Characteristics and Prognosis of Patients with Richter’s Transformation

of Chronic Lymphocytic Leukemia: Experience with FDG/PET

Lorenzo Falchi, Long Trinh, Edith M Marom, Mylene Truong,

Ellen J Schlette, Rachel L Sargent, Xuemei Wang, Susan Smith, Susan Lerner, Michael J Keating and Alessandra Ferrajoli

Departments of Leukemia, Radiology, Hematopathology, and Biostatistics

The University of Texas MD Anderson Cancer Center

Disclosures

• No disclosures

Transformed CLL: Background • CLL transformation:

- Richter’s transformation (RT): evolution of chronic lymphocytic leukemia (CLL) into high-grade neoplasm

- CLL with histologic features of “increased aggressiveness” (IA): grey zone

• FDG/PET: - powerful diagnostic/prognostic tool in most cancers - FDG-avidity (standardized uptake value, SUV)

reflects tumor cell proliferation - SUV: ↓ in CLL;↑ in RT

• Assess the characteristics of patients with transformed CLL referred to MDACC

• Correlate FDG/PET data, histology, and clinical outcome

• Evaluate the accuracy of diagnostic tools for transformed CLL

Transformed CLL: Aims

Transformed CLL: Methods CLL Population: • CLL patients with FDG/PET scan and tissue biopsy

(or BM diagnosis of transformation) • 3 groups: RT, IA and chronic phase (CP) • Definition of IA: increased large cells scattered/in

sheets; increased (>10%) prolymphocytes

Excluded: • FDG/PET at a different time point • concurrent cancer unless: limited pTNM, ≥1 year

after, or remission for ≥5 years before FDG/PET

Transformed CLL: Extent of Disease (FDG/PET)

Limited Extensive

SUV ≥5

SUV ≥5

SUV ≥5 SUV <5

SUV ≥5 SUV <5

At least 1 FDG/PET: 757 patients

RT: 93 IA: 116

EXCLUDED: 51 • concurrent cancer • benign histology • CP histology, past RT/IA • Report/SUV not available

FDG/PET + LN biopsy: 381 patients

EXCLUDED: 376 • no biopsy • no PET at time of biopsy

CP: 119

Study population: 328 patients

Transformed CLL: Patient Population

NOT YET EVALUABLE: 2

PARAMETER CP (119) AP (116) RT (93) P- value

No % No % No % Males 76 64 81 70 61 66 .61 Untreated 73 61 18 15 11 12 <.0001 Const. Symptoms 21 18 26 22 30 33 .04

ECOG PS 2-4 1 1 19 16 21 23 <.0001

Bulky LNs (>5cm) 23 19 37 32 22 24 .08 Median Range Median Range Median Range

Age, ys 60 34-83 62 31-85 63 41-82 .18 WBC, *103/µL 9.1 2.1-362.6 7.9 0.8-292.8 5.9 0.1-127.2 .001 Hgb, g/dL 13.3 4.6-16.5 11.7 7.7-16.1 11 2.8-16.4 <.0001 Plt, *103/µL 186 10-382 121 11-494 119 3-593 <.0001 LDH, U/L 540 332-1,681 751 304-4,225 756 253-14,185 <.0001

β2-micro, mg/L 2.9 1.4-15.8 5 1.6-16.8 4.7 1.6-18 <.0001

Transformed CLL: Patient Characteristics I

PARAMETER CP (119) IA (116) RT (93) P-value

No % No % No % Unmutated IGHV 42 64 60 84 36 73 .020 del17p 11 17 28 34 11 19 .0014 del11q 17 26 13 16 4 7 Tri12 12 18 18 22 9 15 Neg 14 21 14 17 26 45 del13q 12 18 9 11 8 14 Complex karyotype 11 12 35 41 19 32 .0003 CD38+ 61 58 73 69 52 71 .126 ZAP70+ 51 69 68 85 33 67 .027

Transformed CLL: Patient Characteristics II

Parameter CP (119) IA (116) RT (93) P-value

No % No % No %

PET prior to BX 65 55 56 48 52 56 .48

SUVbwmax, median 3.6 (0-14.3) 6.7 (0-37.8) 17.9 (0-56.3) <.0001

SUVbwmax≥5* 40 34 83 72 82 88 <.0001

SUVbwmax≥10 8 7 34 29 71 76 <.0001

Extensive 16 13 44 38 56 60 <.0001

Transformed CLL: Diagnostic PET

*Accuracy for detection of RT: SENSITIVITY 88%, NPV 91% SPECIFICITY 48%, PPV 40%.

PARAMETER CP (119) AP (116) RT (93) P- value

No % No % No %

Procedure .048

FNA 27 23 43 37 25 27 Histology 58 49 52 45 38 41 FNA + histology 34 29 21 18 30 32

ND FNA* 7 21 6 29 16 53 .018

BX on SUVbwmax 40 41 29 26 38 41 .030

Ki67max, median 10 (1-30) 32 (5-100) 70 (15-100) <.0001

Transformed CLL: Tissue Diagnosis

* Non-diagnostic, includes benign histology or histologic downgrading

Transformed CLL: Treatment

1 R-CHOP, R-EPOCH, R-ESHAP, R-MINE, R-ICE, FCR/FCR-based; BR 2 MoAbs ± GM/HDMP/lenalidomide/cidofovir; cell therapy; anti-Bcl2; vaccine therapy 3 ABVD; CNS-specific; XRT; SCT, no info on induction 4 died before therapy/evaluation; no information available

FIRST Regimen CP (119)

AP (116)

RT (93)

No % No % No %

OFAR 9 8 26 22 29 31 R-HCVAD 4 3 16 14 14 15 Other chemoimmunotherapy1 30 25 30 26 13 14 Immunotherapy 2 41 34 32 28 16 17 Other treatments 3 28 24 8 7 13 14 Not evaluable4 7 6 4 3 8 9 Allogeneic transplant 21 18 34 29 22 24

Response AP (116) RT (93)

No % No % CR 24 21 15 16 PR 18 15 10 11 ORR 42 36 25 27 SD 28 24 12 13 PD 18 16 23 25 NE 28 23 33 35

Transformed CLL: Radiologic Response to First Treatment*

*Radiologic response not evaluable for patients with CP

Transformed CLL: Overall Survival RT, IA, CP

p<.0001

Histology Total Died Survival CP 119 32 77 mos AP 116 75 19 mos RT 93 71 7 mos

Transformed CLL: Survival by SUV

p<.0001

SUVbwmax Total Died Survival <10 214 92 56 mos ≥10 114 86 7 mos

Transformed CLL: Survival by Histology & SUV MAX SUV <10 MAX SUV ≥10

AP vs. RT, p=.71

PHASE Total Died Survival (m) CP 110 28 77 AP 82 50 29 RT 22 14 21

PHASE ToT Died Survival (m) CP 8 4 42 AP 44 25 7 RT 72 57 6

AP vs. RT, p=.62

Transformed CLL: Survival by SUV & Extent of Disease

EXTENT Total Died Survival Limited <10 180 75 56 mos Limited ≥10 33 22 12 mos Extensive <10 35 17 57 mos Extensive ≥10 80 74 6 mos

p=.47

p=.06

Covariate HR 95% CI P-value Prior therapy 5.32 3.18 - 8.89 <.0001 SUVbwmax ≥10 2.00 1.39 - 2.87 0.0002 PS≥2 1.97 1.34 - 2.91 0.001 Age ≥65 1.47 1.09 - 1.98 0.01 Bulky disease 1.38 0.99 - 1.91 0.05 (RT histology 1.20 0.82 - 1.75 0.34)

Baseline Characteristics (326 patients) Transformed CLL: Cox Model for OS

Patients with IA or RT Only (n. 208)

Covariate HR 95% CI P-value Prior therapy 3.88 1.96-7.67 <.0001 SUVbwmax ≥10 1.91 1.30-2.80 0.001 PS≥2 1.80 1.21-2.67 0.004 Bulky disease 1.50 1.05-2.14 0.03 (RT histology 1.13 0.77-1.66 0.54)

Transformed CLL: Cox Model for OS

Survival by SUVbwmax Reduction (95 pts)

SUV ↓ Total Died Survival <66% 60 47 15 mos ≥66% 35 13 NR

p<.0001

Transformed CLL: Cox Model for OS Including Response, IA or RT Only (n. 94)

Covariate HR 95% CI P-value Chemosensitivity 0.35 0.19 0.66 0.001 Prior therapy 4.73 1.67-13.35 0.003 Bulky disease 2.09 1.15-3.79 0.02 SUVbwmax ≥10 1.81 1.02-3.21 0.04 (RT histology 1.38 0.75-2.53 0.30) (PS≥2 1.04 0.49-2.19 0.92)

Transformed CLL: Causes of Death

71% 9%

13% 0% 7%

RT

54%

12%

21% 6% 7%

IA

37%

0%

41%

6% 16%

CP

42%

7% 32%

6% 13%

SUVbwmax <10 PD

TOXICITY

COMPLICATIONS

UNRELATED

UNKNOWN

69% 10%

14% 1% 6%

SUVbwmax ≥10

Transformed CLL: Conclusions • FDG/PET is important in the assessment of

patients with CLL and suspected transformation

• FDG/PET independently predicts the risk of death of patients with transformed CLL

• FDG/PET identifies chemosensitive patients and may guide treatment decisions

• Based on the present analysis we are developing a new prognostic model for patients with CLL with IA OR RT incorporating FDG/PET