Chronic Lymphocytic Leukemia: Clinical Correlates and Issues Daniel A. Nikcevich, MD, PhD Duluth Clinic Cancer Center May 13, 2008.

Chronic Lymphocytic Leukemia:Clinical Correlates and Issues

Daniel A. Nikcevich, MD, PhDDuluth Clinic Cancer Center

May 13, 2008

• Chronic lymphocytic leukemia (CLL)– Diagnosis– Clinical features– Pathophysiology– Therapy

Chronic lymphocytic leukemia

• Most common leukemia in adults

• Median age diagnosis 65 years

• Median survival 9 years

• Allogeneic stem cell transplant only curative therapy

• Decision to treat based on age, performance status, symptoms, disease stage

Pathophysiology

• CLL is an uncontrolled clonal accumulation of mature lymphocytes.

• Unclear mechanisms of initiation

• Molecular characterization of CLL correlates with clinical outcomes

• Mutated Ig VH genes

• Unmutated Ig VH genes

Diagnosis• istory and physical examination

• CBC and peripheral blood film– Need absolute lymphocytosis > 5000/ml

• Flow cytometry

• Cytogenetics (FISH)

• CT C/A/P (as indicated)

• Bone marrow biopsy (as indicated)

Diagnosis

• Flow cytometry:– CD5+CD19+CD20+CD23+

• DDx: follicular lymphoma or mantle cell lymphoma with leukemic phase, prolymphocytic leukemia, SLVL, HCL

• Mantle cell lymphoma is a nasty, aggressive NHL– CD5+CD23- cyclinD1+

• What’s the difference between CLL and SLL (small lymphocytic lymphoma)?– the tissue phase of CLL.

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2003;2003:100690

Figure 1. This peripheral smear shows that there can be heterogeneity in the appearance of the abnormal lymphocytes in CLL

Clinical Features of CLL

• Often an incidental diagnosis in an asymptomatic patient.

• Indolent disease common• Progressive adenopathy often correlates with

symptoms: fatigue, malaise, weight loss, fevers• Progressive bone marrow involvement leads to

severe cytopenias, increase risk infection• Autoimmune sequelae and Richter’s

transformation are long-term complications

Autoimmune Complications of CLL

• AIHA– Coombs’ positive

• Pure red cell aplasia

• ITP

• Neutropenia

Staging

• Rai system• Rai 0: lymphocytosis

• Rai 1: lymphadenopathy

• Rai 2: splenomegaly

• Rai 3: HgB < 11 g/dL

• Rai 4: platelets < 100K

• Binet system• A: lymphocytosis +/- 1-3

sites lymphadenopathy

• B: lymphocytosis with > 3 sites lymphadenopathy

• C: lymphocytosis + anemia and/or thrombocytosis

Why is staging important?

• Rai staging• Rai 0: lymphocytosis

• Rai 1: lymphadenopathy

• Rai 2: splenomegaly

• Rai 3: HgB < 11 g/dL

• Rai 4: platelets < 100K

• Median survival• > 10 years

• 7 years

• 2-5 years

Poor Prognostic Factors

• Advanced stage at diagnosis• Rapid lymphocyte doubling time• Diffuse marrow infiltration• Advanced age/male gender• CLL-PLL (secondary PLL)• Abnormal karyotype• Elevated 2-microglobulin, soluble CD23• CD38+ or ZAP-70+

CLL-cytogenetic abnormalities

• 13q-

• Normal karyotype

• Trisomy 12

• 11q-

• 17p-

• ALWAYS get FISH studies with CLL

Fig 1. Kaplan-Meier survival curve comparing CLL patients with mutated and unmutated VH genes. CLL: 117 months; median survival for mutated CLL: 293 months. The difference is significant at the P = .001 level (log-rank test).

What if our lab is unable to perform Ig gene mutation studies?

• CD38 may be a surrogate marker for Ig gene mutations.– Detect via flow cytometry (easily)– CD38+ = unmutated Ig genes = poorer prognosis– CD38- = mutated Ig genes = better prognosis

• CD38+: 9 year median survival

• CD38-: >20 years median survival

ZAP-70 expression

• Correlates with Ig VH gene mutations

• Correlates CD38+ expression

• ZAP-70+ = Poorer prognosis

Crespo, M. et. al. N Engl J Med 2003;348:1764-1775

Correlation of the Level of Expression of ZAP-70 and Immunoglobulin Heavy-Chain Variable-Region (IgVH) Mutational Status (Panel A) and IgVH Sequence Homology (Panel B)

Therapy of CLL: When to Treat?

• Constitutional symptoms• Progressive lymphocytosis• Progressive lymphadenopathy• Progressive splenomegaly• Progressive bone marrow failure• Autoimmune complications• Richter’s transformation or secondary PLL• Your patient is uncomfortable with observation

Therapeutic Options for CLL• Corticosteroids• Alkylating agents

– Chlorambucil– Cyclophosphamide

• Nucleoside analogs– Fludarabine– Pentostatin

• Monoclonal antibodies– Rituximab (anti-CD20)– Alemtuzumab (anti-CD52)

• Combination chemotherapy– PCR– FCR

• Allogeneic stem cell transplantationcell transplantation

What’s the best way to treat CLL?• Indication to treat• Prognostic factors (stage, CD38 expression, ZAP-70, etc.)• Younger, good PS patients

– Clinical trial– PCR or FCR– Best response rates and chance of molecular remission– CAMPATH for purine-analog resistant disease

• Older, more frail patients– Chlorambucil (+/- prednisone)

• Allogeneic transplant the only curative modality for CLL– Need matched-sib donor– Substantial morbidity/mortality– The price of curing CLL is GVHD. Is that acceptable?

Patient L.P.

• 60 yo female in excellent health• Routine exam with new primary care physician.• CBC

– WBC 43K

– HgB 14.0 g/dL

– Plts 350K

– Flow cytometry shows CLL, CD38-

– FISH with 13q-

• Now what?

• Observation

Patient H.S.

• 57 yo male previously in good health• 3 months of fevers, night sweats• What’s next?• HISTORY• Exam• Speaks with hoarse voice• Adenopathy in submandibular, submental, anterior

cervical, supraclavicular, axillary regions. No splenomegaly

• Any tests that you wish to order?

• CBC

• WBC 35K

• HgB 13.7 g/dL

• Plts 135K

• Flow cytometry shows CLL, CD38+

• FISH trisomy 12

• Thoughts?

• Symptomatic disease.

• Needs treatment.

• Clinical trial option?

• I treated him with PCR

• Entered into complete remission with resolution of trisomy 12

Patient W.E.• 47 yo male with known h/o CLL• Initial treatment with FCR and entered into complete

remission for 3 years• Relapse and then treatment with Campath with complete

remission obtained.• Feels well, asymptomatic• Exam normal• CBC

– WBC 26K– HgB 11.3 g/dL– Plts 175K

• What’s next?

• Secondary prolymphocytic leukemia– Richter’s transformation– New 17p-

• Poor prognostic sign

• Demonstrated refractory disease with BM failure and severe cytopenias

Patient W.S.

• 65 yo female with known CLL

• Previous treatment with fludarabine and entered into CR

• PMHx CAD, COPD, DM, HTN

• Notes fatigue, DOE

• What’s next?

• HISTORY

• Generalized fatigue. No PND or orthopnea. No cough. No F/C/NS. No change in medications.

• What’s next?• Exam• Pale, appears tired. Afebrile, 116/76, HR 102, RR

14• Neck veins flat, lungs CTA, RRR, no murmur, no

S3, no HJR, no LE edema

• Any tests?

• CBC– WBC 5.4– Hgb 8.8 g/dL– Plts 274K

• Diagnosis?

• Autoimmune hemolytic anemia

• Common auto-immune sequel of CLL

• Presence of AIHA does NOT necessarily correlate with disease activity

• Treated successfully with prednisone

Patient W.B.

• 52 yo male with known CLL• Treated with PCR x 6 cycles. Obtains complete

remission with absence of presenting 11q-• Arrives to office w/o app’t with cc of fevers• HISTORY• Drenching sweats, fevers.• Recent return to Duluth from travel to Australia,

Africa, Europe

• 40o C, 122/86, HR 116, RR 18• No adenopathy, no splenomegaly• CBC

– WBC 15K– HgB 12.9 g/dL– Plts 307K

• Normal chemistries• What’s next?

• Diagnosis?

• questions?

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