CAR-T treatment: determining the survival gain in patients ... · 1 Letter to the Editor CAR-T...

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Journal Pre-proof CAR-T treatment: determining the survival gain in patients with relapsed or refractory diffuse large B-cell lymphoma Andrea Messori, PharmD, Vera Damuzzo, PhD, Luca Leonardi, PharmD, Laura Agnoletto, PhD, Marco Chiumente, PharmD, Daniele Mengato, PharmD PII: S2152-2650(20)30087-2 DOI: https://doi.org/10.1016/j.clml.2020.02.007 Reference: CLML 1535 To appear in: Clinical Lymphoma, Myeloma and Leukemia Received Date: 27 January 2020 Accepted Date: 9 February 2020 Please cite this article as: Messori A, Damuzzo V, Leonardi L, Agnoletto L, Chiumente M, Mengato D, CAR-T treatment: determining the survival gain in patients with relapsed or refractory diffuse large B-cell lymphoma Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/ j.clml.2020.02.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.

Transcript of CAR-T treatment: determining the survival gain in patients ... · 1 Letter to the Editor CAR-T...

Page 1: CAR-T treatment: determining the survival gain in patients ... · 1 Letter to the Editor CAR-T treatment: determining the survival gain in patients with relapsed or refractory diffuse

Journal Pre-proof

CAR-T treatment: determining the survival gain in patients with relapsed or refractorydiffuse large B-cell lymphoma

Andrea Messori, PharmD, Vera Damuzzo, PhD, Luca Leonardi, PharmD, LauraAgnoletto, PhD, Marco Chiumente, PharmD, Daniele Mengato, PharmD

PII: S2152-2650(20)30087-2

DOI: https://doi.org/10.1016/j.clml.2020.02.007

Reference: CLML 1535

To appear in: Clinical Lymphoma, Myeloma and Leukemia

Received Date: 27 January 2020

Accepted Date: 9 February 2020

Please cite this article as: Messori A, Damuzzo V, Leonardi L, Agnoletto L, Chiumente M, MengatoD, CAR-T treatment: determining the survival gain in patients with relapsed or refractory diffuse largeB-cell lymphoma Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/j.clml.2020.02.007.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.

© 2020 Published by Elsevier Inc.

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Letter to the Editor

CAR-T treatment: determining the survival gain in patients

with relapsed or refractory diffuse large B-cell lymphoma

Andrea Messori PharmD,1 Vera Damuzzo PhD,2 Luca Leonardi PharmD,3

Laura Agnoletto PhD,3 Marco Chiumente PharmD,3 Daniele Mengato PharmD3

1HTA Unit, Regional Health Service, Florence, Italy

2School of Hospital Pharmacy, Department of Pharmaceutical and Pharmacological Sciences,

University of Padua, Padua, Italy

3Scientific Direction, Italian Society for Clinical Pharmacy and Therapeutics, Milan, Italy

Corresponding author:

Andrea Messori, PharmD

HTA Unit, Regional Health Service

Via San Salvi 12

50135 Firenze (Italy)

Email: [email protected]

Phone: +39-338-9513583

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Word count (body of the manuscript only): 968

Kallam and Vose have presented a very extensive landscape of the current information on the

efficacy and safety of treatment with CAR-T in patients with non-Hodgkin lymphoma.1 As regards

efficacy, we have carried out a comparison of overall survival (OS) between patients treated with

tisagenlecleucel and a large sample of historical controls given a standard treatment. Our objective

was to offer a quantivative estimate of the survival gain resulting from CAR-T compared with

standard treatment. This estimate was based on the restricted mean survival time (RMST).

In the last years, an extensive literature has accumulated on the use of restricted mean survival time

(RMST) in the interpretation of survival curves. In comparison with traditional analyses based on

hazard ratio (HR) and medians, the RMST has important advantages because it examines the entire

survival curve (like the HR) and expresses the survival outcomes using time as unit of measurement

(like medians). Most previous experiences on the application of RMST are focused on oncology

(e.g. see Trinquart et al. 2016;2 Royston & Parmar 20113). Quite recently, the application of RMST

has been investigated in cardiovascular4 and infectious diseases.5 Briefly, the RMST combines the

main advantages of HR and medians without possessing their disadvantages.

From a practical point of view, the RMST is characterized by a high mathematical complexity of its

statistical calculations.2-5 However, two recent papers6,7 have suggested an original method of

calculation, drawn from the field of pharmacokinetics, that allows for an extreme simplification of

RMST estimation.

In the present study focused on the treatment of diffuse large B-cell lymphoma (DLBCL), we

assessed the survival gain derived from CAR-T treatment (experimental group) in comparison with

previous treatments not involving any gene manipulations (control group).

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The controls included in our analysis were obtained from an article published by Crump et al.

(SCHOLAR-1 study8). The experimental group (CAR-T group; CAR-T=tisagenlecleucel) was

obtained from the patient series published by Schuster et al. (JULIET trial9). These two populations

of patients (experimental arm: N=48; controls: N=603) were identified through a simple PubMed

search. Their disease consisted of DLBCL including transformed follicular lymphoma and primary

mediastinal B-cell lymphoma. All patients had received at least two previous lines of treatment.

When they received their salvage treatment, they met specific criteria of either relapse or refractory.

Twenty-nine of 48 (60.4%) and 118 of 603 (19.6%) patients were in relapse in the experimental and

in the control groups, respectively. Autologous transplantation had been performed in 49% of

patients in the experimental group and in 19.6% patients of SCHOLAR-1 patients. Further details

on these two populations can be found in the original studies.8,9

Despite the indirect nature of the comparison described herein, one advantage of our analysis lies in

the attempt to estimate for the first time the survival improvement related to the use of CAR-T

under specific circumstances. No direct comparison is in fact available on this issue.

The values of model-independent RMST were 13.46 months for CAR-T and 10.81 for the controls.

Both values were based on a “milestone” set at 22 months of follow-up; the milestone is the time-

point in the follow-up at which the area under the survival curve is truncated. The two AUCs are

shown in Figure 1. The survival gain estimated from the comparison of the two curves was 2.65

months per patient in favor of the CAR-T group.

The main result expected from our indirect comparison was to demonstrate a survival gain for

CAR-T compared with a standard therapeutic approach and to estimate the magnitude of this

benefit. A difference in overall survival was found from our analysis. Apart from the level of

statistical significance of this difference (which is anyhow questionable in such an imbalanced

indirect comparison, 48 vs 603 patients), the survival gain in favor of CART-T was quite small.

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This lack of a clinically relevant incremental efficacy for CAR-T at 22 months is the main finding

of our analysis.

The availability of the SCHOLAR-1 study including patients not given a CAR-T was the main

reason that led us to undertake this analysis. In the comparison between our experimental group

given CAR-T vs the controls, the RMST had the methodological advantage of taking into account

the entire shape of the two survival curves.

More importantly, another consideration is that, at the end of the follow-up of 22 months, the

patients given CAR-T might have, in future perspective, a longer life expectancy than those not

given CAR-T. This hypothesis will need to be verified through a further follow-up for the patients

of the JULIET trial (i.e. beyond 22 months). Fortunately, the SCHOLAR-1 patients already have a

very long follow-up (up to 180 months), and so these controls will remain comparable with CART

patients when, in the future, the further follow-up of these patients will allow to set a milestone at

more than 22 months. The obvious hypothesis is that, with a longer follow-up, the AUC for CAR-T

patients could become much greater than that of the controls, but this demonstration is presently

lacking.

Were the two populations studied in our analysis comparable? In our view, they were sufficiently

comparable. Furthermore, it should be recalled that the information about the efficacy of CAR-T is

still limited, and so the comparison presented herein seems the only one that currently can be made.

Two conclusions are suggested by our study. Firstly, the RMST is confirmed to be a suitable

parameter for managing the survival data of lymphoma patients receiving a CART.10 Secondly, the

RMST analysis based on the outcomes currently available does not demonstrate any breakthrough

survival advantage for tisagenleleucel in comparison with treatments not involving any gene

manipulations. Hence, our analysis provides a quantitative confirmation of the statement by Kallam

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and Vose1 that “despite the promising results from the large multicenter trials, the efficacy of CAR-

T cells in non Hodgkin lymphoma is limited”.

References

1. Kallam A, Vose JM. Recent Advances in CAR-T Cell Therapy for Non-HodgkinLymphoma.

Clin Lymphoma Myeloma Leuk. 2019 Dec;19(12):751-757. doi:10.1016/j.clml.2019.09.598.

2. Trinquart L, Jacot J, Conner SC, Porcher R. Comparison of Treatment Effects Measured by the

Hazard Ratio and by the Ratio of Restricted Mean Survival Times in Oncology Randomized

Controlled Trials. J Clin Oncol. 2016 May 20;34(15):1813-9. doi: 10.1200/JCO.2015.64.2488.

3. Royston P, Parmar MK. The use of restricted mean survival time to estimate the treatment effect in

randomized clinical trials when the proportional hazards assumption is in doubt. Stat Med. 2011

Aug 30;30(19):2409-21. doi:10.1002/sim.4274.

4. McCaw ZR, Yin G, Wei LJ. Using the Restricted Mean Survival Time Difference as an Alternative to

the Hazard Ratio for Analyzing Clinical Cardiovascular Studies. Circulation. 2019 Oct

22;140(17):1366-1368. doi:10.1161/CIRCULATIONAHA.119.040680.

5. Abulizi X, Ribaudo HJ, Flandre P. The Use of the Restricted Mean Survival Time as a Treatment

Measure in HIV/AIDS Clinical Trial: Reanalysis of the ACTG A5257 Trial. J Acquir Immune Defic

Syndr. 2019 May 1;81(1):44-51. doi:10.1097/QAI.0000000000001978.

6. Damuzzo V, Agnoletto L, Leonardi L, Chiumente M, Mengato D, Messori A. Analysis of Survival

Curves: Statistical Methods Accounting for the Presence of Long-Term Survivors. Front Oncol. 2019

Jun 4;9:453. doi: 10.3389/fonc.2019.00453.

7. Messori A, Damuzzo V, Agnoletto L, Leonardi L, Chiumente M, Mengato D. A model-independent

method to determine restricted mean survival time in the analysis of survival curves. SN

Comprehensive Clinical Medicine 2019 (in press), https://doi.org/10.1007/s42399-019-00199-7,

preprint available at http://www.osservatorioinnovazione.net/damuzzo(corrected-proofs).pdf

8. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in

refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood.

2017 Oct 19;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.

9. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. JULIET Investigators.

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med.

2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980.

10. Chiumente M, Mengato D, Messori A. Tisagenlecleucel in non-Hodgkin lymphoma: the restricted

mean survival time as a tool for estimating progression-free life expectancy better than the median

Acta Haematologica 2020 (in press), preprint available at

http://www.osservatorioinnovazione.net/aha-accepted-paper.pdf

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Legends for figures

Figure 1. Values of RMST estimated by model independent methods for CART patients (13.46

months, in blu) and controls (10.81 months, in red). The original data sets were Figure 3 (Panel A)

of Crump et al.7 and Figure S1 (Panel B) of Schuster et al.8

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