine-based therapy is considered inappropriate [8] ; it is also indicated for use in CLL refractory to fludarabine and alemtuzumab. Premedicate all patients with PO acetaminophen, PO or IV antihistamine, and IV corticosteroids.

In previously untreated patients, cycle 1 consists of ofatumumab: 300 mg IV on day 1 followed by 1000 mg on day 8. Subsequent 28-day cycles consist of 1000 mg on day 1 for a minimum of three cycles until best response, or a maximum of 12 cycles.

Treatment with ofatumumab may be extended as a single agent for patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL. For this situation, the regimen is 300 mg IV on Day 1, followed 1 week later by 1,000 mg IV on Day 8, and then 7 weeks later by 1,000 mg IV q8wk up to a maximum of 2 years. [9]

In patients with CLL refractory to fludarabine and alemtuzumab, the ofatumumab regimen is as follows:

  • Dose 1: 300 mg IV, followed 1 week later by
  • Doses 2-8: 2000 mg IV q wk for seven doses, followed 4 weeks later by
  • Doses 9-12: 2000 mg IV q 4 wk for four doses

Ibrutinib therapy

Ibrutinib is an oral inhibitor of Bruton's tyrosine kinase that is indicated for CLL in patients who are treatment-naïve or have been previously treated. [10, 11, 12]  It is also indicated for patients who carry a deletion in chromosome 17 (del 17p CLL), which is associated with poor responses to standard treatment. [13]  The dosage is 420 mg (three 140-mg capsules) PO daily until unacceptable toxicity or disease progression occurs.

Idelalisib therapy

Idelalisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor indicated for use in combination with rituximab for treatment of relapsed CLL. [14] The starting dose is 150 mg PO BID; dosage adjustments are often needed if toxicities occur.

Duvelisib therapy

Duvelisib inhibits PI3K-delta and PI3K-gamma and is indicated for relapsed CLL after at least 2 prior systemic therapies. [15]  Initial dose is 25 mg PO BID; modify dosage for toxicity.

Lenalidomide therapy

Lenalidomide is a thalidomide analog with immunomodulatory and antiangiogenic properties. Lenalidomide, with or without rituximab, is recommended for refractory or relapsed CLL. [16] In a phase 2 study by the CLL Research Consortium, lenalidomide plus rituximab also demonstrated benefit in the initial treatment of CLL. [17] The regimen is as follows:

  • Lenalidomide, 10 mg PO daily (initiated at 2.5 mg/day and escalated as tolerated in treatment-naive patients), for 21 days/cycle; subsequently, maintenance lenalidomide may be continued indefinitely plus
  • Aspirin, 81 mg daily, throughout lenalidomide therapy plus
  • Rituximab, 375 mg/m 2 IV weekly for cycles 1 and 2 and then monthly for cycles 3-12

Treatment for patients ≥65 y or patients who are younger with comorbidities but without 11q or 17p deletion

Treatment options include any of the following:

  • Ibrutinib 420 mg once daily until disease progression 
  • BR regimen [18] : Bendamustine 70-90 mg/m² on days 1-2 plus  rituximab 375 mg/m² on day 1 for cycle 1, then 500 mg/m² on day 1 for cycles 2-6; every 28 d for up to six cycles 

  • Chlorambucil with or without prednisone [18] : Chlorambucil 10 mg/m2/day PO for 7d or 40 mg/m2 PO every 4wk for 12 cycles 

  • Cyclophosphamide and prednisone, with or without rituximab

  • Reduced-dose FCR

  • Alemtuzumab [19] : 30 mg IV over 2 h; three times weekly on alternate days, for a maximum of 12 wk

Treatment for patients < 65 y or patients who are older without comorbidities and without 11q or 17p deletion

Treatment options include any of the following:

  • FCR
  • PCR
  • BR
  • Ibrutinib 420 mg once daily until unacceptable toxicity
  • Venetoclax
  • Venetoclax with obinutuzumab
  • Venetoclax with rituximab

FCR

The FCR regimen is given every 4 wk for six cycles, as follows [20] :

  • Fludarabine 25 mg/m 2/day IV on days 1-3 plus
  • Cyclophosphamide 250 mg/m 2/day IV on days 1-3 plus
  • Rituximab 375 mg/m 2 IV on day 1 of cycle 1 and 500 mg/m 2 IV on day 1 of cycles 2-6; plus
  • Allopurinol 300 mg PO daily on days 1-7 for cycle 1 plus
  • Trimethoprim/sulfamethoxazole DS 1 PO BID three times weekly plus
  • Valacyclovir 500 mg PO daily

PCR

The PCR regimen is given for six cycles, as follows [19] :

  • Pentostatin 2 mg/m 2 IV on day 1 of cycles 1-6 plus
  • Cyclophosphamide 600 mg/m 2 IV on day 1 of cycles 1-6 plus
  • Rituximab 100 mg/m 2 IV on day 1 and 375 mg/m 2 IV on days 3 and 5 for cycle 1, then  375 mg/m 2 IV on day 1 for cycles 2-6; every 3wk for 6 cycles; plus
  • Allopurinol 300 mg PO daily on days 1-15 of cycle 1 plus
  • Filgrastim support plus  trimethoprim/sulfamethoxazole DS 1 PO BID 3 times weekly for 1 y plus  acyclovir 800 PO BID for 1 y

BR

The BR regimen is given every 28 d for up to six cycles, as follows [18] :

  • Bendamustine 90 mg/m² IV on days 1-2 plus
  • Rituximab 375 mg/m² IV for the first cycle and 500 mg/m² IV for subsequent cycles

Venetoclax

Initiate venetoclax with a weekly ramp-up schedule starting at 20 mg PO once daily and increasing to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily; continue until disease progression or unacceptable toxicity.

Prophylaxis and monitoring for tumor lysis syndrome, based on tumor burden, is required during the 5-week ramp-up phase; dosing modification is indicated if tumor lysis syndrome or other severe toxicity develops. [21]

Venetoclax with obinutuzumab

The venetoclax with obinutuzumab regimen is given every 28 days for up to 21 cycles. [21]  

Cycle 1 consists of the following:

  • Day 1: Obinutuzumab 100 mg IV
  • Day 2: Obinutuzumab 900 mg IV
  • Days 8 and 15: Obinutuzumab 1000 mg IV
  • Day 22: Start venetoclax according to 5-week ramp-up schedule

Cycle 2 consists of the following:

  • Day 1: Obinutuzumab 1000 mg IV
  • After completing the venetoclax ramp-up phase on Day 28 of Cycle 2, continue venetoclax 400 mg qDay from Cycle 3 Day 1 until Cycle 12 Day 28

Cycles 3-6 consist of the following:

  • Day 1: Obinutuzumab 1000 mg IV plus
  • Days 1-28: Venetoclax 400 mg PO qDay

Cycles 7-12 consist of the following:

  • Days 1-28: Continue venetoclax 400 mg PO qDay

Venetoclax with rituximab 

Venetoclax with rituximab is given every 28 days for up to six cycles, as follows: [21]

  • Venetoclax: Complete 5-week ramp-up dosing to reach 400 mg PO qDay; continue at that dose for 24 months from Cycle 1 Day 1 of rituximab
  • Rituximab: Initiate 375 mg/m² IV after patient has received venetoclax 400 mg/day x 7 days (ie, this will be Day 1 of Cycle 1); followed by 500 mg/m² IV on Day 1 for Cycles 2-6

Treatment recommendations for patients with del (17p)

Although these patients have a poor prognosis and there is no clear standard of care, the National Comprehensive Cancer Network (NCCN) guidelines list the following as preferred regimens for first-line treatment [16] :

  • Ibrutinib [13]
  • Venetoclax with obinutuzumab (see above)

Other recommended regimens are as follows:

  • Alemtuzumab with or without rituximab
  • High-dose methylprednisolone (HDMP) plus rituximab
  • Obinutuzumab

Rituximab and alemtuzumab

The regimen is as follows [16, 22] :

  • Rituximab 375 mg/m2 IV weekly for 4 wk; first dose of rituximab is divided into 100 mg/m2 IV given on day 1 and 275 mg/m2 IV given on day 2 plus

  • Alemtuzumab at an IV loading-dose schedule of 3 mg, 10 mg, and 30 mg on three consecutive days during week 1, followed by a dose of 30 mg IV on days 3 and 5 of weeks 2-4

  • Patients could receive a second 28-d cycle, depending on response and toxicities

Patients with 17p deletion who have received at least 1 prior therapy

  • Alemtuzumab with or without rituximab
  • HDMP plus rituximab
  • Obinutuzumab

Prognostic considerations are as follows:

  • Patients with 11p deletion have a poorer prognosis; consider treatment with an alkylator as first-line therapy.
  • Patients with isolated 13p deletion have a better prognosis.
  • Patients with mutated immunoglobulin variable heavy chain (IgVH) disease have a better prognosis than those with unmutated IgVH disease. Generally, ZAP 70 (< 20%) and/or CD38 (< 30%) expression is unfavorable, but correlation with prognosis has been inconsistent with both markhave inconsistently been shown to correlate with prognosis.

Treatment recommendations for CLL patients with del (11q)

Patients ≥65 y or younger patients with comorbidities [16]

Treatment options in these patients are as follows:

  • Chlorambucil with or without prednisone (if used first line) [18] : Chlorambucil 30 mg/m2 PO on day 1 plus  prednisone 80 mg PO daily on days 1-5; every 2 wk or

  • BR regimen [18] : Bendamustine 70-90 mg/m2 IV on days 1-2 plus  rituximab 375 mg/m2 IV on day 1 for cycle 1, then  500 mg/m2 IV on day 1 for cycles 1-6; every 28 d for up to six cycles

Patients < 65 y or older patients without significant comorbidities [16]

These patients may be treated with an FCR, BR, or PCR regimen.

The FCR regimen is given every 4 wk for six cycles and consists of the following [20] :

  • Fludarabine 25 mg/m 2/day IV on days 1-3 plus
  • Cyclophosphamide 250 mg/m 2/day IV on days 1-3 plus
  • Rituximab 375 mg/m 2 IV on day 1 of cycle 1, then  500 mg/m 2 IV on day 1 of cycles 2-6; plus
  • Allopurinol 300 mg PO daily on days 1-7 for cycle 1 plus
  • Trimethoprim/sulfamethoxazole DS 1 PO BID 3 times weekly plus
  • Valacyclovir 500 mg PO daily

The BR regimen is given every 28 d for up to six cycles and consists of the following [18] :

  • Bendamustine 70-90 mg/m 2 on days 1-2 plus
  • Rituximab 375 mg/m 2 IV on day 1 for cycle 1, then  500 mg/m 2 IV on day 1 for cycles 2-6

The PCR regimen is given every 21 d, with growth factor support and antibiotic prophylaxis, for six cycles, as follows:

  • Cyclophosphamide 600 mg/m 2 IV over 15-60 min on day 1 plus
  • 2 IV over 20-30 min on day 1 for cycles 1-6
  • Rituximab 375 mg/m2 IV on day 1 for cycles 2-6

Special considerations for treatment

These are as follows:

  • Start tumor lysis prophylaxis for patients with high burden of disease
  • Treatment differs based on age and cytogenetics
  • Consider allogeneic stem cell transplantation for curative intent if patients have a good response to initial therapy; these patients should be referred for a clinical trial, as the optimal timing and type of transplant is still being determined
  • For relapse of disease that occurs more than 3 y later, re-treat with first-line therapy; if relapse occurs after less than 2 y, see the NCCN guidelines for second-line therapies based on age and comorbidities [16]
  • Locoregional radiation therapy is appropriate for patients with Ann Arbor stage I small lymphocytic lymphoma (SLL; ie, CLL largely limited to lymph nodes)
  • In patients with localized SLL (Ann Arbor stage I) that progresses after initial radiation therapy or patients with advanced disease (Ann Arbor stages II-IV) with del (17p), treatment is based on the presence or absence of certain indications (see below)

The presence of any of the following indications in patients with localized SLL or advanced disease with del (17p) should lead to treatment with chemotherapy or chemoimmunotherapy; if none are present, observation until disease progression is recommended:

  • Significant disease-related symptoms (night sweats, fatigue, weight loss, or fever)
  • Threatened end-organ function
  • Progressive bulky disease (splenomegaly to >6 cm below costal margins, lymph nodes >10 cm)
  • Lymphocyte doubling time of 6 mo
  • Progressive anemia
  • Progressive thrombocytopenia

Infectious disease and hematologic precautions

Consider ID prophylaxis with trimethoprim/sulfamethoxazole and acyclovir/valacyclovir for patients receiving idelalisib, fludarabine, or alemtuzumab, and for patients who have a higher risk of infection. Risk factors include the following:

  • Long-term steroid use
  • Human immunodeficiency virus (HIV) infection
  • Recurrent infections
  • Advanced disease
  • Hypogammaglobulinemia

Idelalisib, fludarabine, or alemtuzumab can lead to cytomegalovirus (CMV) reactivation. Patients receiving this agent should be monitored with CMV polymerase chain reaction (PCR) testing every 2-3 wk.

Prophylactic treatment with entecavir is recommended for all patients who have a positive hepatitis B surface antigen assay. In patients with active disease (PCR positive), entecavir is considered therapeutic rather than prophylactic. [16]

Immune thrombocytopenic purpura and autoimmune hemolytic anemia can occur with CLL and should be treated with immunosuppression (steroids, rituximab, intravenous immunoglobulin [IVIG], or chemotherapy if refractory). Autoimmune hemolytic anemia can also occur as an adverse effect of fludarabine.

Response assessment

Complete response is defined as follows [23, 24, 25] :

  • All lymph nodes smaller than 1 cm
  • Normal liver and spleen
  • No constitutional symptoms
  • Leukocyte counts >1500/mm 3
  • Normal circulating B lymphocytes
  • Platelet counts >100,000/mm 3
  • Hemoglobin level >11 g/dL
  • Normocellular bone marrow with < 30% lymphocytes and no B-lymphoid nodules

Partial response is defined as follows [23, 24, 25] :

  • Decrease in lymph nodes by 50% or more
  • Liver and spleen sizes decreased by 50% or more
  • Any constitutional symptoms
  • Leukocyte counts >1500/mm 3 or >50% improvement
  • Circulating B lymphocytes decreased by 50% or more
  • Platelet counts >100,000/mm 3 or >50% increase from baseline
  • Hemoglobin level >2 g/dL from baseline
  • Hypocellular bone marrow or >30% lymphocytes or B-lymphoid nodules

Progressive disease is defined as follows [23, 24, 25] :

  • Increase in lymph nodes by 50% or more
  • Increase in liver and spleen sizes by 50% or more
  • Any constitutional symptoms
  • Any leukocyte count
  • Circulating B lymphocytes increased by 50% or more
  • Platelet counts decreased by 50% or more from baseline
  • Hemoglobin level decreased by more than 2 g/dL from baseline
  • Bone marrow lymphocytes increased >30% above normal

Stable disease is defined as follows [23, 24, 25] :

  • Lymph nodes change from -49% to +49%
  • Liver and spleen sizes change from -49% to +49%
  • Any constitutional symptoms
  • Any leukocyte count
  • Circulating B lymphocyte counts change from -49% to +49%
  • Platelet counts change from -49% to +49%
  • Hemoglobin level increased to < 11.0 g/dL or < 50% from baseline, or decreased < 2 g/dL
  • No change in bone marrow infiltrate