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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 Institute Cleveland Clinic Cleveland, OH. 1960-70s. The Evolution of Treatment Options in CLL. 1980s. 1990s. 2000s. 2010s. Purine Analogs 80% 10-20%.

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long term toxicity of therapy for cll

Long-term toxicity of therapy for CLL

Mitchell R. Smith, M.D., Ph.D.

Director of Lymphoid Malignancy Program

Taussig Cancer Institute

Cleveland Clinic

Cleveland, OH

slide2

1960-70s

The Evolution of TreatmentOptions in CLL

1980s

1990s

2000s

2010s

  • Purine
  • Analogs
  • 80%
  • 10-20%

Purine Analog

+ alkylator

85%

25%

Novel

Agents

Chemo-immuno

therapy

90%

40-50%

  • Alkylators
  • 50%
  • 5%

???

RR

CR

DESIRED Increase CR rate

ENDPOINTS: Achieve MRD status

More durable remissions

what we have heard so far
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 toxicity
CHEMOIMMUNOTHERAPY TOXICITY

MYELOID

Prolonged myelo-suppression

infection

bleeding

Inability to tolerate subsequent therapy

Therapy related myeloid neoplasia (t-MN)

LYMPHOID

Prolonged B- cell suppression

hypogammaglobulinemia and infection

Prolonged T- cell suppression

“opportunistic” infections

autoimmune disorders

OTHER ORGANS FORTUNATELY NOT AN ISSUE

causes of death in cll
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 cll1
INFECTION IN CLL

Therapeutic Interventions:

VACCINATIONS PNEUMOVAX, FLU, NOT ZOSTAVAX

ANTI-MICROBIALS – bacterial, viral, fungal IVIG

MYELOID GROWTH FACTORS

bleeding in cll thrombocytopenia
BLEEDING IN CLL:THROMBOCYTOPENIA
  • DISEASE:
    • BONE MARROW INFILTRATION
    • HYPERSPLENISM
    • AUTO-IMMUNE (ITP)
  • THERAPY
    • MYELOSUPPRESSIVE CHEMOTHERAPY
    • MYELODYSPLASIA
  • EFFECTS OF NOVEL AGENTS?
transformation in cll
TRANSFORMATION IN CLL
  • Prolymphocytic transformation

clonal evolution/selection?

Rx could prevent or cause?

  • Richter’s transformation

if same clone, as for PLL above

if different clone, as another 2nd malignancy

  • 2nd malignancy – incidence and  outcome

Immune dysfunction/surveillance?

Chemotherapy induced?

what are the long term concerns about therapy related toxicity in cll
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 br grade 3 or 4 of patients
ACUTE TOXICITY: FCR VS BRGrade 3 or 4 (% of patients)

Fcr

German CLL8

Br

German CLL sg phase 2

Neutropenia34%

Thrombocytopenia 7%

Infection25%

AIHA1%

Neutropenia 20%

Thrombocytopenia 22%

Infection 8%

AIHA (onset prior to Rx)2%

prolonged cytopenias strati p et al mdacc cancer 2013
Prolonged CytopeniasStrati P, et al MDACC Cancer 2013
  • 207 patients with CR, CRi, nPR after FCR as initial therapy for CLL
slide13

F vs FC as Initial Therapy of CLL: E2997 TRIAL DESIGN

Fludarabine

25 mg/m2 IV 1-5q4w × 6

(n=137)

RANDOMIZE

ASSESS

Pts with previously untreated CLL requiring therapy

(N=278)

Cyclophosphamide

600 mg/m2 IV 1

Fludarabine

20 mg/m2 IV 1-5*q4w × 6

(n=141)

ASSESS

*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

f vs fc as initial therapy of cll short term bone marrow toxicity
F vs FC as Initial Therapy of CLL:Short-term Bone Marrow Toxicity

* % of cycles

Flinn I W et al. JCO 2007;25:793-798

f vs fc as initial therapy of cll long term bone marrow toxicity
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
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 incidence1
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
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)
slide21
Risk of t-MN with F vs FC Initial Therapy of CLL: Possible relation to CLL IgVH Gene Mutation Status
slide22
Risk of t-MN with F vs FC Initial Therapy of CLL: Possible relation to CLL IgVH Gene Mutation Status
risk of t mn with f vs fc initial therapy of cll conclusions
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
  • IgVHeffect requires confirmation
  • t-MN needs consideration in choosing CLL therapy
risk factors for t mn
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
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
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
  • Solh M et al Leuk Lymphoma 2013
second solid neoplasms
“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
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
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