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					 Spotlight on Chronic Lymphocytic Leukemia
 and Indolent Non-Hodgkin's Lymphoma:
 European and US Perspectives on the
 Evolving Standard of Care

Bruce Cheson, MD                            Mathias Rummel, MD, PhD
Professor of Medicine, Head of Hematology   Head, Department for Hematology and
Georgetown University Hospital              Medical Oncology
The Lombardi Comprehensive Cancer Center    The Justus-Liebig-University Hospital
Washington, DC                              Giessen, Germany


Kanti Rai, MD                               Clemens Wendtner, MD
Division of Hematology-Oncology             Professor of Medicine, Department of Internal
The Long Island Jewish Medical Center       Medicine and Head of Laboratory of
New York, NY                                Molecular Biology and Immunology of CLL
                                            The University Hospital of Cologne, Germany
   GCLLSG CLL8 Phase 3 Trial
   FC vs FCR
                  Median Observation Time = 37.7 months
                                   FC               FCR                  P
                               (n = 409)          (n = 408)

                      CR         21.8%              44.1%              < .001

              Median
                                32.8 mo           51.8 mo              < .001
                 PFS
                      OS         79.0%              84.1%               .01

      • The largest benefit for FCR was observed in Binet stage A and B
      • FCR did not improve the PFS or OS of patients with a del(17p)
      • FCR caused more neutropenia without increasing rate of severe infections

N = 817 (Agemed: 61 yr; Binet stage A: 5%, B: 64%, C: 32%; -17p: 8%)
Hallek M, et al. ASH 2009. Abstract 535.
   Progress in CLL Therapy
   F → FC/M → FCR
      Historical Comparison From the M.D. Anderson Cancer Center
                  Overall Survival




                                          Time, months
Tam CS, et al. Blood. 2008;112:975-980.
   FC vs FCR
   Patients With Rai III/IV CLL
       Historical Comparison From the M.D. Anderson Cancer Center
                           FC         FCR           P
                                   (n = 38)    (n = 102)

                        CR           29%         66%       .001


          Median PFS                36 mo       79 mo      .000


           Median OS                55 mo      120 mo      .004


      Compared with historical patients treated with FC, FCR was
   associated with significantly improved response rates and survival

Parikh SA, et al. ASCO 2010. Abstract. 6519.
   GCLLSG Phase 2 Trial in Advanced CLL
   Bendamustine and Rituximab as First-line Therapy
                   Median Observation Time = 15.4 months
                                                                           BR
          B (90 mg/m² on days 1 and 2)                              ORR   90.9%
          +
          R (375 mg/m² for the first cycle and                       CR   32.7%
          500 mg/m² for subsequent cycles)
                                                                     PR   55.5%
          BR administered every 28 days (6 courses max.)
                                                                     SD   9.1%
      •   In patients with unmutated IgVH, ORR = 88.9%
      •   In patients with a del(17p), ORR = 42.9%
      •   Major side effects (myelosuppression and infections) were infrequent
      •   After 18 months, PFSmed has not been reached
N = 117 (Agemed: 64 yr; Binet stage A: 11.1%, B: 41.0%, C: 47.9%)
Fischer K, et al. ASH 2009. Abstract 205.
   Bendamustine-R vs R-CHOP (StiL Trial)
   Randomized Phase 3 Study
                                 B (90 mg/m2; days 1+2)
                                          +
                                 R (375 mg/m2; day 1)     }   every 28 days

                                 6 cycles max.

                                 FL=53%, MZL=14%, WM=8%, SLL=4%, MCL=17%

    549 untreated                Stage IV (76.9%), III (19.2%)                 Primary
       patients                                                               Endpoint:
                                 R (375 mg/m2; day 1→every 28 days)
     randomized                           +                                      PFS
                                 CHOP (standard regimen, every 21 days)
                                 6 cycles max.

                                 FL=55%, MZL=12%, WM=8%, SLL=4%, MCL=19%

                                 Stage IV (77.5%), III (18.6%)
N = 549
Rummel MJ, et al. ASH. 2009. Abstract 405.
   Bendamustine-R vs R-CHOP (StiL Trial)
   Safety: Final Results
            Adverse Event                 B-R    R-CHOP     P
            Neutropenia                   10.7    46.5    < .0001
            grade 3+4 (%)
            Leukocytopenia                12.1    38.2    < .0001
            grade 3+4 (%)
            Alopecia (%)                  15.0    62.0    < .0001
            Infectious                    96      127      .0025
            complications (n)
            Paresthesia (n)               18       73     < .0001
            Stomatitis (n)                16       47     < .0001
            Urticaria and rash (n)        42       23      .0122


N = 549 (n = 513)
Rummel MJ. ASCO 2010/ASH Joint Session.
   Bendamustine-R vs R-CHOP (StiL Trial)
   Efficacy: Final Results
                                                     PFS


            B-R   R-CHOP
                                   P
          (n=260) (n=253)
   ORR     92.7%      91.3%       NA
    CR     39.6%      30.0%      .0262




      B-R has the potential to become a new standard first-line treatment option
            for patients with FL, MCL, and other indolent lymphoma types

N = 549 (n = 513)
Rummel MJ. ASCO 2010/ASH Joint Session.
Front-line Choices for Indolent NHL and CLL:
        FC, CHOP, or Bendamustine?
 Practicing physicians in the United States and
  Europe are likely to use more bendamustine
                  in the future.
   Front-line Lenalidomide
   Elderly Patients With CLL


                                                                                 ORR   60%
      5 mg orally daily for the first 56 days → titrated
      ≤ 25 mg/day as tolerated in 5-mg increments                                 CR   8%

      Every cycle (28 days)                                                      nPR   8%

                                                                                  PR   43%




N = 60
(Agemed: 71 yr; Rai stage III-IV: 30%; -17p or -11q: 33%; unmutated IgVH: 60%)
Badoux X, et al. ASCO 2010. Abstract 6508.
   Front-line Lenalidomide and Rituximab
   Patients With CLL: Early Report


      Lenalidomide started at 2.5 mg/d → 5 mg and 10 mg on day 8, if tolerated
      (L 21/35 days [cycle 1] → 21/28 days [cycles 2-7])

      Rituximab 50 mg/m2 day 29, 325 mg/m2 day 31, 375 mg/m2 day 33 (cycle 1)
      → 375 mg/m2 weekly x 4 (cycle 2) and on day 1 (cycles 3-7)


         Early results of the ongoing study suggest that lenalidomide/rituximab
                                immunotherapy is tolerable



N = 37 (n = 30)
(Agemed: 62 yr; Rai stage III-IV: 50%; -17p or -11q: 9%; unmutated IgVH: 50%)
James DF, et al. ASCO 2010. Abstract 6583.
   Lenalidomide + Rituximab
   Front-line Therapy of Indolent B-Cell NHL
                Lenalidomide (20 mg orally daily; days 1-21)
                         +
                Rituximab (375 mg/m2 IV; day 1)                }   every 28 days

                6 cycles max.

                                                    L-R
                                             ORR    86%
                                        CR + CRu    79%
                                             PR      7%
                                             SD     14%

      • After 6 cycles of therapy, 1 patients with FL achieved CR
      • The grade 3/4 AEs included rash (6 pts), neutropenia (7 pts), myalgia (4 pts),
        neuropathy (1 pt), infection (1 pt), and fatigue (1 pt), and thrombosis (1 pt)
N = 30 (n = 28; agemed: 56 yr)
Fowler N, et al. ASCO 2010. Abstract 8036.
   Ofatumumab-FC in Previously Untreated CLL
   Randomized, 2-Dose, Phase 2 Trial
   Ofatumumab (500 mg or 1000 mg)* on day 1
   +                                                                              Ofatumumab
   Fludarabine (25 mg/m2 IV daily; days 1-3)                                    Group A,   Group B,
   +                                                                             500 mg    1000 mg
   Cyclophosphamide (250 mg/m2 IV daily; days 1-3)                              (n = 31)   (n = 30)

   Administered every 28 days (6 courses max.)                         ORR        77%        73%
   *In both groups, the first dose of ofatumumab was 300 mg

                                                                           CR     32%        50%

       • O-FC is highly active at both ofatumumab doses investigated
       • AEs were manageable with no unexpected toxicities
       • After 8 months, PFSmed has not been reached

N = 61 (Agemed: 56 yr; Rai stage III/IV: 39% [Gr. A], 53% [Gr. B];
-17p: 6% [Gr. A], 20% [Gr. B]; unmutated IgVH: 52% [Gr. A], 30% [Gr. B])
Wierda WG, et al. ASCO 2010. Abstract 6520.
 Novel Options for Rituximab-Refractory
                Patients
Another Anti-CD20 mAb Probably Not the Right
                  Solution
   O-CHOP in Previously Untreated FL
   Randomized, 2-Dose, Phase 2 Trial
  Ofatumumab (1500 mg or 1000 mg)* on day 1
  +                                                                     Ofatumumab
  Cyclophosphamide (750 mg/m2; day 3)                                  Group A,   Group B,
  +                                                                    1500 mg    1000 mg
  Doxorubicin (50 mg/m2; day 3)                                        (n = 29)   (n = 29)
  +
  Vincristine (1.4 mg/m2; day 3)                                ORR      90%       100%
  +
  Prednisolone (100 mg; days 3-7)
                                                            CR + CRu     69%        55%
  Administered every 3 weeks (6 courses max.)
 *In both groups, the first dose of ofatumumab was 300 mg
       • At median follow-up of 9.7 months, high response rates achieved
       • Effective across all FLIPI risk groups
       • Well tolerated with no unexpected toxicities
N = 59 (n = 58; agemed: 55 yr [Gr. A], 54 yr [Gr. B};
FLIPI score 3-5: 34% [Gr. A], 38% [Gr. B])
Czuczman M, et al. ASCO 2010. Abstract 8042.
   Phase 2 VERTICAL Study
   VBR in Patients With Relapsed or Refractory FL
   V (1.6 mg/m2 ; days 1, 8, 15, 22)
   +                                                                                      VBR
   B (90 mg/m2 ; days 1, 2)
   +                                                                                ORR   84%
   R (375 mg/m2 ; days 1, 8, 15, 22, cycle 1;               Preliminary
   day 1, cycles 2-5)                                                               CR    47%
                                                              Results
   5 (35 days) cycles max.                                                          PR    37%


       • The most common treatment-related AEs were primarily grade 1 and 2 and
         included nausea (79%), fatigue (65%), diarrhea (57%), and vomiting (44%)
       • Of the 27% pts with treatment-related PN, only 6% had grade 3 (no grade 4)
       • VBR is active in this heavily pretreated, high-risk population and is
         generally well tolerated


N = 63 (≥ 4 doses of R, but no V or B; 39% refractory to R; 35% high FLIPI score)
Fowler N, et al. ASH 2009. Abstract 933.
   PRIMA Phase 3 Study
   Rituximab Maintenance Therapy in Untreated FL




                 2 years of rituximab maintenance therapy after induction
               immunochemotherapy in previously untreated FL significantly
                         improves PFS with little additional toxicity
N = 1217
Salles GA, et al. ASCO 2009. Abstract 8004.
Evolving Standard of Care
European and US Perspectives
 • Cross-fertilization between the US and Europe
    –   Europe → US: bendamustine
    –   US → Europe: lenalidomide
    –   Europe: large randomized trials
    –   US: new drug development
 • Strategic planning between European and
   US investigators
    – Avoid duplication of studies
    – Move toward the more efficient development of better
      treatment regimens
    – Improve patient outcomes

				
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posted:3/10/2011
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