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Yirnhl_10_cll-sll_ppt_v5si_iphone.ppt

Addition of Rituximabto Fludarabine andCyclophosphamide in Patientswith CLL: A Randomized,Open-Label, Phase III Trial Hallek M et al.
> In patients with CLL, the low expression of CD20 antigen on the leukemic cells (Blood 2001;98:3383) and poor responserates have raised concern regarding the clinical benefits of Rin this particular setting (Blood 2001;98:1326).
> The use of higher doses of R has improved response rates in CLL (JCO 2001;19:2165), and Phase II trial data suggest thatthe combined use of R with chemotherapy may provideadditive or synergistic effects (Blood 2002;100:3115; JCO2005;23:4079).
> Current study objective: – Evaluate the safety and efficacy of combined fludarabine (F), cyclophosphamide (C) and R as first-line therapy for advanced,symptomatic CLL.
Hallek M et al. Lancet 2010;376:1164-74.
German CLL Study Group Phase IIIOpen-Label Trial Chemotherapy (CT) Age 30 to 81 yrsBinet Stage C or confirmed active disease in Binet Stage A or B R 375 mg/m2, d0, cycle 1  500 mg/m2, d1, q4wk, Hallek M et al. Lancet 2010;376:1164-74.
Three-Year Progression-Free Survival (PFS)for All Patients and Subgroups All (n = 817)
Del(17p) (n = 51) Del(11q) (n = 142) Trisomy 12 (n = 61) Del(13q) (n = 224) IgVH mutated (n = 229) IgVH unmutated (n = 390) Median PFS: 51.8 mo (CIT) vs 32.8 mo (CT) Hallek M et al. Lancet 2010;376:1164-74.
Response in All Patients and Subgroups All (n = 817)
Del(17p) (n = 51) Del(11q) (n = 142) Trisomy 12 (n = 61) Del(13q) (n = 224) IgVH mutated (n = 229) IgVH unmutated (n = 390) CR = complete remission Hallek M et al. Lancet 2010;376:1164-74.
Grade 3/4 Hematologic Adverse Events (AEs) Thrombocytopenia Autoimmune hemolytic Hallek M et al. Lancet 2010;376:1164-74.
> The addition of fludarabine and cyclophosphamide to rituximab was associated with substantial increases in complete remissionand progression-free survival at 3 years.
– CR, 44% (CIT) vs 22% (CT); P<0.0001 – 3-year PFS, 65% (CIT) vs 45% (CT); P<0.0001 > CIT also improved the 3-year overall survival (data not shown).
– OS, 87% (CIT) vs 83% (CT); P=0.012 > The incidence of Grade 3/4 adverse events was similar in both groups, with the exception of neutropenia and leukocytopenia(higher with CIT).
> These data may help establish a new treatment model for first- line treatment of CLL in physically fit patients.
Hallek M et al. Lancet 2010;376:1164-74.
DR FOSS: This is the long-term follow-up of the randomized
study evaluating the FCR chemotherapy regimen. The FCR
arm remained superior, with higher overall response rates and
more complete remissions. The median PFS was 51.8 months
for the FCR arm versus 32.8 months for the FC arm.
Most importantly, the OS rates are also clinically andstatistically superior with the FCR regimen. More hematologicalAEs occurred in the FCR arm. This is the first CLL trial that hasclearly demonstrated a survival improvement with up-fronttherapy.
Bendamustine Combined withRituximab (BR) in First-Line Therapyof Advanced CLL: A MulticenterPhase II Trial of the German CLLStudy Group (GCLLSG) Fischer K et al.
Proc ASH 2009;Abstract 205.
> Bendamustine is an alkylating agent that causes cell-cycle inhibition, ultimately resulting in apoptosis (Am J Health SystPharm 2010;67(9):713).
> Bendamustine monotherapy has shown significant activity in patients with untreated chronic lymphocytic leukemia and isFDA approved in this setting (JCO 2009;27:4378).
> In vitro studies have demonstrated a synergistic effect with bendamustine and rituximab (BR) combination therapy (ProcASCO 2005;Abstract 6565).
> Current study objective: – Assess the efficacy and toxicity of BR in previously untreated Fischer K et al. Proc ASH 2009;Abstract 205.
CLL2M: Phase II Study Design B 90 mg/m2 d 1-2+ R 375 mg/m2 (cycle 1) B 90 mg/m2 d 1-2 + R 500 mg/m2 1 cycle = 28 days Fischer K et al. Proc ASH 2009;Abstract 205.
Efficacy Data (median follow-up 15.4 months) Clinical Response (n = 110)
Overall response rate (ORR) Complete response Nodular partial response Partial response Median progression-free survival After 18 months, 75.8% of the patients were still in remission.
Fischer K et al. Proc ASH 2009;Abstract 205.
Responses According to Cytogenetics Fischer K et al. Proc ASH 2009;Abstract 205.
Grade 3/4 Adverse Events (n = 114) % of cycles
* Treatment-related mortality occurred in 2.6% of the patients.
Fischer K et al. Proc ASH 2009;Abstract 205.
> Bendamustine and rituximab combination therapy is tolerable and effective as first-line treatment for patients with CLL: – Median PFS: Not reached > The major side effects, myelosuppression and infections, were not frequent.
> A Phase III study evaluating bendamustine and rituximab combination therapy in comparison to fludarabine-basedimmunochemotherapy (FCR) for first-line treatment of CLL iscurrently under way (NCT00769522).
Fischer K et al. Proc ASH 2009;Abstract 205; www.clinicaltrials.gov.
DR FOSS: This study investigated up-front bendamustine and
rituximab in untreated CLL. The regimen shows good activity
with an overall response rate of more than 90 percent, and
75 percent of patients are still in remission at 18 months of
follow-up. Among the high-risk genetic subgroups, patients
with 11q-minus subtype had a high remission rate, with an
ORR of more than 90 percent. These data support up-front
bendamustine/rituximab as a reasonable regimen in the
setting of untreated CLL.
DR VOSE: The results show bendamustine/rituximab to be an
effective and safe first-line treatment for CLL. A randomized
trial comparing this regimen to fludarabine-based chemo-
immunotherapy is under way.
Ofatumumab Combinedwith Fludarabine andCyclophosphamide (O-FC) ShowsHigh Activity in Patients withPreviously Untreated CLL Wierda WG et al.
Proc ASH 2009;Abstract 207.
> Chemoimmunotherapy regimens have become standard therapy for patients with chronic lymphocytic leukemia (CLL).
> Ofatumumab, a human monoclonal antibody that targets a unique small loop epitope on CD20 cells, elicits complement-dependent cytotoxicity and antibody cellular-dependentcytotoxicity in vitro.
> Recent studies of single-agent ofatumumab have shown high overall response rates in patients with refractory CLL, and itis FDA approved in this setting (Blood 2008;111:1094; J ClinOncol 2010;116:1831).
> Current study objective: – Evaluate the efficacy and tolerability of two different doses of O-FC in untreated CLL.
Wierda WG et al. Proc ASH 2009;Abstract 207.
Multicenter Phase II Study of O-FC inPreviously Untreated CLL Eligibility (N = 61)

18 years with previously untreated CLL, CD5+/20+/23+ (1996 NCI-WG criteria) Lymphocyte count >5 x 109/L No CLL transformation Follow-up at mo 1, mo 3 No CNS involvement No HIV positivity and q3 mos thereafter Cycle 1: Ofatumumab 300 mg, d1; fludarabine 25 mg/m2, d2-4;cyclophosphamide 250 mg/m2, d2-4; Cycles 2-6: Ofatumumab 500 or 1,000mg, d1; fludarabine 25 mg/m2, d1-3; cyclophosphamide 250 mg/m2, d1-3 Wierda WG et al. Proc ASH 2009;Abstract 207.
Efficacy Results* OF-C 500 mg
OF-C 1,000 mg
Complete response (CR) Nodular partial response Overall response rate (ORR)
* 1996 NCI-WG criteria used Wierda WG et al. Proc ASH 2009;Abstract 207.
Efficacy by Cytogenetic Characteristics andTreatment Received All patients
Wierda WG et al. Proc ASH 2009;Abstract 207.
OF-C 500 mg
OF-C 1,000 mg
Grade 3/4 Adverse Events
Febrile neutropenia Herpes virus infection Respiratory infection Unspecified infection Wierda WG et al. Proc ASH 2009;Abstract 207.
> O-FC was highly active at both doses in patients with previously untreated CLL.
– ORR: 73% (1,000 mg); 77% (500 mg) – CR: 32% (500 mg); 50% (1,000 mg) > Myelosuppression is the most common toxicity.
> Time-to-event endpoint analyses are ongoing.
> Adverse events were manageable with no unexpected toxicities.
> Other studies are under way to evaluate ofatumumab 1,000 mg in combination with chemotherapy in patients with CLL(NCT01125787, NCT01131247).
Wierda WG et al. Proc ASH 2009;Abstract 207; www.clinicaltrials.gov.
DR FOSS: This Phase II study shows that ofatumumab
combined with fludarabine and cyclophosphamide is significantly
active in the up-front treatment of CLL. However, the therapy
has not been compared to FCR, which is considered the
standard treatment for these patients.
DR VOSE: The toxicities were easily managed, with
hematological toxicity being the major one. It was believed that
the 1,000-mg dose of ofatumumab is perhaps a bit better based
on this small study, and that dose is currently going forward in
larger trials.
A Phase II Study of Lenalidomideas Initial Treatment ofElderly Patients with ChronicLymphocytic Leukemia Badoux X et al.
Proc ASCO 2010;Abstract 6508.
> The majority of patients with chronic lymphocytic leukemia (CLL) are older than age 70.
> No standard treatment has been established for elderly patients with CLL.
> Elderly patients with CLL are under-represented in clinical trials and experience increased toxicity fromchemoimmunotherapy.
> Lenalidomide is an immunomodulatory drug that is administered orally and is active in patients with relapsed CLL(JCO 2006;24:5343, Blood 2008;111:5291).
> Current study objective: – To evaluate the activity of single-agent lenalidomide as front-line therapy for elderly patients with CLL.
Badoux X et al. Proc ASCO 2010;Abstract 6508.
Phase II Study of Lenalidomide in ElderlyPatients with CLL Eligibility (N = 60)
Untreated and symptomatic CLL Lenalidomide 5 mg/day x 2 cycles (56 days) Increase by 5 mg/cycle (28 days) if well tolerated to maximum 25 mg/day Treatment continued until disease progression Allopurinol 300 mg PO QD days 1-14 (cycle 1) No mandated antibiotic, antiviral, DVT or tumor flare prophylaxisResponse assessed at the end of cycle 3 and then every 6 cycles Badoux X et al. Proc ASCO 2010;Abstract 6508.
Overall response rate (ORR) Complete response (CR)/CRi Nodular partial response (nPR)/PR Response by Baseline Characteristic
Age, ≥75 years (n = 17) IgVH genes, mutated (n = 22) FISH hierarchy, deletion 17p (n = 6) * p < 0.05. CRi = CR with incomplete blood count recovery Badoux X et al. Proc ASCO 2010;Abstract 6508.
Progression-Free and Overall Survival Data Progression-free survival (PFS) Overall survival (OS) Median follow-up = 23 months Badoux X et al. Proc ASCO 2010;Abstract 6508.
Grade 3/4 Adverse Events (N = 60) Toxicity, % of cycles
Grade ≥3, n (%)
All (sepsis, pneumonia/bronchitis, upper respiratory, fever, other) * 50% of patients experienced Grade I/II tumor flare.
Badoux X et al. Proc ASCO 2010;Abstract 6508.
> Lenalidomide as a single agent induces clinical responses in the front-line treatment of elderly patients with CLL.
– 2-year OS: 90% – 2-year PFS: 60% > The most common Grade 3/4 toxicity was myelosuppression.
> No severe tumor flare or tumor lysis syndrome was observed.
Badoux X et al. Proc ASCO 2010;Abstract 6508.
DR VOSE: The study evaluated lenalidomide as initial therapy
for older patients with CLL. The overall response rate was
approximately 62 percent, with 10 percent complete remissions.
The therapy was fairly well tolerated, and the major complicationwas hematological toxicity. Authors believed single-agentlenalidomide to be a fairly good potential treatment for olderpatients with CLL.
Combination Therapy withLenalidomide and Rituximab inPatients with Relapsed ChronicLymphocytic Leukemia (CLL) Ferrajoli A et al.
Proc ASH 2009;Abstract 206.
> Lenalidomide (LEN) with rituximab (R) combination therapy has shown clinical responses in a small number of patients with CLL whoexperienced disease progression while receiving LEN monotherapy(JCO 2006;24:5343).
> R monotherapy has modest activity but significantly synergizes with chemotherapy agents when administered to patients with CLL (JCO2010;28:1756, Lancet 2010;376:1166).
> Current study objective: – Evaluate the safety and efficacy of LEN with R combination therapy in patients with relapsed CLL.
Ferrajoli A et al. Proc ASH 2009;Abstract 206.
Phase II Study Design LEN: 10 mg/d day 9 (cycle 1)  Prior treatment with daily x 28 d (cycles 2-12) purine analog-based R: 375 mg/m2 weekly (cycle 1)  q4wk (cycles 3-12) Median number of prior treatments: 2All patients received prior treatments of R.
Ferrajoli A et al. Proc ASH 2009;Abstract 206.
Efficacy After 6 Cycles of Treatment
Overall response rate Nodular partial response Partial response Failure to respond* * One patient died on day 34 from infectious complications.
Ferrajoli A et al. Proc ASH 2009;Abstract 206.
Responses According to CLL Stage andCytogenetics PR = partial response; nPR = nodular PR; ORR = overall response rate Ferrajoli A et al. Proc ASH 2009;Abstract 206.
Common Grade 3/4 Adverse Events Tumor lysis syndrome (Grade 3) Joint pain (Grade 3) Grade 1 (22%) and Grade 2 (3%) LEN-associated tumor flare reactionwas observed.
Ferrajoli A et al. Proc ASH 2009;Abstract 206.
> When compared to historical data with single-agent LEN, R in combination with LEN may have superior activity in relapsed CLL.
> LEN-associated tumor flare reaction was both less frequent and less severe than has been reported with single-agent LEN.
> When compared to baseline, there were significant differences in the distribution of circulating B, T and NK cell populations afterthree cycles of therapy (data not shown): – B cells: decreased percentage of CD19+CD20+
T cells: increased percentage of CD4+, CD8+, CD4+CD25hiCD127-
NK cells: increased percentage of CD3-CD16+CD56+
> Research is ongoing to determine the clinical relevance of these immune cell changes.
Ferrajoli A et al. Proc ASH 2009;Abstract 206.
DR VOSE: This study was designed on the basis of preclinical
data indicating that lenalidomide and rituximab have potentially
synergistic activity. The patients included in the study had
heavily pretreated disease and had received rituximab in prior
regimens.
The overall response was 68 percent, with 51 percent PR and16 percent nodular PR. None of the patients were reported tohave achieved CR. The regimen was fairly well tolerated withmajor toxicities being hematological.
A correlative part of the study examines proportions of differentimmune cells to see if they might correlate with outcome. Thatresearch is still ongoing.

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