EmergingManagementStrategiesfor Chronic Lymphocytic Leukemia · PDF fileEmergingManagementStrategiesfor Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS 1 ThomasJ.Kipps,MD,PhDis

ChronicLymphocytic

Leukemia

Emerging Management Strategies for

ChronicLymphocytic

LeukemiaIN HIGH-RISK PATIENTS

Sponsored by the

This activity is supported byeducational grants from

GlaxoSmithKline, Genentechand Genzyme


Chronic Lymphocytic LeukemiaIN HIGH-RISK PATIENTS

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Thomas J. Kipps, MD, PhD is the Evelyn and EdwinTasch Chair in Cancer Research, a UCSD Professor ofMedicine, and the Deputy Director of Research at the

Moores UCSD Cancer Center in LaJolla, California. He received hisPhD in Immunology and MD fromHarvard University and completedhis residency and fellowship trainingin Internal Medicine, Hematology,and Genetics at Stanford University.

Prior to serving in his current positions, Dr. Kipps wasHead of Hematology and Oncology, Associate Director ofthe Gene Therapy Program, Director of the TranslationalResearch Program, and Director of the ImmunologyDepartment at UCSD.

Dr. Kipps has a national and international reputationfor his work in cancer research, immunology, and genetherapy. He is the author of more than 200 publicationsand is the PI on several peer-reviewed grants, includingan award from NCI/NIH to fund the Chronic LymphocyticLeukemia Consortium (CRC). The CRC involvescollaboration with 8 other Cancer Centers around thenation. Dr. Kipps has over 20 years experience incombining research and clinical care responsibilities.

Kanti R. Rai, MD is Chief, Division of Hematology-Oncology at the Long Island Jewish Medical Center inNew Hyde Park, New York, and the Joel Finkelstein

Cancer Foundation Professor ofMedicine at the Albert Einstein Collegeof Medicine in the Bronx, New York.In 1955, he received his MB, BS fromSMS Medical College, University ofRajasthan, Jaipur, India, after whichhe did his residency in pediatrics at

Lincoln Hospital of the City of New York, Bronx, NewYork. Dr. Rai then became Chief Resident in Pediatricsat the North Shore Hospital, in Manhasset, New York in1958. He followed his residency as a Fellow in NuclearMedicine and Hematology at the Long Island JewishHospital in 1959, and then became Research Associate inHematology at Brookhaven National Laboratory MedicalResearch Center in Upton, New York.

Before assuming his current position, Dr. Rai servedas Chief, Division of Experimental Medicine, Instituteof Nuclear Medicine, New Delhi, India, and then asAssociate Scientist at Brookhaven National Laboratory.He has also served as Associate Professor of Medicine(1972-80) and Professor of Medicine (1980-1989) atthe School of Medicine, State University of New York atStony Brook, as well as Joel Finkelstein Cancer FoundationProfessor of Medicine (1989-2004), Albert EinsteinCollege of Medicine. He has been Chief at the Divisionof Hematology-Oncology at Long Island Jewish MedicalCenter since 1981. Dr. Rai is Certified by the AmericanBoard of Pediatrics.

Dr. Rai has received numerous awards, among which arethe Eastern Leukemia Society Scholar, National LeukemiaAssociation Scholar, Helena Rubenstein FoundationLeukemia Research Award, Joel Finkelstein CancerFoundation Man of the Year Award, and the Peter JaySharp Foundation Award for CLL Research. He hasserved as Co-chair on the Medical Advisory Board of theLauri Strauss Leukemia Foundation, and he is a FoundingMember and Co-chair of the International Workshopon CLL, as well as a member of the NCI-sponsoredWorking Group on CLL.

Dr. Rai’s major interests focus on hematologicalmalignancies, prognostic markers and improved therapyfor CLL.

Lead Nurse Planner

Carol Marietta, NP

Nurse PractitionerRancho Mirage, California

Faculty

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Intended Audience

This activity was developed for hematologists, oncologists, NPs, RNs, and other

health care professionals working with patients with CLL.

Statement of Need

A number of new therapies have become available and new combination regimens

have been studied for the treatment of CLL in the past few years, yet standard

first- and second-line treatments have yet to be established. Community

hematologists/oncologists are challenged to keep abreast of the latest clinical

study data and expert recommendations on these new treatments or emerging

combination regimens. There are also new tools available for testing for prognostic

markers, and recommendations about which treatment regimens should be used

based on individual patient risk profiles.

Learning Objectives

Upon completion of this activity, participants should be able to:

� Utilize appropriate tests and biomarkers to

quickly and accurately diagnose, stage, and do

risk assessment for patients with CLL

� Design optimal treatment protocols for individual patients

� Provide appropriate supportive care for patients

� Incorporate data from clinical trials to guide

adoption of new treatment options when available

and appropriate

Nursing Learning Objectives

Upon completion of this activity, participants should be able to:

� Incorporate new data into their work to enhance

their care of patients and families

This activity will address professional practice gaps in knowledge.

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Accreditation and Certification

The Annenberg Center for Health Sciences at Eisenhower isaccredited by the Accreditation Council for Continuing MedicalEducation to provide continuing medical education for physicians.

The Annenberg Center designates this educational activity fora maximum of 1 AMA PRA Category 1 Credit. Physiciansshould only claim credit commensurate with the extent of theirparticipation in the activity.

Annenberg Center for Health Sciences is accredited as aprovider of continuing nursing education by the AmericanNurses Credentialing Center’s Commission on Accreditation.

A maximum of 1 contact hour may be earned for successfulcompletion of this activity.

There is no charge for this activity. Statements of Credit maybe printed online.

Disclosure

It is the policy of the Annenberg Center to ensure fair balance,independence, objectivity, and scientific rigor in all programming.All faculty and planners participating in sponsored programsare expected to identify and reference off-label product use anddisclose any relationship with those supporting the activity orany others with products or services available within the scopeof the topic being discussed in the educational presentation.

In accordance with the Accreditation Council for ContinuingMedical Education Standards, parallel documents from otheraccrediting bodies, and Annenberg Center policy, the followingdisclosures have been made:

Thomas J. Kipps, MD

Research Support Biogen-Idec; Celgene Corporation;Cephalon, Inc.; Memgen, LLC;sanofi-aventis

Consultant Igenica, Inc.Speakers Bureau Educational Concepts; PER;

University of Utah

Kanti R. Rai, MD

Consultant Biogen Idec; Cephalon, Inc.;Genentech; GlaxoSmithKline

The faculty for this activity have disclosed that therewill be discussion about the use of products for non-FDAapproved indications.

Additional content planners: In accordance with theAccreditation Council for Continuing Medical EducationStandards, parallel documents from other accrediting bodies,and Annenberg Center policy, the following disclosureshave been made:

The following have no significant relationship to disclose:

Joel Legunn (Medical Writer)Carol Marietta, NP (Lead Nurse Planner)

All staff at the Annenberg Center for Health Sciences atEisenhower have nothing to disclose.

The ideas and opinions presented in this educational activityare those of the faculty and do not necessarily reflect theviews of the Annenberg Center and/or its agents. As in alleducational activities, we encourage practitioners to use theirown judgment in treating and addressing the needs of eachindividual patient, taking into account that patient’s uniqueclinical situation. The Annenberg Center disclaims all liabilityand cannot be held responsible for any problems that mayarise from participating in this activity or following treatmentrecommendations presented.

This activity is supported by educational grants fromGlaxoSmithKline, Genentech and Genzyme.

This activity is an enduring material and consists of a webactivity. Successful completion is achieved by reading andviewing the material, reflecting on its implications in yourpractice, and completing the assessment component.

The estimated time to complete the activity is 1 hour.

This activity was originally released in March 2010 and iseligible for credit through February 28, 2011.

Introduction

The clinical course of patients with chronic lymphocyticleukemia (CLL) is heterogeneous. Whereas some patientsrequire treatment relatively soon after diagnosis, othersmay enjoy a relatively indolent course, free of symptoms,and not require therapy for many years. Because studiesin the 1990s found that early treatment may actuallycompromise patient survival, and because there are nostudies that show early treatment can provide a survivalbenefit, it is currently recommended to withholdtherapy until the patient develops progressive and/orsymptomatic disease.1

In recent years, an impressive number of prognosticmarkers have been identified that can stratify patientsinto subgroups that have different prognoses. Some ofthese markers can help assess the relative risk for diseaseprogression independent of clinical stage.

At the same time, there has been progress in thetreatment of CLL that is providing for an improvedsurvival benefit. Recent years have witnessed theuse of newer drugs, monoclonal antibodies, andmonoclonal antibody/drug combinations (so called“chemoimmunotherapy”) that have provided for

improved response rates and longer progression-freesurvival times after treatment. Even in the face of theseadvances, however, there are still no standard protocolsfor first-line CLL therapy. This discussion highlightsrisk categories most often encountered in clinicalpractice, the prognostic markers used for risk stratification,and the approaches to applying both prognostic markersand new therapeutic options to achieve optimal patientoutcomes in each risk category.

Prognostic Markers –The Key to Risk Stratifications

Based on a better understanding of the biology of CLL,we can better stratify patients into different prognosticsubgroups. It is possible to identify features of CLLcells (Table 1) that are associated with the tendency forprogressive disease that requires treatment relatively soonafter diagnosis. Among these are the mutation status ofthe expressed immunoglobulin variable region (heavychain) genes (IgHV genes), or expression of the 70-kDzeta-chain-associated protein kinase (ZAP-70), or CD38.In addition, there are many other markers that areassociated with more aggressive disease, such as high levelexpression of thymidine kinase or lipoprotein lipase.

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Adapted with permission from Yee KWL, O’Brien SM, Chronic Lymphocytic Leukemia Diagnosis and Treatment. Mayo Clin Proc 2006;81:1105-1129.

TABLE 1 Prognostic Markers for CLL2

MARKER LOW RISK HIGH RISK

Serum markers

Thymidine-kinase Low or normal High

Soluble CD23 levels Low or normal High

Beta-2 microglobulin Low or normal High

FISH cytogenetics (see Table 2)

IgV(H) mutational status Mutated Unmutated

Lactate dehydrogenase Low or normal High

CD38 expression <20%-30% >20%-30%

ZAP-70 expression <20%-30% >20%-30%

Lymphocytic doubling time >12 months ≤12 months

Using one or a combination of these prognostic markers,we can now stratify patients into subgroups that havesignificantly different risks for disease progression. Forexample, patients with leukemia cells that express ZAP-70and/or that use unmutated IgHV gene will have, onaverage, a greater tendency for early disease progressionrequiring treatment than patients with CLL cells that donot express ZAP-70, or that use mutated IgHV. Morerecently, the former subgroup of patients also has beennoted to have a shorter progression-free survival aftersuccessful treatment with chemoimmunotherapy thanthat latter subgroup.

Nevertheless, the expression of these prognostic markershas not been shown to influence the response to treatment.For example, the relatively complete response rates tovarious treatment regimens appear to be the same in bothsubsets of patients.

In contrast, there are certain recurrent genetic changesidentified in CLL cells that are associated with differencesin response to standard therapies and/or survival. Thesegenetic changes can be identified in blood or marrow CLLcells through standard cytogenetics or via Fluorescence InSitu Hybridization (FISH), and are thought to occur duringthe development or evolution of the disease (Table 2).The most common genetic lesion is deletion of a segmentin the long arm of chromosome 13 at 13q14, which, iffound to be the sole genetic abnormality, is associated

with a relatively good prognosis. Less common is thefinding of an extra copy of chromosome 12 (trisomy 12),which is associated with atypical cell morphology, higherleukemia-cell expression levels of CD20, and a strongtendency for relatively rapid disease progression. Othercommon abnormalities include deletions in the long armof chromosome 11 at 11q22.3, or deletions in the shortarm of chromosome 17 at 17p13.1. Each of thesechromosomal abnormalities, particularly deletions at17p13.1, is associated with a poorer response to certaintypes of treatment, particularly those that require activeP53 to function.

The gene located at 17P13.1 encodes TP53, an importanttranscription factor that is activated by a number ofalkylating agents and purine analogs. This activationinduces a range of changes in genes that are involved inregulating growth arrest, and in genes that encode proteinsthat may initiate apoptosis. Therefore, the absence ordeletion of the TP53 gene typically causes the leukemiccells to be less responsive to these chemotherapeuticagents, and to demonstrate chemo-resistance.

The exact cause of the genetic lesion at 11q22.3 is stilluncertain. There is active investigation of regulatory RNAsor micro RNAs that map to this region and that mightaccount for the relative resistance to certain types of drugtherapy. Several clinical trials have demonstrated thatpatients with del 11q have a lower response to single-agent

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TABLE 2 Fluorescence In Situ Hybridization (FISH) Tests for CLL3-5

CYTOGENETIC ABERRATION/LOCUS PARAMETER DETECTED IMPLICATION

11q22.3 Deletions of the ATM gene Found in 11%-18% of cases.Marked by lymphadenopathy and poor survival.

12cen Gain of chromosome 12 Found in 16%-25% of cases. Unresolved pathogenicoutcome, but has been shown to be a negativeprognostic factor with median survival approx 5 yrs.

13q14.3 Deletions of the RB1 region Found in 36%-64% of cases. Good prognosis assole abnormality. Disease-free interval and overallsurvival is better than cases with normal karyotypebecause of slow disease progression.

17p13.1 Deletions of the TP53 gene Found in 7%-8% of cases that are resistant tochemotherapy and have a short survival.

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fludarabine therapy, or to the combination of fludarabineand rituximab, than do patients who do not have eitherthis or the 17p deletion abnormality. However, thesepatients appear to have a response equivalent to that ofpatients without del 11q, if treated with chemotherapyregimens that include fludarabine and an alkylatingagent, such as cyclophosphamide.

CASE 1 An Older Patient With High-Risk Features

MR is a 70-year-old man with CLL diagnosed 3 years ago.He had been doing well until about 4 months ago whenhe began experiencing progressive fatigue, night sweats,and abdominal fullness with early satiety after eating. Heotherwise maintains an excellent performance status of0/5 by the ECOG criteria and lacks significant medicalco-morbidities. On exam he is noted to have significantpalpable cervical lymphadenopathy and a spleen palpable7 cm below the left costal margin. His white blood cellcount (WBC) was noted to be 125,000 with 97% welldifferentiated lymphocytes, which was significantlyincreased from that of his WBC of 13,000 noted atdiagnosis. His hemoglobin was 10.1 gm% and his plateletcount 98,000. His leukemia cells were noted to expresshigh levels of ZAP-70 and to use unmutated IgHV.Cytogenetic analyses demonstrated the cells to havedeletions at 11q22.3.

Interactive Questions (circle your answer before readingthe correct answer below.)

1. This patient is:

a. high risk

b. low risk

Correct Answer (a)

The patient is at high risk (Stage IV), as thepatient’s platelet count is below 100,000. He alsohas anemia, most likely reflecting disease-relatedmarrow suppression. In addition, his prognosticmarkers are unfavorable—unmutated IgV(H) gene,and ZAP-70 positive—and he is symptomatic.

2. This patient should:

a. be placed on wait-and-watch status

b. have treatment started immediately

Correct Answer: (b)

This patient is in need of therapy. He has sympto-matic disease and evidence for compromisedmarrow function. Left untreated he probablywould develop worsening cytopenia and increas-ingly symptomatic disease. Studies have shownthat patients with high-risk stage disease benefitfrom therapy.

3. High risk patients without significantsymptoms should:

a. be placed under observation

b. given a therapeutic regimen thatwill stop progression

c. treated with the goal of achievinga complete response

Correct Answer: (c)

Even if prognostic markers are favorable, sympto-matic high-risk patients should be placed on atherapeutic regimen with the goal of a complete,or maximally achievable response.

4. A preferred therapy for this patient would be:

a. Fludarabine + cyclophosphamide + rituximab

(FCR)

b. Fludarabine + rituximab (FR)

c. Bendamustine-rituximab

Correct Answer: (a)

In view of his adverse leukemia-cell cytogenetics,namely the deletion at 11q, he should be consid-ered for combination chemoimmunotherapy(Table 3 on next page). Clinical studies comparingthe outcome of treatment with fludarabine versusfludarabine and cyclophosphosphamide have

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demonstrated the combination of the purineanalog with an alkylating agent to yield highercomplete response rates and longer progressionfree survival times after therapy than treatmentwith fludarabine alone.6-8

The difference in outcome is particularly apparent forpatients with CLL cells that have the 11q deletion. Aretrospective review of patient outcomes,9 and prospectiverandomized phase III clinical studies10 have demonstratedthat the addition of rituximab to the combination offludarabine and cyclophosphamide significantly improvesresponse rates, progression-free survival after treatment,and overall survival relative to response achieved fromtreatment with the combination of fludarabine andcyclophosphamide alone.

It is important to bear in mind that many of the clinicalCLL treatment trials described in the literature usuallyinvolve patients of a younger median age than the typicalCLL patient. The median ages of the patients in manystudies are typically in the 50s, whereas the median age atdiagnosis for all patients with CLL is closer to 70. However,age can be a factor in the expected tolerance to treatment.Older patients generally have a limited myeloid reserve.A rule of thumb is that marrow cellularity is generally100 minus a patient’s age, reflecting the age-relateddecline in marrow function. Because elderly patients haveless myeloid reserve than younger patients, they mighthave a lower tolerance to myelosuppressive therapy.

In addition, elderly patients often have one or moreco-morbidities, such as impaired renal function, cardio-vascular disease, or diabetes. Renal function needs to beconsidered because a number of therapeutic agents usedin the treatment of CLL undergo renal clearance. Thus,dosage reductions should be implemented in patients withrenal impairment to avoid toxicity. Patients with cardio-vascular disease may not tolerate anemia, and patients withdiabetes have an increased risk for infection that isindependent of the CLL-related decline in immune function.

Thus, older patients’ profiles, with regard to oftencompromising co-morbidities and age-related decline,need to be included as an additional factor when stratifyingthe patients into different prognostic groups.

To reduce the myelotoxicity of the treatment regimens,investigators at the University of Pittsburgh developed whatthey called an “FCR light” regimen, which calls for usinga reduced dose of fludarabine and cyclophosphamide,but an increased dose of rituximab.11 These investigatorsalso gave patients rituximab maintenance therapy every6 months after completing the 6 courses of therapy, in afashion similar to how patients are treated with follicularlymphoma. Because this regimen included rituximabmaintenance therapy, it is difficult to assess progressionfree survival after treatment. Nevertheless, the reportedcomplete response and overall response rates were ona par with those of the conventional FCR regimen,making this regimen a potential option for elderly patientswith del 11q.

TABLE 3 Therapeutic Regimens Used in CLL

DRUG CLASS

Chemotheraphy

Purine analogs

Fludarabine (Fludara®)

Pentostatin (Nipent®)

2-chlorodeoxyadenosine

Alkylating agents

Cyclophosphamide (Cytoxan®)

Chlorambucil (Leukeran®)

Bendamustine (Treanda®)

Biologic Immunotherapies

Rituximab (Rituxan®)

Alemtuzumab (Campath®)

Investigational Agents

Ofatumumab

Lenalidomide (Revlimid®)

Flavopiridol

Combination Therapies

Fludarabine-cyclophosphamide-rituximab (FCR)

Fludarabine-rituximab (FR)

Fludarabine-cyclophosphamide (FC)

Pentostatin-cyclophosphamide-rituximab (PCR)

Oxaliplatin-fludarabine-cytarabine-rituximab (OFAR)

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Another treatment regimen that is well tolerated inpatients with limited myeloid reserve is that involvinguse of high-dose methylprednisolone and rituximab, theso-called HDMP+R regimen. Excellent response rates ofgood duration were observed for patients treated withHDMP+R without inducing significant myelotoxicity.12, 13

Alemtuzumab

There are newer immune therapies being developed toaddress the treatment difficulties encountered with high-risk patients. One of these is alemtuzumab (Campath®), amonoclonal antibody that appears to have activity in thetreatment of patients who have CLL cells with del(17p).14

In a phase II study involving 93 CLL patients who hadfailed treatment with fludarabine, treatment with alem-tuzumab resulted in a 50% reduction in disease burden in33% of the patients and a complete response in 2%.15

Responses to therapy lasted about 7 months on average.These results were similar to those of 2 smaller studiesconducted previously, demonstrating an overall responserate of over 30% in patients previously treated withchemotherapy.16, 17 However, all 3 studies were single-armtrials lacking controls and making it difficult to fully assessefficacy and safety. Nevertheless, these results promptedthe FDA to provide accelerated approval in 2001.

The FDA mandated a phase 3 clinical trial, CAMC307,in which approximately 300 CLL patients wererandomized to receive therapy with either chlorambucilor alemtuzumab.18 Because there was a nearly 30 percentgreater (83% vs 55%) overall response rate amongpatients treated with alemtuzumab versus chlorambucil(p< 0.0001), and a 12-fold increase (24% vs 2%) incomplete response rates in patients receiving alemtuzumab(p< 0.0001), the FDA approved the use of alemtuzumabfor the initial treatment of patients with CLL inSeptember 2007.

Although alemtuzumab is highly effective in clearingblood and marrow leukemic cells, it appears to be lesseffective in clearing cells in the large lymph nodes.19 Theprobability of achieving a complete response to treatmentwith alemtuzumab decreases in patients with large lymphnodes. Treatment of patients with lymph nodes less than

2 cm in diameter apparently can provide for completeresponse rates of up to 50%. However, the probabilityof achieving a complete response to treatment withalemtuzumab apparently falls to less than 20% in patientswith lymph nodes between 2 and 5 cm, and to virtually0% in patients with lymph nodes greater than 5 cm indiameter. As such, alemtuzumab may be best suited forpatients who lack bulky lymphadenopathy or who haveresolution of bulky adenopathy following treatment withother agents. For patients without bulky adenopathy,treatment with alemtuzumab may be the most effectivetherapy for eradicating minimal residual disease in themarrow after therapy.

A challenging toxicity that results from use ofalemtuzumab is immune suppression. The anti-CD52antibody is cytotoxic for both T cells and B cells, andtypically causes significant lymphopenia. Patients treatedwith alemtuzumab experience immune suppression thatenhances their risk for opportunistic infection. As such,there is a need to implement anti-microbial prophylaxisand to monitor the patient for signs or symptoms ofde novo infections, as well as reactivation of latent virusinfection, such as those caused by cytomegalovirus (CMV).

Surprisingly, the incidence of opportunistic infectionswas similar in patients within the two arms of theCAM307 trial who were treated with either alemtuzumabor chlorambucil, with the exception of reactivation ofCMV.18 Therefore, careful monitoring for CMV isneeded in patients treated with alemtuzumab.Reactivation of CMV can be difficult to diagnose asalemtuzumab-treated patients may fail to producedetectable levels of antibodies against CMV. As such,monitoring for CMV using sensitive measures suchas polymerase chain reaction (PCR) is necessary.Conceivably, patients who are seropositive for CMVinfection prior to treatment with alemtuzumab mightbenefit from preemptive therapy with valgancyclovirsimilar to that administered to solid organ transplantrecipients.20

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CASE 2 An Asymptomatic Older Patient

CZ, an 80-year-old white woman has been referred by herhematologist-oncologist for a second opinion regardingmanagement decisions/options. She was diagnosed withCLL about 5 years earlier and, since she has been symptomfree, she has been on “wait-and-watch” for these past5 years. She was in clinical stage 0 at diagnosis. About ayear prior to this consultation the lymph nodes hadbecome clinically palpable, but they have all remainedsmall in size. Her hemogram has been monitored at 3-to 6-month intervals in the past, showing normal plateletsand hemoglobin/hematocrit. However, her white bloodcell count and absolute lymphocyte count (ALC), whichwere 28,000 and 20,000 respectively at the time of initialdiagnosis, had increased steadily thereafter. At 1 year, theALC was 30,000, at 3 years it was 38,000 and now, 5 yearslater, it is 50,000. The patient has no symptoms and leadsan active life for an 80-year-old. The markers show typicalphenotype of CLL that uses a mutated IgV(H) gene andis ZAP-70 negative.


1. This patient is:

a. high risk

b. low risk

Correct Answer (b)

The patient is at low risk (Stage 1). Althoughthe patient has some lymph node enlargement,the nodes remain small in size. Platelets andhemoglobin are normal. In addition, her prognosticmarkers are favorable—mutated IgV(H) gene, andZAP-70 negative—and she is asymptomatic. Herlymphocytosis, however, has increased.

2. This patient should:

a. be placed on wait-and-watch status

b. have treatment started immediately

Correct Answer: (a)

Wait-and-watch is the preferred protocol. Studieshave shown that patients given early treatment donot have an increased life expectancy comparedwith those who are placed under observation.Notably, those patients given early treatment wereat higher risk of developing second malignancies.

3. Low-risk patients with significant symptomsshould:

a. be placed under observation

b. given a therapeutic regimen that willstop progression

c. treated with the goal of achieving acomplete response

Correct Answer: (c)

Even if prognostic markers are favorable,symptomatic low-risk patients should be placedon a therapeutic regimen with the goal of acomplete, or maximally achievable response.

4. If this low-risk patient was symptomatic, the

preferred therapy should be:

a. FCR

b. FR


Correct Answer (b):

FR is preferred in view of the advanced ageof the patient.

Low-risk CLL patients are those who are in clinicalstages zero, 1, or 2, (Table 4 on next page) and can beeither asymptomatic or symptomatic. If these patientspresent with mutated IgV(H) gene status, then theprognosis is more favorable, and a watch-and-waitprotocol can be followed. Moreover, if these patientsalso have other good prognostic markers such as negative(ZAP-70), or a del 13q as the sole aberration evident

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from a FISH panel, then the clinician should feelconfident in placing these patients under an observation-only status. Unfortunately, to date, there are no clinicaltrials that clearly define observation as the standard ofcare for these patients versus some effective treatment.

In a French study conducted several years ago,asymptomatic CLL patients were randomized to treatmentwith chlorambucil or wait-and-watch.22 It was found thatthere was no difference in overall life expectancy whetherthe patients were in the treatment or observation arm.Of note is that in the early treatment group there was ahigher incidence of second malignancies, such as epithelialcancers. As a result, most clinicians do not favor earlytreatment in low-risk patients with favorable prognosticmarkers. A trial is currently in progress (CALGB) that israndomizing asymptomatic, low-risk CLL patients withpoor prognostic markers to either early treatment withFR, or observation only. The results will be available in afew years, and until then, the recommended approach isto keep these patients under observation only.

In an asymptomatic patient with unfavorable prognosticmarkers, such as unmutated IgV(H) gene, positive ZAP-70,positive CD 38 co-expression on leukemic cells, del 11q,12 trisomy, or del(17p), the disease is likely to progresssooner, which mandates treatment intervention.

Low-risk CLL patients with symptoms are another matter.Weight loss is one such symptom, particularly a 10% loss

in baseline body weight within a period of 6 monthswithout dieting or other effort to lose weight. Profounddrenching sweats, profound fatigue that interferes withnormal lifestyle, and frequent bacterial infections requiringantibiotic intervention are also among the constellationof symptoms to monitor. If a patient in the early stage ofdisease presents with one or more of these symptoms,therapeutic intervention becomes justifiable, regardlessof prognostic marker status. It is necessary to consider,when initiating treatment for the first time, what thetherapeutic endpoint should be, that is, what is theobjective of treatment? A recent report from theinternational workshop on CLL has updated existingguidelines and criteria for diagnosis, prognosis, andtreatment of CLL.1 There is emerging evidence suggestingthat those patients who achieve a better response aremore likely to have a longer life expectancy and a betterquality of life, in addition to a longer interval before thenext treatment is required. So, whether the patients aregiven FR or FCR, for example, the objective should be toachieve a complete, or maximally achievable remissionwithout any undue toxicities.

Determining Remission Status

It would be instructive, at this point, to discuss what ismeant by a complete remission. Up until now, the principalcriterion has been the absence of clinical evidence ofdisease. Among these are absence of palpable disease,

TABLE 4 Staging of Chronic Lymphocytic Leukemia21.

Rai Lymphocytosis Lymph Node Spleen/Liver Hemoglobin <<11 g/dL Platelet <<100 x 109/L Survival (years)Enlargement Enlargement

0 Yes No No No No >13

I Yes Yes No No No 8

II Yes ± ± No No 5

III Yes ± ± Yes No 2

IV Yes ± ± ± Yes 1

This research was originally published in Hematology. Kay N, Hamblin TJ, Jelinek DF, et al. Chronic Lymphocytic Leukemia. Hematology. 2002:193-213.

© American Society of Hematology

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such as palpably enlarged lymph nodes, spleen or liver,and normalization of blood count. Recently, however,owing to the success of FR or FCR regimens to achievecomplete remission, attention is being focused on minimal residual disease (MRD) levels in patients whohave achieved complete remission by clinical criteria.Investigators are beginning to look for the presence ofresidual CLL cells in circulating blood or in the bonemarrow using two- or four-color flow cytometry, or withPCR to uncover any molecular markers of residual CLL.These tests would, of course, have to be negative to consider the remission complete. Whether such negativemolecular marker status is achievable is under investigation.At present, then, the best level of achievable clinicalremission without undue toxicity is the accepted standard.

CASE 3 A Younger Patient With High White Cell Count and Poor Prognostic Markers

MJ, a 53-year-old white male is referred by his internistbecause of a high blood white cell count discovered upona routine annual check-up. MJ had been watched by hisinternist over a period of one year before this referral. He has no symptoms and maintains an active and busyprofessional and social life. The TWBC a year ago was62,000 with an ALC of 40,000, hemoglobin, hematocrit,platelets, and neutrophils were all within normal limits.Six months later, the ALC had increased to 66,000, andnow, at the time of this referral a year after the initial discovery, the ALC had further increased to 78,000. There are still no symptoms, and the rest of the bloodcounts have remained normal. Upon examination, therewere palpably enlarged small nodes, measuring about 1 to 1.5 cm diameter in the neck, axillae, and groin bilaterally. Spleen and liver were not clinically palpable.Flow cytometry of blood lymphocytes showed a phenotypecharacteristic of CLL—CD19+, CD20+, CD23+, CD5+,lambda light chains with sIGM and sIGD positivity.IgV(H) showed unmutated genes and ZAP-70 was positive.


1. This patient is:

a. low risk

b. high risk

Correct Answer (b)

This patient has unfavorable prognostic markers—unmutated IgV(H) gene and positive ZAP 70—which implies high risk even though the patient is asymptomatic.

2. Should this patient be placed on therapy?

a. yes

b. no

Correct Answer (a)

Because of the clinical stage, and presence of unfavorable prognostic markers, this high-riskyounger patient will have more to gain by beingplaced on an aggressive therapeutic regimen.Without such aggressive treatment, the patient has a high probability of developing a more rapidly progressing disease.

3. The preferred therapy for this patient should be:

a. FCR

b. Alemtuzumab


Correct Answer (a)

FCR is preferred because 1) There is experiencewith a large number of patients, 2) The patient isrelatively young and has a good performance status, 3) Our overall objective is to try to reach acomplete remission. (b) and (c) are also goodoptions, but our experience is with a lower numberof patients.

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It should be emphasized that high-risk younger patients(age 40 to 55 years) have more to gain and less to lose byreceiving a much more aggressive approach to treatment.For these patients, prognostic markers are criticallyimportant if these patients are being categorized as highrisk because of the clinical stage and the presence ofunfavorable markers, such as an unmutated IgV(H) gene.The objective of their treatment is twofold: 1) to achievea complete clinical response, and 2) once the response hasbeen achieved, to discuss with the patient the option ofreceiving an allogeneic hemopoietic stem cell transplant(SCT); this would be a human-leukocyte-antigen (HLA)-matched sibling transplant, or if a sibling is notavailable, an unrelated HLA-matched donor transplant.

A caveat here is that these transplants should be done witha nonmyeloablative-conditioning-based treatment. Anumber of institutions are conducting prospective clinicaltrials with patients who meet these criteria to determinewhether a complete remission and good success with amarrow transplant will be of benefit.23 There are, in fact,somewhere under 100 patients who are alive today as aresult of allogeneic SCTs done with nonmyeloablativeconditioning. The reason for emphasizing nonmyeloablativeconditioning is that the success of this particular transplantmethod is based on immune modulation rather than onreplacing or seeding an aplastic marrow—that is, one that has been rendered aplastic by prior preparatorychemotherapy. As a result of myeloablative conditioning,there has been an unacceptable mortality rate (40% to50%), within 100 days of the transplant. In contrast, the mortality rate has gone down significantly with nonmyeloablative conditioning. Recently published reportsindicate that with nonmyeloablative conditioning-basedallogeneic transplants, not only is the mortality ratereduced, but also the morbidity with chronic and acutegraft-versus-host disease has been in an acceptable range,and there is rapid patient recovery.24, 25 Thus, for high-riskyounger patients, first-line options should be very aggressive, since these CLL patients have a high probabilityof dying because of the disease. A 5-year follow-up studyevaluated for factors that influence the outcomes ofpatients undergoing allogeneic transplantation for CLL.26

It was found that younger patients with no concomitant

morbidities, and without bulky disease—such as lymphnodes >5 cm in diameter—fare much better with allogeneicSCT than do patients who do not have these characteristics.

Investigational Therapies

There are investigational agents that appear to be effectivein treating elderly high-risk patients. One of these islenalidomide (Revlimid®) an immune modulator derivedfrom thalidomide, which was banned in the 1960s forcausing birth defects in the babies of pregnant womenwho were taking it as a sedative. This class of agentinhibits angiogenesis, a mechanism required by cancercells. Lenalidomide does not appear to have cytotoxiceffects against leukemic cells. In two trials of previouslytreated CLL patients, however, lenalidomide was shownto have activity in this disease.27, 28

Another group of novel agents are the BCL2 antagonists,which are involved in initiating apoptosis. As such, they may obviate the need for induction of P53, whichordinarily is required for the induced expression of pro-apoptotic molecules, such as PUMA, that are respon-sible for the cytotoxic effects of anti-leukemia drugs, such as fludarabine.29 The use of agents that can emulatethe effects of such molecules as PUMA might obviate theneed to induce P53 to provide for leukemia-cell apoptosis.

In addition, there are the newer monoclonal antibodies,such as the humanized anti-CD20 agent ofatumumab,which has striking activity, but has not been comparedwith rituximab.

Refractory or relapse patients have already been treatedwith first-line agents, and now require carefully structuredsecond-line therapeutic regimens. With regard to patientswho have fludarabine-refractory CLL, or who haveRichter’s Syndrome (RS), a group at the MD AndersonCancer Center developed a regimen that employs varyingcombinations of oxaliplatin, fludarabine, cytarabine, andrituximab combination therapy (OFAR).30 This regimenhas the advantage of reduced myelotoxicity comparedwith standard FC combinations, and has demonstratedvery strong activity in RS patients, as well as activity infludarabine-refractory CLL patients. Given the activity

13



of OFAR, particularly in patients with del(17p) and in patients older than 70 years, a larger study of OFAR is currently being pursued by this group. In high-risk elderly patients with del(17p), alkylating agents and purineanalogs do not have high activity. A retrospective review of the literature by the MD Anderson group found that there may be some heterogeneityamong these patients who have del(17p) regarding their response patterns to an FCR regimen.31

A note of caution here is that the presence of del(17p) in CLL cells does not necessarily indicate that the leukemia cell lacks functional P53.32, 33

Conversely, CLL cells that lack del(17p) can have dysfunctional P53.34 Assuch, the association between del(17p) and dysfunctional P53 is not absolute.Conceivably, the patients with CLL cells that harbored del(17p), and whohave a favorable response to chemoimmunotherapy had CLL cells with functional P53. This is possibly reflected in a retrospective analysis of theCLL4 trial patients, which found that the adverse outcome associated withdel(17p) was observed for patients who have more than 20% of theirleukemia cells harboring deletions at 17p.35 A sizable subset of patients, who had fewer than 20% of their CLL cells with del(17p) as defined by FISH analysis, had outcomes similar to those of patients who had CLL cellsthat did not have any detectable deletions at 17p. As such, patients who arenoted to have fewer than 20% of their CLL cells with del(17p) by FISHmight respond well to more standard chemoimmunotherapy regimens.

Conclusion

The management of CLL has advanced from palliative measures to newertherapeutic options such as biologic immune modulators, purine analogsand chemo-immunotherapeutic combinations. At the same time, the evolution of prognostic markers has provided for a greater degree of certaintyin applying risk-adapted first-line therapy. As a result, the perspective offirst-line treatment has changed to one in which complete remission is now a clinically realistic goal, with the possibility of increased survival time for CLL patients.

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References

1. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report

from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group

1996 guidelines. Blood. 2008;111:5446-5456.

2. Yee KWL, O’Brien SM. Chronic Lymphocytic Leukemia Diagnosis and Treatment. Mayo Clin Proc. 2006;81:1105-1129.

3. Mossafa H, Huret JL. Chronic lymphocytic leukaemia (CLL). Atlas Genet Cytogenet Oncol Haematol. August 1997.

http://AtlasGeneticsOncology.org/Anomalies/CLL.html. Accessed December 5, 2009

4. Reddy KS. Chronic lymphocytic leukaemia (CLL). Atlas Genet Cytogenet Oncol Haematol. May 2005.

http://www.infobiogen.fr/services/chromcancer/Anomalies/CLL.html. Accessed December 15, 2009

5. Southwest Medical Center, http://www8.utsouthwestern.edu/vgn/images/portal/cit_56417/12/6/341365neoplasticfish.pdf.

Accessed October 5, 2009.

6. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic

lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230-239.

7. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of

younger patients with chronic lymphocytic leukemia. Blood. 2006;107(3):885-891.

8. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for

patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25:793-798.

9. Tsimberidou AM, Tam C, Abruzzo LV, et al. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q

deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer. 2009;115:373-380.

10. Hallek M, Fingerle-Rowson G, Fink AM, et al. Immunotherapy with Fludarabine (F) Cyclophosphamide (C), and Rituximab

(R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of

Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL). American Society of Hematology.

Orlando, FL; 2008.

11. Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high

dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:498-503.

12. Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment

of chronic lymphocytic leukemia. Leukemia. 2009;23:1779-1789.

13. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for

the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008;22:2048-2053.

14. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene

mutation and resistance to chemotherapy. N Engl J Med. 2002;347 452-453.

15. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine:

results of a large international study. Blood. 2002;99:3554-3561.

16. Lundin J, Osterborg A, Brittinger G, et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade

non-Hodgkin’s lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade

Non-Hodgkin’s Lymphoma. J Clin Oncol. 1998;16:3257-3263.

17. Osterborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic

lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol.

1997;15:1567-1574.

15



18. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic

lymphocytic leukemia. J Clin Oncol. 2007;25:5616-5623.

19. James DF, Kipps TJ. Alemtuzumab in chronic lymphocytic leukemia. Future Oncol. 2007;3:29-42.

20. Diaz-Pedroche C, Lumbreras C, San Juan R, et al. Valganciclovir preemptive therapy for the prevention of cytomegalovirus

disease in high-risk seropositive solid-organ transplant recipients. Transplantation. 2006;82:30-35.

21. Kay N, Hamblin TJ, Jelinek DF, et al. Chronic Lymphocytic Leukemia. Hematology Am Soc Hematol Educ Program.

2002:193-213.

22. Grünwald HW, Rosner F. Secondary acute leukemia in chronic lymphocytic leukemia. N Engl J Med. 1998;339:924.

23. Dreger P. Allotransplantation for chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2009:602-609.

24. Delgado J, Pillai S, Phillips N. Does reduced-intensity allogeneic transplantation confer a survival advantage to patients with

poor prognosis chronic lymphocytic leukaemia? A case-control retrospective analysis. Ann Oncol. 2009;20:2007-2012.

25. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after allogeneic hematopoietic cell

transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic

lymphocytic leukemia. Blood. 2008;111:446-452.

26. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated

with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26:4912-4920.

27. Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic

lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006;24:5343-5349.

28. Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and

refractory chronic lymphocytic leukemia. Blood. 2008;111:5291-5297.

29. Mackus WJ, Kater AP, Grummels A, et al. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma

upregulation. Leukemia. 2005;19:427-434.

30. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab

combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia.

J Clin Oncol. 2008 26:196-203.

31. Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical

heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114:957-964.

32. Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently

predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia. 2009;23:117-124.

33. Thornton PD, Gruszka-Westwood AM, Hamoudi RA, et al. Characterisation of TP53 abnormalities in chronic lymphocytic

leukaemia. Hematol J. 2004;5:47-54.

34. Zenz T, Habe S, Denzel T, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic

leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective

clinical trial. Blood. 2009;114:2589-2597.

35. Rudenko HC, Else M, Dearden C, et al. Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis

of additional cytogenetic abnormalities detected by interphase fluorescence in situ hybridisation and array-based comparative

genomic hybridisation. Leuk Lymphoma. 2008;49:1879-1886.

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