Treatment protocols for chronic lymphocytic leukemia (CLL) are provided below, including the following:
See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, for images and information on CLL identification and treatment.
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-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] :
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] :
Responses to FCR are as follows:
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:
Cycles 2-6 of FR consist of the following::
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:
Responses to PCR are as follows:
Indications for holding treatment with PCR are as follows:
The BR (bendamustine and rituximab) regimen is given every 28 d. Cycle 1 consists of the following:
Cycles 2-6 consist of the following:
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:
Chlorambucil regimens are as follows:
Chlorambucil with obinutuzumab[7] is indicated for previously untreated CLL. Administer for six treatment cycles (28-d cycles).
Cycle 1 consists of the following:
Cycles 2-6 consist of the following:
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:
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, 13] 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.[14] The dosage is 420 mg (three 140-mg capsules) PO daily until unacceptable toxicity or disease progression occurs.
Idelalisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor indicated for use in combination with rituximab for treatment of relapsed CLL.[15] The starting dose is 150 mg PO BID; dosage adjustments are often needed if toxicities occur.
Duvelisib inhibits PI3K-delta and PI3K-gamma and is indicated for relapsed CLL after at least 2 prior systemic therapies.[16] Initial dose is 25 mg PO BID; modify dosage for toxicity.
Lenalidomide is a thalidomide analog with immunomodulatory and antiangiogenic properties. Lenalidomide, with or without rituximab, is recommended for refractory or relapsed CLL.[17] In a phase 2 study by the CLL Research Consortium, lenalidomide plus rituximab also demonstrated benefit in the initial treatment of CLL.[18] The regimen is as follows:
Treatment options include any of the following:
BR regimen[19] : 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[19] : 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[20] : 30 mg IV over 2 h; three times weekly on alternate days, for a maximum of 12 wk
Treatment options include any of the following:
FCR
The FCR regimen is given every 4 wk for six cycles, as follows[21] :
PCR
The PCR regimen is given for six cycles, as follows[20] :
BR
The BR regimen is given every 28 d for up to six cycles, as follows[19] :
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.[22]
Venetoclax with obinutuzumab
The venetoclax with obinutuzumab regimen is given every 28 days for up to 21 cycles.[22]
Cycle 1 consists of the following:
Cycle 2 consists of the following:
Cycles 3-6 consist of the following:
Cycles 7-12 consist of the following:
Venetoclax with rituximab
Venetoclax with rituximab is given every 28 days for up to six cycles, as follows:[22]
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[17] :
Other recommended regimens are as follows:
Rituximab and alemtuzumab
The regimen is as follows[17, 23] :
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
Prognostic considerations are as follows:
Patients ≥65 y or younger patients with comorbidities[17]
Treatment options in these patients are as follows:
Chlorambucil with or without prednisone (if used first line)[19] : Chlorambucil 30 mg/m2 PO on day 1 plus prednisone 80 mg PO daily on days 1-5; every 2 wk or
BR regimen[19] : 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[17]
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[21] :
The BR regimen is given every 28 d for up to six cycles and consists of the following[19] :
The PCR regimen is given every 21 d, with growth factor support and antibiotic prophylaxis, for six cycles, as follows:
These are as follows:
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:
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:
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.[17]
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.
Complete response is defined as follows[24, 25, 26] :
Partial response is defined as follows[24, 25, 26] :
Progressive disease is defined as follows[24, 25, 26] :
Stable disease is defined as follows[24, 25, 26] :