Chronic lymphocytic leukemia medical therapy: Difference between revisions

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__NOTOC__
{{Chronic lymphocytic leukemia}}
{{Chronic lymphocytic leukemia}}
 
{{CMG}} {{AE}}{{S.S}}
{{CMG}}
 
==Overview==
==Overview==
While generally considered incurable, CLL progresses slowly in most cases.  Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. No chemotherapy has clearly prolonged survival in CLL. Instead, the condition is monitored over time.
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]].
The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
==Immunochemotherapy==
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]].  Symptoms are sometimes treated surgically ([[splenectomy]] with removal of the enlarged spleen) or by [[radiation therapy]].
* The mainstay of treatment for [[symptomatic]] chronic lymphocytic leukemia 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.<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 [[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 [[Patient|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
:* [[Patient|Patients]] presenting with [[thrombocytopenia]] or [[anemia]] due to [[bone marrow failure]]
:* [[Patient|Patients]] presenting with refractory [[autoimmune hemolytic anemia]] or refractory [[autoimmune]] [[thrombocytopenia]]
:* 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 ≥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 [[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]] [[Analog (chemistry)|analogues]]''' such as:
::* [[Cladribine]]
::* [[Fludarabine]]
::* [[Pentostatin]]
:* '''[[Alkylation|Alkylating]] agents''' such as:
::* [[Bendamustine]]
::* [[Chlorambucil]]
::* [[Cyclophosphamide]]
:* [[Monoclonal antibodies|'''Monoclonal antibodies''']] such as:
::* [[Rituximab]]
::* [[Ofatumumab]]
::* [[Obinutuzumab]]
::* [[Alemtuzumab]]
:* '''Immunomodulatory agents''' such as:
::* [[Lenalidomide]]
:* '''[[Corticosteroid|Corticosteroids]]''' such as:
::* [[Methylprednisolone]]
::* [[Prednisone]]
:* '''[[Tyrosine kinase]] and [[B cell]] [[Receptor (immunology)|receptor]] pathway [[inhibitor]]<nowiki/>s''' such as:
::* [[Idelalisib]] (targets [[phosphoinositide 3-kinase]] delta)
::* [[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 [[clinical]] presentation of the [[Patient|patients]]
:* The [[performance status]] of the patients
:* The stage of the [[tumor]]
:* The presence of specific [[genetic mutation]]s
:* First line [[therapy]] vs. [[refractory]][[Relapse|/relapsed]] [[therapy]]
*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>
{{familytree/start |summary=PE diagnosis Algorithm.}}
{{familytree | | | | | | A02 | | | | | |A02=<div style="width: 10em; padding:0.2em;">'''Initial patients evaluation'''</div>}}
{{familytree|boxstyle= border-top: 0px;| | | | | | A01 | |A01=<div style="width: 15em; padding:1em;">History<br>Physical examination<br>Complete blood count</div>}}
{{familytree | | | | | | |!| | | }}
{{familytree | | | | | | |!| | | }}
{{familytree | | | | | | A03 | |A03=<div style="width: 15em; padding:1em;">'''Staging'''</div>}}
{{familytree|boxstyle= border-top: 0px;| | | | | |A04 | | |A04=<div style="width: 15em; padding:1em;">Rai Staging System<br>Binet Staging System</div>}}
{{familytree | | | | | | |!| | | | }}
{{familytree | | | | | | |!| | | | }}
{{familytree | | | | |,|-|^|-|.| | }}
{{familytree | | | | B02 | |B01| | |B01=<div style="width: 10em; padding:1em;">'''Rai stage 3-4'''<br>'''Binet stage B-C'''</div>|B02=<div style="width: 15em; padding:1em;">'''Rai stage 0-2'''<br>'''Binet stage A'''</div>}}
{{familytree | | | | |!| | | |!| | }}
{{familytree | | | | |!| | | |!| | }}
{{familytree | | | | C02 | | C01| | |C01=<div style="width: 10em; padding:1em;">'''Evaluate patients by Cumulative Index Illness Rating Scale'''</div>|C02=<div style="width: 15em; padding:1em;">'''Patients managed by observation and close follow-up'''</div>}}
{{familytree | | | | | | | | |!| | | | | }}
{{familytree | | | | | | |,|-|^|-|.| | | }}
{{familytree | | | | | | D02 | | D01 | | D01=<div style="width: 15em; padding:1em;">'''Frail patients (CIRS ≥6)'''</div>|D02=<div style="width: 15em; padding:1em;">'''Fit patients (CIRS <6)'''</div>}}
{{familytree | | | | | | |!| | | |!| | | }}
{{familytree | | | | | | |!| | | |!| | | }}
{{familytree | | | | | | E02 | | E01 | | |E01=<div style="width: 17em; padding:1em;text-align:left">
'''[[Obinutuzumab]] {{and}} [[chlorambucil]]'''<br>
'''[[Ofatumumab]] {{and}} chlorambucil'''<br>
'''[[Rituximab]] {{and}} chlorambucil'''</div>|E02=<div style="width: 13em; padding:1em;">'''FISH chromosomal analysis'''</div>}}
{{familytree | | | | | | |!| | | | | | | }}
{{familytree | | |,|-|-|-|+|-|-|-|.| | | }}
{{familytree | | G01 | | G02 | | G03 | |G01=<div style="width: 13em; padding:1em;">'''Immunochemotherapeutic regimens for the management of patients without chromosome 17p deletion or chromosome 11q deletion can be found [[#Immunochemotherapeutic Regimens for the Management of Patients without Chromosome 17p Deletion or Chromosome 11q Deletion|'''here''']]'''</div>|G02=<div style="width: 15em; padding:1em;">'''Immunochemotherapeutic regimens for the management of patients with chromosome 17p deletion can be found [[#Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 17p Deletion|'''here''']]'''</div>|G03=<div style="width: 15em; padding:1em;">'''Immunochemotherapeutic regimens for the management of patients with chromosome 11q deletion can be found [[#Immunochemotherapeutic Regimens for the Management of Patients with Chromosome 11q Deletion|'''here''']]'''</div>}}
{{familytree/end}}
<br>
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITHOUT</u> Chromosome 17p Deletion or Chromosome 11q Deletion===
====First Line Therapy====
* 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]]
:* [[Ofatumumab]] {{and}} [[chlorambucil]]
:* [[Rituximab]] {{and}} [[chlorambucil]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Obinutuzumab]]
:* [[Fludarabine]] {{withorwithout}} [[rituximab]]
:* [[Chlorambucil]]
:* [[Rituximab]]
:* [[Cladribine]]  
* 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}} [[rituximab]]
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Bendamustine]] {{and}} [[rituximab]]


Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.
====Refractory/Relapsed Therapy====
* 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]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]] (reduced [[dose]])
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]] (reduced [[dose]])
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Obinutuzumab]]
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Alemtuzumab]] {{withorwithout}} [[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'''):<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]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[alemtuzumab]]
:* [[Rituximab]] {{and}} [[cyclophosphamide]] {{and}} [[doxorubicin]] {{and}} [[vincristine]] {{and}} [[cytarabine]]
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Obinutuzumab]]
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]


Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITH</u> Chromosome 17p Deletion===
====First Line Therapy====
* 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]]
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* [[Rituximab]] {{and}} [[chlorambucil]]
:* [[Venetoclax]] {{and}} [[rituximab]]


==Initial Treatment==
====Refractory/Relapsed Therapy====
Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner.  There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref> 
* Preferred immunochemotheraptic regimens for the treatment of such [[Patient|patients]] '''regardless''' the age group include ('''in order of preference'''):
:* [[Ibrutinib]]
:* [[Idelalisib]] {{withorwithout}} [[rituximab]]
:* High-[[dose]] [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Lenalidomide]] {{withorwithout}} [[rituximab]]
:* [[Ofatumumab]]
:* [[Oxaliplatin]] {{and}} [[fludarabine]] {{and}} [[cytarabine]] {{and}} [[rituximab]]


CLL (+12) has the capacity for autoimmune cytopenias.  Although about 20% of patients have Coombs positivity only about 8% actually develop hemolytic anemia and about 20% have decreased platelets as well. For warm autoimmune hemolytic anemia give steroids initially, using immunoglobulin secondarily. Cyclosporine is used if steroids and IV-IgG fail. One might also consider Alemtuzumab +/- fludarabine or cytoxan with dexamethasone. For refractory AIHA do splenectomy or splenic irradiation.  
===Immunochemotherapeutic Regimens for the Management of Patients <u>WITH</u> Chromosome 11q Deletion===
====First Line Therapy====
* 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
:* [[Ofatumumab]] {{and}} chlorambucil
:* [[Rituximab]] {{and}} [[chlorambucil]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Cyclophosphamide]] {{and}} [[prednisone]] {{withorwithout}} rituximab
:* [[Fludarabine]] {{and}} cyclophosphamide {{and}} rituximab (reduced dose)
:* [[Rituximab]]


Corticosteroids are first-line agents for people in whom the immune systems has been altered by CLL.  CLL may cause autoimmune syndromes in which the patient's immune system attacks and destroys his or her own blood cells.  When the red blood cells are affected, the condition is known as immunohemolytic anemia, characterized by decreased numbers of red blood cells, which may cause fatigue, dizziness, and shortness of breath. When the blood platelets are affected, it is called immune-mediated thrombocytopenia, in which a decreased numbers of platelets may lead to bleeding.  
* 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]]
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
:* [[Pentostatin]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]


For younger patients who are experiencing symptoms, the physician may consider early chemotherapy, plus allogeneic or autologous bone marrow transplantation (alloBMT; autoBMT).  
=== 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>


In general, the indications for treatment are:  
==Supportive Therapy==
===Opportunistic Infections Prophylaxis===
* [[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
:* [[Influenza vaccine]] administered annually
:* Live attenuated [[Vaccine|vaccines]] should be avoided among chronic lymphocytic leukemia [[Patient|patients]].
* Other strategies for the prevention of opportunistic infections include:
:* [[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 [[Patient|patients]] receiving [[purine]] [[Analog (chemistry)|analogues]] as a [[prophylaxis]] for [[herpes simplex virus]] [[infection]].


* falling hemoglobin or platelet count
===Autoimmune Cytopenia Prophylaxis===
* progression to a later stage of disease
* [[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>
* painful, disease-related overgrowth of lymph nodes or spleen
:* [[IVIG]]
* lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months
:* [[Splenectomy]]
:* [[Rituximab]]
:* [[Cyclosporin A]]
:* [[Eltrombopag]]
* [[Romiplostim]] is recommended for the management of [[autoimmune]] [[thrombocytopenia]] among chronic lymphocytic leukemia [[Patient|patients]].
===Thromboprophylaxis===
* 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 [[Patient|patients]] who are already on [[warfarin]].


==Transformation of CLL to high-grade disease or aggressive non-Hodgkin's lymphoma==
==Radiation Therapy==
If the patient experiences blood flow problems caused by high numbers of leukemia cells in the circulation, the physician may recommend leukapheresis, also known as apheresis, to separate out white blood cells, prior to chemotherapy.
* [[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>
Symptoms that are related to enlargement of the lymph nodes in one area or an overgrown spleen may be treated by localized, low-dose radiotherapy, or surgical management by splenectomy (removal of the spleen). But if leukemia has invaded the lymph nodes at many different sites, total body irradiation (TBI) may be needed.


==Alkylators==
==References==
Chlorambucil (CHB) should be considered for older patients (>90 years) with severe comorbidities (eg renal insufficiency) where they're likely to live less than a year regardless of treatment.  CHB is associated with a median survival of about 2 years in patients with advanced stage CLL; a higher response rate (RR) may be achieved with more aggressive treatment regimens such as CHOP but without any clear survival advantage.  This agent has been replaced by newer agents.  Cytoxan, Oncovin, Prednisone (COP) is not superior to CHB alone, either in complete response rate (CR) or prolonged survival.  CHOP does improve the RR to stage B patients but, again, with no survival advantage. 
{{reflist|2}}


Bendamustine (treanda) is used in the treatment of CLL (& indolent NHL) that has progressed within 6 months after treatment with Rituxumab.  Administer as 100 mg/m2 / 30" on days 1+2 of a 28 day cycle; up to 6 cycles.  Bendamustine is superior to chlorambucil in the treatment of CLL.  Bendamustine is also given with Ritux for relapsed CLL with the overall response rate (ORR) dependent on chromosomal subtype; 11p deletion = 92%, trisomy 12 = 100%, 17p deletion = 44%, umutated IgVH = 74%. 
{{Hematology}}
{{Hematological malignancy histology}}
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Mature chapter]]


==Purine analogues==
{{WikiDoc Help Menu}}
Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
{{WikiDoc Sources}}
there is no evidence that early use of fludarabine improves overall survival.  Fludara can actually make CLL-AIHA worse.  It is indicated for patients who have refractory and / or relapsed disease refractory to alkylating agents.  Adding prednisone to fludarabine does not increase the RR over fludarabine alone.  Add prednisone to fludara only in the presence of autoimmune anemia or thrombocytopenia.  Note that fludara with steroids increases the likelihood of P. carinii & Listeria infection.  Patients who fail to respond to fludarabine after 2-3 courses should not receive additional courses.  No further treatment is indicated if a CR has been achieved; otherwise 2 courses are given after the maximal response is achieved, not to exceed one year. 
 
==Combination chemotherapy==
 
Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL.  Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:
 
* [[Fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
 
* [[Fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |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 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>   
 
* FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |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 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref>  FCR are well tolerated in previously treated CLL.  However most of their toxicity is myelosuppression.  FCR had a high CR rate (25%), nodular PR (16%) & PR (32%).  Molecular remissions are obtained in 1/3 of patients. 
* CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])
 
==Refractory CLL==
"Refractory" CLL is a disease that no longer responds favorably to treatment.  In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref> 
Prolymphocytic transformation of CLL requires treatment with CHOP. 


==Monoclonal antibodies==
The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<!--
  --><ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10  | id=PMID 11986207}}</ref>  Alemtuzumab (Campath) is an anti-CD52 monoclonal antibody; CD52 is on all B & T lymphocytes.  Its use carries a RR = 33% with a CR = 2%.  Patients with pre-exisiting cytopenias show improvement in bone marrow function due to the lack of  stem cell (CD34) toxicity.  Its toxicity against T-cells can lead to significant immunosuppression and infectious complications (esp CMV reactivation).  Dose modifications are made for drug related cytopenias.  Premedications for its administration are necessary and (almost always) the first dose can be characterized by fever, rigors and nausea.  It is recommended to give benadryl, tylenol, hydrocortisone as well as Bactrin DS and Famciclovir. If a 17p del is found in a young CLL patient one could consider Alemtuzumab and early transplant.  It is otherwise approved for CLL refractory to alkylating agents and fludarabine. Ofatumumab is a novel monoclonal antibody against CD20 but targets a different epitope than Rituximab.  It is also different from Ritux in that it is a completely humanized anti-CD20 antibody whereas Ritux is a chimeric.  Ofatumumab (HuMax-CD20) appears to work well for patients who have lower CD20 levels on the surface of their lymphocytes.  Therefore it should be more effective than Ritux in treating CLL
(Ritux may not work as well because of low CD20 levels).  It is an active treatment option for CLL patients refractory to both fludarabine and alemtuzumab.


==References==
==References==
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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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ Rossier C, Schick U, Miralbell R, Mirimanoff RO, Weber DC, Ozsahin M (November 2011). "Low-dose radiotherapy in indolent lymphoma". Int. J. Radiat. Oncol. Biol. Phys. 81 (3): e1–6. doi:10.1016/j.ijrobp.2010.12.062. PMID 21398049.
  44. ↑ Keating MJ (May 1993). "Immunosuppression with purine analogues--the flip side of the gold coin". Ann. Oncol. 4 (5): 347–8. PMID 8353067.

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