CLL what do I need to know as an Internist in 2018

Taimur Sher MD

Associate Professor of Medicine

Mayo Clinic

• 70 y/o white male for yearly medical evaluation

• Doing well and healthy

• Past medical history

Hypertension

Dyslipidemia

Coronary artery disease

• Normal exam

• CBC:

Hb 12.5

WBC 12.6

Platelet count 156/ uL

Absolute lymphocyte count: 7.1

Absolute neutrophil count 3.5

Case 1

Case 2

• 48 y/o female with 6 months of weight loss, elbow and knee swelling and itchy rash

• 1 year ago rheumatoid arthritis. On Mtx.

• Mother died of non-hodgkin lymphoma.

• Exam: Chronically ill appearing female, inflamed elbow and knee.

• CBC: Hb 7.8; WC 15. platelet 105. ALC 10.5

• CRP-105; Beta-2 microglobulin 14

• Flow: CD 5+, CD 23+ kappa

restricted B-cells.

Chronic Lymphocytic Leukemia (CLL)

• Most prevalent adult B-cell leukemia in west (~15,000 cases / year)

• Median age at diagnosis is 72yrs

• Presentation:

• Incidental

• Disease related tumor burden

• Autoimmune phenomenon

• Infections

Ries LAG et al. http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission. Accessed September 17, 2007; Stilgenbauer S. Hematology. 2004;1:164-170.

Lymph Nodes

CD23+

Bone marrow Blood

• ALC: >5,000/µL—mature-appearing lymphocytes

• Immunophenotype

CD5+ / CD19+ / CD23+ / surface Ig light-chain restricted ( or )

• BM biopsy: not required for diagnosis

>30% lymphocytes on aspirate

• What do I order for work up?

CBC with diff

Flow cytometry peripheral blood

Liver and renal function

LDH, beta-2 microglobulin

Quantitative Igs

FISH in peripheral blood

Somatic hypermutation

CLL Diagnosis

Prognostic Versus Predictive Factors

• Prognostic factor

Situation, condition, or characteristic used to estimate overall outcome of disease, independent of treatment

• Predictive factor

Situation, condition, or characteristic that predicts the efficacy of a therapy

Prognostic factor that provides information on effect of a treatment

Prognostic Factors Associated With Inferior Survival in CLL

• FISH cytogenetic abnormalities

17p deletion

11q deletion

• Complex cytogenetic abnormalities

• Unmutated (<2% homology to germline) IgHV

• Expression of ZAP-70 (20% positive)

• Expression of CD38 (30% positive)

Clinical Stage

• Rai staging

Stage 0 Lymphocytosis

Stage I Lys+adenopathy

Stage II Lys+ Splenomegaly

Stage III Anemia

Stage IV Thrombocytopenia

FISH: Cytogenetics are important

Months

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Pa

tien

ts S

urv

ivin

g, %

17p deletion

11q deletion 12q trisomy

Normal 13q deletion as

sole abnormality

Months 1. Dohner et al. N Engl J Med. 2000;343:1910.

Su

rviv

ing

, %

Survival of CLL Patients With Mutated Versus Unmutated IgHV Gene

1. Hamblin TJ et al. Blood. 1999;94:1848-1854.

All Patients (N = 84) Stage-A CLL Patients (n = 62)

Su

rviv

ing

, %

0 50 100 150 200 250 300 0

20

40

60

80

100

Months

P = .0008

Months

P = .001

0 50 100 150 200 250 300 0

20

40

60

80

100

Mutated

Unmutated Unmutated

Mutated

CLL-International Prognostic Index (CLL-IPI)

Variable Adverse Factor Grading

TP53 / 17p Mutated/deleted 4

IgHV status Unmutated 2

B2M >3.5 mg/L 2

Clinical stage Binet B/C or Rai II-IV 1

Age > 65 y 1

Prognostic score 0-10

Risk Group Score

Low 0-1

Intermediate 2-3

High 4-6

Very high 7-10 1. The International CLL-IPI Working Group. Lancet Oncol. 2016.

1. The International CLL-IPI Working Group. Lancet Oncol. 2016;17:779-790.

CLL-IPI: OS Outcomes

100

0 0

20

60

80

40

24 156 12

Time From Study Entry, mo

OS

, %

Training Dataset

P < .0001

48 60 72 84 96 108 120 132 144 36

341 331 0 339 279 270 224 169 118 81 40 20 8 320

474 441 1 452 352 312 232 143 83 52 27 13 5 415

337 284 0 314 205 178 120 69 40 19 12 4 1 256

62 31 — 46 16 13 5 3 0 —

— — —

25

Low risk

Intermediate risk

High risk

Very high risk

Number at risk

100

0 0

20

60

80

40

24 156 12

Time From Study Entry, mo

OS

, %

MAYO Cohort

P < .0001

48 60 72 84 96 108 120 132 144 36

390 316 3 338 259 226 188 151 105 64 34 19 7 288

272 224 0 247 178 146 111 81 46 27 12 1 1 198

149 110 — 127 82 64 44 28 14 9 3 0 — 100

27 18 — 24 5 1 1 1 0 — — — — 12

Low risk

Intermediate risk

High risk

Very high risk

Number at risk

100

0 0

20

60

80

40

24 156 12

Time From Study Entry, mo

Internal-Validation Dataset

P < .0001

48 60 72 84 96 108 120 132 144 36

186 173 0 181 152 146 125 84 56 39 26 11 3 168

200 180 0 191 137 125 88 55 35 22 10 5 1 168

147 117 0 130 84 69 52 24 17 13 6 2 1 98

52 30 —

43 14 8 2 1 1 0 — — — 20

Low risk

Intermediate risk

High risk

Very high risk

Number at risk

100

0 0

20

60

80

40

24 156 12

Time From Study Entry, mo

SCAN Cohort

P < .0001

48 60 72 84 96 108 120 132 144 36

242 237 80 238 228 223 220 210 192 168 159 144 115 233

104 99 12 103 89 78 71 61 46 42 35 25 17 95

56 51 2 55 39 36 32 25 16 11 10 6 3 47

14 8 — 10 7 4 3 1 1 0 — — — 7

Low risk

Intermediate risk

High risk

Very high risk

Number at risk

Low risk

Intermediate risk

High Risk

Very high risk

Multivariable Model for Time-to-First CLL Treatment (N = 687; 193 treated)

Characteristic HR P

IgHV mutation status (UM vs M) 10.68 <.0001

Diameter of largest cervical LN (cm) 1.32 <.0001

FISH category (11q del vs others) 1.86 .001

FISH category (17p del vs others) 2.12 .01

Number of involved LN sites (3 vs <3) 1.64 .004

LDH (IU/L/100) for IgHV mutated 2.36 .002

Wierda WG et al. J Clin Oncol. 2011;29:4088-4095.

CLL-IPI: Time-to-First CLL Treatment Outcomes1

Low risk Intermediate risk High risk Very high risk

264 253 9 2 44 21 238 261

110 93 2 4 4 73 108

25 17 2 13 23

4 2 1 4

Low risk

Intermediate risk

High risk

Very high risk

Number at risk

74

8

2 1

222 182 151 213

54 31 20 42

10 5 3 7

1 1 1 1

105

12

2

1

390 291 4 2 25 13 257 324

272 140 1 0 110 174

149 59 1 41 77

27 3 2 7

50

3

2 0

219 155 117 183

88 41 23 66

32 10 4 19

1 0

79

11

2

242 202 81 54 111 101 195 212

104 45 8 6 38 70

56 10 2 6 19

14 3 2 4

118

10

2 2

190 168 155 173

28 21 18 23

5 4 4 4

1 1

141

12

3

1 0

5

2

3

1

100

0 0 36

50

156 132

20

60

Tim

e to

Fir

st T

rea

tmen

t, %

90

80

40

30

10

70

144 84 120 48 12

Watch-and-Wait Patients

108 24 60 72 96

P < .0001

100

0 0 36

50

156 132

20

60

90

80

40

30

10

70

144 84 120 48 12

MAYO Cohort

108 24 60 72 96

P < .0001

100

0 0 36

50

156 132

20

60

Tim

e to

Fir

st T

rea

tmen

t, %

90

80

40

30

10

70

144 84 120 48 12

SCAN Cohort

108 24 60 72 96

P < .0001

Time From Diagnosis, mo Time From Diagnosis, mo Time From Diagnosis, mo

1. The International CLL-IPI Working Group. Lancet Oncol. 2016;17:779-790.

IWCLL-NCI: Indications to Initiate Treatment for CLL1

• Constitutional symptoms referable to CLL

• Progressive marrow failure

• Autoimmune anemia +/- thrombocytopenia poorly responsive to steroids or other treatment

• Massive (>6 cm) or progressive splenomegaly

• Massive (>10 cm) or progressive lymphadenopathy

• Progressive lymphocytosis, >50% increase over 2 months or LDT <6 months

• NO EARLY TREATMENT, EVEN FOR HIGH-RISK PATIENTS

1. Hallek M et al. Blood. 2008;111:5446-5456.

Treatment

The cancer cell… does not live in isolation

Cell proliferation survival, and migration

B-cell receptor

CD

79

B

CD

79

A

BTK Blnk

Lyn Syk

Fyn PLCγ2

CD19

CD38

Toll-like receptor(s)

MYD88 L265P

MYD88 L265P

TIR

AP

IRAK4

IRAK1

TRAF6

p50

PI3K p85

PIP3 AKT

mTOR

RAS

RAF

MEK

IkBa

p60 PKC

IP3 DAG

ERK / MAPK NFAT

Ca++

MYC NFkB 4E-BP1

SK60

Proteasome

T-cells

Bcl-2 BAX

BIM

PD-L1 PD-1

?

BTK

FOXO3a p53 IkB

XPO1 p53 IkB FOXO3a

Centrosome

Aurora kinase

p53 MYC IkBa

AKT

Deactivated/degraded

CAR T-cells

1960s / 1970s

Alkylating agents – Chlorambucil – Cyclophosphamide

2000s

Chemoimmunotherapy (FCR) Alemtuzumab CD20 mAbs Bendamustine

1990s

Combination chemotherapy

Evolution of Therapy for CLL

1980s

Purine nucleosides – Fludarabine – Pentostatin – Cladribine

2010s

Small molecule inhibitors – BCR pathway – Bcl-2

Factors affecting treatment choice

Patient related

• Age

• Medical comorbidities

• Concurrent medications

Drug interactions

• Logistics

Disease related

• Cytogenetic risk: FISH

TP 53/ 17p deletion

11q deletion

• IgVH mutation status

CLL10: PFS Outcomes With FCR Versus BR1

1. Eichhorst B et al. ASH 2014.

Choice of initial CIT in younger patients: BR vs. FCR

• FCR superior to BR with respect response rate and progression free survival

• No OS benefit, though survival analysis not mature

• Severe neutropenia and infections more frequently observed with FCR (84% and 39%) vs BR (59% and 25%, respectively)

• Increased frequency of infectious complications and cytopenias with FCR was more pronounced in patients aged >65 y

• No PFS benefit for FCR in patients aged >65 y

1. Eichhorst B et al. ASH 2014.

Predictive factor: PFS by IgHV Mutation Status1

P<0.0001

PF

S, %

Time, y

0

25

50

75

100

0 1 2 3 4 8 9 10 5 6 7 11 12 13 14 15 16

1. Thompson PA et al. Blood. 2016;127:303-309.

Minimal Residual Disease and IgHV Mutation Status1

100

0

0

50

90

20

60

PF

S, %

Months

90

70

40

30

10

6 12

80

84 78 72 66 60 54 48 42 36 30 24 18

IgHV M, MRD neg IgHV UM, MRD neg IgHV M, MRD pos IgHV UM, MRD pos

1. Thompson PA. MDACC unpublished.

P = .02

Phase 3 CLL11 Trial: Obinutuzumab Plus Chlorambucil in Newly Diagnosed CLL1

1:2:2

1. Goede V et al. N Engl J Med. 2014;370:1101-1110.

• Patients with newly diagnosed CLL and significant comorbidities

– CIRS score >6 and/or estimated CrCl <70 mL/min

– N = 781

Chlorambucil 0.5 mg/kg PO, d 1 and 15, x 6 cycles

Obinutuzumab 1,000 mg IV cycle 1, d 1, 8, 15; cycles 2-6 d 1 plus chlorambucil

Rituximab 375 mg/m2 IV, cycle 1 on d 1; 500 mg/m2 cycles 2-6, d 1 plus chlorambucil

CLL11: PFS Outcomes1

Obinutuzumab/chlorambucil was associated with prolonged PFS vs chlorambucil (left) and rituximab/chlorambucil (right)

Obin/Chl vs Chl

Obin/Chl vs Ritux/Chl

1. Goede V et al. N Engl J Med.. 2014;370:1101-1110

Updated CLL11 Results: OS1

No statistically significant difference in OS is noted vs rituximab/chlorambucila

Time to next treatment for obin/chl is about 48 mo

Obinutuzumab/chlorambucil was associated with

significant OS benefit vs chlorambucila

Ibrutinib vs Chlorambucil

All patients All d(11q)

Ibrutinib led to 99% reduction in risk of progression or death in high-risk del(11q) subgroup (82% reduction in those without del(11q) compared with chemotherapy

88% reduction in risk of progression or death in for patients randomized to ibrutinib

1. Barr PM et al. ASH 2016.

Venetoclax in Relapsed CLL: Progression-Free Survival and Duration of Response1

1. Roberts AW et al. N Engl J Med. 2016;374:311-322.

Current “Standards of Care” for the CLL Patient

• Untreated, high-risk: watch and wait

• First-line therapy

Del(17p): ibrutinib

“Elderly”: chlorambucil + CD20 mAb

Fit CIT-eligible: FCR / BR

• Salvage treatments for active disease, including del(17p)

BTK inhibitor (ibrutinib)

PI3K inhibitor (idelalisib) + rituximab

• Rel / Ref del(17p): venetoclax

• Richter’s transformation: intensive CIT, then allo-SCT

Novel agents what to look for

• Ibrutinib:

Oral agent; targets Bruton’s tyrosine kinase

Effective for 17p deletion

Atrial fibrillation

Bleeding

Infections

• Venetoclax:

Oral agent; targets Bcl2

Tumor lysis syndrome

Drug interactions

Cytopenias

Summary

• CLL is the most common adult leukemia

• Diagnosis is made by flowcytometry evaluation of the blood

• FISH studies and IgVH somatic hypermutation are most important prognostic/predictive markers: 17 p deletion, 11q deletion and unmutated are bad

• Not everybody needs treatment at diagnosis

• Chemo-immunotherapy is the frontline of treatment- Age is important

• Ibrutinib is effective in 17p- watch for Afib and bleeding

• Venetoclax is highly effective watch for infections, drug interactions, tumor lysis syndrome

Thank You!

Sher.taimur@mayo.edu