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Long-term survival of sorafenib-treated FLT3-ITD–positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation
European Journal of Cancer 86 (2017) 233e239
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Long-term survival of sorafenib-treated FLT3ITDepositive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation* S.K. Metzelder a, T. Schroeder b, M. Lu¨bbert c, M. Ditschkowski d, K. Go¨tze e, S. Scholl f, R.G. Meyer g, P. Dreger h, N. Basara i, M.F. Fey j, H.R. Salih k, A. Finck c, T. Pabst j, A. Giagounidis l, G. Kobbe b, E. Wollmer a, J. Finke c, A. Neubauer a, A. Burchert a,* a Philipps Universita¨t Marburg, Universita¨tsklinikum Gießen und Marburg, Standort Marburg, Klinik fu¨r Ha¨matologie, Onkologie und Immunologie, Marburg, Germany b University of Duesseldorf, Medical Faculty, Department of Hematology, Oncology and Clinical Immunology, Duesseldorf, Germany c University of Freiburg, Department of Hematology/Oncology, Freiburg, Germany d Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Germany e Department of Internal Medicine III, Technische Universita¨t Mu¨nchen, Munich, Germany f Abteilung Ha¨matologie/Onkologie, Universita¨tsklinikum Jena, Jena, Germany g St.-Johannes-Hospital Dortmund, Klinik fu¨r Innere Medizin II, Dortmund, Germany h Department of Medicine, University of Heidelberg, Heidelberg, Germany i Malteser Krankenhaus St. Franziskus-Hospital, Medizinische Klinik I, Flensburg, Germany j Department of Medical Oncology, Inselspital and University of Bern, Bern, Switzerland k Department of Hematology/Oncology, Eberhard Karls-University, Tuebingen, Germany l Marien Hospital Du¨sseldorf, Klinik fu¨r Onkologie, Ha¨matologie und Palliativmedizin, Du¨sseldorf, Germany
Received 25 June 2017; received in revised form 3 September 2017; accepted 8 September 2017
KEYWORDS Acute myeloid leukemia; FLT3-ITD; Hematopoietic stem
Abstract Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) epositive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available.
*
Presented in part at the annual meeting of the Deutsche Gesellschaft fu¨r Ha¨matologie und Medizinische Onkologie, Leipzig 2016. * Corresponding author: Universita¨tsklinikum Gießen und Marburg, Standort Marburg, Klinik fu¨r Ha¨matologie, Onkologie und Immunologie, Philipps Universita¨t Marburg, Baldingerstr., D-35043 Marburg, Germany. Fax: þ49 6421 5865613. E-mail address: [email protected] (A. Burchert). https://doi.org/10.1016/j.ejca.2017.09.016 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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cell transplantation; Sorafenib
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Methods: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITDepositive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. Findings: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. Interpretation: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD epositive AML relapsing after allo-SCT. ª 2017 Elsevier Ltd. All rights reserved.
Research in context Evidence before this study In relapsed Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)epositive acute myeloid leukaemia patients, clinical responses to tyrosine kinase inhibitor (TKIs) treatment were reported in early-phase clinical trials. Based on the available evidence, singleagent TKI treatment does not induce long-term responses. Previous studies suggested a synergism between targeted FLT3-ITD inhibition and graft versus leukaemia effect. Added value of this study We report a paradigm changing observation. We noticed a curative potential of sorafenib monotherapy in FLT3ITDepositive AML patients relapsing after allogeneic stem cell transplantation. Achievement of molecular negativity for FLT3-ITD mRNA by PCR (complete molecular remission) is associated with long-term survival and treatment-free remission. Implications of all the available evidence Sorafenib is a valuable treatment approach in FLT3ITDepositive AML patients relapsing after allogeneic stem cell transplantation. However, the underlying mechanism need to be further investigated.
1. Introduction The fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukaemia (AML) [1]. Internal tandem duplication mutations in the FLT3 gene (FLT3-ITD) cause aberrant activation of the FLT3 receptor and of several downstream signalling pathways [2]. The presence of FLT3-ITD is associated with a dismal prognosis [3], making this kinase a rational target for therapeutic intervention. Several FLT3-ITDespecific tyrosine kinase inhibitors (TKIs)
are under investigation, of which midostaurin and sorafenib are the most studied compounds so far. Midostaurin is a relatively weak FLT3 inhibitor with low potency in the treatment of FLT3-ITDepositive AML when used as a single agent [4e6]. When combined with chemotherapy, midostaurin improves overall survival in newly diagnosed FLT3-mutated AML [7] resulting in its approval by the U.S. Food and Drug Administration for this indication. Sorafenib is a multikinase inhibitor, which blocks the B-Raf, PDGF, and VEGF receptor, but also FLT3 [8]. In AML patients younger than 61 years, the addition of sorafenib to chemotherapy resulted in an event-free survival benefit irrespective of the FLT3 mutational status [9]. Allogeneic stem cell transplantation (allo-SCT) might improve outcome of FLT3-ITDepositive AML by reducing the risk of relapse [10e12]. Therapeutic options for patients experiencing relapse after allo-SCT are limited. Treatment options comprise best supportive care, chemotherapy, second allo-SCT [13], or experimental treatments such as with FLT3-ITD inhibitors. These include sorafenib, quizartinib, or gilteritinib [14e17]. However, based on the available evidence, use of singleagent TKI in relapsed AML is palliative [18,19]. We have previously noted a synergism between targeted FLT3-ITD inhibition and graft versus leukaemia effect [20]. This hypothesis was strengthened by the results of an observational study of 65 sorafenib-treated relapsed, refractory, or frail FLT3-ITDepositive AML patients. In this study, prolonged remissions were only seen in patients relapsing after a prior allo-SCT [21]. After a median follow-up of more than 7 years, we here show long-term survival of these FLT3-ITDepositive AML patients relapsing after allo-SCT.
2. Methods 2.1. Patients and treatment The objective of this observational study was to assess the long-term outcome of sorafenib monotherapy in
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FLT3-ITDepositive AML patients relapsing after alloSCT. Using routine clinical practice data, we initially performed a retrospective survey in 2011 to assess the time to treatment failure of a “compassionate use” sorafenib monotherapy in relapsed, refractory, or frail FLT3-ITDepositive AML patients who were ineligible for any alternative treatments. A questionnaire was developed and approved by the local ethics committee of the Philipps University Marburg. Patient information was anonymously documented. In total, 23 centres reported 65 patients who started treatment between February 2007 and September 2011. Thirty-six of these patients had not undergone allo-SCT. All became refractory to sorafenib and relapsed [21]. The remaining 29 patients were treated with sorafenib at relapse after allo-SCT. Of them, some experienced a durable remission (Supplementary Fig. S1) [21]. Therefore, here, we only report on the clinical follow-up of these 29 patientsdtheir further treatment, response, potential
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development of resistance, and survival. Detailed patient characteristics are summarised in Table 1. 2.2. Definitions Treatment response was evaluated as previously described [21,22]. In brief, complete remission (CR) was defined as bone marrow blasts <5%, neutrophils >1 G/l, platelets >100 G/l; complete molecular response (CMR): no evidence of disease and molecular negativity for FLT3-ITD mRNA by PCR; CR with incomplete peripheral blood count recovery (CRi); bone marrow response: bone marrow blast reduction by >50% without haematologic recovery; haematologic response: disappearance of peripheral blasts; partial response: peripheral blast reduction by >50%. Patients who were not transplanted in first CR or second CR were either refractory to a minimum of two chemotherapy cycles or were transplanted in relapse. Overall survival was
Table 1 Patient characteristics. Characteristic
Total (n Z 29)
Fatal outcome (n Z 23)
Long-term survivors (n Z 6)
No.
%
No.
%
No.
%
Female Male Age Median (years) Range (years) Pretreatment >3 cycles of therapyb Median Range Disease status before allo CR1/CR2 pr/R Conditioning MA RIC Graft MRD MUD MMUD dUCB Time to relapse after allo-SCT Median (d) Range (d) <6 Months Best response Primary resistance PR HR BMR CRi CR CMR
21 8
72 28
17 6
74 26
4 2
67 33
45 14e70 16 4 3e9
55
46 14e70 14 4 3e9
61
42 32e56 3 3.5 3e4
50
p Z 0$67
14 15
48 52
11 12
48 52
3 3
50 50
pZ1
11 18
38 62
7 16
30 70
4 2
67 33
p Z 0$16
13 8 7 1
45 28 24 3
9 6 7 1
39 26 30 4
4 2
67 33
p Z 0$49
105 27e726 21
72
98 33e726 17
74
1 3 8 2 5 1 9
3 10 28 7 17 3 31
1 3 8 2 4 1 4
4 13 35 9 17 4 17
Statistical significance pZ1 p Z 0$08
p Z 0$5
135 27e723 4
67
1
17a
5
83
pZ1
p Z 0$006
CR1/CR2, first or second complete remission; pr/R, primary refractory or relapse; MA, myeloablative; RIC, reduced intensity conditioning; MRD, matched related donor; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; dUCB, double umbilical cord blood; allo-SCT, allogeneic stem cell transplantation; PR, partial response; HR, haematologic response; BMR, bone marrow response; CRi, complete response with incomplete peripheral blood count recovery; CR, complete response; CMR, complete molecular response. a Patient underwent a second allo-SCT. b Each cycle of induction, consolidation, relapse, and conditioning therapy is considered as one chemotherapy cycle.
S.K. Metzelder et al. / European Journal of Cancer 86 (2017) 233e239
measured from the time of sorafenib start until death or date of last contact. Treatment-free remission (TFR) was defined as the time between cessation in CMR and restart of sorafenib. Patients were censored at date of last contact. Median follow-up was defined for survivors only as the median time from sorafenib start to the date of last contact. Myeloablative and reduced intensity conditioning were defined as published previously [23]. High leukaemic burden was defined as 35% bone marrow blasts or 35% peripheral blood blasts with an absolute blast count of >5 G/l before sorafenib start [24]. Less than 35% bone marrow blasts or <10% peripheral blood blasts with an absolute blast count of <0.2 G/l was regarded as lower leukaemic burden. 2.3. Statistics Statistical analysis was performed using GraphPad Prism Software version 5.0b (La Jolla, CA, USA). Overall survival was estimated using KaplaneMeier curves. Statistical differences between the curves were calculated using the two-tailed log-rank (ManteleCox) test. For categorical and continuous variables, the Fisher’s exact test and the ManneWhitney U test were used, respectively. A p-value < 0$05 was considered as statistically significant.
(n Z 14, 48%), infection (n Z 3, 10%), graft versus host disease (GvHD) (n Z 2, 7%), bleeding (n Z 1, 3%), others (n Z 3, 10%) (Supplementary Fig. S1). 3.2. Long-term survival with sorafenib Of the previously reported cohort of 29 patients who were treated with sorafenib in relapse after allo-SCT, six patients (21%) experienced long-term survival after a median follow-up of 7.5 years (Fig. 1A). Of these, one patient underwent a second allo-SCT after developing sorafenib resistance (Supplementary Fig. S1). The other five patients experienced stable remissions under sorafenib and will be described in more detail
A 100
Overall Survival (%)
236
40 20
0
1
2
3
No. at risk 29
9
6
6
4
5
6
6
6
5
6
5 1
5 1
7
8
Years 6
5
1
B 100
Overall Survival (%)
Twenty-nine patients of a previously reported cohort of 65 relapsed/refractory or frail FLT3-ITDepositive AML patients were treated with sorafenib in relapse after allogeneic stem cell transplantation (allo-SCT) [21] and reanalysed for long-term outcome. Their disease status before allo-SCT was primary refractory/relapsed disease (n Z 15 patients, 52%) or first or second CR (n Z 14 patients, 48%) (Table 1). Overall, they had received a median of four cycles of chemotherapy (range, 3e9), considering each cycle of induction, consolidation, relapse, and conditioning therapy as one chemotherapy cycle. Eighteen patients (62%) underwent dose reduced, 11 patients (38%) myeloablative conditioning. Best response after sorafenib was CRi or CR in six patients (21%) and CMR with no detectable FLT3-ITD mRNA by reverse transcriptase PCR in nine patients (31%). Donor lymphocyte infusions (DLIs) were given in five patients prior, in 4 patients during and in 1 patient after sorafenib treatment. Six patients underwent a second allo-SCT, two of them after developing sorafenib resistance. All but 2 of the 29 patients displayed at least one of the following characteristics before sorafenib start: high leukaemic burden, chemotherapy resistance, or early relapse (less than 6 months after allo-SCT). Causes of death were sorafenib-resistant disease progression
60
0
3. Results 3.1. Patient characteristics
80
80 60
CMR
40 p=0,001
20 no CMR
0
0
No. at risk 9 20
1
2
3
7 2
5 1
5 1
4
7
8
Years 5 1
5 0
1 0
Fig. 1. Overall survival and treatment-free remission. Panel A shows the overall survival of all patients (n Z 29) with a median survival of 215 d. Panel B shows the overall survival according to achievement of sorafenib-induced CMR (molecular negativity for FLT3-ITD mRNA by PCR and no evidence of disease). The only long-term surviving patient with no CMR underwent second allogeneic stem cell transplantation. CMR, complete molecular response.
S.K. Metzelder et al. / European Journal of Cancer 86 (2017) 233e239
(Fig. 2). Patients #2, #3, #4, and #5 were previously enrolled onto the CALGB 10603 (RATIFY) (NCT00651261), AMLCG 2000 (NCT00266136), AMLSG 07-04 (NCT00151242), and AML 2003 (NCT00180102) studies, respectively. Patients #1 and #2 were chemotherapy refractory. Patient #1 relapsed on day þ136 after allo-SCT with 28% blasts in bone marrow, and patient #2 relapsed on day þ27 after allo-SCT with 47% blasts in peripheral blood. They received sorafenib and survived for 8.0 and 7.4 years, respectively. Patient #2 was the only patient to receive DLI following remission induction with sorafenib. Patient #3 was transplanted in CR and relapsed with 90% bone marrow blasts on day þ134 after allo-SCT. He was bridged with sorafenib and underwent a second allo-SCT in CRi. Three months later, he suffered from a molecular relapse which persisted during DLI. Another 4 months later, he relapsed with a chloroma. He was retreated with sorafenib, and radiotherapy for local disease control was applied. He achieved a CMR and is alive and free of relapse 7.6 years after sorafenib start. Patient #4 relapsed on day þ723 after allo-SCT with 75% bone marrow blasts. Refractory after one cycle of azacytidine, she was treated with sorafenib. This patient is in sustained CMR for 7 years today. Patient #5 developed a molecular relapse on day þ385, doubling the molecular FLT3-ITD amount in the peripheral blood to 9% within 2 weeks and was given sorafenib. This patient is in CMR for 7.5 years. All five patients had normal cytogenetics, patients #2 and #3 had a NPM1 mutation, and patient #4 had a partial tandem duplication of the MLL gene. Patients #2 and #3 never experienced GvHD, patients #1 and #5 developed GvHD prior to, patient #4 during sorafenib treatment.
237
3.3. Complete molecular response is associated with longterm survival and treatment-free remission Survival was independent from the time of relapse after allo-SCT (Supplementary Fig. S2A), leukaemia mass at relapse (Supplementary Fig. S2B and C), disease status before allo-SCT, or type of conditioning regimen (Table 1). The only predictor of long-term survival was achievement of CMR with sorafenib at any point of time. In detail, five of nine patients (56%) who achieved CMR experienced long-term survival, whereas only 1 of 20 patients (5%) who did not achieve CMR survived (p Z 0$006, Fisher’s exact test; p Z 0$001, log-rank). However, this latter patient underwent second alloSCT (Table 1, Fig. 1B). The median overall survival of CMR patients was not reached and was 169 d (range, 25e2495 d) for patients not in CMR with sorafenib. Four of the five patients who achieved long-term remission discontinued sorafenib after a median of 23 months (range, 18e39) for reasons of dermal and intestinal toxicities, hyperkeratosis, or myocardial infarction in three patients. Patients #3, #4, and #5 discontinued successfully and are currently in TFR for 3.5, 5.2, and 5.4 years, respectively. Patient #1 was only 18 months on sorafenib and relapsed 13 months after TKI discontinuation with a chloroma. Sorafenib reinduced CMR. For local treatment, radiotherapy was added. Sorafenib was discontinued a second time after additional 3.8 years of drug exposure. This patient remains in ongoing TFR (currently 1.5 years).
4. Discussion Here, we showed for the first time that sorafenib monotherapy may be capable to establish a curative
Fig. 2. Schematic illustration of treatment courses in relation to sorafenib. Individual patient numbers are indicated on the left and correspond to patients in the text. A first diagnosis, chemotherapy cycle, allogeneic stem cell transplantation, treatment refractory, relapse, extramedullar relapse (chloroma), molecular relapse, ongoing remission, sorafenib treatment, donor lymphocyte infusion, and radiation singular chloroma.
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synergism with allo-immune effects in an important minority of FLT3-ITDepositive AML patients relapsing after allo-SCT. We previously suggested that the durability of a sorafenib treatment response requires the context of an allo-SCT [21]. This hypothesis is further supported here. Hence, beyond having cytoreductive effects, sorafenib apparently has FLT3-ITDedependent or FLT3ITDeindependent cellular or humoural anti-AML effects requiring allogeneic haematopoiesis. Whether sorafenib stimulates antileukaemic innate or adaptive immunity in humans as suggested in a mouse model [25] remains speculative. Notably, only patients achieving a CMR under sorafenib had a chance to experience also a durable remission with sorafenib monotherapy. This implies that achievement of CMR is an early prognostic biomarker for sustained treatment success. This information can be used when considering alternative treatments. Another important observation of this study was that TKI cessation after successful treatment is feasible. All patients receiving sorafenib for more than 20 months before discontinuation stayed in CMR. In the case of relapse after TKI stop, retreatment was feasible to reinduce CMR and TFR. This was exemplified by the clinical course of patient #1, who relapsed after a sorafenib treatment duration of 18 months, but not after a second stop, following an additional sorafenib exposure of 3.8 years. The major limitation of this study clearly lies in its retrospective nature and the small number of patients that were included. Thus, the evidence level of our findings is low. However, since durable survival and TFR in patients relapsing after allo-SCT is an unprecedented finding for FLT3-ITDepositive AML, it could still be of significant value to guide treatment decisions in the absence of evidence from randomised trials. A randomised trial, the SORMAIN study (EUDRA-CT: 2010-018539-16), and other studies with newer generations of FLT3 inhibitors such as quizartinib, crenolanib, or gilteritinib will provide important new insights into optimal strategies of incorporating sorafenib and these newer compounds in the treatment algorithm of FLT3ITDepositive AML [15,16,26].
Contributors S.K.M. treated patients, performed, designed, and coordinated the research; analysed the data; compiled the figures; and wrote the paper. A.B. treated patients, designed, and coordinated the research; analysed the data; and wrote the paper. A.N. coordinated the research and discussed the data. All coinvestigators treated patients, collected, and provided clinical data. All authors critically reviewed and edited the manuscript.
Conflict of interest statement None declared. Funding Deutsche Forschungsgemeinschaft, Klinische Forschergruppe 210 ‘Genetics of Drug resistance in Cancer’, TP7 to SKM and AB; Deutsche Jose´ Carreras Leuka¨miestiftung (AR12/12) to AB. Role of the funding source The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.ejca.2017.09.016.
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Original Research
Long-term survival of sorafenib-treated FLT3ITDepositive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation* S.K. Metzelder a, T. Schroeder b, M. Lu¨bbert c, M. Ditschkowski d, K. Go¨tze e, S. Scholl f, R.G. Meyer g, P. Dreger h, N. Basara i, M.F. Fey j, H.R. Salih k, A. Finck c, T. Pabst j, A. Giagounidis l, G. Kobbe b, E. Wollmer a, J. Finke c, A. Neubauer a, A. Burchert a,* a Philipps Universita¨t Marburg, Universita¨tsklinikum Gießen und Marburg, Standort Marburg, Klinik fu¨r Ha¨matologie, Onkologie und Immunologie, Marburg, Germany b University of Duesseldorf, Medical Faculty, Department of Hematology, Oncology and Clinical Immunology, Duesseldorf, Germany c University of Freiburg, Department of Hematology/Oncology, Freiburg, Germany d Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Germany e Department of Internal Medicine III, Technische Universita¨t Mu¨nchen, Munich, Germany f Abteilung Ha¨matologie/Onkologie, Universita¨tsklinikum Jena, Jena, Germany g St.-Johannes-Hospital Dortmund, Klinik fu¨r Innere Medizin II, Dortmund, Germany h Department of Medicine, University of Heidelberg, Heidelberg, Germany i Malteser Krankenhaus St. Franziskus-Hospital, Medizinische Klinik I, Flensburg, Germany j Department of Medical Oncology, Inselspital and University of Bern, Bern, Switzerland k Department of Hematology/Oncology, Eberhard Karls-University, Tuebingen, Germany l Marien Hospital Du¨sseldorf, Klinik fu¨r Onkologie, Ha¨matologie und Palliativmedizin, Du¨sseldorf, Germany
Received 25 June 2017; received in revised form 3 September 2017; accepted 8 September 2017
KEYWORDS Acute myeloid leukemia; FLT3-ITD; Hematopoietic stem
Abstract Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) epositive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available.
*
Presented in part at the annual meeting of the Deutsche Gesellschaft fu¨r Ha¨matologie und Medizinische Onkologie, Leipzig 2016. * Corresponding author: Universita¨tsklinikum Gießen und Marburg, Standort Marburg, Klinik fu¨r Ha¨matologie, Onkologie und Immunologie, Philipps Universita¨t Marburg, Baldingerstr., D-35043 Marburg, Germany. Fax: þ49 6421 5865613. E-mail address: [email protected] (A. Burchert). https://doi.org/10.1016/j.ejca.2017.09.016 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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cell transplantation; Sorafenib
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Methods: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITDepositive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. Findings: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. Interpretation: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD epositive AML relapsing after allo-SCT. ª 2017 Elsevier Ltd. All rights reserved.
Research in context Evidence before this study In relapsed Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)epositive acute myeloid leukaemia patients, clinical responses to tyrosine kinase inhibitor (TKIs) treatment were reported in early-phase clinical trials. Based on the available evidence, singleagent TKI treatment does not induce long-term responses. Previous studies suggested a synergism between targeted FLT3-ITD inhibition and graft versus leukaemia effect. Added value of this study We report a paradigm changing observation. We noticed a curative potential of sorafenib monotherapy in FLT3ITDepositive AML patients relapsing after allogeneic stem cell transplantation. Achievement of molecular negativity for FLT3-ITD mRNA by PCR (complete molecular remission) is associated with long-term survival and treatment-free remission. Implications of all the available evidence Sorafenib is a valuable treatment approach in FLT3ITDepositive AML patients relapsing after allogeneic stem cell transplantation. However, the underlying mechanism need to be further investigated.
1. Introduction The fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukaemia (AML) [1]. Internal tandem duplication mutations in the FLT3 gene (FLT3-ITD) cause aberrant activation of the FLT3 receptor and of several downstream signalling pathways [2]. The presence of FLT3-ITD is associated with a dismal prognosis [3], making this kinase a rational target for therapeutic intervention. Several FLT3-ITDespecific tyrosine kinase inhibitors (TKIs)
are under investigation, of which midostaurin and sorafenib are the most studied compounds so far. Midostaurin is a relatively weak FLT3 inhibitor with low potency in the treatment of FLT3-ITDepositive AML when used as a single agent [4e6]. When combined with chemotherapy, midostaurin improves overall survival in newly diagnosed FLT3-mutated AML [7] resulting in its approval by the U.S. Food and Drug Administration for this indication. Sorafenib is a multikinase inhibitor, which blocks the B-Raf, PDGF, and VEGF receptor, but also FLT3 [8]. In AML patients younger than 61 years, the addition of sorafenib to chemotherapy resulted in an event-free survival benefit irrespective of the FLT3 mutational status [9]. Allogeneic stem cell transplantation (allo-SCT) might improve outcome of FLT3-ITDepositive AML by reducing the risk of relapse [10e12]. Therapeutic options for patients experiencing relapse after allo-SCT are limited. Treatment options comprise best supportive care, chemotherapy, second allo-SCT [13], or experimental treatments such as with FLT3-ITD inhibitors. These include sorafenib, quizartinib, or gilteritinib [14e17]. However, based on the available evidence, use of singleagent TKI in relapsed AML is palliative [18,19]. We have previously noted a synergism between targeted FLT3-ITD inhibition and graft versus leukaemia effect [20]. This hypothesis was strengthened by the results of an observational study of 65 sorafenib-treated relapsed, refractory, or frail FLT3-ITDepositive AML patients. In this study, prolonged remissions were only seen in patients relapsing after a prior allo-SCT [21]. After a median follow-up of more than 7 years, we here show long-term survival of these FLT3-ITDepositive AML patients relapsing after allo-SCT.
2. Methods 2.1. Patients and treatment The objective of this observational study was to assess the long-term outcome of sorafenib monotherapy in
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FLT3-ITDepositive AML patients relapsing after alloSCT. Using routine clinical practice data, we initially performed a retrospective survey in 2011 to assess the time to treatment failure of a “compassionate use” sorafenib monotherapy in relapsed, refractory, or frail FLT3-ITDepositive AML patients who were ineligible for any alternative treatments. A questionnaire was developed and approved by the local ethics committee of the Philipps University Marburg. Patient information was anonymously documented. In total, 23 centres reported 65 patients who started treatment between February 2007 and September 2011. Thirty-six of these patients had not undergone allo-SCT. All became refractory to sorafenib and relapsed [21]. The remaining 29 patients were treated with sorafenib at relapse after allo-SCT. Of them, some experienced a durable remission (Supplementary Fig. S1) [21]. Therefore, here, we only report on the clinical follow-up of these 29 patientsdtheir further treatment, response, potential
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development of resistance, and survival. Detailed patient characteristics are summarised in Table 1. 2.2. Definitions Treatment response was evaluated as previously described [21,22]. In brief, complete remission (CR) was defined as bone marrow blasts <5%, neutrophils >1 G/l, platelets >100 G/l; complete molecular response (CMR): no evidence of disease and molecular negativity for FLT3-ITD mRNA by PCR; CR with incomplete peripheral blood count recovery (CRi); bone marrow response: bone marrow blast reduction by >50% without haematologic recovery; haematologic response: disappearance of peripheral blasts; partial response: peripheral blast reduction by >50%. Patients who were not transplanted in first CR or second CR were either refractory to a minimum of two chemotherapy cycles or were transplanted in relapse. Overall survival was
Table 1 Patient characteristics. Characteristic
Total (n Z 29)
Fatal outcome (n Z 23)
Long-term survivors (n Z 6)
No.
%
No.
%
No.
%
Female Male Age Median (years) Range (years) Pretreatment >3 cycles of therapyb Median Range Disease status before allo CR1/CR2 pr/R Conditioning MA RIC Graft MRD MUD MMUD dUCB Time to relapse after allo-SCT Median (d) Range (d) <6 Months Best response Primary resistance PR HR BMR CRi CR CMR
21 8
72 28
17 6
74 26
4 2
67 33
45 14e70 16 4 3e9
55
46 14e70 14 4 3e9
61
42 32e56 3 3.5 3e4
50
p Z 0$67
14 15
48 52
11 12
48 52
3 3
50 50
pZ1
11 18
38 62
7 16
30 70
4 2
67 33
p Z 0$16
13 8 7 1
45 28 24 3
9 6 7 1
39 26 30 4
4 2
67 33
p Z 0$49
105 27e726 21
72
98 33e726 17
74
1 3 8 2 5 1 9
3 10 28 7 17 3 31
1 3 8 2 4 1 4
4 13 35 9 17 4 17
Statistical significance pZ1 p Z 0$08
p Z 0$5
135 27e723 4
67
1
17a
5
83
pZ1
p Z 0$006
CR1/CR2, first or second complete remission; pr/R, primary refractory or relapse; MA, myeloablative; RIC, reduced intensity conditioning; MRD, matched related donor; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; dUCB, double umbilical cord blood; allo-SCT, allogeneic stem cell transplantation; PR, partial response; HR, haematologic response; BMR, bone marrow response; CRi, complete response with incomplete peripheral blood count recovery; CR, complete response; CMR, complete molecular response. a Patient underwent a second allo-SCT. b Each cycle of induction, consolidation, relapse, and conditioning therapy is considered as one chemotherapy cycle.
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measured from the time of sorafenib start until death or date of last contact. Treatment-free remission (TFR) was defined as the time between cessation in CMR and restart of sorafenib. Patients were censored at date of last contact. Median follow-up was defined for survivors only as the median time from sorafenib start to the date of last contact. Myeloablative and reduced intensity conditioning were defined as published previously [23]. High leukaemic burden was defined as 35% bone marrow blasts or 35% peripheral blood blasts with an absolute blast count of >5 G/l before sorafenib start [24]. Less than 35% bone marrow blasts or <10% peripheral blood blasts with an absolute blast count of <0.2 G/l was regarded as lower leukaemic burden. 2.3. Statistics Statistical analysis was performed using GraphPad Prism Software version 5.0b (La Jolla, CA, USA). Overall survival was estimated using KaplaneMeier curves. Statistical differences between the curves were calculated using the two-tailed log-rank (ManteleCox) test. For categorical and continuous variables, the Fisher’s exact test and the ManneWhitney U test were used, respectively. A p-value < 0$05 was considered as statistically significant.
(n Z 14, 48%), infection (n Z 3, 10%), graft versus host disease (GvHD) (n Z 2, 7%), bleeding (n Z 1, 3%), others (n Z 3, 10%) (Supplementary Fig. S1). 3.2. Long-term survival with sorafenib Of the previously reported cohort of 29 patients who were treated with sorafenib in relapse after allo-SCT, six patients (21%) experienced long-term survival after a median follow-up of 7.5 years (Fig. 1A). Of these, one patient underwent a second allo-SCT after developing sorafenib resistance (Supplementary Fig. S1). The other five patients experienced stable remissions under sorafenib and will be described in more detail
A 100
Overall Survival (%)
236
40 20
0
1
2
3
No. at risk 29
9
6
6
4
5
6
6
6
5
6
5 1
5 1
7
8
Years 6
5
1
B 100
Overall Survival (%)
Twenty-nine patients of a previously reported cohort of 65 relapsed/refractory or frail FLT3-ITDepositive AML patients were treated with sorafenib in relapse after allogeneic stem cell transplantation (allo-SCT) [21] and reanalysed for long-term outcome. Their disease status before allo-SCT was primary refractory/relapsed disease (n Z 15 patients, 52%) or first or second CR (n Z 14 patients, 48%) (Table 1). Overall, they had received a median of four cycles of chemotherapy (range, 3e9), considering each cycle of induction, consolidation, relapse, and conditioning therapy as one chemotherapy cycle. Eighteen patients (62%) underwent dose reduced, 11 patients (38%) myeloablative conditioning. Best response after sorafenib was CRi or CR in six patients (21%) and CMR with no detectable FLT3-ITD mRNA by reverse transcriptase PCR in nine patients (31%). Donor lymphocyte infusions (DLIs) were given in five patients prior, in 4 patients during and in 1 patient after sorafenib treatment. Six patients underwent a second allo-SCT, two of them after developing sorafenib resistance. All but 2 of the 29 patients displayed at least one of the following characteristics before sorafenib start: high leukaemic burden, chemotherapy resistance, or early relapse (less than 6 months after allo-SCT). Causes of death were sorafenib-resistant disease progression
60
0
3. Results 3.1. Patient characteristics
80
80 60
CMR
40 p=0,001
20 no CMR
0
0
No. at risk 9 20
1
2
3
7 2
5 1
5 1
4
7
8
Years 5 1
5 0
1 0
Fig. 1. Overall survival and treatment-free remission. Panel A shows the overall survival of all patients (n Z 29) with a median survival of 215 d. Panel B shows the overall survival according to achievement of sorafenib-induced CMR (molecular negativity for FLT3-ITD mRNA by PCR and no evidence of disease). The only long-term surviving patient with no CMR underwent second allogeneic stem cell transplantation. CMR, complete molecular response.
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(Fig. 2). Patients #2, #3, #4, and #5 were previously enrolled onto the CALGB 10603 (RATIFY) (NCT00651261), AMLCG 2000 (NCT00266136), AMLSG 07-04 (NCT00151242), and AML 2003 (NCT00180102) studies, respectively. Patients #1 and #2 were chemotherapy refractory. Patient #1 relapsed on day þ136 after allo-SCT with 28% blasts in bone marrow, and patient #2 relapsed on day þ27 after allo-SCT with 47% blasts in peripheral blood. They received sorafenib and survived for 8.0 and 7.4 years, respectively. Patient #2 was the only patient to receive DLI following remission induction with sorafenib. Patient #3 was transplanted in CR and relapsed with 90% bone marrow blasts on day þ134 after allo-SCT. He was bridged with sorafenib and underwent a second allo-SCT in CRi. Three months later, he suffered from a molecular relapse which persisted during DLI. Another 4 months later, he relapsed with a chloroma. He was retreated with sorafenib, and radiotherapy for local disease control was applied. He achieved a CMR and is alive and free of relapse 7.6 years after sorafenib start. Patient #4 relapsed on day þ723 after allo-SCT with 75% bone marrow blasts. Refractory after one cycle of azacytidine, she was treated with sorafenib. This patient is in sustained CMR for 7 years today. Patient #5 developed a molecular relapse on day þ385, doubling the molecular FLT3-ITD amount in the peripheral blood to 9% within 2 weeks and was given sorafenib. This patient is in CMR for 7.5 years. All five patients had normal cytogenetics, patients #2 and #3 had a NPM1 mutation, and patient #4 had a partial tandem duplication of the MLL gene. Patients #2 and #3 never experienced GvHD, patients #1 and #5 developed GvHD prior to, patient #4 during sorafenib treatment.
237
3.3. Complete molecular response is associated with longterm survival and treatment-free remission Survival was independent from the time of relapse after allo-SCT (Supplementary Fig. S2A), leukaemia mass at relapse (Supplementary Fig. S2B and C), disease status before allo-SCT, or type of conditioning regimen (Table 1). The only predictor of long-term survival was achievement of CMR with sorafenib at any point of time. In detail, five of nine patients (56%) who achieved CMR experienced long-term survival, whereas only 1 of 20 patients (5%) who did not achieve CMR survived (p Z 0$006, Fisher’s exact test; p Z 0$001, log-rank). However, this latter patient underwent second alloSCT (Table 1, Fig. 1B). The median overall survival of CMR patients was not reached and was 169 d (range, 25e2495 d) for patients not in CMR with sorafenib. Four of the five patients who achieved long-term remission discontinued sorafenib after a median of 23 months (range, 18e39) for reasons of dermal and intestinal toxicities, hyperkeratosis, or myocardial infarction in three patients. Patients #3, #4, and #5 discontinued successfully and are currently in TFR for 3.5, 5.2, and 5.4 years, respectively. Patient #1 was only 18 months on sorafenib and relapsed 13 months after TKI discontinuation with a chloroma. Sorafenib reinduced CMR. For local treatment, radiotherapy was added. Sorafenib was discontinued a second time after additional 3.8 years of drug exposure. This patient remains in ongoing TFR (currently 1.5 years).
4. Discussion Here, we showed for the first time that sorafenib monotherapy may be capable to establish a curative
Fig. 2. Schematic illustration of treatment courses in relation to sorafenib. Individual patient numbers are indicated on the left and correspond to patients in the text. A first diagnosis, chemotherapy cycle, allogeneic stem cell transplantation, treatment refractory, relapse, extramedullar relapse (chloroma), molecular relapse, ongoing remission, sorafenib treatment, donor lymphocyte infusion, and radiation singular chloroma.
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synergism with allo-immune effects in an important minority of FLT3-ITDepositive AML patients relapsing after allo-SCT. We previously suggested that the durability of a sorafenib treatment response requires the context of an allo-SCT [21]. This hypothesis is further supported here. Hence, beyond having cytoreductive effects, sorafenib apparently has FLT3-ITDedependent or FLT3ITDeindependent cellular or humoural anti-AML effects requiring allogeneic haematopoiesis. Whether sorafenib stimulates antileukaemic innate or adaptive immunity in humans as suggested in a mouse model [25] remains speculative. Notably, only patients achieving a CMR under sorafenib had a chance to experience also a durable remission with sorafenib monotherapy. This implies that achievement of CMR is an early prognostic biomarker for sustained treatment success. This information can be used when considering alternative treatments. Another important observation of this study was that TKI cessation after successful treatment is feasible. All patients receiving sorafenib for more than 20 months before discontinuation stayed in CMR. In the case of relapse after TKI stop, retreatment was feasible to reinduce CMR and TFR. This was exemplified by the clinical course of patient #1, who relapsed after a sorafenib treatment duration of 18 months, but not after a second stop, following an additional sorafenib exposure of 3.8 years. The major limitation of this study clearly lies in its retrospective nature and the small number of patients that were included. Thus, the evidence level of our findings is low. However, since durable survival and TFR in patients relapsing after allo-SCT is an unprecedented finding for FLT3-ITDepositive AML, it could still be of significant value to guide treatment decisions in the absence of evidence from randomised trials. A randomised trial, the SORMAIN study (EUDRA-CT: 2010-018539-16), and other studies with newer generations of FLT3 inhibitors such as quizartinib, crenolanib, or gilteritinib will provide important new insights into optimal strategies of incorporating sorafenib and these newer compounds in the treatment algorithm of FLT3ITDepositive AML [15,16,26].
Contributors S.K.M. treated patients, performed, designed, and coordinated the research; analysed the data; compiled the figures; and wrote the paper. A.B. treated patients, designed, and coordinated the research; analysed the data; and wrote the paper. A.N. coordinated the research and discussed the data. All coinvestigators treated patients, collected, and provided clinical data. All authors critically reviewed and edited the manuscript.
Conflict of interest statement None declared. Funding Deutsche Forschungsgemeinschaft, Klinische Forschergruppe 210 ‘Genetics of Drug resistance in Cancer’, TP7 to SKM and AB; Deutsche Jose´ Carreras Leuka¨miestiftung (AR12/12) to AB. Role of the funding source The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.ejca.2017.09.016.
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