Abstract 208

Background:

Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial.

Methods:

All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course.

Results:

A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months.

Patient CharacteristicN%CR%ORTTP (mo)
All Evaluable 59 70 92 38 
Age <60 yrs 33 70 88 32 
 61–70 yrs 26 73 100 38 
Sex Male 44 66 91 32 
 Female 15 87 100 39+ 
Rai Stage I– II 29 72 93 32 
 III–IV 30 70 93 42+ 
ECOG PS 0 13 69 85 32 
 1–2 46 71 96 38 
WBC (x 109/L) ≤ 50 17 70 88 42+ 
 51–150 25 72 92 32 
 >150 17 70 100 28 
β2-microglobulin (mg/L) 4–5.0 25 72 100 38 
 >5.0 34 70 88 42+ 
IgVH Mutated (>2%) 20 70 100 42+* 
 Unmutated (<2%) 37 73 92 33* 
Cytogenetics (FISH) Del 17p 14 57 78 18 
 Del 11q 10 80 90 27 
 Trisomy 12 15 93 100 42+ 
 None 9 55 100 42+ 
 Del 13q (sole) 11 64 100 42+ 
CD 38 expression ≤ 30% 38 63 95 38 
 >30% 21 86 90 28 
ZAP 70 Positive (≥20%) 33 57 82 32 
 Negative (<20%) 16 94 100 42+ 
Patient CharacteristicN%CR%ORTTP (mo)
All Evaluable 59 70 92 38 
Age <60 yrs 33 70 88 32 
 61–70 yrs 26 73 100 38 
Sex Male 44 66 91 32 
 Female 15 87 100 39+ 
Rai Stage I– II 29 72 93 32 
 III–IV 30 70 93 42+ 
ECOG PS 0 13 69 85 32 
 1–2 46 71 96 38 
WBC (x 109/L) ≤ 50 17 70 88 42+ 
 51–150 25 72 92 32 
 >150 17 70 100 28 
β2-microglobulin (mg/L) 4–5.0 25 72 100 38 
 >5.0 34 70 88 42+ 
IgVH Mutated (>2%) 20 70 100 42+* 
 Unmutated (<2%) 37 73 92 33* 
Cytogenetics (FISH) Del 17p 14 57 78 18 
 Del 11q 10 80 90 27 
 Trisomy 12 15 93 100 42+ 
 None 9 55 100 42+ 
 Del 13q (sole) 11 64 100 42+ 
CD 38 expression ≤ 30% 38 63 95 38 
 >30% 21 86 90 28 
ZAP 70 Positive (≥20%) 33 57 82 32 
 Negative (<20%) 16 94 100 42+ 
*

p-value 0.01;

p-value 0.001; + = median not reached

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Conclusion:

CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR.

Disclosures:

Keating:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

Topics:
alemtuzumab, chronic b-cell leukemias, chronic lymphocytic leukemia, cyclophosphamide, fludarabine, rituximab, brachial plexus neuritis, infections, cmv reactivation, follow-up

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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