Aug 11, 2017 - Elisabetta Abruzzese11. | David Andorsky12 ... Stuart L. Goldberg, John Theurer Cancer. Center ...... rose to 97% in 2014/2015. The same was ...
Received: 28 July 2017
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Revised: 11 August 2017
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Accepted: 14 August 2017
DOI: 10.1002/ajh.24887
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RESEARCH ARTICLE
First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY Stuart L. Goldberg1
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Jorge E. Cortes2 | Carlo Gambacorti-Passerini3 |
€ diger Hehlmann4 | H. Jean Khoury5 | Mauricette Michallet6 | Ron L. Paquette7 | Ru Bengt Simonsson8 | Teresa Zyczynski9 | Aimee Foreman10 | Elisabetta Abruzzese11 | David Andorsky12 | Aart Beeker13 | Pascale Cony-Makhoul14 | Richard Hansen15 | Elza Lomaia16 | Eduardo Olavarria17 | Michael J. Mauro18 1 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey; 2The University of Texas, MD Anderson Cancer Center, Houston, Texas; 3University of Milano Bicocca, San Gerardo Hospital, Monza, Italy; 4Universität Heidelberg, Mannheim, Germany; 5Winship Cancer Institute of Emory nite, France; 7UCLA Medical Center, Los Angeles, California; 8Uppsala Universitet, Uppsala, University, Atlanta, Georgia; 6Centre Hospitalier Lyon-Sud, Pierre-Be Sweden; 9Bristol-Myers Squibb, Princeton, New Jersey; 10ICON plc, San Francisco, California; 11S. Eugenio Hospital, Rome, Italy; 12Rocky Mountain Cancer Centers, €r med, Boulder, Colorado; 13Spaarne Hospital, Hoofddorp, The Netherlands; 14Centre Hospitalier Annecy-Genevois, Pringy, France; 15IDGGQ, Institut fu Kaiserslautern, Germany; 16Federal Almazov North-West Medical Research Centre, St Petersburg, Russia; 17Hammersmith Hospital, Imperial College London, London, United Kingdom; 18Memorial Sloan-Kettering Cancer Center, New York City, New York
Correspondence Stuart L. Goldberg, John Theurer Cancer Center, Hackensack University Medical Center, 92 Second Street, Hackensack, NJ 07601. Email: stuart.goldberg@hackensackmeridian. org
Abstract Achieving successful outcomes in chronic phase-chronic myeloid leukemia (CP-CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CPCML receiving first-line imatinib (n 5 416), dasatinib (n 5 418) or nilotinib (n 5 408) in the US and 6 European countries in routine clinical practice. Twelve-month follow-up data of 1242 prospective
Funding information Bristol-Myers Squibb (BMS). No financial support or compensation for publication was received by the authors of this manuscript. BMS funded medical writing services for this manuscript.
patients (enrolled October 01 2010-September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib-treated patients enrolled earlier in the study, with subsequent shift toward dasatinib- and nilotinib-treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P 5 .001). Age 1480. ECOG performance status is defined as: 0, fully active; 1, restricted strenuous activity; 2, ambulatory and capable of all self-care, no work; 3, capable of only limited self-care; 4, completely disabled. TKI: tyrosine kinase inhibitor; ECOG: Eastern Cooperative Oncology Group; IQR: interquartile range. a
b
Overall, CyR testing was done by CBA and FISH separately in the
3.3.2 | MR monitoring patterns
first 12 months in 37% of patients. There is a greater emphasis at Euro-
Of the patients followed, 32% had documentation of MR testing by 3
pean sites to carry out CBA testing compared with US centers (55% vs.
months; this increased to 74% by 6 months and 91% by 12 months
28% of patients; Table 2).
(P < .0001) (Table 2). A greater proportion of patients in Europe were
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The number and % of patients followed for a minimum of 12 months tested for CyR (FISH, bone marrow, or both) or MR (including IS and non-IS) according to region
T AB LE 2
Monitoring patterns
CyR Monitoring patterns Done, date present, n (%) Done/recorded with results availablea “Actionable”b “Not actionable”c Bone marrow karyotyping or FISH FISH, n (%) Bone marrow karyotyping, n (%) Done/recorded with no results available
During first 3 months of first-line TKI therapy
During first 6 months of first-line TKI therapy
During first 12 months of first-line TKI therapy
All (N 5 1233)
Eu (n 5 428)
US (n 5 805)
All (N 5 1224)
Eu (n 5 422)
US (n 5 802)
All (N 5 1195)
Eu (n 5 416)
US (n 5 779)
197 (16) 182 (92) 161 (88) 21 (12)
91 83 65 18
106 (13) 99 (93) 96 (97) 3 (3)
485 (40) 435 (90) 401 (92) 34 (8)
215 (51) 198 (92) 170 (86) 28 (14)
270 (34) 237 (88) 231 (98) 6 (3)
656 (55) 584 (89) 541 (93) 43 (7)
274 (66) 255 (93) 223 (88) 32 (13)
382 (49) 329 (86) 318 (97) 11 (3)
139 (11) 103 (8) 15 (8)
49 (11) 69 (16) 8 (9)
90 (11) 34 (4) 7 (7)
330 (27) 286 (23) 50 (10)
112 (27) 173 (41) 17 (8)
218 (27) 113 (14) 33 (12)
447 (37) 441 (37) 72 (11)
148 (36) 227 (55) 19 (7)
299 (38) 214 (28) 53 (14)
(%)d 739 (60) 271 (56) 173 (36) 24 (5) 17 (4)
207 (49) 118 (55) 74 (34) 10 (5) 13 (6)
532 (66) 153 (57) 99 (37) 14 (5) 4 (2)
539 (45) 226 (35) 218 (33) 115 (18) 97 (15)
142 (34) 89 (33) 95 (35) 44 (16) 46 (17)
397 (51) 137 (36) 123 (32) 71 (19) 51 (13)
(21) (91) (78) (22)
Number of cytogenetic (bone marrow karyotyping or FISH) tests performed, n 0 1036 (84) 337 (79) 699 (87) 1 142 (72) 60 (66) 82 (77) 2 50 (25) 26 (29) 24 (23) 3 1 (1) 1 (1) 0 (0) 41 4 (2) 4 (4) 0 (0) MR Monitoring patterns Done, date present, n (%) Done/recorded with results on IS, n (%) Done/recorded with results not on ISjj, n (%)
148 (35) 125 (85) 20 (14)
241 (30) 160 (66) 79 (33)
910 (74) 672 (74) 218 (24)
353 (84) 303 (86) 40 (11)
557 (69) 369 (66) 178 (32)
1087 (91) 857 (79) 214 (20)
406 (98) 365 (90) 34 (8)
681 (87) 492 (72) 180 (26)
Number of molecular tests performed on the IS or not, n (%) 1 333 (87) 124 (86) 2 47 (12) 18 (12) 3 4 (1) 3 (2) 41 0 (0) 0 (0) Done/not recorded 5 (1) 3 (2) Not done/recorded, n (%) 844 (68) 280 (65)
209 (87) 29 (12) 1 (0) 0 (0) 2 (1) 564 (70)
585 (66) 234 (26) 39 (4) 32 (4) 20 (2) 314 (26)
230 (67) 84 (25) 16 (5) 13 (4) 10 (3) 69 (16)
355 (65) 150 (27) 23 (4) 19 (4) 10 (2) 245 (31)
226 (21) 344 (32) 258 (24) 243 (23) 16 (2) 108 (9)
63 (16) 151 (38) 85 (21) 100 (25) 7 (2) 10 (2)
163 (24) 193 (29) 173 (26) 143 (21) 9 (1) 98 (13)
282 (35) 523 (65) -
1002 (82) 222 (18) -
368 (87) 54 (13) -
634 (79) 168 (21) -
1141 (95) 54 (5) 5 (3–6)
411 (99) 5 (1) 5 (4–6)
730 (94) 49 (6) 5 (3–6)
CyR or MR monitoring patterns Total tested, n (%) Total not tested, n (%)e Median (IQR) number of tests by 12 months
389 (32) 285 (73) 99 (25)
444 (36) 789 (64) -
162 (38) 266 (62) -
a
The denominator is the total number of patients with a CyR test done with date present. Includes available FISH data if % Ph1 known and 200 evaluated nuclei or available bone marrow data if % Ph1 known and 20 examined metaphases; the denominator is the total number of patients with a CyR test done/recorded with results available. c Includes all other available FISH and bone marrow data; the denominator is the total number of patients with a CyR test done/recorded with results available. d The denominator is the total number of patients with CyR test done and a date present. e The proportion of MR tests not on the IS includes “no” and “unknown”. f The proportion of patients not tested includes those with no date reported. May include MR, FISH, or bone marrow data with missing testing dates. May include patients who were not tested due to progression. CyR: cytogenetic response; FISH: fluorescence in situ hybridization; IQR: interquartile range; IS: international scale; MR: molecular response; TKI: tyrosine kinase inhibitor. b
monitored for MR by 12 months compared with the US (98% vs. 87%;
Among patients tested for MR by 12 months, 23% did not have stand-
P < .001). This was also true for the comparison between academic
ardised MR assessments. More patients in Europe had documentation of
centers and community practices (94% vs. 87%, respectively; P < .001).
MR testing performed using the IS, within the first 12 months of TKI
Monitoring of MR in community practices occurred more frequently in
therapy, compared with the US (90% vs. 72%; P < . 001). Use of standar-
Europe compared with the US by 12 months (97% vs. 84%, respec-
dised testing was similar across practice types, with the exception of Euro-
tively; P < .001. In the US, similar proportions of patients had docu-
pean versus US academic centers (93% vs. 68%, respectively; P < .001).
mentation of MR monitoring irrespective of insurance status; 88% and 83%, respectively (P 5 .35).
Throughout the study, both the ELN and NCCN recommended MR monitoring every 3 months during the first year of TKI therapy.
GOLDBERG
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The proportion (%) of SIMPLICITY patients with CyR monitoring for the overall population, and for those patients receiving IM and second-generation TKIs, over the years of enrollment into the study. Both FISH and BM cytogenetic tests were included as long as a date was present. Patients had to be followed for 12 months. Includes assessments performed after index TKI start date, between 30 days and 12 months later. Dotted line corresponds to the proportion of patients with CyR monitoring during the first 12 months across the entire study period. BM: bone marrow; CyR: cytogenetic response; FISH: fluorescence in situ hybridization; IM: imatinib; TKI: tyrosine kinase inhibitor. N indicates the number of patients per cohort
FIGURE 1
Overall, based on MR results on the IS or not, 47% of patients under-
second generation first-line TKI during 2009/2010 and had documenta-
went 3 molecular tests consistent with recommendations in the first
tion of CyR monitoring within the first 12 months after initiation was
year (47% US and 46% Europe) (Table 2); 50% were monitored in line
60%; this fell to 46% in 2013. A somewhat higher proportion of patients
with recommendations at academic centers (54% US and 45% Europe)
who initiated Imatinib in 2009/2010 had CyR monitoring compared
and 43% in community centers (41% US and 50% Europe) (Table 2).
with second generation TKIs; this was relatively consistent through 2013 (Figure 1).
3.4 | CyR and MR monitoring by year of first-line TKI initiation in SIMPLICITY Reviewing monitoring patterns over the duration of the study thus far, between 2009 and 2015, the proportion of patients with documentation of CyR monitoring during the first 12 months decreased (Figure 1). Dur-
Furthermore, reviewing monitoring patterns over the duration of the study thus far also revealed a shift in MR monitoring practices over time, between 2009 and 2015. The proportion of patients who had MR monitoring (whether on IS or not) during the first 12 months following initiation of first-line TKI increased slightly (Supporting Information Figure S5). Analysis comparing MR monitoring patterns between imatinib and second-generation TKIs found no notable differences.
ing 2009/2010, 61% of all patients had documentation of CyR within
During 2009/2010, 87% of all patients who had been followed for
the year; this fell to 47% in 2014/2015. The proportion of patients who
12 months had documentation of MR within the year and this
initiated first-line imatinib during 2009/2010 and had documentation of
rose to 97% in 2014/2015. The same was true for patients who had
CyR monitoring within the first 12 months after initiation was 63%,
MR monitoring on IS: 69% in 2009/2010 and 86% in 2014/2015
which fell to 59% in 2013. The proportion of patients who initiated a
(Figure 2).
The proportion (%) of patients with MR monitoring for the overall population, and for those patients receiving IM and second-generation TKIs, over the years of enrollment into the study. MR monitoring patterns during the first 12 months of treatment according to the year of first-line TKI initiation – result on IS. IM: imatinib; IS: international scale; MR: molecular response; TKI: tyrosine kinase inhibitor. N indicates the number of patients per cohort
FIGURE 2
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3.5 | Predictors of monitoring
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practice, however, treatment choice is influenced by numerous factors,
In the 3- and 6-month multivariable logistic regression models, among the potential predictors considered, the only significant predictors of documented CyR/MR monitoring were whether a patient was followed at an academic center versus community practice (odds ratio [OR] for 3 month model 5 1.45, P 5 .002; OR for 6 month model 5 1.56, P 5 .004), year of index TKI initiation (2011 vs. 2014/2015 OR for 3 month model 5 0.58, P 5 .006; 2011 vs. 2014/2015 OR for 6 month model 5 0.45, P 5 .005; 2012 vs. 2014/2015 OR for 6 month model 5 0.52, P 5 .024), and site location in Europe versus the US (OR for 6 month model 5 1.53, P 5 .017). By 12 months, age
