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 ZOSTAVAXANTI-MICROBIALS – bacterial, viral, fungal

IVIGMYELOID 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 aboveif 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 incidence3 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 FNeutrophils

+ 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 patientsFC 141F 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 TOTALN enrolled

N lab correlatives

141

122

137

113

278

235t-MN 9 4 13Crude 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 13Additional 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 13IgVH 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 13IgVH 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 selectionNot 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 + CRichter’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