On the closing date of January 10, 2023, 263 sufferers have been documented within the registry and 240 shaped the core of the current evaluation. Twenty-three sufferers have been excluded as a consequence of lack of correct analysis of BP, proof for BP earlier than January 1st, 2015, or incomplete knowledge. A move chart of sufferers documented and analyzed is introduced in Fig. 1.
Sufferers’ traits are reported in Desk 1. The supply of TKI by collaborating international locations is detailed in Supplementary Desk 1. Median age at analysis of BP was 49 years and 60.0% of sufferers have been male. Eighty-nine sufferers (37.0%) the place identified with a de novo BP. For these sufferers identified with a earlier CML, median time between CML analysis and evolution to BP was 29.1 months (vary, 1–378). Two BP occurred in sufferers that had stopped TKI inside a therapy free remission idea.
Details about extra chromosomal abnormalities (ACAs) was accessible in 174/240 sufferers, of which 101 (58.0%) had no less than one ACA. Essentially the most frequent high-risk abnormality (29.9%) was a posh karyotype, adopted by +8, extra Philadelphia chromosome (+22q-), deletion of chromosome 7/7q, and abnormalities of chromosome 3q26.2 (Desk 1).
BCR::ABL1 transcript kind was e13a2 and/or e14a2 in 90.7% (117/129) of sufferers. Twelve sufferers had atypical transcripts (Desk 2 and Supplementary Desk 2). BCR::ABL1 mutations occurred in 28.0% of the sufferers. As anticipated, essentially the most ceaselessly BCR::ABL1 mutation reported was T315I (12 circumstances), adopted by E255K (n = 11), F317L (n = 5), and Y253H (n = 5) (Desk 2). Eleven sufferers had a couple of BCR::ABL1 mutation. Thirty mutations in genes aside from BCR::ABL1 have been reported in 21 sufferers investigated (Supplementary Desk 3). The kind of mutation was heterogeneous, with no unifying sample.
Data concerning central nervous system (CNS) and extramedullary involvement have been reported in 214 and 220 sufferers respectively. Of those 9.8% had CNS involvement and 19.5% extramedullary manifestations.
ELTS rating on the time of CML analysis was accessible for all 151 sufferers with a earlier CML, and was low danger in 39.6%, intermediate danger in 36.3% and high-risk in 24.2% of them (Desk 1).
Remedy
Remedy of BP was heterogeneous with regard to websites and particular person affected person. The median variety of strains of remedy for BP was 3. One-hundred and thirty-two out of 240 sufferers (55.0%) acquired no less than one alloSCT for his or her BP through the course of the illness. Further 16 sufferers had beforehand acquired an alloSCT within the CML-CP and progressed to BP after transplant. Concerning therapy given on the first incidence of BP, 232 sufferers had full knowledge and may very well be analyzed. TKIs have been the cornerstone of BP therapy, with solely 16.9% of sufferers not receiving a TKI. The mix employed most ceaselessly was a TKI plus chemotherapy (42.7% of circumstances), adopted by TKI alone (21.1%). TKI plus chemotherapy and alloSCT was utilized in 15.1%, while 10 sufferers acquired TKI and alloSCT. For these sufferers receiving alloSCT, the median time from BP analysis to transplantation was 6 months.
At preliminary remedy, dasatinib was essentially the most ceaselessly used TKI (32.3%), adopted by imatinib and ponatinib (26.7% and 13.4%, respectively). Median length of TKI remedy was 121 days for dasatinib, 94 days for imatinib and nilotinib and 87 days for ponatinib. Bosutinib was given in first line in 4 sufferers solely, with a median length of remedy of 187 days. The totally different therapy mixtures in first line and for all strains of therapy in addition to the frequency of the utilization of the assorted TKIs is reported in Supplementary Tables 3 and 4.
CNS prophylaxis or CNS remedy was utilized in 44 sufferers. Twenty-three extra sufferers acquired systemic chemotherapy containing medication lively on the CNS, reminiscent of methotrexate and lomustine.
Taking a look at elements that may affect alternative of first line therapy, sufferers handled with dasatinib have been extra prone to be youthful than sufferers receiving different TKIs (median: 45 vs. 50 years, p = 0.0291). Equally, sufferers receiving alloSCT have been in median youthful than sufferers not being transplanted (median 43 vs. 50 years, p = 0.010). In distinction, ponatinib sufferers have been older (median 53 vs 47 years, p = 0.0219). Sufferers with a shorter CP length earlier than evolution in BP have been extra prone to be handled with dasatinib (median 16 vs. 34 months, p = 0.0060) and alloSCT (median 14 vs. 31 months, p = 0.0394). Imatinib was given predominantly in circumstances the place no BCR::ABL1 mutations have been current with a frequency of 29.7% in comparison with solely 9.5% within the presence of a BCR::ABL1 mutation (p = 0.0111). Ponatinib was the extra ceaselessly used TKI when BCR::ABL1 mutations have been current (35.7% vs. 11.0%, p = 0.0007). Remedy was influenced additionally by the phenotype of BP. Chemotherapy and alloSCT have been used extra usually in sufferers with a lymphoid BP (LyBP) as in contrast with sufferers with a myeloid BP (MyBP) (odds ratio [OR] 5.10, 95%-confidence interval [CI]: 2.1–12.1, p < 0.0001 and OR 2.37, 95%-CI: 1.2–4.8, p = 0.0181, respectively).
Responses
Responses have been evaluated at three and at 6 months after onset of BP. Three months response knowledge have been evaluable for 134 sufferers, together with 21 (15.7%) sufferers with early loss of life through the first 3 months after analysis of BP. Thirty-four sufferers (25.4%) didn’t obtain any response and remained in BP. Sixty-seven (50.0%) and 38 (28.4%) sufferers achieved no less than an entire hematologic response (CHR) and an entire cytogenetic response (CCyR), respectively. Main molecular response (MMR) was achieved in 27 sufferers (20.1%), with 12 (9.0%) every attaining MR4.5 (BCR::ABL1 transcript ranges ≤0.0032% on the worldwide scale, IS [29]) and MR5 (BCR::ABL1 transcript ranges ≤0.001% IS [29]) (Desk 3). When censoring for alloSCT, outcomes didn’t change considerably, since solely three sufferers had an final result measurement after alloSCT.
Six-month knowledge have been evaluable for 112 sufferers, of which 33 (29.5%) had died earlier than this milestone. Of evaluable sufferers, 57 (50.9%) achieved no less than a CHR and 48 (42.9) achieved a CCyR at 6 months. MMR was achieved in 44 sufferers (39.3%), MR4.5 and MR5 in 27 (24.1%) and 21 (18.8%), respectively. The proportion of sufferers who didn’t reply to therapy was 17.0% (19 sufferers). Eleven of those outcomes have been obtained after alloSCT. Finest response achieved at any time throughout therapy is on the market in 184 sufferers (Desk 3). Finest response outcomes rely closely on particular person commentary instances, as sufferers with shorter commentary instances would possibly nonetheless enhance their responses sooner or later. Because of this, these outcomes are to be interpreted purely descriptive, and, in distinction to the 3- and 6-months’ time-points, shouldn’t be generalized. When censoring responses for alloSCT, the charges of CHR, CCyR, MMR and MR5 was 68.9%, 51.2%, 38.2%, and 12.2%, respectively. After alloSCT, the proportion of sufferers attaining an MMR elevated to 59.2%, with 41.8% of sufferers attaining MR5.
Comparability between BP from beforehand identified CML and de novo BP
Given the comparatively excessive variety of sufferers with de novo BP in our collection, variations between these sufferers and people whose BP developed from a previous CP (secondary BP) have been explored. Age distribution was comparable within the two teams (Desk 4). The proportion of feminine sufferers was greater in de novo BP (47.2% vs. 35.8%), though the distinction was not statistically vital. The phenotypic presentation between de novo BP and secondary BP was comparable, but atypical transcripts have been extra frequent in de novo BP (3.9% vs. 17.0%, p = 0.028). Excessive danger ACAs and mutations within the BCR::ABL1 gene have been extra frequent in secondary BP sufferers. Apparently there was no vital distinction between the 2 teams concerning the proportion of sufferers presenting with CNS or extramedullary involvement (Desk 4).
Sufferers identified with de novo BP acquired most ceaselessly imatinib (OR 13.09, 95%-CI: [6.44; 26.63], p < 0.001) as first line therapy. Solely sufferers with a secondary BP acquired ponatinib in first line (21.4%, p < 0.0001). The opposite remedies have been comparatively balanced between the 2 teams (Supplementary Desk 3).
Concerning therapy efficacy, response distributions at 3 and 6 months weren’t considerably totally different when evaluating secondary BP to de novo BP. Nonetheless, sufferers with de novo BP tended to have a greater final result on the 6-month time-point, though significance was not reached (Mann–Whitney check p = 0.06)
Survival
With a median observe up of 27.8 months, median total survival was 23.8 months (95% CI: 17.0–34.8, Fig. 2). There was nearly no distinction in survival in sufferers with CNS or extramedullary involvement as in comparison with sufferers with out these high-risk traits (median 28.5 vs. 23.8 months, HR 1.17 [95% CI: 0.73–1.88], p = 0.519, Fig. 3A). Conversely, sufferers with de novo BP had a greater final result then sufferers with a previous CP (median 29.7 vs. 18.0 months, HR 0.80 [95% CI: 0.66–0.98], p = 0.032, Fig. 3B), as did sufferers with a lymphoid phenotype (median 32.2 vs. 17.0 months for LyBP vs. MyBP, HR 0.54 [95% CI: 0.34–0.86], p = 0.009, Fig. 3C). Sufferers with a low ELTS rating at analysis of CML [30] and sufferers with de novo BP had moderately comparable outcomes (median 34.8 vs. 29.7 months for low ELTS and de novo BP respectively, HR 1.09 [95% CI: 0.68–1.75], p = 0.713), considerably higher than the end result of sufferers with intermediate (11.4 months, HR 2.35 [95% CI: 1.35–4.11], p = 0.003) or excessive (9.9 months, HR 2.75 [95% CI: 1.57–4.81], p < 0.001) ELTS rating (Fig. 3D). Sufferers with ≥30% blasts had a 1.7-times greater hazard of dying than sufferers with 20–29% blasts, nevertheless, the variations weren’t vital (median survival: 20.7 for sufferers with 20–29% blasts vs. 15.7 months for sufferers with ≥30% blasts). When differentiating between de novo BP and secondary BP, survival was comparable between each blast classes in de novo sufferers (HR: 1.19 [95% CI: 0.47–2.99], p = 0.706). Conversely, a minor and never vital distinction between sufferers with ≥30% and 20–29% blasts (HR: 2.10 [95% CI: 0.94–4.74], p = 0.072) was present in sufferers with previous CP.
Median observe up 27.8 months.
A total survival for affected person with central nervous system (CNS) and/or extramedullary (EM) involvement in comparison with sufferers with out CNS and extramedullary involvement; B Total survival for affected person with de novo blast section (CML-BP) and blast section evolving from a earlier persistent section (CML-CP); C total survival in keeping with illness phenotype (myeloid vs. lymphoid); D total survival in keeping with illness section (de novo) and ELTS rating on the time of persistent section (ELTS low, ELTS intermediate, ELTS excessive) [low ELTS vs. de novo HR 1.09 [95% CI: 0.68–1.75], p = 0.713, low ELTS vs. intermediate ELTS HR 2.35 [95% CI 1.35–4.11], p = 0.003, low ELTS vs. excessive ELTS HR 2.75 [95% CI: 1.57–4.81], p < 0.001]. All p values should be interpreted as exploratory.
