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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
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