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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


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 BR toxicity in CLL?Grade 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 toxicity in CLL?CytopeniasStrati P, et al MDACC Cancer 2013

    • 207 patients with CR, CRi, nPR after FCR as initial therapy for CLL


    F toxicity in CLL?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: toxicity in 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: toxicity in 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 toxicity in 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 toxicity in 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 toxicity in CLL?

    • 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: toxicity in CLL? Possible relation to CLL IgVH Gene Mutation Status


    Risk of t-MN with F vs FC Initial Therapy of CLL: toxicity in 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: toxicity in 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 toxicity in CLL?

    • 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 toxicity in CLL?

    • 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 toxicity in CLL?

    • 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 toxicity in CLL?

    • 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 toxicity in CLL?

    • 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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