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Article: Howard, DR orcid.org/0000-0003-3333-9783, Munir, T, McParland, L et al. (12 more authors) (2017) Results of the randomized phase IIB ARCTIC trial of low dose Rituximab in previously untreated CLL. Leukemia, 31. pp. 2416-2425. ISSN 0887-6924 https://doi.org/10.1038/leu.2017.96
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1 Results of the randomized phase IIB ARCTIC trial of low dose Rituximab in previously
2 untreated CLL
3 Dena R Howard1*, Talha Munir2*, Lucy McParland1, Andy C Rawstron3, Donald Milligan4, Anna
4 Schuh5, Anna Hockaday1, David J Allsup6, Scott Marshall7, Andrew S Duncombe8, John L
5 O’Dwyer9, Alison F Smith9, Roberta Longo9, Abraham Varghese2 and Peter Hillmen10.
6 * These authors contributed equally to this work.
7 Affiliations:
8 1Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds,
9 Leeds, United Kingdom
10 2Department of Haematology, St. James's University Hospital, Leeds, United Kingdom
11 3Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds, United
12 Kingdom
13 4Centre for Haematology and Stem Cell Transplantation, Heartlands Hospital, Birmingham,
14 United Kingdom
15 5Department of Oncology, University of Oxford and Department of Haematology, Oxford
16 University Hospital Trust, Oxford, United Kingdom
17 6Department of Haematology, Hull & East Yorkshire NHS Trust, Hull, United Kingdom and Hull
18 York Medical School, University of Hull, Hull, United Kingdom
19 7City Hospitals Sunderland, Sunderland, United Kingdom 2
20 8Department of Haematology, University Hospital Southampton, Southampton, United Kingdom
21 9Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds,
22 Leeds, United Kingdom
23 10Section of Experimental Haematology, Leeds Institute of Cancer and Pathology (LICAP),
24 University of Leeds, Leeds, United Kingdom.
25
26 Contact details of corresponding author:
27 Peter Hillmen
28 Section of Experimental Haematology
29 Leeds Institute of Cancer and Pathology (LICAP)
30 University of Leeds, Leeds
31 United Kingdom
32 Tel: 0113-343-8604
33 Fax: 0113-206-8177
35
36 Running Title: ARCTIC: FCM with low-dose Rituximab in CLL
37 3
38 Keywords: CLL, Rituximab, FCR, IWCLL, Minimal Residual Disease, Phase II
39
40 Conflicts of interest are noted within the manuscript.
41 4
42 ABSTRACT
43 ARCTIC was a multi-center, randomized-controlled, open, phase IIB non-inferiority trial in
44 previously untreated Chronic Lymphocytic Leukemia (CLL). Conventional frontline therapy in fit
45 patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that
46 including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. 200
47 patients were recruited to assess the primary endpoint of complete remission (CR) rates according
48 to IWCLL criteria. Secondary endpoints were progression-free survival (PFS), overall survival
49 (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-
50 effectiveness. The trial closed at the pre-planned interim analysis. At final analysis, CR rates were
51 76% FCR vs. 55% FCM-miniR [adjusted odds-ratio: 0.37; 95% CI: 0.19-0.73]. MRD-negativity
52 rates were 54% FCR vs. 44% FCM-miniR. More participants experienced Serious Adverse
53 Reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences
54 between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective
55 over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior
56 response and MRD-negativity rate and increased toxicity, and will not be taken forward into a
57 confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to
58 historical series with intravenous chemotherapy.
59
60
61
62
63 5
64 INTRODUCTION
65 Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder accounting for 30% of
66 adult leukaemia and 25% of Non-Hodgkin Lymphoma. It is the most common leukemia above the
67 age of 50 years with a median age of diagnosis of 70 years. The treatment of CLL is tailored around
68 the physical state of the patient due to toxicity associated with the chemotherapy based treatments.
69 CLL is still an incurable disease, and most patients will eventually become resistant to treatment.
70 For physically fit patients, the addition of rituximab (MabThera) to fludarabine and
71 cyclophosphamide (FCR) has become the standard of care based on evidence from large
72 randomized controlled trials(1, 2). However, the dose of rituximab has not been established
73 systematically in CLL or in combination with chemotherapy. Rituximab monotherapy at a dose of
74 375mg/m2 induced an overall response rate (ORR) of 13% in previously-treated CLL/small
75 lymphocytic lymphoma (SLL)(3, 4). Thrice weekly rituximab (375mg/m2) and higher weekly
76 doses of rituximab (0.5-2.5g/m2) in previously untreated patients induced a modest ORR of 43%
77 and 40%, respectively(5-7). The poor response was thought to be due to low CD20 expression on
78 CLL cells and rituximab binding to CD20 positive cellular debris. The loss of CD20 antigen from
79 CLL cells when exposed to rituximab (termed “antigen shaving”) is well described in CLL. Most
80 of the CLL cells were cleared after 30mg of rituximab followed by recrudescence of CLL cells
81 which have lost >90% of CD20 expression. Low-dose rituximab thrice weekly at 20-60mg/m2 may
82 promote enhanced clearance of CLL cells by preserving CD20 expression(8). Subcutaneous
83 rituximab thrice weekly at a dose of 20mg resulted in reduction of CD20 expression on CLL cells
84 but sufficient expression was maintained during the course of 6-12 weeks in another study(9).
85 Thrice weekly rituximab at 20mg/m2 in combination with Alemtuzumab and Pentostatin showed 6
86 that this dose is able to opsonize and clear the majority of circulating cells, but the loss of CD20
87 is less pronounced(10). Hence, rituximab at doses of 20mg/m2 can be effective in CLL.
88 The combination of mitoxantrone with fludarabine and cyclophosphamide (FCM) is reported in
89 60 relapsed or resistant patients with CLL(11) to yield a 78% ORR, with 50% of patients achieving
90 a complete remission (CR) and 10 patients Minimal Residual Disease (MRD) negativity. A non-
91 randomized Phase II trial of FCM plus rituximab (FCM-R)(12) reported 82% CRs and 93% ORR
92 in previously untreated CLL, with 46% achieving MRD-negativity. The NCRI randomized Phase
93 II study including FCM and FCM-R in 52 previously-treated CLL patients reported CRs of 65%
94 (FCM-R) versus 58% (FCM), with MRD-negativity in 5 patients (FCM-R) and 3 patients
95 (FCM)(13).
96 The aim of the ARCTIC (Attenuated dose Rituximab with ChemoTherapy In CLL) trial was to
97 test the hypothesis that a low-dose of rituximab (100mg per cycle) in combination with FCM
98 (FCM-miniR) would be as effective as standard of care (FCR). It is hypothesized that FCM-miniR
99 may result in effective tumor clearance and preservation of CD20 expression on CLL cells.
100 The cost-effectiveness of delivering FCM-miniR as an alternative to the standard therapy FCR is
101 also critical. Six cycles of rituximab at a dose of 500mg/m2 are time consuming to give and
102 expensive compared to low doses (100mg per cycle). The non-inferiority design of the trial helps
103 to establish whether lowering the dose of rituximab and hence reducing the cost of treatment
104 impacts on the efficacy in terms of CR rates, as well as the longer-term progression-free survival
105 (PFS) and overall survival (OS) outcomes.
106
107 PATIENTS AND METHODS 7
108 Trial Design
109 ARCTIC was a multi-center, randomized, controlled, open-label, phase IIB non-inferiority trial
110 including patients with previously-untreated CLL who required treatment by IWCLL criteria(14).
111 Patients were randomized via a central computer-generated minimization programme
112 incorporating a random element 1:1 to FCR or FCM-miniR. Randomization was stratified to
113 ensure balance for center, Binet Stage (Progressive A or B, C), age group (≤65, 65) and sex.
114 The primary objective was to assess whether FCM-miniR was non-inferior to FCR in terms of CR
115 rates, including CR with incomplete marrow recovery (CRi), in patients with previously untreated
116 CLL. The results would be used to determine whether FCM-miniR should be taken forward into a
117 larger definitive Phase III trial.
118 An independent Data Monitoring Committee (DMC) was established to review the safety and
119 ethics of the trial. The DMC reviewed unblinded safety data on a six-monthly basis and unblinded
120 safety and trial progress reports on an annual basis. There was a pre-planned interim assessment
121 of efficacy on half the required number of participants. The DMC reported to an established trial
122 steering committee (TSC) that provided general oversight for the trial.
123 The trial was approved by relevant institutional ethical committees and regulatory review bodies.
124 The trial was registered as an International Standard Randomized Controlled Trial
125 (ISRCTN16544962) and on the European Clinical Trials Database (EudraCT: 2009-010998-20).
126 Patients
127 The intention was to recruit 206 patients from hospitals around the United Kingdom (UK). Eligible
128 participants had progressive CLL requiring treatment by IWCLL criteria(14); no prior treatment 8
129 for CLL; WHO performance status 0-2; Binet Stage progressive A, B or C; and had provided
130 written consent. Patients were not eligible if they had Hepatitis B or C; an active secondary
131 malignancy (excluding basal cell carcinoma of the skin); an active infection or a past history of
132 anaphylaxis following exposure to rat or mouse-derived complementarity determining region
133 (CDR)-grafted humanized monoclonal antibody. Patients with creatinine clearance greater than
134 30ml/min were allowed to enter the trial with guidance on dose reduction for fludarabine. Patients
135 with a 17p-deletion were eligible for enrollment due to lack of treatment options at the time of
136 designing the trial. Participants were able to withdraw from the trial at any time.
137 Treatment and Assessments
138 Treatment with FCR or FCM-miniR was repeated every 28 days for a total of six cycles.
139 Fludarabine and cyclophosphamide were administered orally at doses of 24mg/m2/day and
140 150mg/m2/day respectively for the first five days of each cycle. These doses are pharmacologically
141 equivalent to the doses used when FCR is given intravenously for CLL(15). Full dose rituximab
142 was administered intravenously at 375mg/m2 on day 1 of cycle 1 and 500mg/m2 in cycles 2-6. In
143 participants with lymphocyte counts greater than 25x109/L, the dose of rituximab was split to
144 100mg on day 1 with remaining rituximab given on day 2 to reduce the risk of infusion related
145 reactions. Participants unable to tolerate oral chemotherapy were permitted to receive equivalent
146 intravenous doses of fludarabine (25mg/m2/day for 3 days) and cyclophosphamide (250mg/m2/day
147 for 3 days). FCM-miniR included intravenous mitoxantrone (6mg/m2/day) and 100mg rituximab
148 on day 1 of each cycle. All participants were given allopurinol at least in cycle 1. Prophylaxis for
149 pneumocystis carinii pneumonia (PCP) and aciclovir were given throughout the treatment.
150 Secondary prophylaxis with granulocyte-colony stimulating factor (G-CSF) (lenograstim 9
151 263mcg/day; days 7-13) was recommended for scheduled delays of therapy due to neutropenia.
152 Appropriate dose reductions were recommended in participants with therapy-related cytopenias.
153 Participants were assessed for response to treatment at 3 months post-treatment, 12, 18 and 24
154 months post-randomization or until disease progression requiring treatment. Long-term annual
155 follow-up for survival is performed until death.
156 Endpoints
157 The primary endpoint was CR rate (including CRi) at 3 months post-treatment. Response was
158 centrally assessed according to the IWCLL criteria(14) by two independent, experienced CLL
159 haematologists blinded to treatment allocation. An independent arbiter reviewed discordant
160 reports.
161 Secondary endpoints at 3 months post-treatment included MRD negativity, assessed in the bone
162 marrow by highly sensitive multi-parameter flow cytometry with a level of detection below 1 CLL
163 cell in 10 000 leukocytes(16, 17); ORR defined as at least a partial remission (PR); and safety and
164 toxicity as graded by CTCAE V3.0(18).
165 Longer-term secondary endpoints included PFS, OS, time to MRD relapse in participants who
166 became MRD-negative, and cost-effectiveness.
167 Sample size
168 Previous studies showed FCR CR rates of at least 50%(19, 20). With 80% power to show non-
169 inferiority, where this is defined as FCM-miniR being not more than 10% worse in terms of CR
170 rates than FCR, an assumed 10% difference in favor of FCM-miniR, a 1-sided significance level 10
171 ( ) of 2.5%(21) and 80% power, 98 patients were required per group. 206 patients were planned,
172 allowing for 5% dropout.
173 A formal interim analysis to allow large differences between the treatment groups to be reported
174 early was planned on the short-term efficacy data on half the required participants (n=103). A
175 stringent significance level was required for the interim analysis (0.005, 2-sided) using the
176 O’Brien-Fleming(22) alpha-spending function.
177 Statistical Methods
178 All analyses were conducted on the intention-to-treat (ITT) population, in which participants were
179 included according to their randomized treatment. A per-protocol analysis was planned for the
180 primary endpoint, including participants who received at least one cycle of treatment as
181 protocolled and were not major eligibility violators. Safety analyses included participants
182 according to the treatment they actually received.
183 Methods for handling missing endpoint data were pre-specified and approved by the Chief
184 Investigator. Participants with a missing assessment who died from CLL or treatment-related
185 toxicity prior to their primary endpoint assessment, or discontinued treatment early due to non-
186 response or toxicity were treated as non-responders/MRD-positive. In the formal statistical
187 analysis of the primary endpoint, for participants with at least a PR but missing trephine data to
188 confirm a CR, imputation methods treated MRD-negative participants as having a CR and MRD-
189 positive as not. Participants without an available endpoint assessment were not included in the
190 formal statistical analysis of the primary endpoint. This was appropriate as it can be assumed that
191 data are missing completely at random (MCAR), since assessments were most likely unavailable
192 due to samples being un-assessable or missed in error, rather than participant refusal due to level 11
193 of response or treatment allocation. Sensitivity analyses assessed the robustness of the assumptions
194 regarding missing primary endpoint data.
195 Binary logistic regression models compared CR rates, proportions with undetectable MRD and ORR
196 between the treatment groups, adjusting for the minimization factors, excluding center. The
197 differences in proportions are reported with 95% confidence intervals (CIs). The lower limit of the
198 CI for the CR rates was compared with the non-inferiority margin of 10%, expressed as an odds
199 ratio (OR).
200 Kaplan-Meier curves are presented for the PFS and OS endpoints. Cox regression analysis
201 formally compared time to MRD relapse, PFS and OS. Participants without evidence of an event
202 at the time of analysis were censored at the last date they were known to be alive and event-free.
203 Safety analyses summarized the number of safety events occurring after randomization including
204 treatment-related mortalities and incidence of secondary cancers.
205 Pre-specified exploratory subgroup analyses assessed the heterogeneity of the treatment effect
206 among subgroups of interest for the primary endpoint, PFS and OS. Formal statistical testing
207 between subgroups was not appropriate due to multiple testing errors and the reduced numbers in
208 each subgroup.
209 An economic evaluation was conducted from a National Health Service (NHS) and Personal Social
210 Services (PSS) perspective, with health benefit measured in Quality-Adjusted Life-Years
211 (QALYs), using patient-reported EQ-5D-3L questionnaires(23). A within-trial analysis compared
212 the outcomes and costs over 24 months using individual patient data from the trial, and a modified
213 Markov model was used to estimate lifetime cost-effectiveness. The model included three health 12
214 states: disease free, recurrence and death. Results are reported in 2013 GBP (£), and for
215 information costs are presented in US Dollars ($) using an exchange rate of 1:1.43.
216
217 RESULTS
218 Recruitment and Early Closure
219 Two-hundred participants were recruited between December 2009 and September 2012 (FCR:
220 100, FCM-miniR: 100) from 34 UK institutions with local ethical and management approval. At
221 the time of reporting, it has been approximately 6 years since the trial opened to recruitment, with
222 a median follow-up of just over 4 years.
223 The CONSORT diagram (Figure 1) shows the flow of participants throughout the trial.
224 The trial closed early in September 2012 following recommendation from the DMC and TSC. At
225 the pre-planned interim analysis on 103 participants, 72 (69.9%) received 6 cycles of treatment
226 [FCR: 38/51 (74.5%), FCM-miniR: 34/52 (65.4%)], and 61 (59.2%) achieved a CR [FCR: 34/51
227 (66.7%), FCM-miniR: 27/52 (51.9%)]. Of the participants with an assessable response, 61/85
228 (71.8%) achieved a CR [FCR: 34/41 (82.9%), FCM-miniR: 27/44 (61.4%)], with a difference in
229 response rates (FCM-miniR – FCR) of -21.6% (99.5%CI: -48.0%, 4.8%), adjusted p=0.037.
230 Although not significant at the pre-planned interim level ( =0.005), the results approached
231 significance in favor of FCR. There was also evidence of additional toxicity in the FCM-miniR
232 group with 65.4% (34/52) of participants experiencing a Serious Adverse Event (SAE) compared
233 to 51.0% (26/51) with FCR. The DMC recommended ceasing recruitment immediately; the 23
234 participants still receiving FCM-miniR were recommended to transfer to FCR for the remainder
235 of their treatment cycles. Twenty-one FCM-miniR participants transferred to receive treatment 13
236 with FCR (labelled FCM-miniR/FCR) following discussion with their treating clinician, two
237 participants elected to continue to receive FCM-miniR for their remaining treatment cycles.
238 Patient Characteristics
239 Baseline characteristics are displayed in Table 1. The median age was 63 years (range 36–80) with
240 75 participants (37.5%) aged >65 years. There was a male predominance [135 (67.5%)], and 34
241 participants (17.0%) were Binet Stage progressive A, 95 (47.5%) stage B and 71 (35.5%) stage C.
242 A majority of participants [116 (58.0%)] were WHO performance status (PS) 0, with 77 (38.5%)
243 PS 1 and 7 (3.5%) PS 2. Overall, 103 participants (51.5%) had B-symptoms, a higher proportion
244 with FCM-miniR [FCR: 46 (46.0%), FCM-miniR: 57 (57.0%)] whilst 115 (57.5%) had a 2-
245 microglobulin concentration of ≥4mg/L, and 31 (15.5%) creatinine clearance levels of 30-
246 60mls/min. Of the evaluable participants, 7/183 (3.8%) had a 17p-deletion [FCR: 4 (4.3%), FCM-
247 miniR: 3 (3.3%)]; 30/188 (16.0%) an 11q-deletion [FCR: 10 (10.8%), FCM-miniR: 20 (21.1%)].
248 104/165 participants (63.0%) were considered to be ‘poorer risk’ [FCR: 52 (63.4%), FCM-miniR:
249 52 (62.7%)], in terms of VH mutational status i.e. VH unmutated or involving the VH3-21 gene.
250 Treatment
251 Of the 200 participants, 141 (70.5%) received 6 cycles of treatment [FCR: 70 (70.0%), FCM-
252 miniR: 51 (64.5%), FCM-miniR/FCR: 20 (95.2%)] and 31 (15.5%) received ≤3 cycles of treatment
253 [FCR: 15 (15.0%), FCM-miniR: 16 (20.3%), FCM-miniR/FCR: 0 (0.0%)] (Table 2). Two FCR
254 participants did not receive any trial treatment, one had received prior therapy for CLL, and the
255 other had a 17p deletion and was withdrawn from the trial, patient and clinician decision (Figure
256 1). Overall, 59 participants (29.5%) discontinued treatment prematurely [FCR: 30 (30.0%), FCM-
257 miniR: 28 (35.4%), FCM-miniR/FCR: 1 (4.8%)]. Reasons included: toxicity (n=44); progressive 14
258 disease (n=3); stable disease with no or minimal response (n=3); ineligibility (n=1), patient
259 decision (n=3); clinician decision (n=4); other (n=1). A total of 94 participants (47.0%) received
260 G-CSF during treatment as recommended in the protocol as secondary prophylaxis, with a higher
261 proportion in the FCM-miniR group [FCR: 42 (42.0%), FCM-miniR: 40 (50.6%)] (Table 2).
262 Thirteen participants unable to tolerate oral chemotherapy received equivalent intravenous doses
263 [FCR: 7 (7.0%), FCM-miniR: 5 (6.3%), FCM-miniR/FCR: 1 (4.8%)].
264 Efficacy
265 Of the 200 participants, 124 (62.0%) achieved a CR [FCR: 68 (68.0%), FCM-miniR: 39 (49.4%),
266 FCM-miniR/FCR: 17 (81.0%)]. In the formal analysis of the primary endpoint including
267 imputation based on MRD outcome, 111/167 (66.5%) achieved a CR, [FCR: 70/92 (76.1%), FCM-
268 miniR: 41/75 (54.7%)]. The difference in response rates (FCM-miniR – FCR) was -21.4% in favor
269 of FCR (95%CI: -35.8%, -7.0%). In the logistic regression analysis, the OR for achieving a CR
270 with FCM-miniR compared to FCR was 0.37 (95%CI: 0.19, 0.73) (Table 3). A 10% non-inferiority
271 reduction from the FCR CR rate gives an OR limit of 0.61. Since the lower limit, and in fact the
272 mean of the 95% CI for the treatment effect is less than 0.61, and the upper limit is below 1, there
273 is evidence that FCM-miniR is significantly inferior to FCR. The per-protocol analysis (n=166)
274 concurred with the outcome of the ITT analysis, OR=0.38 (95%CI: 0.19, 0.75). The sensitivity
275 analyses did not alter the findings.
276 There were no large differences in proportions achieving a CR by sex [Males: 76/117 (65.0%),
277 Females: 35/50 (70.0%)], age group [≤65: 75/106 (70.8%), >65: 36/61 (59.0%)], or Binet stage [A
278 progressive/B: 76/111 (68.5%), C: 35/56 (62.5%)]. A significantly higher proportion of 15
279 participants who received >3cycles of treatment achieved a CR [≤3cycles: 7/25 (28.0%), >3cycles:
280 104/142 (73.2%)], with difference [-45.2% (95%CI: -64.3%, -26.2%)].
281 All assessable participants with a 17p deletion failed to achieve a CR (n=6). Lower proportions of
282 participants with an 11q deletion and ‘poorer risk’ VH mutational status achieved a CR [11qdel:
283 14/24 (58.3%), no 11qdel: 90/133 (67.7%)], [VH unmutated or VH3-21: 54/87 (62.1%), VH
284 mutated: 36/52 (69.2%)].
285 Of the 200 participants, 184 (92.0%) achieved at least a PR [FCR: 94 (94.0%), FCM-miniR: 69
286 (87.3%), FCM-miniR/FCR: 21 (100%)]. Of the assessable participants, the ORR was 92.6%
287 (163/176) with a higher proportion in the FCR group than FCM-miniR [FCR: 94/98 (95.9%),
288 FCM-miniR: 69/78 (88.5%), with a difference (FCM-miniR–FCR) of -7.5% (95%CI: -15.6%,
289 0.6%). A binary logistic regression analysis was unable to be performed due to the small number
290 of participants in the non-responders group.
291 Of the 200 participants, 85 (42.5%) achieved MRD negativity assessed in the bone marrow three-
292 months post-therapy [FCR: 45 (45.0%), FCM-miniR: 29 (36.7%), FCM-miniR/FCR: 11 (52.4%)].
293 In the formal analysis of MRD (excluding FCM-miniR/FCR participants and those with a missing
294 MRD assessment) 74/149 (49.7%) achieved MRD negativity [FCR: 45 (54.2%), FCM-miniR: 29
295 (43.9%)]. There was a non-significant trend towards FCM-miniR resulting in lower MRD-
296 negativity rates at three months with a difference (FCM-miniR – FCR) of -10.3% (95%CI: -26.3%,
297 5.8%), adjusted OR: 0.65 (95%CI:0.33, 1.26)] (Table 3).
298 At the time of analysis (3-years post-randomization of the final participant), 33 (16.5%)
299 participants have died [FCR: 14 (14.0%), FCM-miniR: 18 (22.8%), FCM-miniR/FCR: 1 (4.8%)]
300 and 73 (36.5%) have either progressed or died [FCR: 34 (34.0%), FCM-miniR: 35 (44.3%), FCM- 16
301 miniR/FCR: 4 (19.0%)]. Figure 2 presents the PFS and OS Kaplan-Meier curves by treatment
302 group (excluding FCM-miniR/FCR participants). At 36 months post-randomization, the PFS rate
303 is FCR: 75.3% vs. FCM-miniR: 71.3%; with OS rate FCR: 89.1%, FCM-miniR: 84.3%. The
304 hazard ratios (HR) were not significant in the adjusted Cox regression model [PFS: HR=1.29,
305 95%CI:(0.80, 2.07), p=0.298; OS: HR=1.62, 95%CI:(0.80, 3.28), p=0.178].
306 Of the 85 participants who were MRD-negative in the bone marrow at three months post-treatment
307 (Table 3), 9 (10.6%) were reported to have relapsed at the MRD level in the peripheral blood or
308 progressed [FCR: 5/45 (11.1%), FCM-miniR: 4/29 (13.8%)] at the end of the planned two-year
309 follow-up. The curves are not presented due to the small number of events.
310 For the planned subgroup analyses, Kaplan-Meier curves demonstrated an improved PFS in
311 participants who achieved a CR or MRD negativity at 3 months post-treatment (Figure 3). There
312 was a trend towards participants with a VH mutated gene (and not VH3-21) i.e. ‘standard risk’
313 patients showing an improved PFS over those with ‘poor risk’ (Figure3). Subgroup analyses for
314 OS show similar trends.
315 Economic Evaluation
316 Over the planned 24-month trial period, FCM-miniR produced a mean cost saving of £6 619 [$9
317 649] (s.d.£1 061 [$1 518]), and QALY loss of -0.059(s.d.0.06) compared to FCR. Assuming that
318 one QALY is valued at £20 000, as per UK standard, FCM-miniR is cost-effective over the trial
319 period, producing a positive incremental net health benefit (+0.27 QALYs; s.d.0.08) due to the
320 short-term cost savings associated with FCM-miniR treatment. However, FCM-miniR is not
321 expected to be cost-effective over a lifetime horizon, with an expected lifetime cost-saving of £7 17
322 723 [$11 048] (s.d. £3 281 [$4 694]), and QALY loss of -0.73(s.d.0.42), resulting in an incremental
323 net health loss (QALY: -0.34; s.d.0.40) (Table 4).
324 Safety and Toxicity
325 The safety population included 198 participants (Figure 1). 183 SAEs were reported from 104
326 (52.5%) participants, from a lower proportion receiving FCR (49.0%) compared to FCM-miniR
327 (58.2%). 145 Serious Adverse Reactions (SARs) were reported from 89 (44.9%) participants
328 [FCR: 62 events from 41 (41.0%); FCM-miniR: 67 events from 39 (49.4%); FCM-miniR/FCR: 16
329 events from 9 (47.4%)]. The most commonly reported SARs, 62.1% of events (n=90), were
330 infections and infestations (Table 5). Ninety-six (48.5%) participants required hospitalization for
331 an SAE with similar proportions in each treatment group (Table 5).
332 One Suspected Unexpected Serious Adverse Reaction (SUSAR) was reported from a participant
333 receiving FCR. A squamous cell carcinoma, two lesions on the lower back and central chest was
334 diagnosed approximately 4 months after the participant received 6 cycles of treatment.
335 Non-serious adverse events (AE) were reported from 192 (97.0%) participants with similar
336 proportions in each treatment group. Of the 2163 AEs reported, 388 (17.9%) were graded as
337 CTCAE grade 3 or above [FCR: 168 (15.0%); FCM-miniR: 193 (22.4%); FCM-miniR/FCR: 27
338 (14.8%)] (Table 5).
339 There were no treatment-related mortalities reported within 3 months of the end of protocol
340 treatment.
341 Within 4 years following treatment, 26 participants (13.1%) had been diagnosed with a second
342 cancer [FCR: 13 (13.0%); FCM-miniR: 12 (15.2%); FCM-miniR/FCR: 1 (5.3%)]. The most 18
343 commonly reported secondary cancers were non-melanoma skin cancers in 5.1% (n=10) of
344 participants, followed by hematological cancers (AML/MDS) in 3.0% of participants (n=6) (Table
345 5).
346
347 DISCUSSION
348 Participants randomised to FCM-miniR had a significantly lower CR rate than those randomised
349 to FCR (54.7% vs. 76.1%), indicating that FCR is the more effective treatment. This seems, at
350 least in part, due to the higher toxicity associated with the addition of mitoxantrone to FCR with
351 41.1% of participants receiving FCR reporting a SAR compared with 49.4% receiving FCM-
352 miniR. Key secondary endpoints were consistent in demonstrating that FCR has greater efficacy,
353 with a higher proportion of participants achieving MRD negativity (FCR: 54.2%, FCM-miniR:
354 43.9%). Trial follow-up is still relatively immature (median 4 years), and there are a high number
355 of censored observations, but to date the PFS and OS are favorable compared to previous studies.
356 There are no significant differences between the treatment groups for PFS and OS.
357 The cost-effectiveness analysis indicates that whilst FCM-miniR is expected to be cost-effective
358 in the short term, it is unlikely to be cost-effective when taking into account long-term costs and
359 health benefits, although there is significant uncertainty around the long-term results.
360 The design of this trial and its companion trial, ADMIRE comparing FCR with FCM-R (reported
361 in the companion paper), were based on several non-randomised Phase II trials suggesting that the
362 addition of mitoxantrone to FCR improved outcomes in CLL. The lower dose of rituximab was
363 based on pre-clinical and biological responses seen in small studies examining the impact of lower
364 doses of rituximab as a single agent in CLL. Both trials failed to demonstrate the expected 19
365 improvement in outcome for the proposed interventions. The use of randomised Phase II trials
366 allows a more critical assessment of the value of any proposed changes to treatment giving a more
367 robust assessment prior to launching prolonged and expensive Phase III trials. Given the rapidly
368 changing therapy in diseases such as CLL, the use of randomised Phase II trials either as stand-
369 alone trials or as part of seamless Phase II/III designs is an efficient way to prioritise appropriate
370 Phase III trial design and is highly recommended compared to large non-comparative Phase II
371 trials that are commonly performed.
372 In addition the outcomes for both the ARCTIC and ADMIRE trials are consistent with each other
373 and demonstrate that the delivery of fludarabine and cyclophosphamide by the oral route in FCR
374 is at least as effective as, and possibly more effective than, FCR when the chemotherapy
375 component is given intravenously. Oral FCR is also much more convenient for patients and results
376 in less use of valuable medical resources as patients only require a single day case visit per cycle
377 of treatment rather than three that is required if FCR is given intravenously.
378 In summary, we demonstrate that FCM-miniR is not non-inferior to FCR in terms of the primary
379 endpoint of CR at 3-months post-treatment. In addition, FCM-miniR shows evidence of reduced
380 efficacy in terms of MRD and survival, had increased toxicity, and is not cost-effective longer
381 term. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial.
382 The trial demonstrated that oral FCR yields extremely high response and MRD negativity rates
383 compared to historical series in which the chemotherapy was given intravenously, and remains the
384 gold-standard therapy for CLL in participants considered fit for fludarabine-based therapy. We
385 also demonstrate the value of randomised Phase II trials to improve the quality of future Phase III
386 trials.
387 20
388 ACKNOWLEDGEMENTS
389 ARCTIC is funded by the Health Technology Assessment (HTA) programme and is included in
390 the National Institute for Health Research (NIHR) Clinical Research Network Portfolio. The views
391 and opinions expressed there in are those of the authors and do not necessarily reflect those of
392 HTA, NIHR or the NHS.
393 The authors would like to thanks all patients and hospital staff who contributed to this study. In
394 addition, they acknowledge the invaluable support provided by the independent DMC and TSC.
395
396 CONFLICT OF INTEREST
397 Prof. Hillmen received research funding and speakers' fees from Roche Pharmaceuticals. Dr.
398 Rawstron reports personal fees from Roche Pharmaceuticals. Dr. Munir reports personal fees from
399 Roche Pharmaceuticals.
400 There are no other conflicts of interest to declare in relation to the work described.
401
402 21
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483 25
484 FIGURE LEGENDS
485 Figure 1: CONSORT Diagram
486 Figure 2: Kaplan Meier Curves for Progression-Free and Overall Survival
487 a. Progression-Free Survival by treatment group
488 b. Overall Survival by treatment group
489 Figure 3: Progression-Free Survival Subgroup Analyses
490 a. PFS by CR status at three months post-treatment
491 b. PFS by MRD status at three months post-treatment (assessed in the bone marrow)
492 c. PFS by VH mutational risk status
493 Table 1 Baseline Characteristics
494 Table 2 Treatment Summaries
495 Table 3 Efficacy Summaries
496 Table 4 Cost-Effectiveness Results (NHS and PSS perspective)
497 Table 5 Safety and Toxicity Summaries
498
499
500 26
501 FIGURES AND TABLES
Assessed for eligibility (n=548) 502 Figure 1 CONSORT Diagram
503 Excluded (n=348) - Patient clinically ineligible (n=228) - Patient did not wish to participate (n=39) - Patient too ill to participate (n=4) - Other reason (n=77)
Randomised (n=200)
Allocated to FCR (n=100): Allocated to FCM-miniR (n=100):
Received FCR throughout the trial (n=98) Received FCM-miniR throughout the trial (n=79) Commenced FCM-miniR but transferred over to FCR as a result of the Did not receive any FCR (n=2): interim analysis (n=19) - Clinical decision due to 17p deletion (n=1) - Breach of eligibility criteria, prior therapy for CLL (n=1) Did not receive any FCM-miniR (n=2): - Received FCR from cycle one as a result of the interim analysis (n=2)
Withdrawn consent from trial (n=5): Withdrawn consent from trial (n=4): - From trial treatment only (n=1) - From trial treatment only (n=1) - From trial treatment and follow-up data collection (n=4) - From trial treatment and follow-up data collection (n=2) - From follow-up data collection only (n=1) Post-randomisation ineligibility (n=2): - Prior therapy for CLL (n=1) Post-randomisation ineligibility (n=0) - Active or prior Hepatitis B or C (n=1)
Lost to follow-up: missing primary endpoint data (n=8): Lost to follow-up: missing primary endpoint data: (n=5) - Missing trephine sample (n=6) - Missing trephine sample (n=4) - Withdrew from follow-up data collection prior to assessment of - Unable to assess due to insufficient clinical evaluations performed primary endpoint (n=2) at 3 month post-treatment visit (n=1)
Analysis populations: Analysis populations:
Intention-to-treat (n=92): Intention-to-treat (n=75): - Excluded from ITT analysis (n=8): - Excluded from ITT analysis (n=25): o Missing primary endpoint data (n=8) o Missing primary endpoint data (n=5b) o Received FCR (n=21b) Per-protocol (n=91): - Excluded from PP analysis (n=9): Per-protocol (n=75): o Missing primary endpoint data (n=8a) - Excluded from PP analysis (n=25): o Did not receive any FCR (n=1a) o Missing primary endpoint data (n=5b) o Breach of eligibility criteria (prior therapy for CLL) and did not o Received FCR (n=21b) receive any FCR (n=1)
Safety population (n=100): Safety population (n=98): - Excludes 2 FCR participants who failed to receive any treatment - FCM-miniR (n=79) - Includes 2 FCM-miniR participants who received FCR from cycle 1 - FCM-miniR/FCR (n=19)
a One participant did not receive any FCR and also had missing primary b One participant received FCR and had missing primary endpoint data endpoint data and is therefore recorded twice and is therefore recorded twice
27
504 Table 1 Baseline Characteristics
FCR FCM-miniR Total
(n=100) (n=100) (n=200) Age (at randomization) ≤65 63 (63.0%) 62 (62.0%) 125 (62.5%) >65 37 (37.0%) 38 (38.0%) 75 (37.5%) Mean (s.d.) 61.8 (8.3) 62.6 (8.3) 62.2 (8.3) Median (range) 63 (41, 77) 63 (36, 80) 63 (36, 80) Sex Male 68 (68.0%) 67 (67.0%) 135 (67.5%) Female 32 (32.0%) 33 (33.0%) 65 (32.5%) Binet Stage Progressive A 20 (20.0%) 14 (14.0%) 34 (17.0%) B 41 (41.0%) 54 (54.0%) 95 (47.5%) C 39 (39.0%) 32 (32.0%) 71 (35.5%) B-symptoms Yes 46 (46.0%) 57 (57.0%) 103 (51.5%) No 54 (54.0%) 43 (43.0%) 97 (48.5%) WHO performance status 0 55 (55.0%) 61 (61.0%) 116 (58.0%) 1 40 (40.0%) 37 (37.0%) 77 (38.5%) 2 5 (5.0%) 2 (2.0%) 7 (3.5%) Beta-2 microglobulin concentration
(mg/L) <4 mg/L 37 (37.0%) 35 (35.0%) 72 (36.0%) ≥4 mg/L 53 (53.0%) 62 (62.0%) 115 (57.5%) Missing 10 (10.0%) 3 (3.0%) 13 (6.5%) Creatinine clearance (mls/min) 30-60mls/min 17 (17.0%) 14 (14.0%) 31 (15.5%) >60mls/min 83 (83.0%) 86 (86.0%) 169 (84.5%) 17p deletion Yes (poorer risk) 4 (4.0%) 3 (3.0%) 7 (3.5%) 28
FCR FCM-miniR Total
(n=100) (n=100) (n=200) No (standard risk) 88 (88.0%) 88 (88.0%) 176 (88.0%) Missing 8 (8.0%) 9 (9.0%) 17 (8.5%) 11q deletion Yes (poorer risk) 10 (10.0%) 20 (20.0%) 30 (15.0%) No (standard risk) 83 (83.0%) 75 (75.0%) 158 (79.0%) Missing 7 (7.0%) 5 (5.0%) 12 (6.0%)
VH mutational risk status
VH unmutated or VH3-21 (poorer risk) 52 (52.0%) 52 (52.0%) 104 (52.0%)
VH mutated and not VH3-21 (standard risk) 30 (30.0%) 31 (31.0%) 61 (30.5%) Missing 18 (18.0%) 17 (17.0%) 35 (17.5%) 505
506 WHO: World Health Organisation
507
508
509
510
511
512
513
514
515
516
517
518
519
520 29
521 Table 2 Treatment Summaries
FCM- FCR FCM-miniR Total miniR/FCR (n=100) (n=79) (n=200) (n=21) Discontinued treatment prematurely (received <6 cycles)? Yes 30 (30.0%) 28 (35.4%) 1 (4.8%) 59 (29.5%) No 70 (70.0%) 51 (64.5%) 20 (95.2%) 141 (70.5%) Treatment cycles
received ≤ 3 cycles 15 (15.0%) 16 (20.3%) 0 (0.0%) 31 (15.5%) > 3 cycles 85 (85.0%) 63 (79.7%) 21 (100.0%) 169 (84.5%) Received G-CSF during treatment (cycles 2 - 6)? Yes 42 (42.0%) 40 (50.6%) 12 (57.1%) 94 (47.0%) No 53 (53.0%) 34 (43.0%) 9 (42.9%) 96 (48.0%) Unknown 5 (5.0%) 5 (6.3%) 0 (0.0%) 10 (5.0%) 522
523 G-CSF: Granulocyte-colony stimulating factor was given if there was significant neutropenia on 524 a previous cycle of treatment
525
526
527
528
529
530
531
532 30
533 Table 3 Efficacy Summaries
534 31
MRD NEGATIVITY FCM- FCR FCM-miniR Total MRD status miniR/FCR (n=100) (n=79) (n=200) (n=21) MRD negative 45 (45.0%) 29 (36.7%) 11 (52.4%) 85 (42.5%) MRD positive 38 (38.0%) 37 (46.8%) 9 (42.9%) 84 (42.0%) Missing 17 (17.0%) 13 (16.5%) 1 (4.8%) 31 (15.5%) Difference in MRD- FCR FCM-miniR Total negative rates & 95% MRD status (n=83) (n=66) (n=149) CIs (FCM-miniR - FCR) MRD negative 45 (54.2%) 29 (43.9%) 74 (49.7%) -10.3% (-26.3%, 5.8%) MRD positive 38 (45.8%) 37 (56.1%) 75 (50.3%) Logistic regression analysis for the % of participants achieving MRD-negativity Parameter Parameter* SE OR 95% CIs for OR estimate FCM-miniR vs. FCR -0.44 0.34 0.65 (0.33, 1.26) COMPLETE RESPONSE CR status (prior to FCM- FCR FCM-miniR Total imputation using miniR/FCR (n=100) (n=79) (n=200) MRD) (n=21) Achieved a CR 68 (68.0%) 39 (49.4%) 17 (81.0%) 124 (62.0%) Did not achieve a 18 (18.0%) 28 (35.4%) 3 (14.3%) 49 (24.5%) CR Missing 14 (14.0%) 12 (15.2%) 1 (4.8%) 27 (13.5%) CR status (post FCM- FCR FCM-miniR Total imputation using miniR/FCR (n=100) (n=79) (n=200) MRD) (n=21) Achieved a CR 70 (70.0%) 41 (51.9%) 17 (81.0%) 128 (64.0%) Did not achieve a 22 (22.0%) 34 (43.0%) 3 (14.3%) 59 (29.5%) CR Missing 8 (8.0%) 4 (5.1%) 1 (4.8%) 13 (6.5%)
CR status (post Difference in CR rates FCR FCM-miniR Total imputation using & 95% CIs (n=92) (n=75) (n=167) MRD) (FCM-miniR - FCR) Achieved a CR 70 (76.1%) 41 (54.7%) 111 (66.5%) -21.4% (-35.8%, -7.0%) 32
Did not achieve a 22 (23.9%) 34 (45.3%) 56 (33.5%) CR PRIMARY ENDPOINT ANALYSIS Logistic regression analysis for the % of participants achieving a CR Parameter Parameter* SE OR 95% CIs for OR estimate FCM-miniR vs. FCR -0.98 0.34 0.37 (0.19, 0.73) 535
536 CR: Complete remission (CR/CRi)
537 MRD: Minimal Residual Disease
538 SE: Standard error
539 OR: Odds ratio
540 *Adjusted estimate of the treatment effect from the multivariable logistic regression model, 541 adjusted for the minimization factors
542
543
544
545
546
547
548
549
550
551
552
553
554
555 33
556 Table 4 Cost-Effectiveness Results (NHS and PSS perspective)
Total Total Inc. Inc. INB Strategy Cost QALY Cost QALY ICER (QALYs) (sd) (sd) (sd) (sd) (sd)
Within-trial analysis (24-month horizon)*
£17 241 1.610 FCR (745) (0.04)
£10 622 1.551 -£6 619 -0.059 0.27 FCM- miniR £112 193** (758) (0.05) (1,061) (0.06) (0.08)
Decision model analysis (Lifetime horizon)*
£31 314 7.76 FCR (7 237) (0.26)
£23 590 7.04 -£7 723 -0.73 -0.34 FCM- miniR £10 651** (6 997) (0.36) (3 281) (0.42) (0.40)
557 558 *For the cost in dollars ($), use an exchange rate of 1:1.43
559 **Pounds saved per QALY lost
560 NHS: National Health Service
561 PSS: Personal and Social Services
562 QALY: Quality-Adjusted Life-Years
563 ICER: Incremental Cost-Effectiveness Ratio
564 INB: Incremental Net Benefit
565 34
566 Table 5 Safety and Toxicity Summaries
FCM- FCR FCM-miniR Total miniR/FCR (n=100) (n=79) (n=198) (n=19) Serious Adverse Events (SAEs) Number of participants 49 (49.0%) 46 (58.2%) 9 (47.4%) 104 (52.5%) experiencing an SAE
Total number of 80 81 22 183 SAEs reported Number of participants requiring 46 (46.0%) 41 (51.9%) 9 (47.4%) 96 (48.5%) hospitalization for an SAE Serious Adverse Reactions (SARs) Number of participants 41 (41.0%) 39 (49.4%) 9 (47.4%) 89 (44.9%) experiencing a SAR
Total number of 62 67 16 145 SARs reported SARs by MedDRA System Organ Class* Blood and lymphatic 8 (12.9%) 8 (11.9%) 0 (0.0%) 16 (11.0%) system disorders Gastrointestinal 4 (6.5%) 4 (6.0%) 2 (12.5%) 10 (6.9%) disorders General disorders and administration 10 (16.1%) 6 (9.0%) 3 (18.8%) 19 (13.1%) site conditions Immune system 0 (0.0%) 1 (1.5%) 0 (0.0%) 1 (0.7%) disorders Infections and 36 (58.1%) 43 (64.2%) 11 (68.8%) 90 (62.1%) infestations 35
FCM- FCR FCM-miniR Total miniR/FCR (n=100) (n=79) (n=198) (n=19) Musculoskeletal and connective tissue 0 (0.0%) 1 (1.5%) 0 (0.0%) 1 (0.7%) disorders Neoplasms benign, malignant and unspecified 1 (1.6%) 1 (1.5%) 0 (0.0%) 2 (1.4%) (including cysts and polyps) Psychiatric disorders 1 (1.6%) 0 (0.0%) 0 (0.0%) 1 (0.7%) Renal and urinary 0 (0.0%) 2 (3.0%) 0 (0.0%) 2 (1.4%) disorders Skin and subcutaneous tissue 2 (3.2%) 1 (1.5%) 0 (0.0%) 3 (2.1%) disorders Adverse Events (AEs) Number of participants 96 (96.0%) 77 (97.5%) 19 (100%) 192 (97.0%) experiencing an AE Total number of 1117 863 183 2163 AEs reported CTCAE grade <3 943 (84.4%) 667 (77.3%) 156 (85.2%) 1766 (81.6%) ≥3 168 (15.0%) 193 (22.4%) 27 (14.8%) 388 (17.9%) Missing 6 (0.5%) 3 (0.3%) 0 (0.0%) 9 (0.4%) Secondary Cancers Number of participants reporting each secondary cancer Hematological 2 (2.0%) 2 (2.5%) 0 (0.0%) 4 (2.0%) (Lymphoma) 36
FCM- FCR FCM-miniR Total miniR/FCR (n=100) (n=79) (n=198) (n=19) Hematological 3 (3.0%) 3 (3.8%) 0 (0.0%) 6 (3.0%) (AML/MDS) Skin (Non- 4 (4.0%) 5 (6.3%) 1 (5.3%) 10 (5.1%) melanoma) Skin (Melanoma) 2 (2.0%) 1 (1.3%) 0 (0.0%) 3 (1.5%) Non-hematological 4 (4.0%) 1 (1.3%) 0 (0.0%) 5 (2.5%) (Solid tumors) 567
568 *Percentages are out of total number of SARs reported
569 MedDRA: Medical Dictionary for Regulatory Activities
570 CTCAE: Common Terminology Criteria for Adverse Events
571 AML: Acute myeloid leukemia
572 MDS: Myelodysplastic syndrome
573
574
575
576
577
578
579
580
581
582
583 37
584 Figure 2 Kaplan Meier Curves for Progression-Free and Overall Survival
a. Progression-Free Survival by treatment group
1.0 XX XX
0.9 X
X
X XXXX 0.8 X XX XX XXXXXX XXXX X XXXXXXXX X XX XXXX X X XXXX 0.7 X X
X 0.6 XXXXXXXXXXXXXXXXXX X XX X XXXXXXXXX XX XXX 0.5 XX XX XXX XXXXX X
0.4 XX FCMminiR 0.3 FCR Progression-freeprobability
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60
Months from randomization
Number at Risk FCMminiR 79 75 71 66 62 56 45 38 24 9 4 FCR 100 97 95 90 85 79 53 38 21 11 4 b. Overall Survival by treatment group
1.0 XX XX
XXX
0.9 X X XXXXXXXXXXXXXXXXXXX X XX XXXXXXXXXXXX X XXXXX X X XXX XXXXXXX X XX X XXXXXXXXXXXXXXXXXXXXXX X 0.8 X X XXXX X XXXXXX XX XX XXXXXXXXXXXXXXXXX
XX
0.7 XXXXX X X X XXXX
0.6
0.5
0.4
Survivalprobability FCMminiR 0.3 FCR
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60
Months from randomization
Number at Risk FCMminiR 79 77 74 70 69 65 51 44 30 12 5 585 FCR 100 97 96 94 92 89 60 43 26 14 6
586 38
587 Figure 3 Kaplan Meier Curves for Subgroup Analyses for Progression-Free Survival
a. PFS by CR status at 3 months post-treatment
1.0 X XX
X X X X X X XXXX 0.9 XX XXXXXX XXXXXXX XXXXX XXX X X 0.8
XX X XXXXXXXXXXXXXXXXXXXXXXXXXXXX 0.7 XX XXXX
XX XXX X XX 0.6
0.5 X XXX X X
0.4 1: Achieved a CR X 0.3 2: CR not achieved X XX Progression-free probability
0.2 XX
X 0.1
0.0
0 6 12 18 24 30 36 42 48 54 60
Months from randomization
Number at Risk 1: Achieved a CR 111 111 111 108 103 99 72 57 37 17 7 2: CR not achieved 56 50 44 38 34 27 20 15 7 2 1 b. PFS by MRD status at 3 months post-treatment
1.0 XX
XX X X XXXX X 0.9 XXXXXXXX X X X X XX XXXXXXXXXXXXXXXXXXXXXXXXX
0.8 XXXX XX
XXX X X 0.7 X
X XXXXXXX XXX 0.6 XX X
X 0.5
0.4 X MRD negative XXX X 0.3 MRD positive XX Progression-free probability
0.2 X XX
0.1
0.0 0 6 12 18 24 30 36 42 48 54 60
Months from randomization
Number at Risk MRD negative 74 74 74 72 70 68 53 47 31 14 6 MRD positive 75 71 68 61 57 48 32 21 13 5 2 c. PFS by VH mutational risk status
1.0 XXXX
0.9
X X
XX XX 0.8 X XXXXXX X X X
X XX X XX 0.7 XXX XXXXX X XXXXXXXXXXXXXX X XX X X X X X
XXX X X 0.6
X X X XXXXXXX 0.5 XXX XXX X XX
0.4
0.3 XX Progression-free probability
0.2
1: VH mut/not VH3-21 0.1 2: VH unmut/VH3-21
0.0
0 6 12 18 24 30 36 42 48 54 60
Months from randomization
Number at Risk 1: VH mut/not VH3-21 58 56 54 51 49 48 36 31 18 8 4 588 2: VH unmut/VH3-21 91 86 83 77 72 63 48 34 20 8 4