Chronic Lymphocytic Leukemia Treatment Protocols

Chronic Lymphocytic Leukemia Treatment Protocols

Treatment Protocols

Treatment protocols for chronic lymphocytic leukemia (CLL) are provided below, including general considerations, treatment for symptomatic disease, various single-agent and combination regimens, response assessment, and special considerations.

General considerations

• CLL and small lymphocytic lymphoma (SLL) are different manifestations of the same disease; SLL is diagnosed when the disease is mainly nodal, and CLL is diagnosed when the disease is seen in the blood and bone marrow
• CLL is diagnosed by > 5000 monoclonal lymphocytes/mm³ for longer than 3mo; the bone marrow usually has more than 30% monoclonal lymphocytes and is either normocellular or hypercellular
• Monoclonal B lymphocytosis is a precursor form of CLL that is defined by a monoclonal B cell lymphocytosis < 5000 monoclonal lymphocytes/mm³; all lymph nodes smaller than 1.5 cm; no anemia; and no thrombocytopenia
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Treatment recommendations for symptomatic CLL

Low risk (formerly Rai stage 0):

• Patients with no indications should be observed

Intermediate risk (formerly Rai stages I and II):

• Patients with no indications should be observed

High risk (formerly Rai stages III and IV):

• The overall survival rates for all of the recommended treatments are similar; therapies should be chosen based on the individual patient characteristics and a review of toxicities
• Fludarabine-based therapy is preferred for patients with CLL

Fludarabine-based therapy

FCR (fludarabine, cyclophosphamide, and rituximab) regimen every 28d and infectious disease (ID) prophylaxis:

Cycle 1^{[1, 2, 3, 4]} :

• Rituximab 375 mg/m² IV at 50 mg/h (adjust every 30min by 50 mg/h until goal of 400 mg/h) on day 1plus cyclophosphamide 250 mg/m² IV over 10-30min on days 1-3 plus fludarabine 25 mg/m² IV over 20-30min on days 1-3

Cycles 2-6^{[1, 2, 3, 4]} :

• Rituximab 500 mg/m² IV at 50 mg/h (adjust every 30min by 50 mg/h until goal of 400 mg/h) on day 1plus  cyclophosphamide 250 mg/m² IV over 10-30min on days 1-3 plus  fludarabine 25 mg/m² IV over 20-30min on days 1-3^[5]
• Overall response for FCR is 95%; complete response, 70%; near partial response, 10%; partial response, 15%; response duration, 69% at 4y
• 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 1wk; if the parameters remain below the threshold or there is a major infection, then 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 (fludarabine and rituximab) regimen every 28d and ID prophylaxis:

Cycle 1:

• Rituximab 375 mg/m² on days 1 and 4 plus  fludarabine 25 mg/m² IV over 20-30min on days 1-5

Cycles 2-6:

• Rituximab 375 mg/m² on day 1 plus  fludarabine 25 mg/m² IV over 20-30min on days 1-5

Pentostatin-based therapy

PCR (pentostatin, cyclophosphamide, and rituximab) regimen every 21d with growth factor support and ID prophylaxis:

Cycles 1-6:

• Rituximab 375 mg/m² IV on day 1 plus  cyclophosphamide 600 mg/m² IV over 15-60min on day 1plus pentostatin 4 mg/m² IV over 20-30min on day 1
• Overall response to PCR is 95%; complete response, 42%; near partial response, 27%; partial response, 27%; response duration, 50% at 32mo
• Hold treatment if creatinine level is > 2 mg/dL or has risen 20% over baseline; hold treatment if any grade 2-4 toxicity is present

Bendamustine-based therapy

BR (bendamustine and rituximab) regimen every 28d:

Cycle 1:

• Rituximab 375 mg/m² IV on day 1 plus bendamustine 70 mg/m² IV on days 1-2

Cycles 2-6:

• Rituximab 500 mg/m² IV on day 1 plus  bendamustine 70 mg/m² IV on days 1-2

Alemtuzumab therapy

• Alemtuzumab has been approved for CLL and has shown superior response rates when compared with chlorambucil
• Premedicate with acetaminophen and diphenhydramine; 8d after first treatment, start prophylactic antibiotics with trimethoprim/sulfamethoxazole and valacyclovir^[6]
• Alemtuzumab 3 mg IV on day 1 in 100 mL of 0.9% NaCl infused over 2h
• Alemtuzumab 10 mg IV on day 2 in 100 mL of 0.9% NaCl infused over 2h (maximum dose that can be given SC if IV access is lost)
• Alemtuzumab 30 mg IV in 100 mL of 0.9% NaCl infused over 2h on day 3 or 5; then, maintain on MWF (Monday/Wednesday/Friday) schedule as tolerated up to 12wk

Chlorambucil therapy

• Chlorambucil 40 mg/m² PO on day 1; every 28d for a maximum of 12 cycles^[6] or
• Chlorambucil 0.3 mg/kg for days 1-5; every 28d or
• Chlorambucil 0.1 mg/kg PO daily; every 28d until disease progression

Chlorambucil with obinutuzumab ^[7]

• Indicated for previously untreated CLL
• Administer for 6 treatment cycles (28-d cycles)
• Cycle 1: Obinutuzumab 100 mg IV on day 1, 900 mg on day 2, and 1000 mg IV on days 8 and 15 plus chlorambucil 0.5 mg/kg PO on days 1 and 15
• Cycles 2-6: Obinutuzumab 1000 mg IV on day 1 plus chlorambucil 0.5 mg/kg PO on days 1 and 15

Ofatumumab

• Premedicate all patients with PO acetaminophen, PO or IV antihistamine, and IV corticosteroids

Previously untreated^[8]

• Indication in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate
• Cycle 1: 300 mg IV on Day 1 followed 1 week later by 1000 mg on Day 8, then
• Subsequent 28-day cycles: 1000 mg on Day 1 for a minimum of 3 cycles until best response or a maximum of 12 cycles

Refractory to fludarabine and alemtuzumab

• Dose 1: 300 mg IV, followed 1 week later by
• Doses 2-8: 2000 mg IV qWeek for 7 doses, followed 4 weeks later by
• Doses 9-12: 2000 mg IV q4Weeks for 4 doses

Ibrutinib^{[9, 10]}

• Indicated for CLL in patients who have received at least 1 previous therapy
• 420 mg (three 140-mg capsules) PO qDay until unacceptable toxicity or disease progression

Patients ≥70y or patients who are younger with comorbidities with CLL but without 11q or 17p deletion

• BR regimen^[11] : 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 28d for up to 6 cycles or
• Chlorambucil with or without prednisone^[11] : Chlorambucil 10 mg/m²/day PO for 7d or 40 mg/m² PO every 4wk for 12 cycles or
• Cytoxan, prednisone with or without rituximab
• Reduced-dose fludarabine, cyclophosphamide, and rituximab
• Alemtuzumab^[12] : 30 mg IV over 2h; 3 times weekly on alternate days (maximum of 12wk)
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Patients < 70y or patients who are older without comorbidities with CLL and without 11q or 17p deletion

• FCR regimen^[13] : Fludarabine 25 mg/m²/day IV on days 1-3 plus  cyclophosphamide 250 mg/m²/day IV on days 1-3 plus  rituximab 375 mg/m² IV on day 1 of cycle 1 and 500 mg/m² IV on day 1 of cycles 2-6; every 4wk for 6 cycles; 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 or
• PCR regimen^[12] : Pentostatin 2 mg/m² IV on day 1 of cycles 1-6 plus  cyclophosphamide 600 mg/m² IV on day 1 of cycles 1-6 plus  rituximab 100 mg/m² IV on day 1 and 375 mg/m² IV on days 3 and 5 for cycle 1,then  375 mg/m² 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 1y plus acyclovir 800 PO BID for 1y or
• BR regimen^[11] : 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; every 28d for up to 6 courses

Treatment recommendations for CLL patients with del (17p)

• Although these patients do have a poor prognosis and there is no clear standard of care, the National Comprehensive Cancer Network (NCCN) guidelines for CLL/SLL ["CSLL-D"] recommends the fludarabine regimens as first-line treatment^[14] )
• For 11p deletion, the patients have a poorer prognosis; consider treatment with an alkylator as first-line therapy
• For isolated 13p deletion, the patients have a better prognosis
• Treat with rituximab and alemtuzumab^{[14, 15]} : Rituximab 375 mg/m² IV weekly for 4wk; first dose of rituximab 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 3 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 or
• BR regimen^[11] : 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 28d for up to 6 cycles
• 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 both have inconsistently been shown to correlate with prognosis

Treatment recommendations for CLL patients with del (11q)

Patients ≥70y or younger patients with comorbidities^[14] :

• Chlorambucil with or without prednisone (if used first line)^[11] : Chlorambucil 30 mg/m² PO on day 1 plus prednisone 80 mg PO daily on days 1-5; every 2wk or
• BR regimen^[11] : 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 28d for up to 6 cycles

Patients < 70y or patients who are older without significant comorbidities^[14] :

• FCR regimen^[13] : Fludarabine 25 mg/m²/day IV on days 1-3 plus  cyclophosphamide 250 mg/m²/day IV on days 1-3 plus  rituximab 375 mg/m² IV on day 1 of cycle 1, then  500 mg/m² IV on day 1 of cycles 2-6; every 4wk for 6 cycles; 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 or
• BR regimen^[11] : Bendamustine 70-90 mg/m² 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 28d for up to 6 cycles or
• PCR regimen: Cyclophosphamide 600 mg/m² IV over 15-60min on day 1 plus  pentostatin 4 mg/m² IV over 20-30min on day 1 for cycles 1-6; begin rituximab 375 mg/m2 IV on day 1 for cycles 2-6; every 21d with growth factor support and antibiotic prophylaxis

Special considerations for treatment

• 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 relapsed disease that occurs more than 3y later, retreat with first-line therapy; if it has been less than 2y, see the NCCN guidelines for second-line therapies based on age
• Locoregional radiation therapy is appropriate for Ann Arbor Stage I SLL patients
• In patients with localized small SLL (Ann Arbor stage I) progression 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)
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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 (spleen > 6 cm below costal margins, lymph nodes > 10 cm)
• Lymphocyte doubling time = 6mo
• Progressive anemia
• Progressive thrombocytopenia

ID and hematologic precautions:

• Consider ID prophylaxis with trimethoprim/sulfamethoxazole and acyclovir/valacyclovir for patients receiving fludarabine and patients who have a higher risk of infection (chronic steroid use, human immunodeficiency virus [HIV] infection, recurrent infections, advanced disease, or hypogammaglobulinemia)
• Alemtuzumab can lead to cytomegalovirus (CMV) reactivation; the CMV polymerase chain reaction should be monitored every 2-3wk
• Immune thrombocytopenic purpura and autoimmune hemolytic anemia can occur with the disease 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^{[16, 17, 18]} :

• All lymph nodes smaller than 1 cm; normal liver and spleen; no constitutional symptoms; leukocyte counts > 1500/mm³; normal circulating B lymphocytes; platelet levels > 100,000/mm³; hemoglobin level > 11 g/dL; normocellular bone marrow with < 30% lymphocytes; no B-lymphoid nodules

Partial response^{[16, 17, 18]} :

• Decrease in lymph nodes by 50% or more; liver and spleen sizes decreased by 50% or more; any constitutional symptoms; leukocyte counts > 1500/mm³ or > 50% improvement; circulating B lymphocytes decreased by 50% or more; platelet levels > 100,000/mm³ or > 50% increase from baseline; hemoglobin level > 2 g/dL from baseline; hypocellular bone marrow or > 30% lymphocytes or B-lymphoid nodules

Progressive disease^{[16, 17, 18]} :

• 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 levels decreased by 50% or more from baseline; hemoglobin level decreased by more than 2 g/dL from baseline; bone marrow increase in lymphocytes > 30% from normal

Stable disease^{[16, 17, 18]} :

• 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 levels change from -49% to +49%; hemoglobin level increased < 11.0 g/dL or < 50% from baseline, or hemoglobin level decreased < 2 g/dL; no change in bone marrow infiltrate