How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Ing Soo Tiong^{1

2

3}, Meaghan Wall^{3

4}, Ashish Bajel^{1

5

6}, Akash Kalro⁷, Shaun Fleming², Andrew W Roberts^{1

5

6

8}, Nisha Thiagarajah⁵, Chong Chyn Chua^{2

3

9}, Maya Latimer^{10

11

12}, David Yeung^{7

13}, Paula Marlton^{14

15}, Amanda Johnston¹⁶, Anoop Enjeti¹⁷, Chun Yew Fong¹⁸, Gavin Cull^{19

20

21}, Stephen Larsen²², Glen Kennedy²³, Anthony Schwarer²⁴, David Kipp²⁵, Sundra Ramanathan²⁶, Emma Verner²⁷, Campbell Tiley^{28

29}, Edward Morris³⁰, Uwe Hahn^{7

31

32}, John Moore³³, John Taper³⁴, Duncan Purtill^{20

35}, Pauline Warburton³⁶, William Stevenson^{37

38}, Nicholas Murphy³⁹, Peter Tan⁴⁰, Ashanka Beligaswatte^{7

41

42}, Howard Mutsando⁴³, Mark Hertzberg⁴⁴, Jake Shortt^{3

45}, Ferenc Szabo⁴⁶, Karin Dunne⁴⁷, Andrew H Wei^{48

49

50

51}; Australasian Leukaemia and Lymphoma Group (ALLG)

Affiliations

¹ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² The Alfred Hospital, Melbourne, VIC, Australia.
³ Monash University, Melbourne, VIC, Australia.
⁴ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁵ Royal Melbourne Hospital, Parkville, VIC, Australia.
⁶ The University of Melbourne, Melbourne, VIC, Australia.
⁷ Royal Adelaide Hospital, Adelaide, SA, Australia.
⁸ Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁹ The Northern Hospital, Epping, VIC, Australia.
¹⁰ Canberra Hospital, Garran, ACT, Australia.
¹¹ ACT Pathology, Garran, ACT, Australia.
¹² Australian National University, Canberra, ACT, Australia.
¹³ South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
¹⁴ Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
¹⁵ University of Queensland, Brisbane, QLD, Australia.
¹⁶ Westmead Hospital, Westmead, NSW, Australia.
¹⁷ Calvary Mater Newcastle, Waratah, NSW, Australia.
¹⁸ Austin Hospital, Heidelberg, VIC, Australia.
¹⁹ Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
²⁰ PathWest Laboratory Medicine, Nedlands, WA, Australia.
²¹ University of Western Australia, Perth, WA, Australia.
²² Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
²³ Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
²⁴ Box Hill Hospital, Box Hill, VIC, Australia.
²⁵ Barwon Health, Geelong, VIC, Australia.
²⁶ St George Hospital, Kogarah, NSW, Australia.
²⁷ Concord Hospital, Concord, NSW, Australia.
²⁸ Gosford Hospital, Gosford, NSW, Australia.
²⁹ University of Newcastle, Callaghan, NSW, Australia.
³⁰ Townsville University Hospital, Douglas, QLD, Australia.
³¹ The Queen Elizabeth Hospital, Woodville South, SA, Australia.
³² SA Pathology, Adelaide, SA, Australia.
³³ St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia.
³⁴ Nepean Hospital, Kingswood, NSW, Australia.
³⁵ Fiona Stanley Hospital, Murdoch, WA, Australia.
³⁶ Wollongong Hospital, Wollongong, NSW, Australia.
³⁷ Royal North Shore Hospital, St Leonards, NSW, Australia.
³⁸ Northern Clinical School, University of Sydney, Sydney, NSW, Australia.
³⁹ Royal Hobart Hospital, Hobart, TAS, Australia.
⁴⁰ Royal Perth Hospital, Perth, WA, Australia.
⁴¹ Flinders Medical Centre, Bedford Park, SA, Australia.
⁴² Flinders University, Bedford Park, SA, Australia.
⁴³ Toowoomba Hospital, Toowoomba, QLD, Australia.
⁴⁴ Prince of Wales Hospital, Randwick, NSW, Australia.
⁴⁵ Monash Medical Centre, Clayton, VIC, Australia.
⁴⁶ Royal Darwin Hospital, Tiwi, NT, Australia.
⁴⁷ Australasian Leukaemia and Lymphoma Group (ALLG), Melbourne, VIC, Australia.
⁴⁸ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. andrew.wei@petermac.org.
⁴⁹ Royal Melbourne Hospital, Parkville, VIC, Australia. andrew.wei@petermac.org.
⁵⁰ The University of Melbourne, Melbourne, VIC, Australia. andrew.wei@petermac.org.
⁵¹ Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. andrew.wei@petermac.org.

PMID: 38531863
PMCID: PMC10965987
DOI: 10.1038/s41408-024-00996-x

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Ing Soo Tiong et al. Blood Cancer J. 2024.

. 2024 Mar 26;14(1):54.

doi: 10.1038/s41408-024-00996-x.

Authors

Affiliations

¹ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² The Alfred Hospital, Melbourne, VIC, Australia.
³ Monash University, Melbourne, VIC, Australia.
⁴ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁵ Royal Melbourne Hospital, Parkville, VIC, Australia.
⁶ The University of Melbourne, Melbourne, VIC, Australia.
⁷ Royal Adelaide Hospital, Adelaide, SA, Australia.
⁸ Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁹ The Northern Hospital, Epping, VIC, Australia.
¹⁰ Canberra Hospital, Garran, ACT, Australia.
¹¹ ACT Pathology, Garran, ACT, Australia.
¹² Australian National University, Canberra, ACT, Australia.
¹³ South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
¹⁴ Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
¹⁵ University of Queensland, Brisbane, QLD, Australia.
¹⁶ Westmead Hospital, Westmead, NSW, Australia.
¹⁷ Calvary Mater Newcastle, Waratah, NSW, Australia.
¹⁸ Austin Hospital, Heidelberg, VIC, Australia.
¹⁹ Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
²⁰ PathWest Laboratory Medicine, Nedlands, WA, Australia.
²¹ University of Western Australia, Perth, WA, Australia.
²² Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
²³ Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
²⁴ Box Hill Hospital, Box Hill, VIC, Australia.
²⁵ Barwon Health, Geelong, VIC, Australia.
²⁶ St George Hospital, Kogarah, NSW, Australia.
²⁷ Concord Hospital, Concord, NSW, Australia.
²⁸ Gosford Hospital, Gosford, NSW, Australia.
²⁹ University of Newcastle, Callaghan, NSW, Australia.
³⁰ Townsville University Hospital, Douglas, QLD, Australia.
³¹ The Queen Elizabeth Hospital, Woodville South, SA, Australia.
³² SA Pathology, Adelaide, SA, Australia.
³³ St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia.
³⁴ Nepean Hospital, Kingswood, NSW, Australia.
³⁵ Fiona Stanley Hospital, Murdoch, WA, Australia.
³⁶ Wollongong Hospital, Wollongong, NSW, Australia.
³⁷ Royal North Shore Hospital, St Leonards, NSW, Australia.
³⁸ Northern Clinical School, University of Sydney, Sydney, NSW, Australia.
³⁹ Royal Hobart Hospital, Hobart, TAS, Australia.
⁴⁰ Royal Perth Hospital, Perth, WA, Australia.
⁴¹ Flinders Medical Centre, Bedford Park, SA, Australia.
⁴² Flinders University, Bedford Park, SA, Australia.
⁴³ Toowoomba Hospital, Toowoomba, QLD, Australia.
⁴⁴ Prince of Wales Hospital, Randwick, NSW, Australia.
⁴⁵ Monash Medical Centre, Clayton, VIC, Australia.
⁴⁶ Royal Darwin Hospital, Tiwi, NT, Australia.
⁴⁷ Australasian Leukaemia and Lymphoma Group (ALLG), Melbourne, VIC, Australia.
⁴⁸ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. andrew.wei@petermac.org.
⁴⁹ Royal Melbourne Hospital, Parkville, VIC, Australia. andrew.wei@petermac.org.
⁵⁰ The University of Melbourne, Melbourne, VIC, Australia. andrew.wei@petermac.org.
⁵¹ Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. andrew.wei@petermac.org.

PMID: 38531863
PMCID: PMC10965987
DOI: 10.1038/s41408-024-00996-x

Abstract

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

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Conflict of interest statement

AB: Advisory role with honoraria for AbbVie, Amgen, Astellas, Pfizer, Novartis, Jazz, Takeda, Gilead-Kite, SentiBio; speaker fees from BMS, Amgen. AWR: Clinical research funding to Institution from AbbVie and Amgen. Inventor on a patent related to venetoclax, and receives a fraction of royalty payments to the Walter and Eliza Hall Institute of Medical Research related to venetoclax. CC: Advisory role with honoraria for AbbVie, Pfizer, Sumitomo Pharma. PM: Advisory Board and/or speaker for AbbVie, AstraZeneca, Astellas, Beigene, Gilead, Janssen, Minarine, MSD, Novartis, Otsuka, Pfizer, Roche. CYF: has received honoraria from AbbVie, Amgen, Beigene, Bristol-Myers Squibb, Jazz, Novartis, Pfizer and Servier; has acted as a consultant/advisor for AbbVie, Amgen, Astellas Pharma, Bristol-Myers Squibb, Jazz, Novartis, Pfizer and Servier; and has received research funding from Amgen, Astellas and Jazz. DP: Honoraria from Bristol Meyers Squibb, Jazz Pharmaceuticals, Link, Bastion Education, Gilead. All honoraria paid to institution only. MH: Advisory role with honoraria for Gilead, Roche, Otsuka, Takeda, Janssen, Beigene. JS: Advisory role with honoraria for Astellas, BMS, Mundipharma, Novartis, Otsuka, Pfizer; research funding to institution from Amgen, Astex, BMS; speakers fees from Mundipharma, Novartis. AW: Advisory role with honoraria for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Roche, BMS, Celgene, Gilead, Pfizer, Janssen, Jazz, Novartis, Servier; clinical research funding to Institution from AbbVie, Servier, Celgene-BMS, Astra Zeneca, Amgen, Novartis; receives a fraction of royalty payments to the Walter and Eliza Hall Institute of Medical Research related to venetoclax.

Figures

**Fig. 1. Kaplan Meier survival curves among the key subgroups of ALLG NBCR cohort. Log-rank statistics are used for comparisons.**
A Overall survival (OS) among all patients aged 18–59 years with *FLT3*-ITD and TKD mutated AML who received intensive chemotherapy, and according to the induction intensity (high or intermediate-dose cytarabine with anthracycline [H/IDAC + 3] versus standard 7 + 3). Missing induction regimen data for 1 patient. B OS and event-free survival (EFS) among patients aged 50–70 years with de novo AML who received intensive chemotherapy. Missing OS and EFS outcome data for 4 and 5 patients, respectively. C OS among patients aged 60–75 years with secondary or therapy-related AML who received intensive chemotherapy. Missing data for 2 patients. (D + E) OS (with 4-month landmark) among patients aged ≥55 years in first remission (CR1) according to (D) allogeneic HCT in CR1, and (E) number of consolidation chemotherapy received among patients (n = 185) not proceeding to HCT in CR1. F OS among patients who were unfit for intensive chemotherapy, according to the low-intensity regimens received.

See this image and copyright information in PMC

References

1. Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood. 2017;130:2469–74. doi: 10.1182/blood-2017-08-784066. - DOI - PubMed
1. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl J Med. 2017;377:454–64. doi: 10.1056/NEJMoa1614359. - DOI - PMC - PubMed
1. Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie J-N, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379:1508–16. doi: 10.1016/S0140-6736(12)60485-1. - DOI - PubMed
1. Lambert J, Pautas C, Terre C, Raffoux E, Turlure P, Caillot D, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104:113–9. doi: 10.3324/haematol.2018.188888. - DOI - PMC - PubMed
1. DiNardo C, Jonas B, Pullarkat V, Thirman M, Garcia J, Wei A, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl J Med. 2020;383:617–29. doi: 10.1056/NEJMoa2012971. - DOI - PubMed

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How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Affiliations

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Medical