Sorafenib for refractory FMS-like tyrosine kinase receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogenic stem cell transplantation

Sorà, Federica; Chiusolo, Patrizia; Metafuni, Elisabetta; Bellesi, Silvia; Giammarco, Sabrina; Laurenti, Luca; Ausoni, Giuseppe; Zini, Gina; Bayer, A; Boccadoro, Mario; Leone, Giuseppe; Sica, Simona

doi:10.1016/j.leukres.2010.10.025

Cited by 19 publications

(14 citation statements)

References 9 publications

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“…This notion is also in keeping with other reports showing long-term survival of sorafenib-treated FLT3-ITD patients relapsing after allo-SCT. 32,33 A reporting bias in favor of preferably documenting good responses of allo-SCT patients in our survey seemed not likely, because CR/CMR patients in the CT group would have had the same chance of being reported. Based on this, we propose a potentially curative synergism between the kinase inhibitor sorafenib and allo-immune-mediated anti-leukemic Figure 2.…”

Section: Discussionmentioning

confidence: 92%

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

et al. 2012

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Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P ¼ 0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

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Section: Discussionmentioning

confidence: 92%

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

et al. 2012

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“…FLT3 inhibition could also be used as maintenance therapy after allogeneic transplantation, as is commonly done with BCR-ABL inhibitors, 62 particularly in light of the mounting anecdotal evidence of activity in this setting. 63,64 Finally, consideration could be given to targeting FL with monoclonal antibodies.…”

Section: Introductionmentioning

confidence: 99%

FLT3/ITD AML and the law of unintended consequences

Levis

2011

Blood

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Acute myeloid leukemia with a FLT3 internal tandem duplication (FLT3/ITD) mutation is an aggressive hematologic malignancy with a generally poor prognosis. It can be successfully treated into remission with intensive chemotherapy, but it routinely relapses. At relapse, the blasts tend to have higher mutant allelic ratios and, in vitro, are more addicted to the aberrant signaling from the FLT3/ITD oncoprotein. They remain highly responsive to FLT3 ligand, the levels of which rise several-fold during the course of chemotherapy. The question now arises as to whether these high levels of FLT3 ligand are actually promoting relapse, and, if so, how we can use this information to adjust our therapeutic approach and improve the cure rate for acute myeloid leukemia with FLT3/ITD. (Blood. 2011;117(26): 6987-6990) IntroductionThe law of unintended consequences teaches us that, when we intervene in a complex system, we invariably create unanticipated and sometimes undesirable outcomes. Our attempts to treat the disease known as acute myeloid leukemia with a FLT3 internal tandem duplication (FLT3/ITD AML) mutation certainly could be characterized as an intervention in a complex system, and the question can now be raised as to whether we are creating an unintended consequence with our therapeutic approach.FLT3 is a cytokine receptor that is expressed on the leukemic blasts in most cases of acute leukemia. 1-5 On binding FLT3 ligand (FL), FLT3 dimerizes and undergoes a conformational change, causing its activation loop to assume an open conformation and to allow ATP access to the ATP-binding pocket. Ligand-activated FLT3 undergoes autophosphorylation and, through a series of kinase cascades, transduces signals promoting cell growth and inhibiting apoptosis through proteins such as Ras-GTPase activating protein, phospholipase C ␤, STAT5, and ERK1/2. 6-12 The ligand, FL, is expressed in virtually all cell types thus far examined, including leukemia cells. [13][14][15] In contrast, the receptor, FLT3, has a fairly narrow range of cell expression, being localized primarily to hematopoietic and neural tissues, which presumably confines its functions to these cell types. 16 FL acts in synergy with other cytokines to promote hematopoietic precursor expansion, and targeted disruption of either FLT3 or FL in mice, although not embryonically lethal, leads to a reduction in hematopoietic precursors. [17][18][19][20][21][22][23][24] FLT3/ITDs were first described in patients with AML in 1996 by Nakao et al. 25 These mutations, which disrupt the autoinhibitory function of the receptor's juxtamembrane domain, result in constitutive autophosphorylation of FLT3 within the blasts that harbor them. 26,27 Fifteen years after this initial discovery, FLT3/ITD AML now stands as a distinct clinical entity, an often lethal subtype of AML that has been a considerable challenge to those of us who treat it. 28 Some recent clinical and laboratory findings about this disease may provide insight into why these patients relapse so quickly, and how we mi...

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“…46,47 In addition, there are several published patient series describing the activity of single-agent sorafenib in the postallogeneic transplant setting. [48][49][50] Although all of this is encouraging, the benefit of FLT3 inhibition needs to be established with a well-designed randomized study. Until that time, sporadic off-label usage of agents such as sorafenib is likely to continue based on limited data published to date.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

“…FLT3 TKIs clearly have single-agent activity (eg, see Patients 1 and 2), 58,59 and there are numerous reports of the benefit of these agents in combination with an allogeneic effect. 47,48,50,60 These agents are associated with some toxicities such as nausea, hypertension, palmar-plantarerthrodysesthesia, QTc interval prolongation, and diarrhea. Although they appear to be generally safe in the post-transplant setting, 46 there have simply been no randomized trials establishing their benefit.…”

Section: Patientmentioning

confidence: 99%

How I treat FLT3-mutated AML

Pratz

Levis

2017

Blood

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FLT3-mutated acute myeloid leukemia (AML), despite not being recognized as a distinct entity in the World Health Organization (WHO) classification system, is readily recognized as a particular challenge by clinical specialists who treat acute leukemia. This is especially true with regards to the patients harboring the most common type of FLT3 mutation, the internal tandem duplication (FLT3-ITD) mutation. Here we present 4 patient cases from our institution and discuss how our management reflects what we have learned about this subtype of the disease. We also reflect on how we anticipate the management might change in the near future, with the emergence of clinically useful tyrosine kinase inhibitors.

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Sorafenib for refractory FMS-like tyrosine kinase receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogenic stem cell transplantation

Cited by 19 publications

References 9 publications

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

FLT3/ITD AML and the law of unintended consequences

How I treat FLT3-mutated AML

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