Chronic lymphocytic leukemia medical therapy: Difference between revisions

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==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.
==Immunochemotherapy==
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.
* The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is combination immunochemotherapy.<ref name="pmid25461996">{{cite journal| author=Nabhan C, Rosen ST| title=Chronic lymphocytic leukemia: a clinical review. | journal=JAMA | year= 2014 | volume= 312 | issue= 21 | pages= 2265-76 | pmid=25461996 | doi=10.1001/jama.2014.14553 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461996  }} </ref>
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]].
* '''[[Asymptomatic]]''' chronic lymphocytic leukemia patients are managed with observation, whereas '''[[symptomatic]]''' chronic lymphocytic leukemia  patients are treated with immunochemotherapy.
* Indications to initiate immunochemotherapy among patients with chronic lymphocytic leukemia include:<ref name="pmid25908509">{{cite journal| author=Hallek M| title=Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. | journal=Am J Hematol | year= 2015 | volume= 90 | issue= 5 | pages= 446-60 | pmid=25908509 | doi=10.1002/ajh.23979 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25908509  }} </ref>
:* [[Symptomatic]] chronic lymphocytic leukemia patients presenting with:
::* [[Fever]] of unknown origin (>38.1°C for a period greater than two weeks)
::* [[Night sweats]] for more than one month
::* Unintentional significant [[weight loss]] over a period of six months
:* Patients presenting with [[thrombocytopenia]] or [[anemia]] due to [[bone marrow failure]]
:* Patients presenting with refractory [[autoimmune hemolytic anemia]] or refractory [[autoimmune]] [[thrombocytopenia]]
:* Evidence of symptomatic [[splenomegaly]], with the [[spleen]] being palpated more than 6cm below the [[costal margin]]
:* Evidence of symptomatic progressive [[lymph node]]s swelling, with a size greater than 10 cm in diameter
:* Evidence of a rapidly progressive [[lymphocytosis]], which may be indicated by:
::* An increase of greater than 50% over a 2-month period
::* A [[lymphocyte]] doubling period shorter than six months
* Immunochemotherapies for chronic lymphocytic leukemia include [[purine]] analogues, [[alkylating agent]]s, [[monoclonal antibodies]], [[steroids]], [[corticosteroids]], [[Tyrosine kinase]] inhibitors, and [[B-cell]] [[receptor]] pathway inhibitors.<ref name="pmid25461996">{{cite journal| author=Nabhan C, Rosen ST| title=Chronic lymphocytic leukemia: a clinical review. | journal=JAMA | year= 2014 | volume= 312 | issue= 21 | pages= 2265-76 | pmid=25461996 | doi=10.1001/jama.2014.14553 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461996 }} </ref><ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</ref>
:* '''Purine analogues''' used for the management of chronic lymphocytic leukemia patines may include:
::* [[Cladribine]]
::* [[Fludarabine]]
::* [[Pentostatin]]
:* '''Alkylating agents''' used for the management of chronic lymphocytic leukemia patients may include:
::* [[Bendamustine]]
::* [[Chlorambucil]]
::* [[Cyclophosphamide]]
:* '''Monoclonal antibodies''' used for the management of chronic lymphocytic leukemia patients may include:
::* [[Rituximab]]
::* [[Ofatumumab]]
::* [[Obinutuzumab]]
::* [[Alemtuzumab]]
:* '''Immunomodulatory agents''' used for the management of chronic lymphocytic leukemia patients may include:
::* [[Lenalidomide]]
:* [[Corticosteroids]] used for the management of chronic lymphocytic leukemia patients may include:
::* [[Methylprednisolone]]
::* [[Prednisone]]
:* '''Tyrosine kinase and B-Cell receptor pathway inhibitors''' used for the management of chronic lymphocytic leukemia patients may include:
::* [[Idelalisib]] (targets phosphoinositide 3-kinase delta)
::* [[Ibrutinib]] (targets bruton tyrosine kinase)
* The optimal immunochemotherapeutic regimens used for the management of chronic lymphocytic leukemia depends on a number of factors which include:<ref name="pmid25908509">{{cite journal| author=Hallek M| title=Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. | journal=Am J Hematol | year= 2015 | volume= 90 | issue= 5 | pages= 446-60 | pmid=25908509 | doi=10.1002/ajh.23979 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25908509 }} </ref>
:* The clinical presentation of the patients
:* The [[performance status]] of the patients
:* The stage of the [[tumor]]
:* The presence of specific [[genetic mutation]]s
:* First line therapy vs. refractory/relapsed therapy
*The algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:<ref name="pmid25461996">{{cite journal| author=Nabhan C, Rosen ST| title=Chronic lymphocytic leukemia: a clinical review. | journal=JAMA | year= 2014 | volume= 312 | issue= 21 | pages= 2265-76 | pmid=25461996 | doi=10.1001/jama.2014.14553 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461996  }} </ref><ref name="pmid25908509">{{cite journal| author=Hallek M| title=Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. | journal=Am J Hematol | year= 2015 | volume= 90 | issue= 5 | pages= 446-60 | pmid=25908509 | doi=10.1002/ajh.23979 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25908509  }} </ref><ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</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 | | | B01 | | | |  B02| | |B01=<div style="width: 15em; 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 | | | C01 | | | | C02| | |C01=<div style="width: 15em; 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 | D01 | | D02 | | | | | | | | | | | | | | | |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 | E01 | | E02 | | | | | | | | | | | | | | | |E01=<div style="width: 15em; padding:1em;">'''Retixumab/obinutuzumab {{and}} chlorambucil'''</div>|E02=<div style="width: 15em; padding:1em;">'''FISH chromosomal analysis'''</div>}}
{{familytree | | | | | |!| | | | | | | | | | | | | | | | | }}
{{familytree | |,|-|-|-|+|-|-|-|.| | | | | | | | | | | | | }}
{{familytree | G01 | | G02 | | G03 | | | | | | | | | | | | |G01=<div style="width: 15em; padding:1em;">'''Immunochemotherapeutic regimens for 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 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 management of patients with chromosome 17p deletion can be found [[#Immunochemotherapeutic regimens for management of patients with chromosome 11q deletion|'''here''']]'''</div>}}
{{familytree/end}}
<br>
===Immunochemotherapeutic regimens for the management of patients without chromosome 17p deletion or chromosome 11q deletion===


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.
====First line therapy====
* Preferred immunochemotheraptic regimens for the treatment of such patients who are '''older than 70 years''' of age include ('''in order of preference'''):<ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</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 patients who are '''younger than 70 years''' of age include ('''in order of preference'''):
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
:* Fludarabine {{and}} rituximab
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab
:* [[Bendamustine]] {{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>
====Refractory/relapsed therapy====
* Preferred immunochemotheraptic regimens for the treatment of such patients who are '''older than 70 years''' of age include ('''in order of preference'''):<ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</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 include ('''in order of preference'''):
:* [[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


==Initial Treatment==
===Immunochemotherapeutic regimens for the management of patients with chromosome 17p deletion===
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> 
====First line therapy====
* Preferred immunochemotheraptic regimens for the treatment of such patients regardless the age group include ('''in order of preference'''):<ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</ref>
:* [[Ibrutinib]]
:* High-dose [[methylprednisolone]] {{and}} [[rituximab]]
:* [[Fludarabine]] {{and}} rituximab
:* Fludarabine {{and}} cyclophosphamide {{and}} rituximab
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
:* [[Alemtuzumab]] {{withorwithout}} [[rituximab]]
:* Rituximab {{and}} [[chlorambucil]]


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.
====Refractory/relapsed therapy====
* Preferred immunochemotheraptic regimens for the treatment of such 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


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.
===Immunochemotherapeutic regimens for management of patients with chromosome 11q deletion===


For younger patients who are experiencing symptoms, the physician may consider early chemotherapy, plus allogeneic or autologous bone marrow transplantation (alloBMT; autoBMT).
====First line therapy====
* Preferred immunochemotheraptic regimens for the treatment such patients who are '''older than 70 years''' of age include (in order of preference):<ref name="NCCN">NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015</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


In general, the indications for treatment are:
* Preferred immunochemotheraptic regimens for the treatment such patients who are '''younger than 70 years''' of age include (in order of preference):
 
:* [[Fludarabine]] {{and}} [[cyclophosphamide]] {{and}} [[rituximab]]
* Falling hemoglobin or platelet count
:* [[Bendamustine]] {{withorwithout}} [[rituximab]]
* Progression to a later stage of disease
:* [[Pentostatin]] {{and}} cyclophosphamide {{and}} rituximab
* Painful, disease-related overgrowth of lymph nodes or spleen
:* [[Obinutuzumab]] {{and}} [[chlorambucil]]
* Lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months
 
==Transformation of CLL to high-grade disease or aggressive non-Hodgkin's lymphoma==
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.
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==
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. 
 
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%. 
 
==Purine analogues==
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>
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==

Revision as of 22:10, 16 October 2015

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Risk calculators and risk factors for Chronic lymphocytic leukemia medical therapy

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

Overview

Immunochemotherapy

  • The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is combination immunochemotherapy.[1]
  • Asymptomatic chronic lymphocytic leukemia patients are managed with observation, whereas symptomatic chronic lymphocytic leukemia patients are treated with immunochemotherapy.
  • Indications to initiate immunochemotherapy among patients with chronic lymphocytic leukemia include:[2]
  • Symptomatic chronic lymphocytic leukemia patients presenting with:
  • Fever of unknown origin (>38.1°C for a period greater than two weeks)
  • Night sweats for more than one month
  • Unintentional significant weight loss over a period of six months
  • An increase of greater than 50% over a 2-month period
  • A lymphocyte doubling period shorter than six months
  • Purine analogues used for the management of chronic lymphocytic leukemia patines may include:
  • Alkylating agents used for the management of chronic lymphocytic leukemia patients may include:
  • Monoclonal antibodies used for the management of chronic lymphocytic leukemia patients may include:
  • Immunomodulatory agents used for the management of chronic lymphocytic leukemia patients may include:
  • Corticosteroids used for the management of chronic lymphocytic leukemia patients may include:
  • Tyrosine kinase and B-Cell receptor pathway inhibitors used for the management of chronic lymphocytic leukemia patients may include:
  • Idelalisib (targets phosphoinositide 3-kinase delta)
  • Ibrutinib (targets bruton tyrosine kinase)
  • The optimal immunochemotherapeutic regimens used for the management of chronic lymphocytic leukemia depends on a number of factors which include:[2]
  • The algorithm below summarizes the management approach for chronic lymphocytic leukemia patients:[1][2][3]


 
 
 
 
 
Initial patients evaluation
 
 
 
 
 
 
 
 
 
 
History
Physical examination
Complete blood count
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staging
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rai Staging System
Binet Staging System
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rai stage 3-4
Binet stage B-C
 
 
 
Rai stage 0-2
Binet stage A
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluate patients by cumulative index illness rating scale
 
 
 
Patients managed by observation and close follow-up
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Frail patients (CIRS ≥6)
 
Fit patients (CIRS <6)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retixumab/obinutuzumab AND chlorambucil
 
FISH chromosomal analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunochemotherapeutic regimens for management of patients without chromosome 17p deletion or chromosome 11q deletion can be found here
 
Immunochemotherapeutic regimens for management of patients with chromosome 17p deletion can be found here
 
Immunochemotherapeutic regimens for management of patients with chromosome 17p 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 include (in order of preference):[3]
  • Preferred immunochemotheraptic regimens for the treatment of such patients who are younger than 70 years of age include (in order of preference):

Refractory/relapsed therapy

  • Preferred immunochemotheraptic regimens for the treatment of such patients who are older than 70 years of age include (in order of preference):[3]
  • Preferred immunochemotheraptic regimens for the treatment of such patients who are younger than 70 years of age include (in order of preference):

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):[3]

Refractory/relapsed therapy

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

Immunochemotherapeutic regimens for management of patients with chromosome 11q deletion

First line therapy

  • Preferred immunochemotheraptic regimens for the treatment such patients who are older than 70 years of age include (in order of preference):[3]
  • Preferred immunochemotheraptic regimens for the treatment such patients who are younger than 70 years of age include (in order of preference):

References

  1. ↑ 1.0 1.1 1.2 Nabhan C, Rosen ST (2014). "Chronic lymphocytic leukemia: a clinical review". JAMA. 312 (21): 2265–76. doi:10.1001/jama.2014.14553. PMID 25461996.
  2. ↑ 2.0 2.1 2.2 Hallek M (2015). "Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment". Am J Hematol. 90 (5): 446–60. doi:10.1002/ajh.23979. PMID 25908509.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 NCCN Guidelines Version 2.2015 CLL/SLL. National Comprehensive Cancer Network. (2015) http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf Accessed on October, 15 2015

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