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Long-term toxicity of therapy for CLL
Mitchell R. Smith, M.D., Ph.D.Director of Lymphoid Malignancy Program
Taussig Cancer InstituteCleveland ClinicCleveland, OH
2000s
Chemo-immuno therapy
90%40-50%
1960-70s
Alkylators
50%5%
1980s
Purine Analogs
80%10-20%
1990s
Purine Analog+ alkylator
85%25%
The Evolution of TreatmentOptions in CLL
RRCR
2010s
NovelAgents
DESIRED Increase CR rateENDPOINTS: Achieve MRD status
More durable remissions
???
What we have heard so far• CLL is a disease of the immune system• CLL involves aberrant cell proliferation and cell death
– BCR signaling is important target in CLL– (Apoptosis is important target in CLL)– p53 function important in CLL
• CLL has a genetic component• Current initial therapy is based on chemotherapy +
anti-CD20 antibody (BR/FCR)• Until we can cure CLL, goal is to prolong survival• Since survival is long, long term toxicity of our
interventions is important consideration
CHEMOIMMUNOTHERAPY TOXICITYMYELOID
Prolonged myelo-suppressioninfectionbleeding
Inability to tolerate subsequent therapyTherapy related myeloid neoplasia (t-MN)
LYMPHOIDProlonged B- cell suppression
hypogammaglobulinemia and infection
Prolonged T- cell suppression“opportunistic” infectionsautoimmune disorders
OTHER ORGANS FORTUNATELY NOT AN ISSUE
CAUSES OF DEATH IN CLL
• “The most frequent causes of death are severe systemic infection (especially pneumonia and septicemia) [~50%], bleeding, and inanition with cachexia.”
– Up-to-Date accessed 10/1/13
• Prolymphocytic transformation [5-10%]
clonal evolution/selection?• Richter’s transformation [1-2%]• 2nd malignancy – incidence and outcome
INFECTION IN CLL
CLL CHEMOTHERAPY RITUXIMAB NOVEL AGENTSFLU BENDA
NEUTROPENIA ?
B CELL DYSFUNCTION/HYPOGAMMAGLOBULIN
?
T CELL DYSFUNCTION ? ?
SPLEEN FUNCTION ?
INFECTION IN CLL
CLL CHEMOTHERAPY RITUXIMAB NOVEL AGENTSFLU BENDA
NEUTROPENIA ?
B CELL DYSFUNCTION/HYPOGAMMAGLOBULIN
?
T CELL DYSFUNCTION ? ?
SPLEEN FUNCTION ?
Therapeutic Interventions:VACCINATIONS PNEUMOVAX, FLU, NOT ZOSTAVAX
ANTI-MICROBIALS – bacterial, viral, fungal IVIG
MYELOID GROWTH FACTORS
BLEEDING IN CLL:THROMBOCYTOPENIA
• DISEASE:– BONE MARROW INFILTRATION– HYPERSPLENISM– AUTO-IMMUNE (ITP)
• THERAPY– MYELOSUPPRESSIVE CHEMOTHERAPY– MYELODYSPLASIA
• EFFECTS OF NOVEL AGENTS?
TRANSFORMATION IN CLL• Prolymphocytic transformation
clonal evolution/selection?
Rx could prevent or cause?
• Richter’s transformationif same clone, as for PLL above
if different clone, as another 2nd malignancy
• 2nd malignancy – incidence and outcomeImmune dysfunction/surveillance?
Chemotherapy induced?
What are the long-term concerns about therapy-related toxicity in CLL?
• Neutropenia• B Cell Dysfunction (Hypogammaglobulinemia)• T Cell Dysfunction• Thrombocytopenia• Infection• Transformation (Richter’s or Prolymphocytic)• Second neoplasm• Therapy-related Myeloid Neoplasia (t-MN)• Inability to collect stem cells
ACUTE TOXICITY: FCR VS BRGrade 3 or 4 (% of patients)
FCR
GERMAN CLL8
BR
GERMAN CLL SG PHASE 2
Neutropenia 34%
Thrombocytopenia 7%
Infection 25%
AIHA 1%
Neutropenia 20%
Thrombocytopenia 22%
Infection 8%
AIHA (onset prior to Rx) 2%
Prolonged CytopeniasStrati P, et al MDACC Cancer 2013
• 207 patients with CR, CRi, nPR after FCR as initial therapy for CLL
Months post-FCR Grade 2-4 cytopenia Late Infection incidence
3 35%
6 24%
9 12% 38% (2/3 bacterial)
F vs FC as Initial Therapy of CLL: E2997 TRIAL DESIGN
*Patients in the FC arm received filgrastim 5 mg/kg SC and antiviral prophylaxis
All patients received allopurinol cycle 1 and PCP prophylaxis
Flinn et al. J Clin Oncol 2007; 25:793-798
Pts with previously untreated
CLL requiring therapy(N=278)
RANDOMIZE
ASSESS
ASSESS
Fludarabine25 mg/m2 IV 1-5
q4w × 6 (n=137)
Cyclophosphamide600 mg/m2 IV 1
Fludarabine20 mg/m2 IV 1-5*
q4w × 6 (n=141)
F vs FC as Initial Therapy of CLL:Short-term Bone Marrow Toxicity
Grade 3 or 4 Toxicity* FC F
Neutrophils+ G-CSF in FC
69% 63%
Platelets 28% 16%
Hemoglobin 30% 20%
Flinn I W et al. JCO 2007;25:793-798
* % of cycles
F vs FC as Initial Therapy of CLL: Long term Bone Marrow Toxicity
¨ HYPOTHESES:
Short term bone marrow toxicity of FC indicates additive DNA damage that will be reflected in long term toxicity
Specifically, therapy related myelodysplasia (MDS) or acute myeloid leukemia (AML)
Collectively termed:
therapy-related myeloid neoplasia (t-MN)
¨ METHODS:
t-MN cases ascertained by review of E2997 case report forms and by required AdEERS reporting
F vs FC Initial Therapy of CLL Results: t-MN Incidence
¨ E2997 enrolled 278 patients
FC 141
F 137
¨ Median follow-up: 6.4 years
¨ Cases of t-MN: 13
crude incidence 4.7%
¨ Median age at study entry:– for t-MN 60 – for entire population 61
F vs FC Initial Therapy of CLL Results: t-MN Incidence
¨ Median time from CLL therapy to t-MN:
5 yrs (0.7-8 yrs) not different between FC and F
¨ 10 of 13 t-MN patients received 6 cycles of therapy
¨ Cytogenetics of t-MN available in 12– 10 had abnormal 5 and/or 7
– 8 of these had complex cytogenetics– 1 had 45 XY, -7, del(12)(p11.2)– 1 had 45 XY, -7
– 1 was 46 XX, +1, der(1;15)– 1 was 47 XY +add(12)(q13),t(14;19)(q32;q13)
c/w residual CLL
Cumulative Incidence Method
¨ Second malignancies reportable per NCI for all patients– Includes SMNs occurring after subsequent
therapy
¨ Death competes with ability to detect second malignancy
¨ Competing risk methods identify times to:– t-MN– Competing risk (death)– Censoring (alive without t-MN)
Risk of t-MN with F vs FC Initial Therapy of CLL: Results
Therapy FC F TOTAL
N enrolled
N lab correlatives
141
122
137
113
278
235
t-MN 9 4 13
Crude Incidence 6.4% 2.9% 4.7%
Cumulative Incidence Method
8.2% 4.6%
Risk of t-MN with F vs FC Initial Therapy of CLL: Results
FC F TOTAL
# of t-MN 9 4 13
Additional therapy prior to t-MN:
Yes
No
2
7
3
1
5
8
Outcome after t-MN
Alive (range in months)
Dead (range in months)
3 (1-12)
6 (1-20)
2 (10, 13)
2 (4, 30)
Risk of t-MN with F vs FC Initial Therapy of CLL: Possible relation to CLL IgVH Gene Mutation Status
FC F TOTAL
# of t-MN 9 4 13
IgVH gene status
un-mutated
mutated
unknown
For entire cohort, 44% mutated IgVH
0
7
2
3
1
0
3
8
2
Risk of t-MN with F vs FC Initial Therapy of CLL: Possible relation to CLL IgVH Gene Mutation Status
FC F TOTAL
# of t-MN 9 4 13
IgVH gene status
un-mutated
mutated
unknown
For entire cohort, 44% mutated IgVH
0
7
2
3
1
0
3
8
2
Risk of t-MN with F vs FC Initial Therapy of CLL: CONCLUSIONS
¨ Incidence of t-MN increased after FC
¨ Median time to t-MN 5 years– Longer follow-up may reveal ongoing risk (or not?)
¨ Cytogenetics/FISH of t-MN suggests DNA damage– No evidence of antecedent abnormalities on CLL FISH
¨ Consistent with prior F-chlorambucil and FCR data
¨ FC yields longer PFS, so most t-MN occur in absence of additional chemotherapy
¨ IgVH effect requires confirmation
¨ t-MN needs consideration in choosing CLL therapy
Risk of t-MN with F ± C as Initial CLL TherapyRegimen N Median
F/UMedian
age (yrs)# MDS cases
RISK
MDACCTam
FCR 300 72 57 8 2.8% @ 6 yr
MDACCZhou
FCR 426 44 19 4.5% (1.9-8.3)
CALGBMorrison
F-chlorF
chlor
142188141
50 510
3.5%0.5%
0
AustraliaCarney
FCR 61 41 59 3 6.4% @ 5 yr
E2997Smith
FCF
141137
76 60 94
8.2% @ 7 yr4.6% @ 7 yr
Risk Factors for t-MN
• Fludarabine combination therapy• Additional courses of DNA-damaging agents• Higher Age? in MDACC data• Use of myeloid growth factors?• Not much “signal” yet for bendamustine
Not looked for enough?
More single agent use?
Less persistent DNA damage?
Less immunosuppressive?
CHARACTERISTICS OF t-MN
• Earlier onset if persistent cytopenia, but can arise from recovered marrow as well*
• May be difficult to differentiate from hypoplasia• Usually abnormal chromosome 5 and/or 7, not 11q23• Typical poor outcomes
*Zhou Y et al Modern Pathology 2012
RISK OF PLL and RICHTER’S TRANSFORMATION
• Variable incidence and variable definition• PLL usually clonally related, but evolved• Richter’s Syndrome
• Clonally related 50-70% of cases, likely “2nd hit” or selection
Not likely to be Rx induced• Clonally unrelated 20-50%, some of these EBV+
Hypothesize these may be due to immunosuppression and could be influenced by therapy
• CALGB 9011 analysis
ALL FLU CHLOR F + C
Richter’s 34 (7%) 7% 5% 8%
PLL 10 (2%) 2% 2% 2%
Solh M et al Leuk Lymphoma 2013
“SECOND” SOLID NEOPLASMS
• Increased incidence in CLL
(Morton LM JCO 2010)
• Worse outcomes in patients with CLL• Theoretically increasing immune
suppression might predispose • No data these are fludarabine-induced
(Cheson et al JCO 1999)
• Reports of rapid growth early after Rx
CONCLUSIONS
• Long term toxicity of therapy for CLL is primarily marrow and immune suppression
• Main concerns are:– prolonged cytopenias and infection– t-MN
• Fludarabine combinations appear to confer higher risk
• “Novel” agents are expected to reduce these risks, but long-term follow-up is
prudent