Abstract
Deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events in acute myeloid leukemia (AML). We retrospectively analyzed 243 treatment-naive patients with AML and del(7) (168/243; 69%) or del(7q) (75/243; 31%) who did not receive any myeloid-directed therapy prior to AML diagnosis. This is the largest comprehensive clinical and molecular analysis of AML patients with del(7) and del(7q). Our results show that Relapse-free survival was significantly longer for AML patients with del(7q) compared to del(7), but the overall survival and remission duration were similar. TP53 mutations and del5/5q were the most frequent co-occurring mutations and cytogenetic abnormalities, and conferred worse outcomes in del(7) and del(7q) patients. Venetoclax-based treatments were associated with worse outcomes in TP53 mutated AML patients with del(7) or del(7q), as well as del(7) with TP53 wildtype status, requiring further investigation.
Introduction
Chromosomal abnormalities occur in more than 50% of adult patients with acute myeloid leukemia (AML) and are independently associated with clinical outcomes1, 2. First described in 1973,3,4 deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events, seen in approximately 20–30% of newly diagnosed AML) and portend worse outcomes.5 These deletions often co-occur in the context of complex karyotype and TP53 alterations2, 6. Also, del(7) and del(7q) are associated with older age7, prior exposure to alkylating agents i.e. therapy-related, and transformation from an antecedent hematologic disease such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN)8.
The Medical Research Council (MRC) AML10 trial which included children and adults up to 55 years of age, categorized AML with del(7q) as an intermediate risk factor5 initially, but an updated analysis considered it as an adverse event2. In the absence of adverse-defining molecular features, the European Lekemia Network (ELN) 2017 classification in adult AML patients1 considers AML patients with del7q as an intermediate risk. Interestingly, more favorable karyotypes in AML such as the core binding factor leukemias with t(8;21) or inv(16), have been associated with del(7q), but not del(7)9. However, in both MRC and ELN, del(7) was classified as adverse risk. Yet, for the purpose of clinical studies and therapeutic decisions, AML with del(7) and del(7q) are often consolidated as one cytogenetic group and able patients are generally recommended to undergo stem cell transplantation in first remission to mitigate the risk of relapse10–12. However, in-depth clinical and molecular characterization comparing AML patients with del(7) versus del(7q) have been limited to small patient cohorts12–14. Further, characterization of the outcomes of patients with AML with del(7) and del(7q) in the setting of venetoclax-based therapies has not been previously explored.
Herein, we conducted a retrospective analysis of 243 previously untreated patients with AML with del(7) (168/243; 69%) or del(7q) (75/243; 31%) who received initial therapy at MD Anderson. Our study had two objectives. First, we aimed at comparing the clinical, demographic, molecular and cytogenetic characteristics of patients with del(7) versus del(7q). Second, we aimed at evaluating the impact of venetoclax based therapies on responses to therapy in AML with del(7) and del(7q) with and without TP53 alterations.
Material and methods
Patient population
We conducted a retrospective analysis that included adult patients (>18 years of age) with newly diagnosed, previously untreated AML with del(7) or del(7q) treated at The University of Texas MD Anderson Cancer Center (MDACC) between January 2010 and October 2020. We excluded patients with inconclusive conventional cytogenetic profile, acute promyelocytic leukemia (APL) i.e. French-American-British (FAB) M3, core binding factor acute myeloid leukemia (CBF-AML) defined by inv(16), t(16;16), or t(8;21), or patients with AML who had both del(7) and del(7q) (Figure 1a). All transformed AML patients who had received myeloid-directed therapy prior to AML transformation were also excluded from this analysis. High-intensity included standard or high dose cytarabine-based therapy. Low-intensity regimens included either hypomethylating agents (i.e., azacitidine or decitabine), low-dose cytarabine, or nucleoside analog based therapy (cladribine or clofarabine). An institutional review board (IRB) approval has been received prior to conducting this retrospective analysis.
Figure 1.
(a) Consort diagram for patient selection showing the exclusion criteria and the number of patients in each subgroup. (b) Spider plot showing the chromosome 7 alterations in our filtered AML cohort of 243 patients. (c) overall survival (OS), (d) event-free survival (EFS), and (e) remission duration (RD) of patients with del(7) or del(7q).
Outcome Analysis
Responses were defined according to the International Working Group recommendations15. Overall survival (OS) was calculated from the time treatment start date to the time of death or last follow-up. Relapse free survival (RFS) was calculated from the time of best response in patients with complete response (CR) or CR with incomplete count recovery (CRi) to the time of relapse, and censored for last follow-up or death. Remission duration (RD) was calculated from the time of complete response (CR) or CR with incomplete count recovery (Cri) until relapse, censored for death in morphological remission or if the patient was alive at last follow-up.
Molecular profiling: NGS and cytogenetic analysis
Patients with monosomy 7 or del(7q) had mutational analysis done with amplicon-based targeted next generation sequencing (NGS) panels at our CLIA-certified molecular diagnostic laboratory. These panels included genes frequently involved in hematologic malignancies (panels of either 28, 53, or 81 genes depending on the time period)16. Cytogenetic studies were performed by G-banding technique at CLIA-certified cytogenetic laboratory using standard techniques. At least 20 metaphases were evaluated. Karyotypes were reported using the International System for Cytogenetic Nomenclature criteria. TP53 alterations included any patient with either TP53-mutations, loss in chromosome 17 (monosomy 17), or segmental loss in chromosome 17p [del(17p)]. Patients with intact 17p on conventional cytogenetics who were not genotyped for TP53 (n=48/243, 20%) were omitted from the TP53-subgroup analysis.
Statistical Analysis
Patient characteristics were summarized using medians and ranges for continuous variables and frequencies or percentages for categorical variables. Continuous variables were compared using the Wilcoxon rank-sum test for pairwise comparisons. Categorical variables were compared using Fisher’s exact test. The Kaplan–Meier method was used to estimate the probability of OS, RFS, or RD and were compared by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to assess the association between patient characteristics and outcomes. Variables with p ≤ 0.05 in the univariate analysis were included in the initial multivariate analysis. Analyses were performed using R version 4.0.3.
Results
Patient characteristics
Out of the 2025 consecutive newly diagnosed patients with AML who did not receive prior myeloid-directed therapy and were treated at our institution, 243 (12%) patients had deletions in del(7) (168/243; 69%) or del(7q) (75/243; 31%) confirmed by conventional cytogenetics (Figure 1a-b). The baseline characteristics overall and within each group are summarized in Table 1. Briefly, the median age of the population was 70.3 years (range: 23.4 – 87.8), and 143/243 (59%) were men, similarly distributed in both AML cytogenetic subgroups. A total of 69% of patients had complex cytogenetics. Concomitant TP53 mutations and/or deletions in chromosome 17/17p were found in 97/178 (54%) and 56/243 (23%) of evaluable patients, respectively, hereafter referred to as TP53 alterations. Among AML with del(7q), 54/75 (72%) and 21/75 (28%) were classified as having coocurring poor and non-poor cytogenetics, respectively. Treatment with venetoclax-based regimen and by intensity were similarly distributed between the two cytogenetic subgroups. In summary, there were no significant differences in baseline demographic and clinical characteristics between the two AML cytogenetic subgroups.
Table 1:
The treatment response and clinical outcomes in our AML cohort of patients with del(7) or del(7q).
| Characteristic | Overall, N = 243 | del(7), N = 168 | del(7q), N = 75 | p-value1 |
|---|---|---|---|---|
| Age (years), Mean+/−SD; Median (Range) | 67.5+/−12.6; 70.3 (23.4 – 87.8) | 67.5+/−12.1; 70.2 (23.4 – 87.8) | 67.6+/−13.7; 71.0 (25.0 – 84.2) | 0.6 |
| Gender, n/N (%) | 0.2 | |||
| Female | 100/243 (41%) | 74/168 (44%) | 26/75 (35%) | |
| Male | 143/243 (59%) | 94/168 (56%) | 49/75 (65%) | |
| Cytogenetics, n/N (%) | 0.5 | |||
| Complex (>=3) | 168/243 (69%) | 114/168 (68%) | 54/75 (72%) | |
| Other (<3) | 75/243 (31%) | 54/168 (32%) | 21/75 (28%) | |
| ELN based on Cytogenetics, n/N (%) | <0.0001 | |||
| Non-poor | 21/243 (8.6%) | 0/168 (0%) | 21/75 (28%) | |
| Poor | 222/243 (91%) | 168/168 (100%) | 54/75 (72%) | |
| Secondary AML, n/N (%) | 0.5 | |||
| De novo AML | 142/243 (58%) | 96/168 (57%) | 46/75 (61%) | |
| Secondary AML | 101/243 (42%) | 72/168 (43%) | 29/75 (39%) | |
| TP53 Mutations, n/N (%) | 0.9 | |||
| TP53 wild type | 81/178 (46%) | 56/124 (45%) | 25/54 (46%) | |
| TP53 mutant | 97/178 (54%) | 68/124 (55%) | 29/54 (54%) | |
| Chr17/17p Loss, n/N (%) | 56/243 (23%) | 35/168 (21%) | 21/75 (28%) | 0.2 |
| Venetoclax, n/N (%) | 39/243 (16%) | 31/168 (18%) | 8/75 (11%) | 0.13 |
| Intensity, n/N (%) | 0.6 | |||
| High Intensity | 60/243 (25%) | 40/168 (24%) | 20/75 (27%) | |
| Low Intensity | 183/243 (75%) | 128/168 (76%) | 55/75 (73%) | |
| Best Response, n/N (%) | 0.9 | |||
| CR | 92/243 (38%) | 64/168 (38%) | 28/75 (37%) | |
| CRi | 26/243 (11%) | 19/168 (11%) | 7/75 (9.3%) | |
| NR | 125/243 (51%) | 85/168 (51%) | 40/75 (53%) |
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
Treatment Responses and clinical outcomes
We next evaluated the treatment response and clinical outcomes of the AML cytogenetic subgroups based on chromosome 7 and 7q deletion. The composite complete response (CCR) rate, defined as CR/CRi, following the first induction was 49% in the overall population, without significant differences in the two groups (Table 1). The median OS for the overall population was 7.3 months (range, 0.1–115.8). There were no significant differences between AML patients witih del(7) compared to del(7q) for OS (median of 7.4 vs 8.4 months; p=0.20) or remission duration (median of 5.3 vs 6.2 months; p=0.16) (Figure 1c-e). However, RFS was significantly longer among AML patients del(7q) compared to del(7) (median of 6.0 vs 2.7 months; p=0.049). Of note, AML patients with del(7q) and co-occuring poor cytogenetics had worse outcomes compared to those with co-occuring non-poor cytogenetics (Supplementary Figure 1 A-C). Except for longer RFS in del(7q) patients, these data suggest that AML patients with chromosome 7 and 7q have similar clinical features and outcomes.
Molecular characterization of AML patients with del7 and del7q
Conventional cytogenetics and targeted panels of next-generation sequencing (NGS) were performed in 243/243 (100%) and 125/243 (51%) of patients, respectively. Of note, an additional 113/243 (46%) of patients also had targeted mutations of select genes as part of their diagnostic work-up. The number of genes tested in each patient is shown in Supplementary Figure 2. The mutation profile yielded 374 mutations in 40 genes, and 169/243 (69.5%) patients had ≥1 mutation (Figure 2a). The median number of mutations per patient in this cohort was 1 mutation (range, 0–9). TP53 mutations were the most common occurring in 97/178 (54%) of patients tested. Of those with TP53 mutations, 32/97 (33%) had concomitant deletions in chromosome 17 or 17p, the loci of TP53. Also, 7/81 (8.6%) of patients who did not have TP53 mutations detected harbored deletions in chromosome 17 or 17p. The frequency of TP53 mutations in del(7) and del(7q) patients was similar (68/124 55%; versus 29/54; 54%, respectively p=0.9) (Table 1, Figure 2b). There was a significant correlation between TP53 alterations and complex cytogenetics in the overall cohort (χ2= 102.93, p<0.0001 ). Among TP53-wildtype and normal chromosome 17 karyotpe patients, 26% (19/74) had complex cytogenetics. There was no significant differences between rate of TP53 alterations in de novo or secondary AML (X2=1.2616, p =0.261). The most common co-occuring cytogenetic abnormality in our cohort was chromosome 5q deletion, which similarly occurred in 63/168 (37.5%) and 32/75 (42.7%) of del(7) and del(7q) AML patients, respectively (p =0.4) (Figure 2d). The frequency of co-occuring mutations in del(7) versus del(7q) were similar. Del(20q) had slightly increased odds of co-occuring with AML patients with del(7q) versus del(7) (Figure 2e). Therefore, similar to the clinical and outcome characteristics, AML patients with deletion 7 and 7q had very similar molecular and co-occuring cytogenetic profiles.
Figure 2.
(a) Oncoprint of mutations detected. Each column represents a patient and each row represents a gene. Patients were grouped into 4 groups: patients with del(7) or del(7q) treated with or without Venetoclax. Red, mutated. (b-c) Circos plot depicting patterns of co-occurrence between mutations (red), chromatin abnormalities (green), and del(7) (yellow) or del(7q) (blue). (de) Odds ratio analysis of mutations (d) or chromatin abnormalities (e) detected in del(7) (yellow) vs del(7q) (blue).
TP53 Alterations Conferred Worse Outcomes in AML with deletion in Chromosome 7 or 7q
TP53 mutations primarily occurred in the DNA-binding domain (DBD), and N-terminal transactivation domain (TD), as previously reported for TP53 mutations17 (Figure 3a-b). Since missense and non-sense mutations in TP53 were the most common in our AML cohort, and TP53 mutations are generally associated with poor outcomes in AML1, we investigated the significance of TP53 alterations on the outcomes of AML patients with chromosome 7 or 7q deletions. Except for higher rate of complex cytogenetics in AML patients with TP53 alterations (p<0.0001), the clinical and demographic characteristics were similar among patients with del(7) or del(7q) with or without TP53 alterations (Table 2). However, patients with del(7) or del(7q) who harbored TP53 alterations had significantly worse OS (5.5 vs 10.5 months p < 0.0001) and remission duration (4.7 vs 6.8 months p=0.0035) but not RFS (3.5 vs 3.4 months p=0.16) compared to those with TP53 wildtype (Figure 3e-g). Specifically, the median OS for del(7) TP53-mut, del(7) TP53-wt, del(7q) TP53-mut, and del(7q) TP53-mut were 5.2, 10.5, 6.8, and 9.9 months respectively. The RFS median time for for del(7) TP53-mut, del(7) TP53-wt, del(7q) TP53-mut, and del(7q) TP53-mut were 2.3, 2.6, 5.3, and 6.8 months respectively. The remission duration median time for del(7) TP53-mut, del(7) TP53-wt, del(7q) TP53-mut, and del(7q) TP53-mut were 4.1, 6.5, 5.3, and 7.5 months respectively. Therefore, TP53 alterations conferred worse outcomes in AML patients with del7 and 7q.
Figure 3.
Lolliplot showing somatic mutation spectra throughout the TP53 gene in patients with del(7) (a) or del(7q) (b). Yellow dots depict missense mutations and red dots depict truncating mutations. Odds ratio analysis of mutations (d) or chromatin abnormalities (e) detected in del(7) (yellow) vs del(7q) (blue) in patients with TP53-wt (c) or TP53-mut (d). (e) overall survival (OS), (f) event-free survival (EFS), and (g) remission duration (RD) of AML patients with del(7) or del(7q) who harbor TP53 alterations.
Table 2:
The treatment response and clinical outcomes in our AML cohort of patients with del(7) or del(7q) with or without TP53 alterations.
| Characteristic | Overall, N = 195 | del(7) Tp53-alt1, N = 83 | del(7) Tp53-wt1, N = 53 | del(7q) Tp53-alt1, N = 38 | del(7q) Tp53-wt1, N = 21 | p-value2 |
|---|---|---|---|---|---|---|
| Age (years), Mean+/−SD; Median (Range) | 68.8+/−11.6; 71.0 (23.4 – 87.8) | 68.6+/−10.6; 69.0 (32.0 – 87.6) | 67.7+/−12.6; 70.6 (23.4 – 87.8) | 71.9+/−9.7; 73.0 (33.9 – 84.2) | 66.9+/−15.2; 71.4 (25.0 – 83.9) | 0.3 |
| Gender, n/N (%) | 0.037 | |||||
| Female | 79/195 (41%) | 42/83 (51%) | 18/53 (34%) | 15/38 (39%) | 4/21 (19%) | |
| Male | 116/195 (59%) | 41/83 (49%) | 35/53 (66%) | 23/38 (61%) | 17/21 (81%) | |
| Cytogenetics, n/N (%) | <0.001 | |||||
| Complex (>=3) | 135/195 (69%) | 78/83 (94%) | 15/53 (28%) | 38/38 (100%) | 4/21 (19%) | |
| Other (<3) | 60/195 (31%) | 5/83 (6.0%) | 38/53 (72%) | 0/38 (0%) | 17/21 (81%) | |
| ELN based on Cytogenetics, n/N (%) | <0.001 | |||||
| Non-poor | 17/195 (8.7%) | 0/83 (0%) | 0/53 (0%) | 0/38 (0%) | 17/21 (81%) | |
| Poor | 178/195 (91%) | 83/83 (100%) | 53/53 (100%) | 38/38 (100%) | 4/21 (19%) | |
| Secondary AML, n/N (%) | 0.6 | |||||
| De novo AML | 118/195 (61%) | 48/83 (58%) | 35/53 (66%) | 21/38 (55%) | 14/21 (67%) | |
| Secondary AML | 77/195 (39%) | 35/83 (42%) | 18/53 (34%) | 17/38 (45%) | 7/21 (33%) | |
| TP53 Mutations, n/N (%) | <0.001 | |||||
| TP53 wild type | 81/178 (46%) | 3/71 (4.2%) | 53/53 (100%) | 4/33 (12%) | 21/21 (100%) | |
| TP53 mutant | 97/178 (54%) | 68/71 (96%) | 0/53 (0%) | 29/33 (88%) | 0/21 (0%) | |
| Unknown | 17 | 12 | 0 | 5 | 0 | |
| Chr17/17p Loss, n/N (%) | 56/195 (29%) | 35/83 (42%) | 0/53 (0%) | 21/38 (55%) | 0/21 (0%) | <0.001 |
| Venetoclax, n/N (%) | 39/195 (20%) | 20/83 (24%) | 11/53 (21%) | 5/38 (13%) | 3/21 (14%) | 0.5 |
| Intensity, n/N (%) | 0.13 | |||||
| High Intensity | 41/195 (21%) | 13/83 (16%) | 15/53 (28%) | 6/38 (16%) | 7/21 (33%) | |
| Low Intensity | 154/195 (79%) | 70/83 (84%) | 38/53 (72%) | 32/38 (84%) | 14/21 (67%) | |
| Best Response, n/N (%) | 0.14 | |||||
| CR | 75/195 (38%) | 28/83 (34%) | 25/53 (47%) | 15/38 (39%) | 7/21 (33%) | |
| CRi | 22/195 (11%) | 7/83 (8.4%) | 9/53 (17%) | 2/38 (5.3%) | 4/21 (19%) | |
| NR | 98/195 (50%) | 48/83 (58%) | 19/53 (36%) | 21/38 (55%) | 10/21 (48%) |
TP53-alt indicates patients with TP53 mutations, chr17 loss, or chr17p loss
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
Outcomes in Context of Venetoclax-therapy
Venetoclax is the major element of AML therapeutic arsenal specially in older patients when combined with hypomethylating agents or low dose cytarabine18, 19. We therefore investigated the clinical outcomes of patients with del(7) and del(7q) treated with venetoclax-based (VEN-based) therapies in the context of TP53 alterations. A total of 39/243 (16%) of patients received VEN-based therapy as part of their frontline therapy (31/168 (18%) in del(7) versus 8/75 (11%) in del(7q), p= 0.13). The clinical characteristics and outcomes by subgroup in the context of VEN-based therapy are summarized in Table 3. Remarkably, AML patients with del(7) who received VEN-based therapy (Rx + Ven) had significantly worst outcomes than patients treated without VEN-based (Rx) regimens (Figure 4a-c). Specifically, the median OS, RFS and remission duration for del(7) Rx + Ven were the shortest at 5.8 months (p=0.47), 0.1 months (p<0.0001) and 2.2 months (p=0.0015), respectively, compared to the other treatment groups (Figure 4a-c). Of note, the rate of CR/CRi in all groups were not significantly different suggesting that earlier relapses were likely driving the worse outcomes.
Table 3:
The treatment response and clinical outcomes in our AML cohort of patients with del(7) or del(7q) treated with or without Venetoclax.
| Characteristic | Overall, N = 243 | del(7) Others, N = 137 | del(7) Ven, N = 31 | del(7q) Others, N = 67 | del(7q) Ven, N = 8 | p-value1 |
|---|---|---|---|---|---|---|
| Age (years), Mean+/−SD; Median (Range) | 67.5+/−12.6; 70.3 (23.4 – 87.8) | 67.6+/−11.8; 70.2 (26.3 – 87.8) | 67.3+/−13.6; 70.0 (23.4 – 85.7) | 67.3+/−14.4; 71.0 (25.0 – 84.2) | 69.9+/−6.5; 71.7 (59.3 – 78.3) | >0.9 |
| Gender, n/N (%) | ||||||
| Female | 100/243 (41%) | 62/137 (45%) | 12/31 (39%) | 21/67 (31%) | 5/8 (62%) | |
| Male | 143/243 (59%) | 75/137 (55%) | 19/31 (61%) | 46/67 (69%) | 3/8 (38%) | |
| Cytogenetics, n/N (%) | 0.9 | |||||
| Complex (>=3) | 168/243 (69%) | 94/137 (69%) | 20/31 (65%) | 48/67 (72%) | 6/8 (75%) | |
| Other (<3) | 75/243 (31%) | 43/137 (31%) | 11/31 (35%) | 19/67 (28%) | 2/8 (25%) | |
| ELN based on Cytogenetics, n/N (%) | <0.001 | |||||
| Non-poor | 21/243 (8.6%) | 0/137 (0%) | 0/31 (0%) | 19/67 (28%) | 2/8 (25%) | |
| Poor | 222/243 (91%) | 137/137 (100%) | 31/31 (100%) | 48/67 (72%) | 6/8 (75%) | |
| Secondary AML, n/N (%) | 0.5 | |||||
| De novo AML | 142/243 (58%) | 78/137 (57%) | 18/31 (58%) | 43/67 (64%) | 3/8 (38%) | |
| Secondary AML | 101/243 (42%) | 59/137 (43%) | 13/31 (42%) | 24/67 (36%) | 5/8 (62%) | |
| TP53 Mutations, n/N (%) | 0.6 | |||||
| TP53 wild type | 81/178 (46%) | 45/93 (48%) | 11/31 (35%) | 22/46 (48%) | 3/8 (38%) | |
| TP53 mutant | 97/178 (54%) | 48/93 (52%) | 20/31 (65%) | 24/46 (52%) | 5/8 (62%) | |
| Unknown | 65 | 44 | 0 | 21 | 0 | |
| Chr17/17p Loss, n/N (%) | 56/243 (23%) | 30/137 (22%) | 5/31 (16%) | 19/67 (28%) | 2/8 (25%) | 0.6 |
| Venetoclax, n/N (%) | 39/243 (16%) | 0/137 (0%) | 31/31 (100%) | 0/67 (0%) | 8/8 (100%) | <0.001 |
| Intensity, n/N (%) | 0.3 | |||||
| High Intensity | 60/243 (25%) | 36/137 (26%) | 4/31 (13%) | 19/67 (28%) | 1/8 (12%) | |
| Low Intensity | 183/243 (75%) | 101/137 (74%) | 27/31 (87%) | 48/67 (72%) | 7/8 (88%) | |
| Best Response, n/N (%) | 0.4 | |||||
| CR | 92/243 (38%) | 52/137 (38%) | 12/31 (39%) | 24/67 (36%) | 4/8 (50%) | |
| CRi | 26/243 (11%) | 14/137 (10%) | 5/31 (16%) | 5/67 (7.5%) | 2/8 (25%) | |
| NR | 125/243 (51%) | 71/137 (52%) | 14/31 (45%) | 38/67 (57%) | 2/8 (25%) |
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
Figure 4.
(a) overall survival (OS), (b) event-free survival (EFS), and (c) remission duration (RD) of AML patients with del(7) or del(7q) who are treated with or without Venetoclax. d. overall survival (OS), (e) event-free survival (EFS), and (f) remission duration (RD) of AML patients with del(7) who harbor TP53 alterations and treated with or without Venetoclax. (g) overall survival (OS), (h) event-free survival (EFS), and (i) remission duration (RD) of AML patients with del(7q) who harbor TP53 alterations and treated with or without Venetoclax.
We next evaluated the responses to venetoclax in context of TP53 alterations since the addition of venetoclax to standard treatment regimens did not improve outcomes in younger or older patients who had TP53-mut AML20. Table 2 summarizes the clinical characteristics of patients by TP53-mutation status. As expected, patients with TP53-mutations were more likely to have complex cytogenetics (p<0.0001) and to have co-occurrence of del(17) or del(17p) (p<0.0001). Among patients with TP53 alterations (TP53-alt) in del(7) and del(7q) subgroups, the addition of venetoclax to induction therapy did not significantly improve the OS, RFS or remission duration. The median OS for del(7) TP53-alt Rx vs del(7) TP53-alt Rx+Ven was 5.2 months vs 4.5 months, respectively (p = 0.6) (Figure 4d-f, Table 4). The median OS for del(7q) TP53-alt Rx vs del(7q) TP53-alt Rx+Ven was 6.4 months vs 7.9 months respectively (p = 0.69). Surprisingly, patients with del(7) and TP53-wt treated with VEN-based regimens had significantly lower overall survival compared with del(7) and TP53-wt AML patients treated without VEN-based regimens (Figure 4g-i, Table 5). Specifically, the median OS for del(7) TP53-wt Rx vs del(7) TP53-wt Rx+Ven was 11.2 months vs 5.8 months, respectively (p = 0.0017).
Table 4:
The treatment response and clinical outcomes in our AML cohort of patients with del(7) only treated with or without Venetoclax with or without TP53 alterations.
| Characteristic | Overall, N = 136 | del(7) Tp53-alt1, Others N = 63 | del(7) Tp53-alt1, Ven N = 20 | del(7) Tp53-wt1, Others N = 42 | del(7) Tp53-wt1, Ven N = 11 | p-value2 |
|---|---|---|---|---|---|---|
| Age (years), Mean+/−SD; Median (Range) | 68.2+/−11.4; 70.1 (23.4 – 87.8) | 68.0+/−10.9; 68.5 (32.0 – 87.6) | 70.3+/−9.6; 70.6 (42.7 – 85.7) | 69.2+/−10.5; 71.1 (48.1 – 87.8) | 62.0+/−18.1; 69.0 (23.4 – 81.3) | 0.7 |
| Gender, n/N (%) | 0.3 | |||||
| Female | 60/136 (44%) | 33/63 (52%) | 9/20 (45%) | 15/42 (36%) | 3/11 (27%) | |
| Male | 76/136 (56%) | 30/63 (48%) | 11/20 (55%) | 27/42 (64%) | 8/11 (73%) | |
| Cytogenetics, n/N (%) | <0.001 | |||||
| Complex (>=3) | 93/136 (68%) | 60/63 (95%) | 18/20 (90%) | 13/42 (31%) | 2/11 (18%) | |
| Other (<3) | 43/136 (32%) | 3/63 (4.8%) | 2/20 (10%) | 29/42 (69%) | 9/11 (82%) | |
| ELN based on Cytogenetics, n/N (%) | ||||||
| Poor | 136/136 (100%) | 63/63 (100%) | 20/20 (100%) | 42/42 (100%) | 11/11 (100%) | |
| Secondary AML, n/N (%) | 0.8 | |||||
| De novo AML | 83/136 (61%) | 37/63 (59%) | 11/20 (55%) | 28/42 (67%) | 7/11 (64%) | |
| Secondary AML | 53/136 (39%) | 26/63 (41%) | 9/20 (45%) | 14/42 (33%) | 4/11 (36%) | |
| TP53 Mutations, n/N (%) | <0.001 | |||||
| TP53 wild type | 56/124 (45%) | 3/51 (5.9%) | 0/20 (0%) | 42/42 (100%) | 11/11 (100%) | |
| TP53 mutant | 68/124 (55%) | 48/51 (94%) | 20/20 (100%) | 0/42 (0%) | 0/11 (0%) | |
| Unknown | 12 | 12 | 0 | 0 | 0 | |
| Chr17/17p Loss, n/N (%) | 35/136 (26%) | 30/63 (48%) | 5/20 (25%) | 0/42 (0%) | 0/11 (0%) | <0.001 |
| Venetoclax, n/N (%) | <0.001 | |||||
| Others | 105/136 (77%) | 63/63 (100%) | 0/20 (0%) | 42/42 (100%) | 0/11 (0%) | |
| Venetoclax | 31/136 (23%) | 0/63 (0%) | 20/20 (100%) | 0/42 (0%) | 11/11 (100%) | |
| Intensity, n/N (%) | 0.14 | |||||
| High Intensity | 28/136 (21%) | 12/63 (19%) | 1/20 (5.0%) | 12/42 (29%) | 3/11 (27%) | |
| Low Intensity | 108/136 (79%) | 51/63 (81%) | 19/20 (95%) | 30/42 (71%) | 8/11 (73%) | |
| Best Response, n/N (%) | 0.2 | |||||
| CR | 53/136 (39%) | 20/63 (32%) | 8/20 (40%) | 21/42 (50%) | 4/11 (36%) | |
| CRi | 16/136 (12%) | 5/63 (7.9%) | 2/20 (10%) | 6/42 (14%) | 3/11 (27%) | |
| NR | 67/136 (49%) | 38/63 (60%) | 10/20 (50%) | 15/42 (36%) | 4/11 (36%) |
TP53-alt indicates patients with TP53 mutations, chr17 loss, or chr17p loss
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
Table 5:
The treatment response and clinical outcomes in our AML cohort of patients with del(7q) only treated with or without Venetoclax with or without TP53 alterations.
| Characteristic | Overall, N = 59 | del(7q) Tp53-alt1, Others N = 33 | del(7q) Tp53-alt1, Ven N = 5 | del(7q) Tp53-wt1, Others N = 18 | del(7q) Tp53-wt1, Ven N = 3 | p-value2 |
|---|---|---|---|---|---|---|
| Age (years), Mean+/−SD; Median (Range) | 70.1+/−12.1; 72.3 (25.0 – 84.2) | 72.5+/−10.0; 73.1 (33.9 – 84.2) | 67.6+/−6.9; 65.0 (59.3 – 76.1) | 65.7+/−16.2; 70.0 (25.0 – 83.9) | 73.9+/−3.9; 72.3 (71.0 – 78.3) | 0.3 |
| Gender, n/N (%) | 0.037 | |||||
| Female | 19/59 (32%) | 12/33 (36%) | 3/5 (60%) | 2/18 (11%) | 2/3 (67%) | |
| Male | 40/59 (68%) | 21/33 (64%) | 2/5 (40%) | 16/18 (89%) | 1/3 (33%) | |
| Cytogenetics, n/N (%) | <0.001 | |||||
| Complex (>=3) | 42/59 (71%) | 33/33 (100%) | 5/5 (100%) | 3/18 (17%) | 1/3 (33%) | |
| Other (<3) | 17/59 (29%) | 0/33 (0%) | 0/5 (0%) | 15/18 (83%) | 2/3 (67%) | |
| ELN based on Cytogenetics, n/N (%) | <0.001 | |||||
| Non-poor | 17/59 (29%) | 0/33 (0%) | 0/5 (0%) | 15/18 (83%) | 2/3 (67%) | |
| Poor | 42/59 (71%) | 33/33 (100%) | 5/5 (100%) | 3/18 (17%) | 1/3 (33%) | |
| Secondary AML, n/N (%) | 0.4 | |||||
| De novo AML | 35/59 (59%) | 19/33 (58%) | 2/5 (40%) | 13/18 (72%) | 1/3 (33%) | |
| Secondary AML | 24/59 (41%) | 14/33 (42%) | 3/5 (60%) | 5/18 (28%) | 2/3 (67%) | |
| TP53 Mutations, n/N (%) | <0.001 | |||||
| TP53 wild type | 25/54 (46%) | 4/28 (14%) | 0/5 (0%) | 18/18 (100%) | 3/3 (100%) | |
| TP53 mutant | 29/54 (54%) | 24/28 (86%) | 5/5 (100%) | 0/18 (0%) | 0/3 (0%) | |
| Unknown | 5 | 5 | 0 | 0 | 0 | |
| Chr17/17p Loss, n/N (%) | 21/59 (36%) | 19/33 (58%) | 2/5 (40%) | 0/18 (0%) | 0/3 (0%) | <0.001 |
| Venetoclax, n/N (%) | <0.001 | |||||
| Others | 51/59 (86%) | 33/33 (100%) | 0/5 (0%) | 18/18 (100%) | 0/3 (0%) | |
| Venetoclax | 8/59 (14%) | 0/33 (0%) | 5/5 (100%) | 0/18 (0%) | 3/3 (100%) | |
| Intensity, n/N (%) | 0.2 | |||||
| High Intensity | 13/59 (22%) | 5/33 (15%) | 1/5 (20%) | 7/18 (39%) | 0/3 (0%) | |
| Low Intensity | 46/59 (78%) | 28/33 (85%) | 4/5 (80%) | 11/18 (61%) | 3/3 (100%) | |
| Best Response, n/N (%) | 0.14 | |||||
| CR | 22/59 (37%) | 12/33 (36%) | 3/5 (60%) | 6/18 (33%) | 1/3 (33%) | |
| CRi | 6/59 (10%) | 2/33 (6.1%) | 0/5 (0%) | 2/18 (11%) | 2/3 (67%) | |
| NR | 31/59 (53%) | 19/33 (58%) | 2/5 (40%) | 10/18 (56%) | 0/3 (0%) |
P53-alt indicates patients with TP53 mutations, chr17 loss, or chr17p loss
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
We next performed a Cox proportional hazard model to investigate the role of other potential confounding variables, specifically the intensity of the treatment and the cytogenetic complexity, that may contribute to this remarkably difference. Our Intensity and cytogenetics corrected model showed a significantly higher hazard ratio (HR 2.56 (CI, 1.16–5.7), p=0.02) in patients with del(7) and TP53-wt treated with VEN-based regimens, which was a similar hazard ratio to AML patients with with chromosome 7 deletion and TP53-mut treated with or without VEN-based regimens (p= 0.005, and 0.003 respectively). Of note, the CR/CRi rates between the TP53-wt del(7) AML patients who received VEN-based versus other therapy were similar (4/11 (36%) vs 21/42 (50%) p >0.9). Alternatively, the addition of venetoclax to standard treatment regimens showed a trend toward improved outcomes in TP53-wt AML with del(7q). Specficially, the median OS for del(7q) TP53-wt Rx vs del(7q) TP53-wt Rx+Ven was 8.6 months vs 16.4 months respectively (p=0.25) (Figure 4g-i, Table 5). This suggests that the finding of worst outcomes in AML patients receiving VEN-based therapy was particular to the del(7) cytogenetic subgroup.
Discussion
Cytogenetic profiling provides a valuable tool in risk stratifying and prognosticating patients with AML1, 5, 21. Deletions in chromosome 7 or its long arm 7q constitute the most common high-risk cytogenetic abnormality in AML1, 13. Patients with del(7) or del(7q) have often been considered as one cytogenetic group for clinical studies and therapeutic purposes12, 22. However, studies comparing these two cytogenetic groups were limited to small cohorts. We herein conducted a large retrospective analysis to provide a comprehensive clinical characterization and molecular landscape of AML patients with del(7) or del(7q). We also aimed to evaluate the overall outcomes of patients with AML with del(7) and del(7q) and in the context of venetoclax therapy.
The prevalence of del(7) or del(7q) in our cohort was 12% (243/2025), with almost a 2:1 frequency for del(7) versus del(7q). We also found that a total of 42% of patients had secondary AML as would be expected. However, these rates are likely underestimating the true prevalence of del(7) or del(7q) in AML, as we excluded transformed patients who had previously received myeloid-directed therapy for antecedent hematologic disroders. Our rationale for this exclusion criteria was based on the a priori analysis plan to allow a for robust characterization of clinical outcomes and respones to frontline AML-directed therapies independent of prior myeloid-directed therapy.
We found that patients with del(7) and del(7q) had similar clinical characteristics, and rates of co-occuring mutations and cytogenetic abnormalities. While RFS in patients with del(7q) was signficiantly longer than that in patients with del(7) (p=0.047), the overall survival, and remission duration were not significantly different. Of note, the MRC AML 10 trial categorized del(7q) as an intermediate prognostic factor initially5 with later analysis supporting an adverse role2. We found that the outcomes of del(7q) was dependent on the co-occurrence of other adverse cytogenetics. Specifically, among del(7q), the co-occurrence of non-adverse cytogenetics as defined by ELN1 and ALFA 120023 studies translated into significantly improved outcomes compared to del(7q) with concomitant poor cytogenetics. Therefore, the prognosis of AML patients with del(7q) should be considered in the context of co-occuring cytogenetic abnormalities.
A total of 70% of AML patients in our study had complex cytogenetics which was also significantly associated with TP53 alterations as has been previously shown6. This is consistent with the role of TP53 in maintaining genomic stability6. However, even among the 30% of patients without detectable TP53 alterations (n=74), we found 19 of 74 (26%) patients with complex cytogenetic, suggesting that the loss of chromosome 7 or 7q could confer genomic instability independent of TP53 alterations. Of importance, the co-occurrence of TP53 alterations with del(7) or del(7q) translated into significantly worse clinical outcomes than in patients without TP53 alterations. This further highlights the urgent need to design treatments that can improve outcomes in patients with TP53 altered AML, quickly emerging as the area of most unmet need in myeloid malignancies.
The wide adoption of venetoclax-based regimens in the treatment of patients with AML warranted our evaluation of its effectiveness in AML patients with del(7) and del(7q). In patients with TP53 alterations, the addition of venetoclax did not translate into improved clinical outcomes in AML with del(7) or del(7q). This is consistent with prior findings demonstrating the lack of benefit of venetoclax in TP53 altered AML20. Remarkably, TP53-wildtype AML patients with del(7) who received venetoclax-based therapies had significantly shorter OS, RFS, and remission duration compared to patients who did not receive venetoclax, despite similar rate of CR or CRi. This suggests that venetoclax treatment may be eradicating a subset of AML with del(7) clones but new clones are expanding or emerging following venetoclax therapy. This finding requires further validation in other independent cohorts.
Conclusions:
To our knowledge, this is the largest study focusing only on del(7) and del(7q) abnormalities in patients with AML. This afforded us to conduct a comprehensive and robust analysis of the demographics and clinical characteristics of these two cytogenetic abnormalities. Our analysis also included comprehensive cytogenetic information in all patients beyond del7 / del7q and NGS targeted mutation analysis of 125/243 (51%) patients at time of diagnosis providing a molecular landscape of AML with del(7) and del(7q). Our finding relating to worse outcomes of del(7) and wildtype TP53 patients treated with venetoclax-based regimens is limited by the small sample size and require a larger cohort for validation. A better biologic understanding of the inferior outcomes in TP5-wildtype del(7) patients with venetoclax-based therapies versus non venetoclax containing therapies is still needed. Also, the utilization of venetoclax-based therapies in AML with del(7) may need further assessment if these findings are confirmed in subsequent analysis. Further, among del(7q) AML patients, the co-occuring cytogenetic abnormalities impact the outcomes. In conclusion, our study demonstrates that AML patients with del(7) and del(7q) have similar demographic and molecular characteristics, have poor clinical outcomes and highlights the importance of understanding the underlying biological processes associated with chromosome 7 abnormalities to eventually devise more effective therapies.
Supplementary Material
Figure 5.
Univariate and multivariate analyses of factors predicting risks of death in newly diagnosed del(7) or del(7q) AML: Variables with p = 0.05 were included in the multivariate analysis. HR hazard ratio, Low Intensity, High Intensity, Complex cytogenetics (>=3), Other karyotype (<3).
Acknowledgements:
Funding:
This work was partially funded by partial funding to HAA from Ladies Leukemia League Foundation, Conquer Cancer Foundation Young Investigator Award and MD Anderson Institutional Start-up Grant. EA was supported by the CPRIT Training Award (RP210028), and NIH NCI (F32CA271697).
Footnotes
Ethics approval and consent to participate: Not applicable
Consent for publication: Not applicable.
Availability of data and Materials: Upon request.
Competing Interest: Naval Daver: research grants and consultancy fees from Daiichi-Sankyo Bristol-Meyers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Hanmi, Trovagene, FATE Therapeutics, Novimmune, Glycomimetics, Arog, Novartis, Jazz, Celgene, Syndax, Shattuck Labs, Agios. Elias Jabour: research grants and consultancy fees from Amgen, Adaptive biotechnologies, Pfizer, BMS, Takeda, Abbvie, Novartis, BMS, Genentech. Hussein Abbas: consultancy fees from Molecular Partners.
References
- 1.Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017. 01; 129(4): 424–447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010. Jul 22; 116(3): 354–365. [DOI] [PubMed] [Google Scholar]
- 3.Petit P, Alexander M, Fondu P. Letter: Monosomy 7 in erythroleukaemia. Lancet 1973. Dec 08; 2(7841): 1326–1327. [DOI] [PubMed] [Google Scholar]
- 4.Rowley JD. Letter: Deletions of chromosome 7 in haematological disorders. Lancet 1973. Dec 15; 2(7842): 1385–1386. [DOI] [PubMed] [Google Scholar]
- 5.Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998. Oct 01; 92(7): 2322–2333. [PubMed] [Google Scholar]
- 6.Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012. Mar 01; 119(9): 2114–2121. [DOI] [PubMed] [Google Scholar]
- 7.Hussain FT, Nguyen EP, Raza S, Knudson R, Pardanani A, Hanson CA, et al. Sole abnormalities of chromosome 7 in myeloid malignancies: spectrum, histopathologic correlates, and prognostic implications. Am J Hematol 2012. Jul; 87(7): 684–686. [DOI] [PubMed] [Google Scholar]
- 8.Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003. Jul 01; 102(1): 43–52. [DOI] [PubMed] [Google Scholar]
- 9.Han SY, Mrózek K, Voutsinas J, Wu Q, Morgan EA, Vestergaard H, et al. Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21). Blood Adv 2021. 05 25; 5(10): 2481–2489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020. 08; 383(7): 617–629. [DOI] [PubMed] [Google Scholar]
- 11.Kalwinsky DK, Raimondi SC, Schell MJ, Mirro J, Santana VM, Behm F, et al. Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia. J Clin Oncol 1990. Jan; 8(1): 75–83. [DOI] [PubMed] [Google Scholar]
- 12.Poiré X, Labopin M, Polge E, Blaise D, Chevallier P, Maertens J, et al. Hematopoietic stem cell transplantation for adult patients with isolated NPM1 mutated acute myeloid leukemia in first remission. Am J Hematol 2019. 02; 94(2): 231–239. [DOI] [PubMed] [Google Scholar]
- 13.McNerney ME, Brown CD, Peterson AL, Banerjee M, Larson RA, Anastasi J, et al. The spectrum of somatic mutations in high-risk acute myeloid leukaemia with −7/del(7q). Br J Haematol 2014. Aug; 166(4): 550–556. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hartmann L, Haferlach C, Meggendorfer M, Kern W, Haferlach T, Stengel A. Myeloid malignancies with isolated 7q deletion can be further characterized by their accompanying molecular mutations. Genes Chromosomes Cancer 2019. 10; 58(10): 698–704. [DOI] [PubMed] [Google Scholar]
- 15.Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2004. Aug 15; 22(16): 3432–3433. [DOI] [PubMed] [Google Scholar]
- 16.Luthra R, Patel KP, Reddy NG, Haghshenas V, Routbort MJ, Harmon MA, et al. Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Haematologica 2014. Mar; 99(3): 465–473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Joerger AC, Fersht AR. The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb Perspect Biol 2010. Jun; 2(6): a000919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Killock D Venetoclax in AML: efficacy confirmed. Nat Rev Clin Oncol 2020. 10; 17(10): 592. [DOI] [PubMed] [Google Scholar]
- 19.Pollyea DA, Pei S, Stevens BM, Smith CA, Jordan CT. The Intriguing Clinical Success of BCL-2 Inhibition in Acute Myeloid Leukemia. Annual Review of Cancer Biology 2021; 5(1): 277–289. [Google Scholar]
- 20.Kim K, Maiti A, Loghavi S, Pourebrahim R, Kadia TM, Rausch CR, et al. Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax. Cancer 2021. Oct 15; 127(20): 3772–3781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988. Jul; 2(7): 403–412. [PubMed] [Google Scholar]
- 22.El-Menoufy MAM, Mourad ZI, Farahat NM. The prognostic impact of loss of chromosome 7 material detected by fluorescence in situ hybridization (FISH) in myeloid malignancies. J Egypt Natl Canc Inst 2018. Dec; 30(4): 133–138. [DOI] [PubMed] [Google Scholar]
- 23.Gardin C, Pautas C, Fournier E, Itzykson R, Lemasle E, Bourhis JH, et al. Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results. Blood Adv 2020. 05 12; 4(9): 1942–1949. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.