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
  • An increase of greater than 50% over a 2-month period
  • A lymphocyte doubling in a period shorter than six months
  • 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 algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:[12][13][14]


 
 
 
 
 
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
 

Obinutuzumab AND chlorambucil
Ofatumumab AND chlorambucil

Rituximab AND chlorambucil
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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):[15][16][17][18]
  • 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):[19][20][21][22][23]

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):[24][25][26]
  • 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):[27][28][29]

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):[30][31][32][33][34]

Refractory/Relapsed Therapy

  • Preferred immunochemotheraptic regimens for the treatment of such patients regardless the age group include (in order of preference):

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):[35]
  • 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):[36][37]

Allogeneic stem cell transplantation

  • Allogeneic stem cell transplantation (alloSCT) is the only potentially curative end stage treatment option in chronic lymphocytic leukemia patients.[38]

Supportive Therapy

Opportunistic Infections Prophylaxis

  • Vaccines recommended for chronic lymphocytic leukemia patients include:
  • Other strategies for the prevention of opportunistic infections include:

Autoimmune Cytopenia Prophylaxis

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

  1. ↑ "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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M (March 2014). "Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions". N. Engl. J. Med. 370 (12): 1101–10. doi:10.1056/NEJMoa1313984. PMID 24401022.
  11. ↑ Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW (January 2019). "Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial". Lancet Oncol. 20 (1): 43–56. doi:10.1016/S1470-2045(18)30788-5. PMID 30522969.
  12. ↑ Eichhorst, B.; Robak, T.; Montserrat, E.; Ghia, P.; Hillmen, P.; Hallek, M.; Buske, C. (2015). "Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology. 26 (suppl 5): v78–v84. doi:10.1093/annonc/mdv303. ISSN 0923-7534.
  13. ↑ Shanafelt, T. (2013). "Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers". Hematology. 2013 (1): 158–167. doi:10.1182/asheducation-2013.1.158. ISSN 1520-4391.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M (October 2009). "First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia". Blood. 114 (16): 3382–91. doi:10.1182/blood-2009-02-206185. PMID 19605849.
  17. ↑ Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM (September 2012). "Bendamustine in combination 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. 30 (26): 3209–16. doi:10.1200/JCO.2011.39.2688. PMID 22869884.
  18. ↑ Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M (July 2016). "First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial". Lancet Oncol. 17 (7): 928–942. doi:10.1016/S1470-2045(16)30051-1. PMID 27216274.
  19. ↑ Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A (February 2009). "Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia". J. Clin. Oncol. 27 (4): 498–503. doi:10.1200/JCO.2008.17.2619. PMID 19075274.
  20. ↑ 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.
  21. ↑ Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC (January 2007). "Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia". Blood. 109 (2): 405–11. doi:10.1182/blood-2006-07-033274. PMC 1785105. PMID 17008537.
  22. ↑ Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM (September 2012). "Bendamustine in combination 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. 30 (26): 3209–16. doi:10.1200/JCO.2011.39.2688. PMID 22869884.
  23. ↑ Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H (June 2005). "Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia". J. Clin. Oncol. 23 (18): 4079–88. doi:10.1200/JCO.2005.12.051. PMID 15767648.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM (September 2012). "Bendamustine in combination 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. 30 (26): 3209–16. doi:10.1200/JCO.2011.39.2688. PMID 22869884.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M (March 2014). "Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions". N. Engl. J. Med. 370 (12): 1101–10. doi:10.1056/NEJMoa1313984. PMID 24401022.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J, Kimby E, Michallet M, Moreno C, Stilgenbauer S, Montserrat E (December 2014). "Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents?". Blood. 124 (26): 3841–9. doi:10.1182/blood-2014-07-586826. PMC 4276025. PMID 25301705.
  39. ↑ Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O (May 2009). "Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis". Leuk. Lymphoma. 50 (5): 764–72. doi:10.1080/10428190902856824. PMID 19330654.
  40. ↑ Koehrer S, Keating MJ, Wierda WG (May 2010). "Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP". Leukemia. 24 (5): 1096–8. doi:10.1038/leu.2010.45. PMID 20339441.
  41. ↑ Hodgson K, Ferrer G, Montserrat E, Moreno C (May 2011). "Chronic lymphocytic leukemia and autoimmunity: a systematic review". Haematologica. 96 (5): 752–61. doi:10.3324/haematol.2010.036152. PMC 3084923. PMID 21242190.

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