CALGB 10404 - "A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients with Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia"

Treatment Plan    (Supplied Drug:  Lenalidomide)

NOTES: 

1)  The embedded companion CALGB 20702 (Leukemia Correlative Study), is part of the main study and does not need additional consent.  It is MANDATORY.

2)  Bi-weekly teleconference of all sites is required for 1st 20 pts enrolled on Arms B & D.

3)  ALL pts must be re-registered prior to initiation of Cycle 2 to ensure proper tx assignment, based on presence or absence of del(11q22.3).

4)  Each site must have two trained counselors available for counseling all patients receiving Lenalidomide.  Training is provided free by Celgene.  Training certificate must be provided.  Lenalidomide may not be ordered until trained counselor information is provided. 

REGISTRATION / RANDOMIZATION*

Remission Induction (Months 1-6 [28 days cycles])

See protocol for pre-medication regimen & infusion rates

Arm A (Remission Induction Therapy w/Fludarabine + Rituximab)

Rituximab:  3 infusions during Cycle 1, then once per cycle thereafter

50mg/m2, IV over 4 hrs, Day 1 of Cycle 1

325mg/m2, IV, Day 3 of Cycle 1

375mg/m2, IV, Day 5 of Cycle 1

375mg/m2, single IV, Day 1 of Weeks 5, 9, 13, 17, & 21

Fludarabine Monophosphate:  25mg/m2/day, IV over 30 mins, after Rituximab on Days 1-5 of each tx cycle (40mg/m2/day for PO Fludarabine)

     â

Observe x 3 months (Months 7-9)

     â

Assess response & minimal residual disease (Month 10)**

     â

Assess response & minimal residual disease (Month 25)***

Arm B (Remission Induction Therapy w/Fludarabine + Rituximab à Remission Consolidation Therapy w/Lenalidomide)

Rituximab:  3 infusions during Cycle 1, then once per cycle thereafter

50mg/m2, IV over 4 hrs, Day 1 of Cycle 1

325mg/m2, IV, Day 3 of Cycle 1

375mg/m2, IV, Day 5 of Cycle 1

375mg/m2, single IV, Day 1 of Weeks 5, 9, 13, 17, & 21

Fludarabine Monophosphate:  25mg/m2/day, IV over 30 mins, after Rituximab on Days 1-5 of each tx cycle (40mg/m2/day for PO Fludarabine)

     â

Observe x 3 months (Months 7-9)

     â

Assess response & minimal residual disease (Month 10)**

Begin Remission Consolidation Therapy

Lenalidomide:  5mg/day, PO, Days 1-21, Month 1

Lenalidomide:  10mg/day, PO, Days 1-21, Months 2-6, continued x 6 mos

     â

Completion of Consolidation Therapy (Month 15)#

     â

Assess response & minimal residual disease (Month 25)***

Arm C (Remission Induction Therapy w/Fludarabine + Cyclophosphamide + Rituximab)

Rituximab:  3 infusions during Cycle 1, then once per cycle thereafter

50mg/m2, IV over 4 hrs, Day 1 of Cycle 1

325mg/m2, IV, Day 3 of Cycle 1

500mg/m2, single IV, Day 1 of Weeks 5, 9, 13, 17, & 21 (non-standard dose - may require prolonged administration)

Fludarabine Monophosphate (prior to Cyclophosphamide, pts <70 yrs):  25mg/m2, IVPB over 30 mins after Rituximab, Days 1-3 of each cycle (40mg/m2/day for PO Fludarabine)

Fludarabine Monophosphate (prior to Cyclophosphamide, pts >=70 yrs):  20mg/m2, IVPB over 30 mins after Rituximab, Days 1-3 of each cycle (32mg/m2/day for PO Fludarabine)

Cyclophosphamide (after Rituximab, pts <70 yrs):  250mg/m2/day, IVPB over 30 mins, Days 1-3 of each cycle

Cyclophosphamide (after Rituximab, pts >=70 yrs):  150mg/m2/day, IVPB over 30 mins, Days 1-3 of each cycle

     â

Observe x 3 months (Months 7-9)

     â

Assess response & minimal residual disease (Month 10)**

     â

Assess response & minimal residual disease (Month 25)***

Arm D (Remission Induction Therapy w/Fludarabine + Cyclophosphamide + Rituximab)

Months 2-6 (after 1 cycle of tx on Arms A or B & del(11q22.3) reassignment)

Rituximab:  500mg/m2, single IV, Day 1 of Weeks 5, 9, 13, 17, & 21 (non-standard dose - may require prolonged administration)

Fludarabine Monophosphate (prior to Cyclophosphamide, pts <70 yrs):  25mg/m2, IVPB over 30 mins after Rituximab, Days 1-3 of each cycle (40mg/m2/day for PO Fludarabine)

Fludarabine Monophosphate (prior to Cyclophosphamide, pts >=70 yrs):  20mg/m2, IVPB over 30 mins after Rituximab, Days 1-3 of each cycle (32mg/m2/day for PO Fludarabine)

Cyclophosphamide (after Rituximab, pts <70 yrs):  250mg/m2/day, IVPB over 30 mins, Days 1-3 of each cycle

Cyclophosphamide (after Rituximab, pts >=70 yrs):  150mg/m2/day, IVPB over 30 mins, Days 1-3 of each cycle

     â

Observe x 3 months (Months 7-9)

     â

Assess response & minimal residual disease (Month 10)**

Begin Remission Consolidation Therapy

Lenalidomide:  5mg/day, PO, Days 1-21, Month 1

Lenalidomide:  10mg/day, PO, Days 1-21, Months 2-6, continued x 6 mos

     â

Completion of Consolidation Therapy (Month 15)#

     â

Assess response & minimal residual disease (Month 25)***

Eligibility

• Absolute lymphocytosis of >5000/uL

  • Morphologically, lymphocytes must appear mature w/<55% prolymphocytes.

  • BM exam must include at least a unilateral aspirate & bx.  Aspir smear must show >30% of all nucleated cells to be lymphoid OR BM core bx must show lymphoid infiltrates compatible w/marrow involvement by CLL.  Overall celluarity must be normocellular or hypercellular.

  • Local institution lymphocyte phenotype must reveal predominant B-cell monoclonal population sharing B-cell marker (CD19, CD20, CD23) w/the CD5 antigen, in the absence of other pan-T cell markers.  Also, B-cells must be monoclonal in expression of either kappa or lambda and have surface immunoglobulin expression of low density.  Pts w/bright surface immunoglobulin levels must have CD23 co-expression.

• Symptomatic & active intermediate- or high-risk categories of modified 3-stage Rai staging system:

  • Intermediate Risk (Rai Stg I):  L + enlarged lymph nodes (LN)

  • Intermediate Risk (Rai Stg II):  L + spleen &/or liver (LN + or -)

  • High Risk (Rai Stg III):  L + anemia (Hgb <11gm/dL)

  • High Risk (Rai Stg IV):  L + thrombocytopenia (platelets <100,000/uL)

• Pts in intermediate-risk group must have active disease (>1 of following): 

  • Massive or progressive splenomegaly, hepatomegaly, &/or lymphadenopathy

  • Wt loss >10% over past 6 mos

  • Grade 2 or 3 fatigue

  • Fever >100.5^oF or night sweats >2 wks w/o evidence of infection

  • Progressive lymphocytosis w/increase of >50% over 2 mo period or anticipated doubling time of <6 mos

• No prior therapy for CLL, including no corticosteroids for autoimmune complications developing since initial CLL dx).

• No medical condition requiring chronic uses of oral corticosteroids.

• Age >18.

• Perf status 0-2.

• HIV pts may be eligible if: 

  • no evidence of infection w/HepB or C

  • CD4+ cell count >350/mm3

  • no evidence of resistant strains of HIV

  • if not on anti-HIV therapy, an HIV viral load <10,000 copies HIV RNA/mL

  • if on HIV therapy, HIV viral load <50 copies HIV RNA/mL

  • no hx of AIDS-defining condition

  Pts receiving concurrent Zidovudine or Stavudine are not eligible.

• No pregnant or nursing women.  Men/Women of reproductive potential randomized to Arm B or reassigned to Arm D must adhere to protocol's contraception requirements.  Women must have negative urine or serum pregnancy test (if applicable) w/sensitivity >=25 mIU/mL ,10-14 days prior to beginning Lenalidomide consolidation therapy & w/i 24 hrs prior to 1st dose of Lenalidomide consolidation therapy.

• Creat <1.5x ULN.

• PRESTUDY REQUIREMENTS:

  Within 16 days pre-regist:   All bloodwork, H&P

  Within 42 days pre-regist:   BM aspir & bx; any xray, scan, or US of uninvolved organs not used for tumor msmt

  • H&P, progress notes, ht, wt, BSA, perf status, tumor msmt

  • CBC/diff/platelets

  • Serum creat, CrCl (estim by Cockroft-Gault formula), BUN

  • Serum lytes

  • Uric acid/glucose/phosphate/Ca++

  • SGOT, SGPT, alk phos, bili

  • LDH, albumin

  • T3, T4, TSH

  • Quant immunoglobulins

  • Direct antiglobulin test

  • b2 microglobulin

  • Varicella Zoster IgG & CMV IgG (optional, but strongly recommended)

  • Serum or urine HCG (if applicable)

  • HBsAg, HBsAb, Hep C, HB core antibody (pts at high risk of Hep B should be screened b/f starting tx)

  • PB immunophenotyping*

  • PB immunophenotyping for CD4, CD8, & CD19*

  • CT (chest, abdomen, & pelvis)

  • Correlative science sample submission (embedded companion CALGB 20702 [Leukemia Correlative Studies] is MANDATORY [BM aspir & blood])#

  • BM aspir & bx**

  • Central histologic review (mandatory)**

  *      For dx & response asmt (must include CD5, CD19, CD 20, CD23, surface immunoglobulins).  CD16, CD20, CD56, CD19/CD5, CD38, & CD52 are recommended but not required (CD19/CD5 denotes co-expression of surface markers on same cell). 

  **    Submit w/i 1-2 wks of sampling & collect prior to initiation of therapy:  3 air-dried, unstained BM smears (films) & 6 unstained blood smears (films) for confirmatory cytologic & cytochemical studies.  Also submit 3 unstained BM bx sections (if aspirate could not be obtained, submit 2 unstained BM bx touch preparations).  Include final path, cytochemistry, cytogenetic, & immunophenotyping reports (if possible).  Give priority of marrow collection to CALGB 9665 tissue bank collection, if applicable (strongly encouraged).  Minimize amount of marrow in each smear.

  #     5mL BM aspir & either 30mL perip blood (if WBC >100,000/uL) or 50mL perip blood (if WBC <100,000/uL) in green-top (heparin) tubes.  Ship same day as obtained to:  CALGB Leukemia Tissue Bank (Attn:  Michael Caligiuri, MD); Columbus, OH.  All pts will undergo interphase cytogenetic screening of CLL cells using specimens submitted for CALGB 20702.  Within 10 business days, investigator will be notified if del(11q22.3) is present in >20% of cells. 

• Signed informed consent.