Chronic lymphocytic leukemia medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{Chronic lymphocytic leukemia}}
{{Chronic lymphocytic leukemia}}
{{CMG}} {{AE}}{{HL}}
{{CMG}} {{AE}}{{S.S}}
==Overview==
==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 agent]]s, [[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.
The mainstay of treatmen for [[symptomatic]] chronic lymphocytic leukemia [[Patient|patients]] is immunochemotherapy.  '''[[Asymptomatic]]''' chronic lymphocytic leukemia [[Patient|patients]] are managed with [[observation]] and follow up, whereas '''[[symptomatic]]''' chronic lymphocytic leukemia [[Patient|patients]] are treated with immunochemotherapy. Immunochemotherapies used for the treatment of chronic lymphocytic leukemia [[Patient|patients]] include [[purine]] [[Analog (chemistry)|analogues]], [[alkylating agent]]s, [[monoclonal antibodies]], [[corticosteroids]], [[tyrosine kinase]] inhibitors, and [[B-cell]] [[receptor]] pathway [[Inhibitor|inhibitors]].  [[Radiation therapy]] is not recommended for the management of chronic lymphocytic leukemia [[Patient|patients]].
==Immunochemotherapy==
==Immunochemotherapy==
* The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy.
* The mainstay of treatment 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.<ref name="pmid10340906">{{cite journal |vauthors= |title=Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group |journal=J. Natl. Cancer Inst. |volume=91 |issue=10 |pages=861–8 |date=May 1999 |pmid=10340906 |doi= |url=}}</ref>
* '''[[Asymptomatic]]''' chronic lymphocytic leukemia [[Patient|patients]] are managed with [[observation]] and follow up, whereas '''[[symptomatic]]''' chronic lymphocytic leukemia [[Patient|patients]] are treated with immunochemotherapy.<ref name="pmid10340906">{{cite journal |vauthors= |title=Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group |journal=J. Natl. Cancer Inst. |volume=91 |issue=10 |pages=861–8 |date=May 1999 |pmid=10340906 |doi= |url=}}</ref>
* '''Indications''' to initiate immunochemotherapy among patients with chronic lymphocytic leukemia include:<ref name="pmid295403482">{{cite journal |vauthors=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 |title=iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL |journal=Blood |volume=131 |issue=25 |pages=2745–2760 |date=June 2018 |pmid=29540348 |doi=10.1182/blood-2017-09-806398 |url=}}</ref>
* '''Indications''' to initiate immunochemotherapy among [[Patient|patients]] with chronic lymphocytic leukemia include:<ref name="pmid295403482">{{cite journal |vauthors=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 |title=iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL |journal=Blood |volume=131 |issue=25 |pages=2745–2760 |date=June 2018 |pmid=29540348 |doi=10.1182/blood-2017-09-806398 |url=}}</ref>
:* [[Symptomatic]] chronic lymphocytic leukemia patients presenting with:
:* [[Symptomatic]] chronic lymphocytic leukemia [[Patient|patients]] presenting with:
::* [[Fever]] of unknown origin (>38.1°C for a period greater than two weeks)
::* [[Fever]] of unknown origin (>38.1°C for a period greater than two weeks)
::* [[Night sweats]] for more than one month
::* [[Night sweats]] for ≥ one month
::* Unintentional significant [[weight loss]] (≥10%) over a period of six months
::* Unintentional significant [[weight loss]] (≥10%) over a period of six months
:* Patients presenting with [[thrombocytopenia]] or [[anemia]] due to [[bone marrow failure]]
:* [[Patient|Patients]] presenting with [[thrombocytopenia]] or [[anemia]] due to [[bone marrow failure]]
:* Patients presenting with refractory [[autoimmune hemolytic anemia]] or refractory [[autoimmune]] [[thrombocytopenia]]
:* [[Patient|Patients]] presenting with refractory [[autoimmune hemolytic anemia]] or refractory [[autoimmune]] [[thrombocytopenia]]
:* Evidence of symptomatic [[splenomegaly]], with the [[spleen]] being palpated more than 6cm below the [[costal margin]]
:* Evidence of [[symptomatic]] [[splenomegaly]], with the [[spleen]] being [[Palpate|palpated]] ≥ 6 cm below the [[costal margin]]
:* Evidence of symptomatic progressive [[lymph node]]s swelling, with a size greater than 10 cm in diameter
:* Evidence of [[symptomatic]] progressive [[lymph node]]s [[swelling]], with a size ≥10 cm in [[diameter]]
:* Evidence of a rapidly progressive [[lymphocytosis]], which might be observed as:
:* Evidence of a rapidly progressive [[lymphocytosis]], which might be observed as:
::* An increase of greater than 50% over a 2-month period
::* An increase of greater than 50% over a 2-month period
::* A [[lymphocyte]] doubling in a period shorter than six months  
::* A [[lymphocyte]] doubling in a period shorter than six months  
* Immunochemotherapeutic agents used for the treatment of chronic lymphocytic leukemia patients include:
* Immunochemotherapeutic agents used for the treatment of chronic lymphocytic leukemia [[Patient|patients]] include:<ref name="pmid20888994">{{cite journal |vauthors=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 |title=Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial |journal=Lancet |volume=376 |issue=9747 |pages=1164–74 |date=October 2010 |pmid=20888994 |doi=10.1016/S0140-6736(10)61381-5 |url=}}</ref><ref name="pmid26492934">{{cite journal |vauthors=Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ |title=Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia |journal=Blood |volume=127 |issue=3 |pages=303–9 |date=January 2016 |pmid=26492934 |pmc=4760129 |doi=10.1182/blood-2015-09-667675 |url=}}</ref><ref name="pmid23152253">{{cite journal |vauthors=Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N |title=Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia |journal=Cochrane Database Syst Rev |volume=11 |issue= |pages=CD008079 |date=November 2012 |pmid=23152253 |doi=10.1002/14651858.CD008079.pub2 |url=}}</ref><ref name="pmid23233702">{{cite journal |vauthors=Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, Appelbaum FR, Tallman MS, Belch AR, Morrison VA, Larson RA, Byrd JC |title=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 |journal=J. Clin. Oncol. |volume=31 |issue=4 |pages=440–7 |date=February 2013 |pmid=23233702 |pmc=3731920 |doi=10.1200/JCO.2011.41.5646 |url=}}</ref><ref name="pmid12393429">{{cite journal |vauthors=Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA |title=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) |journal=Blood |volume=101 |issue=1 |pages=6–14 |date=January 2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258 |url=}}</ref><ref name="pmid14726385">{{cite journal |vauthors=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 |title=Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions |journal=Blood |volume=103 |issue=9 |pages=3278–81 |date=May 2004 |pmid=14726385 |doi=10.1182/blood-2003-10-3729 |url=}}</ref><ref name="pmid16847886">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref><ref name="pmid24401022">{{cite journal |vauthors=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 |title=Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions |journal=N. Engl. J. Med. |volume=370 |issue=12 |pages=1101–10 |date=March 2014 |pmid=24401022 |doi=10.1056/NEJMoa1313984 |url=}}</ref><ref name="pmid30522969">{{cite journal |vauthors=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 |title=Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial |journal=Lancet Oncol. |volume=20 |issue=1 |pages=43–56 |date=January 2019 |pmid=30522969 |doi=10.1016/S1470-2045(18)30788-5 |url=}}</ref>
:* '''Purine analogues''' such as:
:* '''[[Purine]] [[Analog (chemistry)|analogues]]''' such as:
::* [[Cladribine]]  
::* [[Cladribine]]  
::* [[Fludarabine]]
::* [[Fludarabine]]
::* [[Pentostatin]]
::* [[Pentostatin]]
:* '''Alkylating agents''' such as:
:* '''[[Alkylation|Alkylating]] agents''' such as:
::* [[Bendamustine]]
::* [[Bendamustine]]
::* [[Chlorambucil]]
::* [[Chlorambucil]]
::* [[Cyclophosphamide]]
::* [[Cyclophosphamide]]
:* '''Monoclonal antibodies''' such as:
:* [[Monoclonal antibodies|'''Monoclonal antibodies''']] such as:
::* [[Rituximab]]  
::* [[Rituximab]]  
::* [[Ofatumumab]]  
::* [[Ofatumumab]]  
Line 35: Line 35:
:* '''Immunomodulatory agents''' such as:
:* '''Immunomodulatory agents''' such as:
::* [[Lenalidomide]]
::* [[Lenalidomide]]
:* '''Corticosteroids''' such as:
:* '''[[Corticosteroid|Corticosteroids]]''' such as:
::* [[Methylprednisolone]]
::* [[Methylprednisolone]]
::* [[Prednisone]]
::* [[Prednisone]]
:* '''Tyrosine kinase and B-Cell receptor pathway inhibitors''' such as:
:* '''[[Tyrosine kinase]] and [[B cell]] [[Receptor (immunology)|receptor]] pathway [[inhibitor]]<nowiki/>s''' such as:
::* [[Idelalisib]] (targets phosphoinositide 3-kinase delta)
::* [[Idelalisib]] (targets [[phosphoinositide 3-kinase]] delta)
::* [[Ibrutinib]] (targets bruton tyrosine kinase)
::* [[Ibrutinib]] (targets [[Bruton's tyrosine kinase|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 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 [[clinical]] presentation of the [[Patient|patients]]
:* The [[performance status]] of the patients
:* The [[performance status]] of the patients
:* The stage of the [[tumor]]
:* The stage of the [[tumor]]
:* The presence of specific [[genetic mutation]]s
:* The presence of specific [[genetic mutation]]s
:* First line therapy vs. refractory/relapsed therapy
:* First line [[therapy]] vs. [[refractory]][[Relapse|/relapsed]] [[therapy]]
*The algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:
*The algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:<ref name="EichhorstRobak2015">{{cite journal|last1=Eichhorst|first1=B.|last2=Robak|first2=T.|last3=Montserrat|first3=E.|last4=Ghia|first4=P.|last5=Hillmen|first5=P.|last6=Hallek|first6=M.|last7=Buske|first7=C.|title=Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up|journal=Annals of Oncology|volume=26|issue=suppl 5|year=2015|pages=v78–v84|issn=0923-7534|doi=10.1093/annonc/mdv303}}</ref><ref name="Shanafelt2013">{{cite journal|last1=Shanafelt|first1=T.|title=Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers|journal=Hematology|volume=2013|issue=1|year=2013|pages=158–167|issn=1520-4391|doi=10.1182/asheducation-2013.1.158}}</ref><ref name="pmid208889942">{{cite journal |vauthors=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 |title=Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial |journal=Lancet |volume=376 |issue=9747 |pages=1164–74 |date=October 2010 |pmid=20888994 |doi=10.1016/S0140-6736(10)61381-5 |url=}}</ref>
<br>
<br>
{{familytree/start |summary=PE diagnosis Algorithm.}}
{{familytree/start |summary=PE diagnosis Algorithm.}}
Line 77: Line 77:
{{familytree/end}}
{{familytree/end}}
<br>
<br>
===Immunochemotherapeutic Regimens for the Management of Patients without Chromosome 17p Deletion or Chromosome 11q Deletion===
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITHOUT</u> Chromosome 17p Deletion or Chromosome 11q Deletion===
====First Line Therapy====
====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'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|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'''):<ref name="pmid168478862">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref><ref name="pmid19605849">{{cite journal |vauthors=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 |title=First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia |journal=Blood |volume=114 |issue=16 |pages=3382–91 |date=October 2009 |pmid=19605849 |doi=10.1182/blood-2009-02-206185 |url=}}</ref><ref name="pmid22869884">{{cite journal |vauthors=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 |title=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 |journal=J. Clin. Oncol. |volume=30 |issue=26 |pages=3209–16 |date=September 2012 |pmid=22869884 |doi=10.1200/JCO.2011.39.2688 |url=}}</ref><ref name="pmid27216274">{{cite journal |vauthors=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 |title=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 |journal=Lancet Oncol. |volume=17 |issue=7 |pages=928–942 |date=July 2016 |pmid=27216274 |doi=10.1016/S1470-2045(16)30051-1 |url=}}</ref>
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Ofatumumab]] {{and}} chlorambucil
:* [[Ofatumumab]] {{and}} [[chlorambucil]]
:* [[Rituximab]] {{and}} chlorambucil
:* [[Rituximab]] {{and}} [[chlorambucil]]
:* [[Bendamustine]] {{withorwithout}} rituximab
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Obinutuzumab]]  
:* [[Obinutuzumab]]  
:* [[Fludarabine]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{withorwithout}} [[rituximab]]
:* Chlorambucil
:* [[Chlorambucil]]
:* Rituximab
:* [[Rituximab]]
:* [[Cladribine]]  
:* [[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'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|patients]] who are '''younger than 70 years''' of age with a good performance status include ('''in order of [[Preferences|preference]]'''):<ref name="pmid19075274">{{cite journal |vauthors=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 |title=Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=27 |issue=4 |pages=498–503 |date=February 2009 |pmid=19075274 |doi=10.1200/JCO.2008.17.2619 |url=}}</ref><ref name="pmid168478863">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref><ref name="pmid170085372">{{cite journal |vauthors=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 |title=Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia |journal=Blood |volume=109 |issue=2 |pages=405–11 |date=January 2007 |pmid=17008537 |pmc=1785105 |doi=10.1182/blood-2006-07-033274 |url=}}</ref><ref name="pmid228698842">{{cite journal |vauthors=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 |title=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 |journal=J. Clin. Oncol. |volume=30 |issue=26 |pages=3209–16 |date=September 2012 |pmid=22869884 |doi=10.1200/JCO.2011.39.2688 |url=}}</ref><ref name="pmid15767648">{{cite journal |vauthors=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 |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079–88 |date=June 2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051 |url=}}</ref>
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* Fludarabine {{and}} rituximab
:* [[Fludarabine]] {{and}} [[rituximab]]
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Bendamustine]] {{and}} rituximab
:* [[Bendamustine]] {{and}} [[rituximab]]


====Refractory/Relapsed Therapy====
====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'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|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'''):<ref name="pmid24735962">{{cite journal |vauthors=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 |title=Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL |journal=Blood |volume=123 |issue=21 |pages=3255–62 |date=May 2014 |pmid=24735962 |doi=10.1182/blood-2014-01-547737 |url=}}</ref><ref name="pmid147263852">{{cite journal |vauthors=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 |title=Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions |journal=Blood |volume=103 |issue=9 |pages=3278–81 |date=May 2004 |pmid=14726385 |doi=10.1182/blood-2003-10-3729 |url=}}</ref><ref name="pmid168478864">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref>
:* [[Ibrutinib]]
:* [[Ibrutinib]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} rituximab (reduced dose)
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]] (reduced [[dose]])
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab (reduced dose)
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]] (reduced [[dose]])
:* [[Bendamustine]] {{withorwithout}} rituximab
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* High-dose [[methylprednisolone]] {{and}} rituximab
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Ofatumumab]]
:* [[Obinutuzumab]]  
:* [[Obinutuzumab]]  
:* [[Lenalidomide]] {{withorwithout}} rituximab
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Alemtuzumab]] {{withorwithout}} rituximab
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* Dose-dense 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'''):
* 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'''):<ref name="pmid247359622">{{cite journal |vauthors=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 |title=Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL |journal=Blood |volume=123 |issue=21 |pages=3255–62 |date=May 2014 |pmid=24735962 |doi=10.1182/blood-2014-01-547737 |url=}}</ref><ref name="pmid168478865">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref><ref name="pmid228698843">{{cite journal |vauthors=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 |title=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 |journal=J. Clin. Oncol. |volume=30 |issue=26 |pages=3209–16 |date=September 2012 |pmid=22869884 |doi=10.1200/JCO.2011.39.2688 |url=}}</ref>
:* [[Ibrutinib]]
:* [[Ibrutinib]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Bendamustine]] {{withorwithout}} rituximab
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[alemtuzumab]]  
:* [[Fludarabine]] {{and}} [[alemtuzumab]]  
:* Rituximab {{and}} cyclophosphamide {{and}} [[doxorubicin]] {{and}} [[vincristine]] {{and}} [[cytarabine]]  
:* [[Rituximab]] {{and}} [[cyclophosphamide]] {{and}} [[doxorubicin]] {{and}} [[vincristine]] {{and}} [[cytarabine]]  
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} rituximab
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Ofatumumab]]
:* [[Obinutuzumab]]  
:* [[Obinutuzumab]]  
:* [[Lenalidomide]] {{withorwithout}} rituximab
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Alemtuzumab]] {{withorwithout}} rituximab
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* High-dose [[methylprednisolone]] {{and}} rituximab
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]


===Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 17p Deletion===
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITH</u> Chromosome 17p Deletion===
====First Line Therapy====
====First Line Therapy====
* Preferred immunochemotheraptic regimens for the treatment of such patients '''regardless''' the age group include ('''in order of preference'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|patients]] '''regardless''' the age group include ('''in order of preference'''):<ref name="pmid251507982">{{cite journal |vauthors=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 |title=Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study |journal=Lancet Oncol. |volume=15 |issue=10 |pages=1090–9 |date=September 2014 |pmid=25150798 |doi=10.1016/S1470-2045(14)70335-3 |url=}}</ref><ref name="pmid24652989">{{cite journal |vauthors=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 |title=Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial |journal=Blood |volume=123 |issue=21 |pages=3247–54 |date=May 2014 |pmid=24652989 |doi=10.1182/blood-2014-01-546150 |url=}}</ref><ref name="pmid22493413">{{cite journal |vauthors=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 |title=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 |journal=J. Clin. Oncol. |volume=30 |issue=14 |pages=1647–55 |date=May 2012 |pmid=22493413 |doi=10.1200/JCO.2011.35.9695 |url=}}</ref><ref name="pmid247359623">{{cite journal |vauthors=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 |title=Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL |journal=Blood |volume=123 |issue=21 |pages=3255–62 |date=May 2014 |pmid=24735962 |doi=10.1182/blood-2014-01-547737 |url=}}</ref><ref name="pmid147263853">{{cite journal |vauthors=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 |title=Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions |journal=Blood |volume=103 |issue=9 |pages=3278–81 |date=May 2004 |pmid=14726385 |doi=10.1182/blood-2003-10-3729 |url=}}</ref>
:* [[Ibrutinib]]
:* [[Ibrutinib]]
:* High-dose [[methylprednisolone]] {{and}} [[rituximab]]
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} rituximab
:* [[Fludarabine]] {{and}} [[rituximab]]
:* Fludarabine {{and}} cyclophosphamide {{and}} rituximab
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* Rituximab {{and}} [[chlorambucil]]
:* [[Rituximab]] {{and}} [[chlorambucil]]
:* Venetoclax {{and}} rituximab
:* [[Venetoclax]] {{and}} [[rituximab]]


====Refractory/Relapsed Therapy====
====Refractory/Relapsed Therapy====
* Preferred immunochemotheraptic regimens for the treatment of such patients '''regardless''' the age group include ('''in order of preference'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|patients]] '''regardless''' the age group include ('''in order of preference'''):
:* [[Ibrutinib]]
:* [[Ibrutinib]]
:* Idelalisib {{withorwithout}} [[rituximab]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* High-dose [[methylprednisolone]] {{and}} rituximab
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Lenalidomide]] {{withorwithout}} rituximab
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Ofatumumab]]
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} rituximab
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} [[rituximab]]


===Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 11q Deletion===
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITH</u> Chromosome 11q Deletion===
====First Line Therapy====
====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'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|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'''):<ref name="pmid244010222">{{cite journal |vauthors=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 |title=Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions |journal=N. Engl. J. Med. |volume=370 |issue=12 |pages=1101–10 |date=March 2014 |pmid=24401022 |doi=10.1056/NEJMoa1313984 |url=}}</ref>
:* [[Obinutuzumab]] {{and}} chlorambucil
:* [[Obinutuzumab]] {{and}} chlorambucil
:* [[Ofatumumab]] {{and}} chlorambucil
:* [[Ofatumumab]] {{and}} chlorambucil
Line 153: Line 153:
:* [[Cyclophosphamide]] {{and}} [[prednisone]] {{withorwithout}} rituximab
:* [[Cyclophosphamide]] {{and}} [[prednisone]] {{withorwithout}} rituximab
:* [[Fludarabine]] {{and}} cyclophosphamide {{and}} rituximab (reduced dose)
:* [[Fludarabine]] {{and}} cyclophosphamide {{and}} rituximab (reduced dose)
:* Rituximab  
:* [[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'''):
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|patients]] who are '''younger than 70 years''' of age with a good performance status include ('''in order of preference'''):<ref name="pmid168478866">{{cite journal |vauthors=Polizzotto MN, Tam CS, Milner A, Januszewicz EH, Prince HM, Westerman D, Wolf MM, Seymour JF |title=The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders |journal=Cancer |volume=107 |issue=4 |pages=773–80 |date=August 2006 |pmid=16847886 |doi=10.1002/cncr.22022 |url=}}</ref><ref name="pmid232337022">{{cite journal |vauthors=Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, Appelbaum FR, Tallman MS, Belch AR, Morrison VA, Larson RA, Byrd JC |title=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 |journal=J. Clin. Oncol. |volume=31 |issue=4 |pages=440–7 |date=February 2013 |pmid=23233702 |pmc=3731920 |doi=10.1200/JCO.2011.41.5646 |url=}}</ref>
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
=== Allogeneic stem cell transplantation ===
* [[Allogeneic stem cell transplantation]] (alloSCT) is the only potentially curative end stage treatment option in chronic lymphocytic leukemia [[Patient|patients]].<ref name="pmid25301705">{{cite journal |vauthors=Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J, Kimby E, Michallet M, Moreno C, Stilgenbauer S, Montserrat E |title=Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? |journal=Blood |volume=124 |issue=26 |pages=3841–9 |date=December 2014 |pmid=25301705 |pmc=4276025 |doi=10.1182/blood-2014-07-586826 |url=}}</ref>


==Supportive Therapy==
==Supportive Therapy==
===Opportunistic Infections Prophylaxis===
===Opportunistic Infections Prophylaxis===
* [[Vaccine]]s recommended for chronic lymphocytic leukemia patients include:
* [[Vaccine]]s recommended for chronic lymphocytic leukemia [[Patient|patients]] include:<ref>{{Cite journal|last=|first=|date=March 18, 2014|title=Prevention and treatment of cancer-related infections|url=https://oralcancerfoundation.org/wp-content/uploads/2016/09/infections.pdf|journal=NCCN Guidelines|volume=|pages=154|via=}}</ref>
:* [[Pneumococcal vaccine]] administered every five years
:* [[Pneumococcal vaccine]] administered every five years
:* [[Influenza vaccine]] administered annually
:* [[Influenza vaccine]] administered annually
:* Live attenuated vaccines should be avoided among chronic lymphocytic leukemia patients.
:* Live attenuated [[Vaccine|vaccines]] should be avoided among chronic lymphocytic leukemia [[Patient|patients]].
* Other strategies for the prevention of opportunistic infections include:
* 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.
:* [[Sulfamethoxazole]]/ [[trimethoprim]] can be administered to [[Patient|patients]] receiving [[purine]] [[Analog (chemistry)|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.
:* [[Acyclovir]] can be administered to [[Patient|patients]] receiving [[purine]] [[Analog (chemistry)|analogues]] as a [[prophylaxis]] for [[herpes simplex virus]] [[infection]].


===Autoimmune Cytopenia Prophylaxis===
===Autoimmune Cytopenia Prophylaxis===
* [[Corticosteroid]]s is recommended for the management of [[autoimmune]] [[cytopenia]] among chronic lymphocytic leukemia patients. Other therapeutic measures may include:
* [[Corticosteroid]]s is recommended for the management of [[autoimmune]] [[cytopenia]] among chronic lymphocytic leukemia patients. Other [[Therapy|therapeutic]] measures may include:<ref name="pmid19330654">{{cite journal |vauthors=Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O |title=Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis |journal=Leuk. Lymphoma |volume=50 |issue=5 |pages=764–72 |date=May 2009 |pmid=19330654 |doi=10.1080/10428190902856824 |url=}}</ref><ref name="pmid20339441">{{cite journal |vauthors=Koehrer S, Keating MJ, Wierda WG |title=Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP |journal=Leukemia |volume=24 |issue=5 |pages=1096–8 |date=May 2010 |pmid=20339441 |doi=10.1038/leu.2010.45 |url=}}</ref><ref name="pmid21242190">{{cite journal |vauthors=Hodgson K, Ferrer G, Montserrat E, Moreno C |title=Chronic lymphocytic leukemia and autoimmunity: a systematic review |journal=Haematologica |volume=96 |issue=5 |pages=752–61 |date=May 2011 |pmid=21242190 |pmc=3084923 |doi=10.3324/haematol.2010.036152 |url=}}</ref>
:* [[IVIG]]
:* [[IVIG]]
:* [[Splenectomy]]  
:* [[Splenectomy]]  
Line 178: Line 181:
:* [[Cyclosporin A]]
:* [[Cyclosporin A]]
:* [[Eltrombopag]]
:* [[Eltrombopag]]
* [[Romiplostim]] is recommended for the management of [[autoimmune]] [[thrombocytopenia]] among chronic lymphocytic leukemia patients.
* [[Romiplostim]] is recommended for the management of [[autoimmune]] [[thrombocytopenia]] among chronic lymphocytic leukemia [[Patient|patients]].
===Thromboprophylaxis===
===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.
* A daily [[aspirin]] dose is recommended among chronic lymphocytic leukemia [[Patient|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]].
* However, [[aspirin]] administration is not needed for such chronic lymphocytic leukemia [[Patient|patients]] who are already on [[warfarin]].


==Radiation Therapy==
==Radiation Therapy==
* Radiation therapy is not recommended for the management of chronic lymphocytic leukemia patients.
* [[Radiation therapy]] is recommended for the management of chronic lymphocytic leukemia [[Patient|patients]] in the presence of large [[lymphoid]] [[Mass|masses]] causing compression [[Symptom|symptoms]] and refractory to [[chemotherapy]].<ref name="pmid21398049">{{cite journal |vauthors=Rossier C, Schick U, Miralbell R, Mirimanoff RO, Weber DC, Ozsahin M |title=Low-dose radiotherapy in indolent lymphoma |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=81 |issue=3 |pages=e1–6 |date=November 2011 |pmid=21398049 |doi=10.1016/j.ijrobp.2010.12.062 |url=}}</ref><ref name="pmid8353067">{{cite journal |vauthors=Keating MJ |title=Immunosuppression with purine analogues--the flip side of the gold coin |journal=Ann. Oncol. |volume=4 |issue=5 |pages=347–8 |date=May 1993 |pmid=8353067 |doi= |url=}}</ref>


==References==
==References==

Latest revision as of 16:11, 28 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2]

Overview

The mainstay of treatmen 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 treatment 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]
  • 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
  • Immunomodulatory agents such as:
  • 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

Supportive Therapy

Opportunistic Infections Prophylaxis

  • Other strategies for the prevention of opportunistic infections include:

Autoimmune Cytopenia Prophylaxis

Thromboprophylaxis

Radiation Therapy

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. ↑ "Prevention and treatment of cancer-related infections" (PDF). NCCN Guidelines: 154. March 18, 2014.
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