Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Farooqui MZH, Valdez J, Martyr S, et al. Ibrutinib for previously
untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53
aberrations: a phase 2, single-arm trial. Lancet Oncol 2014; published online Dec 31.
http://dx.doi.org/10.1016/S1470-2045(14)71182-9.
1
Supplementary Index
Farooqui et al
Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic
leukaemia with TP53 aberrations: a phase 2, single-arm trial
Supplementary table S1.
Reason for treatment discontinuation and disposition of patients who discontinued
treatment by last follow-up.
Enrollment deviation (ineligible diagnosis)
Subject Age Cohort Time off study (months)
Pathologic diagnosis
PCI B6 56 TN 6.3 Hodgkin’s lymphoma*
* Hodgkin’s lymphoma diagnosed at 24 weeks, which on review of pre-treatment biopsy was already present pre-treatment but the CLL component predominated.
Disease progression:
Subject Age Cohort Time to progression Time to death (months)
Pathologic diagnosis
PCI B12 62 TN 0.4
2.0
No biopsy performed; presumed Richter’s transformation. In retrospect, transformation likely present pre-enrollment, but no conclusive evidence was found that transformation had occurred
PCI B24 66 RR 7.2
8.7
Richter’s transformation
PCI B30 57 RR 7.5
13.6
Prolymphocytic transformation. Pre-treatment pathologic evaluation was suspicious be not definitive for transformation. PCI B2 66 RR 15 23.2 Prolymphocytic transformation PCI B23 56 TN 15.7 23.3 Richter’s transformation Death:
Subject Age Cohort Time to death (months)
Cause of death
PCI B29 62 TN 0.13 Died at home, presumed uro-sepsis. Not neutropenic.
No cultures obtained. Autopsy without specific findings.
PCI B11 59 RR 1.4 Biliary tract infection, sepsis. Not neutropenic.
Suggestive laboratory data but no microbial cultures obtained. Treated at outside hospital.
PCI B51 49 TN 7.8 Sudden, unexplained death at home. History of
palpitations pre-dating study enrollment. Unremarkable cardiac workup prior to and during study participation.
2
Supplementary table S2.
Response criteria.
Response criteria based on the International Workshop on Chronic Lymphocytic Leukemia 2008, incorporating the
2012 and 2013 clarifications.
1-4Response CR PR PRL PD
Group A
Lymphadenopathy1 None > 1.5cm Decrease ≥ 50% Decrease ≥ 50% Increase ≥ 50% or any new lesion > 1.5 cm
Hepatomegaly None Decrease ≥ 50% Decrease ≥ 50% Increase ≥ 50% or any
new hepatomegaly
Splenomegaly None Decrease ≥ 50% Decrease ≥ 50% Increase ≥ 50% or new
splenomegaly Blood Lymphocytes2 < 4000/µl Decrease ≥ 50% from
baseline
Increase or <50% decrease over baseline
Increase ≥ 50% over baseline or > 5000/µL Marrow3 Normocellular, <30% lymphocytes, no B-lymphoid nodules. Hypocellular marrow defines CRi
Not applicable Not applicable Not applicable
Group B
Platelet count > 100,000/µL > 100,000/µL or increase ≥ 50% over baseline > 100,000/µL or increase ≥ 50% over baseline Decrease ≥50% from baseline secondary to CLL Hemoglobin > 11.0 g/dL > 11.0 g/dL or increase ≥ 50% over baseline > 11.0 g/dL or increase ≥ 50% over baseline Decrease ≥50% from baseline secondary to CLL Neutrophils > 1500/µL > 1500/µL or or increase
≥ 50% over baseline Not applicable Not applicable 1
Sum of the products of multiple lymph nodes as evaluated by CT scans 2
Patients with treatment-related lymphocytosis remain on study unless associated with other signs of progressive disease. 3
Complete response requires confirmation with bone marrow biopsy.
CR: Disease related constitutional symptoms resolved and all above criteria met, includes bone marrow biopsy. CRi: CR with incomplete hematopoietic recovery.
PR: Two criteria from Group A if abnormal at baseline plus one of the criteria from Group B must be met, requires the absence of growth factor or transfusion support.
PRL: All PR criteria met except blood lymphocyte count. SD: Failure to achieve a response and in the absence of PD
3
Supplementary figure S1. Treatment response in subgroups defined by clinical and biologic criteria.
Shown is the overall response divided into rate of partial response (PR) and partial response with lymphocytosis
(PRL) for defined subgroups at 24 weeks. The rate of overall response rate was similar for all subgroups. However,
patients with Rai stage ≥ 3 more often had partial response (60%) than partial response with lymphocytosis (28%),
while patients with Rai stage ≤ 2 more often had partial response with lymphocytosis (69%) than partial response
(31%). The difference in the type of response between these two subgroups was significant by Fischer’s exact test
(
P
= 0.029). This is consistent with the different kinetics of treatment-induced lymphocytosis we previously
described in a partially overlapping cohort of patients.
50 20 40 60 80 100 β2 microglobulin ≥ 3 mg/dL β2 microglobulin < 3 mg/dL IGHV-unmutated IGHV-mutated Spleen volume ≥ 315 ml Spleen volume < 315 ml Lymph nodes ≥ 5 cm Lymph nodes < 5 cm ≥ 65 years old < 65 years old Rai Stage ≥ 3 Rai Stage ≤ 2 Relapsed / Refractory Previously untreated Overall Response
Patients with response %
4
Supplementary figure S2. Change in the prevalence of subclones with deletion 17p13.1 at 24 weeks compared
to baseline.
The Waterfall plot summarizes the cytogenetic response at 24 weeks; red bars represent patients with relapsed or
refractory disease, blue bars previously untreated patients. Five patients had complete resolution of the deletion
17p13·1 subclone. The % change for the patient marked with * was capped at 100% (the effective change was
634%).
Supplementary references:
1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio E, Dighiero G, Dohner H, et al. Response Assessment in Chronic Lymphocytic Leukemia Treated with Novel Agents Causing an Increase of Peripheral Blood Lymphocytes. Blood 2012; [e-Letter](http://www.bloodjournal.org/content/111/12/5446.e-letters).
2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio E, Dighiero G, Dohner H, et al. Clarification Of iwCLL Criteria For A Partial Response To Therapy. Blood. 2013; [e-Letter]( http://www.bloodjournal.org/content/111/12/5446.e-letters).
3. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12): 5446-56.
4. Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012; 30(23): 2820-2.
5. Herman SE, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014; 28(11): 2188-96.
