Introduction: The ELN classification of cytogenetic aberrations in acute myeloid leukemia (AML) distinguishes favorable risk, intermediate risk I and II and adverserisk. The adverse-risk group ...contains patients (pts) with inv(3) and t(3;3). These pts have a significantly poorer outcome compared to other cytogenetic aberrations. The MRC classification considers both pts with inv(3) and t(3;3) as well as patients with other abn(3q) as adverse risk, but excludes t(3;5). Pts with inv(3) or t(3;3) have breakpoints located on the long arm of chromosome 3 at q21 and q26. As a result of these chromosomal modifications, an enhancer-protein is deregulated and the stem-cell regulator zinc finger protein EVI1 on 3q26 is over expressed. Other 3q aberrations do not involve EVI1. We conducted a comparative analysis on the impact of abn(3q) with likely EVI1 alteration versus abn(3q) without EVI1 involvement. Analyses were done both in the entire group of abn(3q) pts and in the subgroup of pts treated with allogeneic hematopoietic stem-cell transplantation (HSCT).
Methods: We performed a retrospective analysis on 163 patients with an abnormality on the q arm of chromosome 3 (abn(3q)). These pts were treated between 1996 and 2009 in three multicenter studies by the German SAL study group (AML2003, AML96, AML60+). Pts with t(3;5) were excluded (n=11). The remaining 152 patients were divided into two groups. Group 1 (EVI1) contained 56 patients with a chromosomal aberration likely to alter EVI1, i.e. t(3;3), inv(3) and abn(3)(q26). Group 2 (noEVI1) comprised the remaining 96 patients displaying other abn(3q) aberrations. We compared groups for baseline characteristics, complete remission (CR), relapse-free survival (RFS) and overall survival (OS) in total and stratified for treatment.
Results: Descriptive comparison of the groups (EVI1 vs noEVI1) revealed a significantly higher WBC count (14.3 vs 4.6 Gpt/l), PLT count (62 vs 47 Gpt/l) and -7 incidence (29% vs 16%) in the EVI1 group, whereas in the noEVI1 group, complex aberrations (25% vs 74%) and 17p alterations (0% vs 24%) occurred in a higher proportion of pts. CR rates (52% vs 47%), median RFS (7 vs 6 months) and median OS (6 vs 7 months) did not differ significantly between the two groups. In order to explore the clinical behavior of the different abn(3q) aberrations in relation to allogeneic HSCT, we compared EVI1 pts (n=21) versus noEVI1 pts (n=38) who received an allogeneic HSCT at any time during treatment. Patients with aberrant EVI1 were significantly younger (median age 44 vs 52 years), had a higher incidence of -7 (29% vs 13%), but less frequent karyotype complexity (10% vs 74%) or 17p alterations (0% vs 24%). More patients in the EVI1 group achieved a first CR before HSCT (95% vs 84%). Amongst CR pts, median RFS was slightly higher in the EVI1group (9 vs 6 months). In all abn(3q) pts with allogeneic HSCT, median OS was 30 months in the EVI1 group and only 12.5 months in the noEVI1 group. According to the log-rank test, this difference did not reach statistical significance (p=0.137). The advantage in mean OS for EVI1 patients is most likely due to the higher proportion of patients transplanted in CR while the accumulation of complex karyotypes in the noEVI1 group caused more primary resistant AML cases with a rapid progression even after allogeneic HSCT.
Conclusions: Although AML development may be based on different molecularbiological mechanisms in patients with different abn(3q) aberrations depending on EVI1 alteration, the prognosis of the two groups is very similar. The most likely reason is the equal balance of favorable and adverse prognostic factors between the two groups such as age, karyotype complexity, 17p alteration and -7. Patients of both groups benefit from allogeneic HSCT to a similar extent. Confirmation of these results on larger data sets is desirable and under way.
Baldus:Novartis: Research Funding. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership.
Summary
Treatment success in patients with acute myeloid leukaemia (
AML
) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize ...treatment. Here, we studied the impact of
TP
53
mutations on the outcome of
AML
patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (
HSCT
). Samples of 97 patients with
AML
and adverse‐risk cytogenetics who had received a
HSCT
within three randomized trials were analysed. Complete sequencing of the
TP
53
coding region was performed using next generation sequencing. The median age was 51 years. Overall,
TP
53
mutations were found in 40 patients (41%). With a median follow up of 67 months, the three‐year probabilities of overall survival (
OS
) and event‐free survival for patients with
TP
53
wild type were 33% 95% confidence interval (
CI
), 21% to 45% and 24% (95%
CI
, 13% to 35%) compared to 10% (95%
CI
, 0% to 19%) and 8% (95%
CI
, 0% to 16%) (
P
=
0·002 and
P
=
0·007) for those with mutated
TP
53,
respectively. In multivariate analysis, the
TP
53
‐mutation status had a negative impact on
OS
(Hazard Ratio = 1·7;
P
=
0·066). Mutational analysis of
TP
53
might be an important additional tool to predict outcome after
HSCT
in patients with adverse karyotype
AML
.
Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL ...treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany have been uncertain given the fact that ATO is not formally licensed for front-line therapy of APL.
Aim:In order to provide evidence and a reflection of the clinical reality of APL patient care in Germany an intergroup APL registry (National acute promyelocytic leukemia (APL) observational study, NAPOLEON) was recently initiated by several AML study groups.
Methods:Eligible patients are adults at least 18 years of age with newly diagnosed or relapsed APL not beyond the first year of diagnosis. Here we report the first analysis on the series of patients prospectively enrolled into this registry. The study was conducted in accordance with the Declaration of Helsinki, received IRB approval by all participating centers and was registered at ClinicalTrials.gov (NCT02192619).
Results: As of August 1st 2016, 88 patients have been included into the study with a median age of 57 years (range 22-87). All had newly diagnosed APL (100%) with 66% (n=58) being of low/intermediate risk according to the Sanz score. Out of those patients 76% (n=44) received an ATO-ATRA based induction regimen followed by a median of 4 courses of consolidation (according to the APL 0406 study).Of 41 patients evaluable for response to induction, 40/41 (98%) patients achieved complete remission (CR) with the ATRA-ATO arms. Early death rate within 30 days of therapy was 2% (1/44). After a median follow-up of 12 months, the event-free survival, cumulative incidence of relapse and overall survival at 12 months for these patients were 97%, 0% and 97%, respectively. Therapy was well tolerated and no new safety signals have been obtained.
Conclusion:These real life data from a prospective German registry provide further evidence for the safety and sustained anti-leukemic efficacy of ATRA-ATO in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting.
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Platzbecker:TEVA: Honoraria, Research Funding. Greiner:BMS: Research Funding. Thiede:AgenDix: Employment, Other: Ownership. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.
Prophylactic platelet transfusion Wandt, Hannes; Schäfer-Eckart, Kerstin; Ehninger, Gerhard
The New England journal of medicine,
08/2013, Letnik:
369, Številka:
6
Journal Article
The treatment success in patients (pts) with acute myeloid leukemia (AML) is very heterogeneous. Cytogenetic and molecular alterations present at diagnosis are strong prognostic factors, which have ...been used to individualize treatment. As shown by several groups, the subgroup of pts with deletion of the short arm of chromosome 17 are at high risk for treatment failure (e.g. Seifert, Leukemia 2009), which persists even after allogeneic hematopoietic stem cell transplantation (HSCT) (Middeke, Blood 2012; Mohr, Br J Haematol 2013). Besides allelic loss of TP53 located on the short arm of chromosome 17, other mechanisms of inactivation have been shown for this key tumor suppressor gene, most importantly missense point mutations or small deletions. These alterations have also been linked to poor outcome in AML after chemotherapy (Grossmann, Blood 2012). Here, we studied the impact of TP53 mutations on the outcome of AML pts with adverse cytogenetic risk treated with HSCT.
We selected AML pts with complex karyotype (CK), monosomy 7, monosomy 5/del5q and/or abnl(17p) who had received HSCT within 3 randomized controlled trials (NCT numbers 00180115, 00180102, and 00180167). All pts were treated with intensive induction chemotherapy and HSCT according to a risk adapted strategy.
Complete sequencing of the TP53coding region was done using next generation sequencing (NGS) on a 454 GS Junior instrument (Roche) using the IRONII-study amplicon panel. Amplicons were generated from genomic DNA isolated at the time of diagnosis. Data analysis was done using the Sequence Pilot software package (JSI Medical Systems), a 10% cut-off was used for mutation calling.
Nonsynonymous mutations were classified into bi-allelic TP53 mutations if detected allelic frequency as determined by NGS was >50% and mono-allelic TP53 mutations for frequencies between 10% and 50%. All samples with synonymous mutations or no detectable mutations according to the predefined cut-off of 10% were classified as TP53wild type (wt).
Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT were analyzed according to the mutational status.
Samples from 97 pts with AML were analysed, the median age was 51 years (range 18 to 67), 83% suffered from de novo AML, while 13% had sAML and 3% therapy-related myeloid neoplasms. CK and monosomal karyotype (MK) were present in 61% and 42% of the pts, respectively. Twenty-nine pts (30%) had abnl(17p) detected by conventional karyotyping or FISH analysis. Twenty-six pts (27%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts received reduced intensity conditioning (RIC). Donors were siblings in 36 pts (37%) and matched or mismatched unrelated donors in all other pts.
Overall, TP53 mutations were found in 40 pts (41%). Twenty-eight (29%) pts had a bi-allelic TP53 mutation while 12 (12%) pts had a mono-allelic TP53 mutation. We identified 15 pts with TP53 mutations without abnl(17p). Four pts with abnl(17p) had wt TP53. Pts with TP53 mutations were significantly older than pts with wt TP53 AML (median age 55 vs. 43, p=.004). Donor type, type of conditioning and the rate of transplantation in first complete remission were not statistically different among pts with or without TP53mutations.
With a median follow up of 67 months the three-year probabilities of OS and EFS for pts with wt TP53 were 33% (95% CI, 21% to 45%) and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (p=.002 and p=.007) for those with mutated TP53, respectively. CIR at three years was 42% for pts with wt TP53 and 60% for those with mutated TP53 (p=.05). NRM was not different in both groups. In multivariate analysis including age, donor type (sibling vs. all other), type of conditioning (RIC vs. MAC) and disease status (CR1 vs. advanced disease) only the TP53-mutation status had a significant influence on EFS (HR=1.72; p=.03). In our analysis, classification according to MK did not significantly influence OS, EFS, CIR or NRM.
In this cohort of pts with cytogenetic adverse risk abnormalities, who had received HSCT, TP53 mutations were present in 41% of the pts. OS and EFS were significantly worse in pts with mutated TP53. Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in pts with adverse karyotype AML.
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No relevant conflicts of interest to declare.
Patients with acute myeloid leukemia (AML) and abnormalities (abnl) of the short arm of chromosome 17 (17p) are considered to be at high risk of treatment failure after conventional chemotherapy. ...Small studies have suggested that this abnormality may portend a poor prognosis even after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to assess the prognostic role of abnl(17p) in a larger cohort of patients with AML undergoing allogeneic HSCT, and to analyse the impact of disease status, conditioning regimen, and type of abnormality. Here, we present data on the outcome of 201 patients with abnl(17p) AML transplanted since 2000.
We performed a retrospective cohort analysis based on study-registries from two AML groups, HOVON and SAL, and transplant-registries of the Fred Hutchinson Cancer Research Center (FHCRC) and the German Cooperative Transplant Study Group (GCTSG). Inclusion criteria were AML diagnosed according to the current WHO criteria with 17p abnormalities and a first HSCT between January, 1, 2000 and January, 1, 2011. Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT are reported for the whole cohortand for patients receiving HSCT in first complete remission (CR1). We tested for center effects (FHCRC, HOVON, SAL, GCTSG) in a multivariate Cox regression model.
Data from 201 patients with full information on the karyotype were analysed. The median age was 54 years with a range from 2 years to 75 years. Five patients were younger than 18 years. Sixty-one percent of the patients suffered from de novo AML, while 26% had secondary AML and 11% therapy-related myeloid neoplasm. Complex and monosomal karyotypes were present in 90% and 77% of patients, respectively. Eighty-four patients (42%) were in CR1 at the time of HSCT. Seventy patients (35%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining patients received reduced intensity conditioning (RIC). Donors were matched siblings in 34%, matched unrelated donors in 43% and partially matched or mismatched unrelated donors in 18% of the patients. Eight patients (4%) had a haploidentical donor.
At the time of analysis 30 patients were alive with a median follow-up of 30 months (range 1 to 121 months). At three years, the probabilities of OS and EFS were 15% (95% CI, 10% to 20%) and 12% (95% CI, 7% to 16%), respectively, whereas the CIR was 49%. For patients transplanted in CR1 the probability of OS at three years was 22% (95% CI, 13% to 32%) compared to 9% (95% CI, 3% to 15%) for those with advanced disease (p=<.001). The main cause of treatment failure was relapse. The CIR at three years was 57% in patients who were transplanted in CR1 compared to 42% in patients with more advanced disease (p=.0912). Notably, 70% of the observed relapses occurred within the first six months after HSCT. NRM was also high within the first six months, mainly among patients with advanced disease (40% NRM in advanced stages compared to 14% in CR1; p=<.001). In multivariate analysis only age (HR=1.02; p=.01) and disease status (HR=0.52; p=.007) had a significant influence on OS. No significant differences in outcomes were observed between the different types of abnormalities regarding OS, EFS, CIR and NRM, but patients with a monosomal karyotype had worse outcome compared to patients with a non-MK karyotype (3-year OS 11% versus 29%, p=.003).
The incidence of grade II to IV acute GvHD up to day 100 was 32% while grade III to IV occurred in 11% of the patients. Due to the high frequency of competing events (death or relapse before onset of GvHD) the cumulative incidence for chronic GvHD at one year was very low with 8%.
Patients with abnl(17p) AML have a poor outcome after HSCT. The observation of better outcome in patients with less advanced disease stages and without MK argues against primary resistance to allogeneic immune effects of 17p abnormalities. While transplantation in CR1 may still be considered the treatment of choice due to the lack of more promising alternatives, novel strategies to prevent relapse are highly warranted for this group of patients. For patients with abnl(17p) AML in more advanced stages experimental approaches should be considered.
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No relevant conflicts of interest to declare.
Background:
Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of acute myeloid leukemia (AML). In-vitro data and results ...from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. We present the results of the randomized placebo-controlled SORAML trial testing sorafenib versus placebo as add-on to standard induction and consolidation treatment in AML patients ≤60 years.
Patients and Methods:
Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1-3 plus mitoxantrone 10 mg/m2 days 3-5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a sibling donor and for all high-risk patients with a matched related or unrelated donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial was event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were relapse-free survival (RFS), overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the final analysis of the primary endpoint EFS (intent to treat) after the occurrence of 134 events.
Results:
Out of 276 enrolled patients, 267 received study treatment, 134 in the sorafenib arm and 133 in the placebo arm. Demographic and disease characteristics were equally distributed between the two arms; the incidence of FLT3-ITD was 17%. The median cumulative dose of administered study medication was similar in both arms. The CR rates were 59% versus 60% in the placebo versus sorafenib arm (p=0.764). After a median observation time of 36 months, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm, corresponding to a 3-year EFS of 22% versus 40% (p=0.013). Median RFS after standard treatment plus placebo was 23 months and not yet reached after sorafenib treatment, corresponding to a 3-year RFS of 38% and 56%, respectively (p=0.017). The median OS had not been reached in either arm; the 3-year OS was 56% with placebo versus 63% with sorafenib (p=0.382). In 46 FLT3-ITD positive patients, no difference in EFS, but a trend for prolonged RFS and OS in favor of sorafenib was observed. The most common reported AEs Grade ≥3 were fever (40%), infections (22%) and bleeding events (2%). The risk for fever, bleeding events and hand-foot syndrome was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences.
Conclusions:
In younger AML patients, the addition of sorafenib to standard chemotherapy in a sequential manner is feasible and associated with antileukemic efficacy. We observed a higher incidence of infections and bleeding events under sorafenib. Whereas OS in both treatment arms was similar, sorafenib treatment resulted in a significantly prolonged EFS and RFS.
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Off Label Use: sorafenib for treatment of aml. Serve:Bayer HealthCare: Research Funding. Ehninger:Bayer HealthCare: Research Funding.
Background: In relapsed or refractory acute myeloid leukemia (AML), long-term disease-free survival may only be achieved with allogeneic hematopoietic stem cell transplantation (HSCT). Within the ...BRIDGE Trial, the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT was studied. Here, we report long-term survival data and the impact of donor availability at the time of study enrollment. The BRIDGE trial (NCT 01295307) was a phase II, multicenter, intent-to-transplant study.
Patients and Methods: Between March 2011 and May 2013, 84 patients with relapsed or refractory AML older than 40 years were enrolled. Patients were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1-5). Patients with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 on day -2. In patients with partially matched unrelated donors, ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil.
Results: Forty-four patients suffered from relapsed AML and 40 patients had refractory disease. The median patient age was 61 years (range 40 – 75). According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as intermediate I, 17% as intermediate II and 20% as adverse risk.
The overall response rate assessed at day 15 after start of CLARA was 80% (defined as at least a marked reduction in BM blasts or BM cellularity and absence of blasts in the peripheral blood) with 31% of patients having less than 5% BM blasts at that time. Seventeen patients did not respond to CLARA, and were subsequently treated off-study. Due to early death, three patients were not evaluable for treatment response. Overall, 66% of the patients received HSCT within the trial. Donors were HLA-identical siblings in eight cases (14%), HLA-compatible unrelated donors in 30 cases (55%) and unrelated donors with one mismatch in 17 cases (31%). Treatment success was defined as complete remission (CR), CR with incomplete recovery (CRi) or CRchim (BM donor chimerism >95% and absolute neutrophil count >0.5/nL) on day 35 after HSCT. Treatment success was achieved in 61% of the patients. With a median follow up of 25 months, the OS for all enrolled patients at two years was 42% (95% CI, 32% to 54%). (Figure 1) The Leukemia-free survival at two years for those 51 patients who achieved the primary endpoint was 52% (95% CI, 40% to 69%). (Figure 2)
At the time of enrollment, 14% of patients had a related donor and 33% had an unrelated donor available. In 46% of the patients, donor search was initiated at the time of enrollment. For 7% of patients, donor search was unsuccessful prior to enrollment and reinitiated. The OS at 2 years for patients with a related or an unrelated donor available was 75% (95% CI, 54% to 100%) and 47% (95% CI, 31% to 71%), respectively, while it was 29% (95% CI, 18% to 48%) for patients for whom donor search was initiated at time of enrollment (p = .09).
Conclusions:
Salvage therapy with CLARA, and subsequent conditioning with clofarabine and melphalan prior to allogeneic HSCT, provides good anti-leukemic activity in patients with relapsed or refractory AML. Fast unrelated donor search and work up, with conditioning in aplasia allowed a high rate of successful HSCTs. The leukemia-free survival for this group of elderly, high risk AML patients is very promising.
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Middeke:Genzyme: Speakers Bureau. Off Label Use: Clofarabine for AML. Schetelig:Genzyme: Research Funding; DKMS German Bone Marrow Donor Center: Employment.
▪
Background Induction triplets with at least one of the “novel drugs” and steroids with or without chemotherapy are deemed standard of care in newly diagnosed multiple myeloma (MM). Medically fit ...patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while the use of allogeneic (allo) SCT is an ongoing matter of debate. We had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory disease. Based on the overall results we decided to further evaluate the combination in first-line treatment. Methods The current phase II trial was designed to include pts up to 65 years of age with newly diagnosed, symptomatic MM. Four 4-week RAD induction cycles (lenalidomide 25 mg/day, d 1-21; infusional adriamycin 9 mg/m², d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) were followed by stem cell chemomobilization. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel) or auto followed by allo SCT. Allo SCT (conditioning regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Target dose for subsequent lenalidomide maintenance (R-maint; for one year) was 10 mg/d for tandem Mel and 5mg/d for auto/allo pts. Primary endpoint was response (at least VGPR) following second SCT. Results 190 pts with a median age of 55 (range, 30-66) years were recruited by 17 German centers between 8/2009 and 4/2012. 103 pts (56%) had ISS stage II/III disease and 165 pts are evaluable for molecular cytogenetic abnormalities assessed by fluorescence in situ hybridisation (FISH). Incidences were as follows: 29.6% had deletion of (del) chromosome 13q, 11.5% showed translocation (t) (4;14), 9% presented with del 17p, and 0.6% had a t(14;16). 163 pts completed all 4 RAD cycles and 47 underwent allogeneic SCT. 60 pts following tandem Mel and 15 pts after auto-allo SCT proceeded to R-maint. Median number of maintenance cycles was significantly higher in tandem Mel compared with auto-allo pts (12 versus 3; p=.01). Rate of at least (≥) VGPR increased from 47.9% following RAD induction to 60.6% following double SCT. Accordingly, post-induction complete response (CR)/stringent CR rate of 7.9% increased to 31%. In pts with FISH results, ≥ VGPR rate was 44% with t(4;14)/t(14;16)/del 17p versus 53% without those abnormalities, respectively (p=.34). Following double SCT, ≥ VGPR was increased to 63% t(4;14)/t(14;16)/del 17 pts. versus 65%, respectively (p=.84). Response was not different with either transplant strategy. No treatment-related mortality occurred during RAD induction, while non-relapse mortality at one year from allo SCT was 10.6%. Incidences of pneumonia, venous thromboembolism, and febrile neutropenia were 11, 7.2, and 5.3%, respectively. Preliminary overall survival results will be presented. Conclusions Our data show RAD induction to be very effective in newly diagnosed MM and to be well tolerated. By subsequent double SCT, a high number of CR/sCR was added. Correlative studies suggests response to be independent of known unfavourable cytogenetic prognosticators, such as t(4;14) and del 17p while time-to-event data will be needed to ultimately confirm a lenalidomide-based triple regimen being able to overcome adverse cytogenetic risk. Administration of R-maint to auto-allo pts was challenging despite a lenalidomide target dose of 5 mg/day.
Knop:Celgene GmbH: Consultancy, Honoraria. Off Label Use: Use of lenalidomide, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma. Einsele:Celgene GmbH: Consultancy, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria, Other.
In relapsed or refractory acute myeloid leukemia (AML) long-term disease-free survival may only be achieved with allogeneic stem cell transplantation (HSCT). However, only about 40% of patients (pts) ...with relapsed AML receive HSCT. A number of factors contribute to this low rate, among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy. Clofarabine is considered to have a favorable risk-benefit ratio in this indication and has been successfully used in conditioning regimens. Our goal was to study the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT. Here, we report the results of the BRIDGE trial (NCT 01295307), a phase II, multicenter, intent-to-transplant study.
Between March 2011 and May 2013, 84 pts with relapsed or refractory AML older than 40 years were enrolled. Pts were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2 days 1-5). Pts with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2 day -6 to -3 and melphalan 140 mg/m2 on day -2. In pts with partially matched unrelated donors ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil.
Median age was 61 years (range 40 – 75). Forty-four pts suffered from relapsed AML and 40 pts had refractory disease. According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as interm. I, 17% as interm. II and 20% as adverse risk. Complex and monosomal karyotypes were present in only 12% and 10% of pts, respectively. FLT3, NPM1 and CEPBA mutations were found in 16%, 24%, and 4% of the pts. The mean value of the HCT-CI score was 1.6 (range 0 - 7) at the time of study enrollment and 2.3 (range 0 - 7) at the time of conditioning.
The overall response rate assessed at day 15 after start of CLARA was 80% (46% good response defined as less than 10% blast in the bone marrow (BM) and 33% moderate response with at least a marked reduction in BM blasts or BM cellularity and absence of blast in the peripheral blood). Seventeen pts did not respond to CLARA and were subsequently treated off study. Due to early death, three pts were not evaluable for treatment response. Overall, 66% of the pts received HSCT within the trial. Donors were HLA-identical siblings in eight pts (14%), HLA-compatible unrelated donors in 30 pts (55%) and unrelated donors with one mismatch in 17 pts (31%). Treatment success defined as complete remission, CR with incomplete recovery or >95% BM donor chimerism and an absolute neutrophil count >0.5 /nL on day 35 after HSCT was achieved in 62% of the pts. Disease-free survival (DFS) is shown in Figure 1. With a median follow up of 16 months the OS for all enrolled patients at one year is 51% (95% CI, 39% to 63%).
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At the time of enrollment, 14% had a related donor and 33% had an unrelated donor. In 46% of the pts donor search was initiated at the time of enrollment. For 7% of pts donor search was not successful. Time from study entry to HSCT was remarkably low with a median of 33 days (range 19 – 116 days). Of note, time interval did not differ between related and unrelated donors (Figure 2).
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Day 30 and day 100 mortality, which covered salvage therapy and HSCT, was 9% and 27%, respectively. Six out of seven pts who died within the first 30 days hat refractory AML and thus entered the trial already with a history of long-lasting neutropenia. Liver toxicity was the most frequent adverse event. Fifty percent of the pts had transiently elevated liver enzymes CTCAE grade III considered to be related to clofarabine. Twenty-one patients developed CTCAE grade III – IV sepsis throughout the study treatment. GvHD grade II – IV and III-IV until day 100 after HSCT occurred in 36% and 21% of the pts, respectively.
This intent-to transplant study allows for a realistic estimate for the outcome of elderly pts with relapsed or refractory AML. We demonstrate a high rate of leukemia-control by CLARA. Fast unrelated donor search and work up and conditioning with clofarabine and melphalan in aplasia allowed for a high rate of successful HSCTs. While the long-term results require longer follow-up the overall results are promising.
Middeke:Genzyme: Speakers Bureau. Schetelig:Genzyme: Research Funding. Off Label Use: Clofarabine, not approved for AML.
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