Chronic lymphocytic leukemia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]
Overview
The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy. Asymptomatic chronic lymphocytic leukemia patients are managed with observation and follow-up, whereas symptomatic chronic lymphocytic leukemia patients are treated with immunochemotherapy. Immunochemotherapies used for the treatment of chronic lymphocytic leukemia patients include purine analogues, alkylating agents, monoclonal antibodies, corticosteroids, tyrosine kinase inhibitors, and B-cell receptor pathway inhibitors. Radiation therapy is not recommended for the management of chronic lymphocytic leukemia patients.
Immunochemotherapy
- The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy.
- Asymptomatic chronic lymphocytic leukemia patients are managed with observation and follow-up, whereas symptomatic chronic lymphocytic leukemia patients are treated with immunochemotherapy.[1]
- Indications to initiate immunochemotherapy among patients with chronic lymphocytic leukemia include:[2]
- Symptomatic chronic lymphocytic leukemia patients presenting with:
- Fever of unknown origin (>38.1°C for a period greater than two weeks)
- Night sweats for ≥ one month
- Unintentional significant weight loss (≥10%) over a period of six months
- Patients presenting with thrombocytopenia or anemia due to bone marrow failure
- Patients presenting with refractory autoimmune hemolytic anemia or refractory autoimmune thrombocytopenia
- Evidence of symptomatic splenomegaly, with the spleen being palpated ≥ 6cm below the costal margin
- Evidence of symptomatic progressive lymph nodes swelling, with a size ≥10 cm in diameter
- Evidence of a rapidly progressive lymphocytosis, which might be observed as:
- An increase of greater than 50% over a 2-month period
- A lymphocyte doubling in a period shorter than six months
- Immunochemotherapeutic agents used for the treatment of chronic lymphocytic leukemia patients include:[3][4][5][6][7][8][9]
- Purine analogues such as:
- Alkylating agents such as:
- Monoclonal antibodies such as:
- Immunomodulatory agents such as:
- Corticosteroids such as:
- Tyrosine kinase and B-Cell receptor pathway inhibitors such as:
- Idelalisib (targets phosphoinositide 3-kinase delta)
- Ibrutinib (targets bruton tyrosine kinase)
- The optimal immunochemotherapeutic regimen used for the management of chronic lymphocytic leukemia patients depends on a number of factors which include:
- The clinical presentation of the patients
- The performance status of the patients
- The stage of the tumor
- The presence of specific genetic mutations
- First line therapy vs. refractory/relapsed therapy
- The algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:
Initial patients evaluation | |||||||||||||||||||||||||||
History Physical examination Complete blood count | |||||||||||||||||||||||||||
Staging | |||||||||||||||||||||||||||
Rai Staging System Binet Staging System | |||||||||||||||||||||||||||
Rai stage 0-2 Binet stage A | Rai stage 3-4 Binet stage B-C | ||||||||||||||||||||||||||
Patients managed by observation and close follow-up | Evaluate patients by Cumulative Index Illness Rating Scale | ||||||||||||||||||||||||||
Fit patients (CIRS <6) | Frail patients (CIRS ≥6) | ||||||||||||||||||||||||||
FISH chromosomal analysis | |||||||||||||||||||||||||||
Immunochemotherapeutic regimens for the management of patients without chromosome 17p deletion or chromosome 11q deletion can be found here | Immunochemotherapeutic regimens for the management of patients with chromosome 17p deletion can be found here | Immunochemotherapeutic regimens for the management of patients with chromosome 11q deletion can be found here | |||||||||||||||||||||||||
Immunochemotherapeutic Regimens for the Management of Patients without Chromosome 17p Deletion or Chromosome 11q Deletion
First Line Therapy
- Preferred immunochemotheraptic regimens for the treatment of such patients who are older than 70 years of age (or younger than 70 years of age with a poor performance status) include (in order of preference):[10]
- Obinutuzumab AND chlorambucil
- Ofatumumab AND chlorambucil
- Rituximab AND chlorambucil
- Bendamustine ± rituximab
- Obinutuzumab
- Fludarabine ± rituximab
- Chlorambucil
- Rituximab
- Cladribine
- Preferred immunochemotheraptic regimens for the treatment of such patients who are younger than 70 years of age with a good performance status include (in order of preference):[11]
- Fludarabine AND cyclophosphamide AND rituximab
- Fludarabine AND rituximab
- Pentostatin AND cyclophosphamide AND rituximab
- Bendamustine AND rituximab
Refractory/Relapsed Therapy
- Preferred immunochemotheraptic regimens for the treatment of such patients who are older than 70 years of age (or younger than 70 years of age with a poor performance status) include (in order of preference):[12][13][14]
- Ibrutinib
- Idelalisib ± rituximab
- Fludarabine AND cyclophosphamide AND rituximab (reduced dose)
- Pentostatin AND cyclophosphamide AND rituximab (reduced dose)
- Bendamustine ± rituximab
- High-dose methylprednisolone AND rituximab
- Ofatumumab
- Obinutuzumab
- Lenalidomide ± rituximab
- Alemtuzumab ± rituximab
- Dose-dense rituximab
- Preferred immunochemotheraptic regimens for the treatment of such patients who are younger than 70 years of age with a good performance status include (in order of preference):[15][16]
- Ibrutinib
- Idelalisib ± rituximab
- Fludarabine AND cyclophosphamide AND rituximab
- Pentostatin AND cyclophosphamide AND rituximab
- Bendamustine ± rituximab
- Fludarabine AND alemtuzumab
- Rituximab AND cyclophosphamide AND doxorubicin AND vincristine AND cytarabine
- Oxaliplatin AND fludarabine AND cytarabine AND rituximab
- Ofatumumab
- Obinutuzumab
- Lenalidomide ± rituximab
- Alemtuzumab ± rituximab
- High-dose methylprednisolone AND rituximab
Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 17p Deletion
First Line Therapy
- Preferred immunochemotheraptic regimens for the treatment of such patients regardless the age group include (in order of preference):[17][18][19][20][21]
- Ibrutinib
- High-dose methylprednisolone AND rituximab
- Fludarabine AND rituximab
- Fludarabine AND cyclophosphamide AND rituximab
- Obinutuzumab AND chlorambucil
- Alemtuzumab ± rituximab
- Rituximab AND chlorambucil
- Venetoclax AND rituximab
Refractory/Relapsed Therapy
- Preferred immunochemotheraptic regimens for the treatment of such patients regardless the age group include (in order of preference):
- Ibrutinib
- Idelalisib ± rituximab
- High-dose methylprednisolone AND rituximab
- Lenalidomide ± rituximab
- Ofatumumab
- Oxaliplatin AND fludarabine AND cytarabine AND rituximab
Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 11q Deletion
First Line Therapy
- Preferred immunochemotheraptic regimens for the treatment of such patients who are older than 70 years of age (or younger than 70 years of age with a poor performance status) include (in order of preference):
- Obinutuzumab AND chlorambucil
- Ofatumumab AND chlorambucil
- Rituximab AND chlorambucil
- Bendamustine ± rituximab
- Cyclophosphamide AND prednisone ± rituximab
- Fludarabine AND cyclophosphamide AND rituximab (reduced dose)
- Rituximab
- Preferred immunochemotheraptic regimens for the treatment of such patients who are younger than 70 years of age with a good performance status include (in order of preference):[22]
- Fludarabine AND cyclophosphamide AND rituximab
- Bendamustine ± rituximab
- Pentostatin AND cyclophosphamide AND rituximab
- Obinutuzumab AND chlorambucil
Supportive Therapy
Opportunistic Infections Prophylaxis
- Vaccines recommended for chronic lymphocytic leukemia patients include:
- Pneumococcal vaccine administered every five years
- Influenza vaccine administered annually
- Live attenuated vaccines should be avoided among chronic lymphocytic leukemia patients.
- Other strategies for the prevention of opportunistic infections include:
- Sulfamethoxazole/trimethoprim can be administered to patients receiving purine analogues as a prophylaxis for pneumocystis pneumonia infection.
- Acyclovir can be administered to patients receiving purine analogues as a prophylaxis for herpes simplex virus infection.
Autoimmune Cytopenia Prophylaxis
- Corticosteroids is recommended for the management of autoimmune cytopenia among chronic lymphocytic leukemia patients. Other therapeutic measures may include:
- Romiplostim is recommended for the management of autoimmune thrombocytopenia among chronic lymphocytic leukemia patients.
Thromboprophylaxis
- A daily aspirin dose is recommended among chronic lymphocytic leukemia patients who receive lenalidomide while their platelet count is greater than 50000 per microliter.
- However, aspirin administration is not needed for such chronic lymphocytic leukemia patients who are already on warfarin.
Radiation Therapy
- Radiation therapy is not recommended for the management of chronic lymphocytic leukemia patients.
References
- ↑ "Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group". J. Natl. Cancer Inst. 91 (10): 861–8. May 1999. PMID 10340906.
- ↑ Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O'Brien S, Robak T, Seymour JF, Kipps TJ (June 2018). "iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL". Blood. 131 (25): 2745–2760. doi:10.1182/blood-2017-09-806398. PMID 29540348.
- ↑ Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S (October 2010). "Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial". Lancet. 376 (9747): 1164–74. doi:10.1016/S0140-6736(10)61381-5. PMID 20888994.
- ↑ Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ (January 2016). "Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia". Blood. 127 (3): 303–9. doi:10.1182/blood-2015-09-667675. PMC 4760129. PMID 26492934.
- ↑ Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N (November 2012). "Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia". Cochrane Database Syst Rev. 11: CD008079. doi:10.1002/14651858.CD008079.pub2. PMID 23152253.
- ↑ Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, Appelbaum FR, Tallman MS, Belch AR, Morrison VA, Larson RA, Byrd JC (February 2013). "Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies". J. Clin. Oncol. 31 (4): 440–7. doi:10.1200/JCO.2011.41.5646. PMC 3731920. PMID 23233702.
- ↑ Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA (January 2003). "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. 101 (1): 6–14. doi:10.1182/blood-2002-04-1258. PMID 12393429.
- ↑ Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC (May 2004). "Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions". Blood. 103 (9): 3278–81. doi:10.1182/blood-2003-10-3729. PMID 14726385.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.
- ↑ Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH (May 2014). "Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL". Blood. 123 (21): 3255–62. doi:10.1182/blood-2014-01-547737. PMID 24735962.
- ↑ Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC (May 2004). "Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions". Blood. 103 (9): 3278–81. doi:10.1182/blood-2003-10-3729. PMID 14726385.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.
- ↑ Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH (May 2014). "Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL". Blood. 123 (21): 3255–62. doi:10.1182/blood-2014-01-547737. PMID 24735962.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.
- ↑ Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S (September 2014). "Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study". Lancet Oncol. 15 (10): 1090–9. doi:10.1016/S1470-2045(14)70335-3. PMID 25150798.
- ↑ Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, Bühler A, Böttcher S, Ritgen M, Kneba M, Winkler D, Tausch E, Hoth P, Edelmann J, Mertens D, Bullinger L, Bergmann M, Kless S, Mack S, Jäger U, Patten N, Wu L, Wenger MK, Fingerle-Rowson G, Lichter P, Cazzola M, Wendtner CM, Fink AM, Fischer K, Busch R, Hallek M, Döhner H (May 2014). "Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial". Blood. 123 (21): 3247–54. doi:10.1182/blood-2014-01-546150. PMID 24652989.
- ↑ Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P (May 2012). "Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial". J. Clin. Oncol. 30 (14): 1647–55. doi:10.1200/JCO.2011.35.9695. PMID 22493413.
- ↑ Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH (May 2014). "Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL". Blood. 123 (21): 3255–62. doi:10.1182/blood-2014-01-547737. PMID 24735962.
- ↑ Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC (May 2004). "Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions". Blood. 103 (9): 3278–81. doi:10.1182/blood-2003-10-3729. PMID 14726385.
- ↑ Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF (August 2006). "The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders". Cancer. 107 (4): 773–80. doi:10.1002/cncr.22022. PMID 16847886.