Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
2017 · paper · Clinical trials
A multicenter phase 2 trial of axicabtagene ciloleucel CAR T-cell therapy in 111 patients with refractory large B-cell lymphoma. The objective response rate was 82% and complete response 54%; serious side effects included cytokine release syndrome and neurologic events.
2 findings
Substance Fig. 1B, Activated B-cell–like subtype row: 17 evaluated, 13 with event, printed "0.76 (0.50–0.83)". The upper bound of 0.83 does not fit 13/17, and the plotted whisker runs to about 0.92.
- p. 13 Figure 1B, Cell of origin, Activated B-cell–like subtype row
0.76 (0.50–0.83)
Only the authors can say what is right here.
Judge's note: I read p13. For 13/17 = 0.765, an exact Clopper–Pearson 95% interval is about 0.50–0.93. An upper bound only 0.07 above the point estimate is not possible for n=17 when the lower bound is 0.26 below it. Rows of similar size are printed with wider intervals (12/17 gives 0.44–0.90; 6/8 gives 0.35–0.97). In the image, the whisker for this row extends past 0.9, so the printed label disagrees with the plot. The authors need to supply the correct upper bound.
Second check: another model agreed
Report a problem with this finding
Substance Table 2 lists "Thrombocytopenia 59 (58) 21 (21) 38 (38)" twice in the adverse-event block: once after Hypotension and again between Encephalopathy (34) and Vomiting (34). The second copy breaks the descending-frequency order.
- p. 20 Table 2, Adverse event section, row after Hypotension
Thrombocytopenia 59 (58) 21 (21) 38 (38)
- p. 20 Table 2, adverse events
Thrombocytopenia
Only the authors can say what is right here.
Judge's note: The p20 image confirms two identical Thrombocytopenia rows. Apart from this row, the list is in descending order of any-grade count. The second row is either a stray duplicate or has replaced a different event of about 34 patients. Only the authors can say which.
Second check: another model agreed
Report a problem with this finding
7 minor (typos and the like; most checked by the judge only)
Wording The conclusion says "adult patients with relapsed or refractory large B-cell lymphoma after at least two prior systemic therapies". The Methods define the population as refractory disease or relapse within 12 months after ASCT, and Table 1 lists 2 patients (2%) as "Primary refractory" at study entry.
- p. 9 Discussion, concluding paragraph
adult patients with relapsed or refractory large B-cell lymphoma after at least two prior systemic therapies
- p. 3 Methods, Patients and Study Design
Patients had refractory disease, which was defined as progressive or stable disease as the best response to the most recent chemotherapy regimen
- p. 18 Table 1, Refractory subgroup at study entry
Primary refractory
Only the authors can say what is right here.
Judge's note: I looked at p9 (the conclusion), the p3 eligibility definition in the text layer, and Table 1 on p18. The eligibility definition covers refractory disease and progression or relapse within 12 months after ASCT, not relapsed disease in general. The 2 primary-refractory patients at study entry need not have had two prior therapies. The conclusion's population wording differs from the enrolled population, so this is a wording mismatch to put to the authors.
Second check: another model agreed
Report a problem with this finding
Wording Discussion paragraph 1 opens with "82% of the 101 patients ... had an objective response" and then says "responses were ongoing in 42% of the patients, including in 40% who had a complete response" and "an overall survival rate at 18 months of 52%". These figures come from the updated analysis of 108 phase 1 and 2 patients, but the paragraph never names that population.
- p. 7 Discussion, paragraph 1
82% of the 101 patients with refractory large B-cell lymphoma who were treated had an objective response
- p. 7 Discussion, paragraph 1
responses were ongoing in 42% of the patients, including in 40% who had a complete
- p. 5 Results, Updated Analysis
updated analysis when the 108 patients in the phase 1 and 2 portions of ZUMA-1
Only the authors can say what is right here.
Judge's note: I looked at p7 (Discussion) and p5 (Updated Analysis). Page 5 gives the 42% and 40% for the updated analysis of 'the 108 patients in the phase 1 and 2 portions', and the Fig. 2C OS numbers at risk start at 108. The '15.4 months' wording does point to the updated cutoff (Results p4: the updated cutoff gave a median follow-up of 15.4 months). However, the denominator changes from the 101 named in the previous sentence to 108 without saying so. This is an unresolved ambiguity, not a wrong number.
Second check: another model agreed
Report a problem with this finding
Wording The Figure 2 legend says "the median duration of response was 8.1 months (range, 3.5 to could not be estimated [NE])". A range cannot have an inestimable upper end, and elsewhere the paper reports medians with a 95% CI in this format.
- p. 15 Figure 2 legend
the median duration of response was 8.1 months (range, 3.5 to could not be estimated [NE])
- p. 5 Efficacy, Primary Analysis
The median duration of response was 8.1 months (95% CI, 3.3 to could not be estimated)
- p. 15 Figure 2 legend
the median duration of response was 8.1 months (range, 3.5 to could not be estimated
Only the authors can say what is right here.
Judge's note: I looked at p15 (the Fig. 2 legend) and p5. On p5 the medians are given as '95% CI, 3.3 to could not be estimated' and '95% CI, 3.9 to could not be estimated'. A 'range' with an NE upper limit looks like a mislabelled CI. The difference between 3.3 and 3.5 is not a defect: the p5 value is investigator-assessed (Methods: response assessed by the investigators), while the legend value is by independent central review, so the two are different assessments.
Second check: another model agreed
Report a problem with this finding
Typo The affiliation list gives "Colorado Blood Cancer Institute, Denver (P.M.S.)", but the author list names "Peter McSweeney, M.D." (initials P.M.), and no author has the initials P.M.S.
- p. 10 Appendix, affiliations
Colorado Blood Cancer Institute, Denver (P.M.S.)
- p. 10 Affiliations
Denver (P.M.S.)
Judge's note: On p10 the author list reads 'Peter McSweeney, M.D.' with no middle initial, and the affiliation list reads '(P.M.S.)'. The other disambiguated tags, 'A. Ghobadi' and 'A. Goy', use a different style. No other author has the initials P.M., so there is no reason for an extra letter. This is a cosmetic initials error.
Second check: none (judge only)
Report a problem with this finding
Typo The Figure 1 legend defines "transformed follicular lymphoma (TLF)", but the figure panel ("PMBCL or TFL (N=24)") and Table 1 use "TFL".
- p. 13 Figure 1 legend
transformed follicular lymphoma (TLF)
- p. 13 Figure 1A axis label
PMBCL or TFL (N=24)
- p. 19 Table 1 footnote
TFL transformed follicular lymphoma
- p. 13 Figure 1 legend
axi-cabtagene ciloleucel (axi-cel)
Judge's note: On the p13 image, the legend reads 'TLF' and the panel A axis label reads 'PMBCL or TFL'. Table 1 on p18 uses TFL. The abbreviation is inconsistent; this is cosmetic. The 'axi-cabtagene' misspelling that is also mentioned here is judged separately under C007.
Second check: none (judge only)
Report a problem with this finding
Typo The Figure 1 legend misspells the drug name as "axi-cabtagene ciloleucel (axi-cel)" instead of "axicabtagene ciloleucel".
- p. 13 Figure 1 legend
axi-cabtagene ciloleucel (axi-cel)
- p. 13 Figure 1 legend
axi-cabtagene ciloleucel
Judge's note: On the p13 image, 'axi-cabtagene' appears in the middle of a line, so it is not a line-break hyphen. Everywhere else the paper writes 'axicabtagene'. This is a cosmetic misspelling.
Second check: none (judge only)
Report a problem with this finding
Typo The Table 1 row heading reads "CD-19 status — no./total no. (%)", while the rest of the paper writes "CD19".
- p. 18 Table 1 row heading
CD-19 status — no./total no. (%)
Judge's note: The p18 image shows 'CD-19 status'. Fig. 1B and the text use 'CD19'. This is a cosmetic inconsistency.
Second check: none (judge only)