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Keywords:

  • acute myeloid leukaemia;
  • abnl(17p);
  • stem cell transplantation;
  • 17p;
  • TP53

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

The role of allogeneic stem cell transplantation (HSCT) as compared to chemotherapy in acute myeloid leukaemia (AML) patients with abnormalities of chromosome 17p [abnl(17p)] has not yet been defined. Therefore, we analysed 3530 AML patients treated in three randomized, prospective, controlled clinical trials and compared post-remission therapies using a multivariate Cox regression analysis to determine whether allogeneic HSCT is superior than chemotherapy in overcoming the detrimental impact of patients with abnl(17p) AML. One hundred and forty-three patients (4%) were identified with abnl(17p) AML. All patients had received intensive induction chemotherapy. Forty-seven patients with a median age of 54 years (18–69 years) proceeded to allogeneic HSCT in first or second remission. The 3-year overall survival (OS) rate for the entire cohort of patients was 4% [95% confidence interval (CI), 1–7%]. OS and event-free survival at 3 years, calculated from the day of HSCT, was 11% (95% CI, 2–20%) and 6% (95% CI, 0–13%), respectively. Multivariate Cox regression analysis showed no benefit of allogeneic HSCT compared to chemotherapy (Hazard Ratio 0·97, 95% CI 0·56–1·67, P = 0·9). In conclusion, allogeneic HSCT does not improve survival in patients with abnl(17p) AML as compared to other adverse cytogenetic risk abnormalities.

The cytogenetic analysis of leukaemic blasts in the diagnosis of acute myeloid leukaemia (AML) is recognized as one of the most valuable prognostic factors and is instrumental in the stratification of post-remission therapy (Slovak et al, 2000; Suciu et al, 2003). Abnormalities of chromosome 17p [abnl(17p)] are detected in about 4% of adult de novo AML patients and even higher rates in therapy-related AML (Grimwade et al, 2010). They are considered to be high-risk markers with a negative impact on the complete remission (CR) rate, the cumulative incidence of relapse (CIR), and overall survival (OS) (Nahi et al, 2008a; Dohner et al, 2010). In one series, all 22 patients with abnl(17p) AML died within 11 months despite intensive chemotherapy (Nahi et al, 2008a). Our group reported results on 105 patients with abnl(17p) that were treated with intensive induction chemotherapy (Seifert et al, 2009). OS at 2 years was zero in 20 patients with abnl(17p) without a complex karyotype (CK) and 8% [95% confidence interval (CI), 2–14%] in 85 patients with abnl(17p) as part of a CK.

Allogeneic haematopoietic stem cell transplantation (HSCT) is the most powerful therapeutic option to prevent relapse in AML. Generally, patients with adverse karyotype AML who proceed to allogeneic HSCT have a significant survival benefit compared to patients treated with consolidation chemotherapy (Slovak et al, 2000; Suciu et al, 2003; Schlenk et al, 2010). However, analyses focusing specifically on the subgroup of patients with abnl(17p) AML have not been conducted so far. Supplementary findings reported by two studies that did not primarily evaluate the role of allogeneic HSCT in patients with abnl(17p) AML identified an inferior outcome of 15 and 19 patients in this setting, respectively (Fang et al, 2011; Rücker et al, 2012). The objective of the present study was to address the question of whether allogeneic HSCT might improve outcome as compared to chemotherapy in overcoming the detrimental impact of abnl(17p) in patients with AML in a large patient cohort.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

Study population

Between February 1996 and November 2009, a total of 3530 patients with AML entered randomized controlled first-line trials of the Study Alliance Leukaemia (SAL). Patients with acute promyelocytic leukaemia were excluded. The studies were approved by the ethics committees of all participating centres of the SAL. The protocols were in agreement with the Helsinki declaration and registered with the National Clinical Trial (NCT) numbers 00180115 (AML96), 00180102 (AML2003), and 00180167 (AML60+). Written informed consent was obtained from each patient. Of the 143 patients reported here, 105 patients were previously described in a report on the outcome of chemotherapy in abnl(17p) as a single aberration or in combination with additional abnormalities (Seifert et al, 2009).

Treatment protocols

In the AML96 protocol, patients below 60 years of age were treated with double induction therapy including standard- and intermediate-dose mitoxantrone, cytosine arabinoside (ara-C), etoposide, and amsacrine and stratified post-remission therapy in different cytogenetic risk groups (Schaich et al, 2011). Intermediate risk patients with a human leucocyte antigen (HLA)-identical sibling donor were referred for allogeneic HSCT. High-risk patients were referred to related or unrelated HLA-compatible allogeneic HSCT. Patients without donors were randomized to intermediate-dose or high-dose ara-C and mitoxantrone (I-MAC or H-MAC) and subsequent autologous HSCT. Patients aged over 60 years received double induction chemotherapy with daunorubicin and ara-C followed by consolidation therapy consisting of intermediate-dose ara-C and amsacrine.

In the AML60+ trial, patients above 60 years of age were included and randomized between the treatment arm of the AML96 study for elderly patients and induction with intermediate dose ara-C and mitoxantrone (Rollig et al, 2010). Allogeneic HSCT was optional for fit patients.

The AML2003 trial included patients below the age of 61 years. Patients were randomized to a risk-adapted intensified treatment strategy or standard and between two consolidation chemotherapies. All patients received the 3 + 7 regimen as induction chemotherapy. In the intensified arms, high-risk patients, defined by cytogenetics or early marrow assessment, were scheduled for HLA-compatible related or unrelated allogeneic HSCT in aplasia (Platzbecker et al, 2006). Patients without an HLA-compatible donor were preferentially consolidated with autologous HSCT. Intermediate-risk patients in the intensified arms were scheduled for sibling HSCT in first remission or autologous HSCT. In the non-intensified arms only cytogenetically defined high-risk patients should receive HLA-compatible sibling or unrelated HSCT in first remission. Intermediate-risk patients, patients who did not have a donor, and patients with mobilization failure were randomized between three cycles of high-dose ara-C or two cycles of intermediate-dose ara-C and mitoxantrone and one cycle of intermediate-dose ara-C and amsacrine (Parmentier et al, 2011).

Patients in first CR received either standard myeloablative conditioning based on 12 Gray total-body irradiation (TBI) and cyclophosphamide, or 8 Gray TBI and fludarabine (Bornhauser et al, 2011). Allogeneic HSCT in aplasia was performed after reduced-intensity conditioning with fludarabine and melphalan (Platzbecker et al, 2006). No ex vivo T-cell depletion was employed, but patients with unrelated donors received antithymocyte globulin (ATG) intravenously before HSCT (Finke et al, 2009).

Cytogenetic investigations

At diagnosis, samples of bone marrow aspirates and blood were cultured for 1 and 2 d and examined using standard G-banding techniques and karyotyping according to the International System for Human Cytogenetic Nomenclature (Shaffer et al, 2009). GTG-banding techniques and fluorescent in situ hybridization (FISH) were performed according to the conventional procedures and to the manufacturers' recommendations, respectively. In selected patients with karyotype failure, indefinite complex aberrant karyotypes metaphase, or interphase FISH with the LSI p53 (TP53) and CEP 17 probes (Abbott, Wiesbaden, Germany) were performed in order to confirm or exclude abnl(17p) AML. For interphase FISH the internal cut-off level for the detection of a deletion was 13%. A CK was defined as the presence of three or more independent aberrations. A monosomal karyotype was defined as published (Breems et al, 2008).

Statistical analysis

Complete remission (CR) was defined according to standard criteria (Cheson et al, 2003). Overall survival (OS) and event-free survival (EFS) were measured from the date of entering the study to the date of event or the last follow up. Death, induction failure, and relapse were considered events for EFS. Leukaemia-free survival (LFS) was calculated from the date of the first CR to the date of event, with relapse and death as events. Survival after HSCT was measured from the date of HSCT to the date of event. After HSCT, relapse and non-relapse mortality were considered as competing events. Event-probabilities were calculated according to Kaplan–Maier for OS, EFS, and LFS and using competing event statistics for the cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Risk factor analyses for CR-rate were carried out by logistic regression and for survival endpoints by Cox regression analysis. 95% confidence intervals (CI) were provided for major endpoints. For frequencies, 95% CI was calculated according to Agresti and Coull (1998) while approximate point-wise CI was provided for survival endpoints. Allogeneic HSCT was tested as a time-dependent covariate in a Cox regression model for overall survival from study enrolment with age and the WBC count at diagnosis as covariates. Statistical analyses were performed using the Statistical Package for the Social Sciences (spss) software package, version 19.0.0 (IBM SPSS Inc, Chicago, IL, USA) and r version 2.12.1 (R Development Core Team, 2012, Vienna, Austria).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

Patients

Abnl(17p) was detected in 143 out of 3530 patients (4%) who were enrolled in the SAL trials between February 1996 and November 2009. Eighty patients (56%) were treated in the AML96 trial, 44 patients (31%) in the AML 2003 trial, and 19 patients (13%) in the AML60+ trial. Detailed patient characteristics are given in Table 1. Differences in age are attributed to the inclusion criteria of the respective studies.

Table 1. Patient characteristics
 All patients (n = 143)No allogeneic HSCT (n = 96)Allogeneic HSCT (n = 47)P-valuea
  1. AML, acute myeloid leukaemia; HSCT, haematopoietic stem cell transplantation; mdsAML, AML with preceding myelodsplastic syndrome (MDS); tAML, therapy-related AML; WBC, white blood cells.

  2. a

    P values were calculated using the Mann–Whitney U-test for numerical variables and chi-square test for categorical variables.

  3. b

    Refers to 124 patients (100%) with informative karyotypes for abnl(17p).

  4. c

    t(12;17)(p11.2;p13), TP53 deletion was confirmed by fluorescent in situ hybridization.

Gender, n (%)

Female

64 (45)46 (48)18 (38)0·3
Median age at diagnosis, years (range)60 (18–81)66 (33–81)54 (18–69)<0·001
AML status, n (%)
De novo 106 (74)72 (75)34 (72)0·5
mdsAML24 (17)17 (18)7 (15)
tAML12 (8)6 (6)6 (13)
Unknown1 (1)1 (1)0 (0)
Study, n (%)
AML9680 (56)67 (70)13 (28) 
AML200344 (31)12 (13)32 (68)
AML60+19 (13)17 (18)2 (4) 
Median WBC count × 109/l (range)4·1 (0·7–466)5·4 (0·7–466)3·4 (0·8–110)0·05
Unknown110
Type of abnl(17p), n (%)b
add(17p)26 (21)18 (21)8 (22) 
iso(17)(q10)20 (16)15 (17)5 (14) 
del(17p)10 (8)6 (7)4 (11) 
der(17;v)11 (9)7 (8)4 (11) 
der(17)9 (7)5 (6)4 (11) 
dic(17;v)5 (4)2 (2)3 (8) 
−1743 (35)34 (39)9 (24) 
Balanced translocation1 (1)c1 (1)0 (0) 
Median number of aberrations (range)7 (1–23)b6 (1–23)8 (1–19)0·6
Monosomal karyotype85 (69)b59 (68)26 (70)0·8
Complex karyotype101 (81)b70 (81)31 (84)0·7

Cytogenetic characteristics

The diagnosis of abnl(17p) AML relied on the karyotype information confirmed by FISH analysis in 84 patients (59%), on informative karyotypes without FISH results in 40 patients (28%), and on a non-informative karyotype but positive FISH result in 19 patients (13%). Only one out of 143 patients exposed a balanced translocation resulting in a cryptic del(17p) detected by FISH. Monosomies represented the most common type of unbalanced abnl(17p) followed by the addition of foreign material, isochromosomes, deletions and derivative chromosomes due to arm translocations (see Table 1 for further details).

Response to induction therapy

Induction mortality in patients with abnl(17p) AML was 17% (95% CI, 12–24%). Fifty-one patients (36%, 95% CI, 28–44%) achieved a CR [including six patients who achieved first CR (CR-1) after allogeneic HSCT in aplasia], and 67 patients (47%, 95% CI, 39–55%) had primary refractory disease to the study treatment.

The CR-rate was 36% in the AML96 study, 39% in the AML 2003 study (including six patients who achieved CR-1 after allogeneic HSCT in aplasia) and 26% in the AML60+ study. In univariate logistic regression analyses neither AML type, lactate dehydrogenase, leucocyte or platelet count, the number of concomitant abnormalities nor the presence of an isolated abnl(17p) predicted CR-1. The only factor associated with the CR-rate was age (P = 0·001): 49% of patients below the age of 60 years achieved a CR compared to 23% of patients aged 60 years or more.

Of these, 45 patients achieved a CR with induction therapy, 16 proceeded to allogeneic HSCT first CR-1, 21 patients received postremission chemotherapy, and eight patients received no consolidation chemotherapy. Thirty-nine patients (58%) with primary refractory disease received salvage therapy. Eighteen patients with refractory disease received allogeneic HSCT after salvage therapy. Out of this group, nine patients proceeded to allogeneic HSCT in aplasia after salvage therapy, and only three patients were transplanted in morphological CR.

Haematopoietic stem cell transplantation

Forty-seven patients received an allogeneic HSCT, which was delivered as consolidation therapy in first remission in 23 patients (CR-1 in 16 patients and in aplasia after induction therapy in seven patients) and after salvage therapy in primary refractory or relapsed disease in 24 patients. The conditioning regimen was myeloablative (busulfan or 12 Gy total body irradiation combined with cyclophosphamide) in 13 patients (28%), dose-intensive (FLAMSA) in five patients (11%), or reduced intensity (combinations of fludarabine together with busulfan, melphalan, treosulfan or 8 Gy total body irradiation) in the remaining 29 patients (62%). Twenty-two patients (47%) received ATG as graft-versus-host disease prophylaxis.

Stem cell donors were HLA-identical siblings in 14 patients (30%), matched unrelated donors in 21 patients (45%), partially mismatched, unrelated donors in seven patients (15%), and haploidentical related donors in five patients (11%).

Treatment outcome

Four out of 143 patients were alive at last follow up with a median observation time of 59 months (range, 34–134 months). OS and EFS calculated from diagnosis for the whole cohort of patients were 23% (95% CI, 16–30%) and 8% (95% CI, 4–12%) at 1 year, and 4% (95% CI, 1–7%) and 2% (95% CI, 0–4%) at 3 years, respectively (Fig 1A). In patients who had achieved a CR, leukaemia-free survival was 4% (95% CI, 0–9%) at 3 years (Fig 1B).

image

Figure 1. Survival endpoints for all patients. (A) Event-free survival and overall survival for all patients. (B) Leukaemia-free survival of 51 patients who were not primary refractory including those patients who received allogeneic HSCT in aplasia after induction therapy. The broken lines represent the point-wise 95% confidence intervals. HSCT denotes haematopoietic stem cell transplantation.

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Twenty-one patients received chemotherapy as postremission therapy in CR-1. At last follow up only one patient was alive and in ongoing CR 11 years after diagnosis (3-year LFS: 5%, 95% CI, 0–14%) (Fig 2A). This patient exposed a partial monosomy 17 as a result of an unbalanced translocation der(21)t(17;21)(q?21;p13) in 28% of the metaphases. The 17p deletion had not been confirmed by FISH. However, this patient had a primary t(9;11)(p22;q23) referring to an intermediate outcome not influenced by secondary abnormalities (Grimwade et al, 2010). Postremission therapy in this patient consisted of high-dose chemotherapy and autologous HSCT.

image

Figure 2. Leukaemia-free survival by postremission therapy. (A) Leukaemia-free survival in 21 patients with CR-1 who received postremission chemotherapy. (B) Leukaemia-free survival in 16 patients, who received allogeneic HSCT in CR-1. Broken lines represent the point-wise 95% confidence intervals. HSCT denotes haematopoietic stem cell transplantation.

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Altogether, 47 patients received allogeneic HSCT. OS and EFS were 11% (95% CI, 2–20%) and 6% (95% CI, 0–13%) 3 years post-transplantation. Relapse-incidence and non-relapse mortality (NRM) were 9% (95% CI, 0·5–17%) and 27% (95% CI, 15–41%) at day +100 and 50% (95% CI, 34–65%) and 45% (95% CI, 30–59%) 3 years after HSCT (Fig 3).

image

Figure 3. Treatment failure after allogeneic HSCT. (A) Event-free survival after allogeneic HSCT in 47 patients with abnl(17p) AML together with point-wise 95%-CI intervals (broken lines). (B) Stacked cumulative incidences of relapse and non-relapse mortality after allogeneic HSCT. The black area represents the incidence of non-relapse mortality after HSCT over time. The dark grey area represents the incidence of mortality after relapse, while the light grey are represents patients who are alive after relapse. HSCT denotes haematopoietic stem cell transplantation.

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Sixteen patients received allogeneic HSCT in first CR. All patients died within 39 months (Fig 2B). The cause of death was relapse in eleven patients (69%) and non-relapse mortality in five patients (31%).

Five patients with primary induction failure received haploidentical HSCT. Four of five patients died from non-relapse related complications within 6 months after haploidentical HSCT while one patient relapsed 7 months after haploidentical HSCT.

Only two patients were alive and relapse-free after allogeneic HSCT with a follow-up of 32 and 59 months. Abnl(17p) AML was confirmed by FISH in both cases. Both patients had been transplanted in aplasia after induction/salvage-therapy and received reduced-intensity conditioning with fludarabine and melphalan.

Comparison of allogeneic HCST compared to chemotherapy

Allogeneic HSCT was tested as a time-dependent covariate in a Cox regression model with age and white blood cell (WBC) count at diagnosis as covariates. The time-dependent covariate allows for a ‘group switch’ of transplanted patients at the time of HSCT from the control group (patients treated with chemotherapy only) into the group of transplanted patients in parallel to a Mantel–Byar analysis. In this model, age [HR 1·02 (95% CI, 1·002–1·05, = 0·03)] and WBC count [HR 1·33 for the logarithm of WBC count (×109/l) (95% CI, 1·14–1·54, < 0·001)] at diagnosis contributed significantly to the prediction of OS while allogeneic HSCT did not confer a survival advantage [HR 0·97 (95% CI, 0·56–1·67, = 0·9)].

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

Abnormalities of 17p in AML predict a detrimental outcome when they are part of CK but also when found as a single abnormality (Haferlach et al, 2008; Nahi et al, 2008a; Seifert et al, 2009). In the majority of AML patients with abnl(17p), as shown in other malignancies, the tumour-suppressor effect of the remaining TP53 allele disappears through mutation (Nigro et al, 1989; Fenaux et al, 1991; Soenen et al, 1998; Nahi et al, 2008a; Rücker et al, 2012). Current AML chemotherapy is at least partly dependent on the function of TP53 as an apoptosis mediator. This may explain one important finding of this study, namely that consolidation chemotherapy obviously was insufficient to fully eradicate the leukaemic clone, although 36% of our patients achieved CR.

Even more astonishing when comparing allogeneic HSCT versus consolidation chemotherapy in patients with abnl(17p) AML in multivariate analysis was that no difference in OS was found (HR 0·97). It is generally accepted that AML patients with adverse risk cytogenetics benefit substantially through allogeneic HSCT (Slovak et al, 2000; Suciu et al, 2003; Schlenk et al, 2010). Our findings indicate that this might not be true for the adverse cytogenetic risk trait abnl(17p) in AML. Remarkably, 22 of 23 patients who had received allogeneic HSCT in first remission or aplasia after induction therapy relapsed (70%) or died (26%) from complications within 3 years. This is in line with smaller studies reporting similar poor survival data after allogeneic HSCT in this subgroup. Only one out of 15 patients was alive 48 months after HSCT in a small series of patients with CK and TP53 mutations transplanted in CR-1 (Rücker et al, 2012). Fang et al (2011) reported 4-year OS of 13% in 19 patients with monosomy 17. These disappointing data resulted from independent patient cohorts. However, all these studies were retrospective in nature and the number of patients with abnl(17p) who proceeded to HSCT in CR-1 was small.

Taking into consideration that the present cohort of 47 transplanted patients was derived from 3530 patients treated within front line trials, only future cooperative group studies will sufficiently be able to include numbers of AML patients that are large enough in order to analyse the impact of allogeneic HSCT in patients with abnl(17p) prospectively. Another option to confirm our findings may thus be registry-based studies. These approaches should also address whether the use of myeloablative conditioning or reduced-intensity conditioning regimens prior to allogeneic HSCT are of differential impact in these patients.

The reason why current approaches for patients with abnl(17p) AML are insufficient remains speculative, but one reason could be the high degree of genetic instability reflected by the strong association with CK-AML. Genetic instability may give rise to sub-clones resistant to chemotherapy but also to sub-clones resistant to graft-versus-leukaemia effects via down-regulation of co-stimulatory molecules or reduced expression of HLA molecules on the cell surface. Interestingly, wild-type TP53 peptides can themselves induce CD4+ T-helper cells that are capable of enhancing the expansion and function of anti-tumour CD8+ cytotoxic T cells (Ito et al, 2006).

The dismal outcome of patients with abnl(17p) AML after chemotherapy and allogeneic HSCT warrants research on agents that reactivate the TP53-pathway in AML. The introduction of wildtype-TP53 through recombinant adenovirus has been studied in pivotal trials in solid cancer (Vousden & Lu, 2002; Snyder et al, 2004). Furthermore, small molecules which restore the mutant TP53 function (e.g. PRIMA-1 or MIRA-1) (Bykov et al, 2002; Nahi et al, 2006) or which act through TP53 stabilization (RITA) (Nahi et al, 2008b), or through MDM2- and MDM4-antagonism are investigated (Tovar et al, 2006; Popowicz et al, 2007; Long et al, 2010). The safety and the efficacy of any of these approaches, however, have not been demonstrated so far.

Abnl(17p) may occur rarely in the context of favourable abnormalities, such as t(15;17) (Grimwade et al, 2010). We want to emphasize that the poor prognosis of abnl(17p) AML reported here only applies to patients who do not expose concurrent favourable abnormalities.

In conclusion, patients with abnl(17p) AML have a very poor prognosis that cannot be improved by HLA compatible allogeneic HSCT and is in strong contradiction to other cytogenetic adverse risk abnormalities. The introduction of investigational drugs targeting the dysfunctional TP53 pathway is therefore highly warranted.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

The contribution of all the patients and physicians in the various trials of the German Study Alliance Leukaemia (SAL) is highly appreciated.

Authors' contributions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References

BM, JS, JMM, GE, MB, MS, and FS performed the research. BM, JS, JMM, MS, and FS designed the research study. BM performed cytogenetic analyses. JS, KSE, NS, MH, WR, NF, HL, AN, US, UP, JMM, GE, MB, MS, and FS treated patients and included patient data. BM, JS, MB, MS, and FS analysed the data. BM, JS, MB, MS, and FS wrote the manuscript. All authors approved the final version of the manuscript.

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  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors' contributions
  8. Conflict of interest
  9. References
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