Compassionate Use of Sorafenib in Relapsed and Refractory Flt3-ITD Positive Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2060-2060 ◽  
Author(s):  
Stephan Metzelder ◽  
Sebastian Scholl ◽  
Kröger Matthias ◽  
Andreas Reiter ◽  
Ralf G. Meyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Side Effects ◽  
Myeloid Leukemia ◽  
Treatment Duration ◽  
Growth Factor Receptor ◽  
Compassionate Use ◽  
Median Treatment ◽  
Acute Myeloid

Abstract Abstract 2060 Poster Board II-37 Introduction: The Flt3-internal tandem duplication can be found in up to 30% of all acute myeloid leukemia (AML) patients and confers a poor risk status characterized by an increased relapse rate and poor overall survival. Moreover, Flt3-ITD-positive AML patients relapsing after allogenic stem cell transplantation (SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor that is approved for the treatment of metastatic renal cell and hepatocellular carcinoma. Besides targeting Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR) it has also significant inhibitory activity against the Flt3 receptor tyrosine kinase, and, specifically the mutated variant of Flt3, Flt3-ITD. It has previously been shown that sorafenib monotherapy may have considerable activity in relapsed Flt3-ITD positive AML. Nevertheless, clinical experience is still limited. Here we report compassionate use experience on 18 relapsed or refractory Flt3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 28 centers in Germany in order to obtain more insight into the clinical efficacy and tolerablilty of sorafenib monotherapy in Flt3-ITD positive AML. Forms were returned from 13 centers, reporting 26 patients. Among them, eight had to be excluded from further analysis. Five of them were Flt3-ITD mutation negative and three received contemporary chemotherapy. Available patient information included age, FAB-classification, karyotype, type and response to prior therapy, sorafenib dosing, tolerability, treatment duration, and response. Results: Of the 18 patients (12 male, 6 female), five were primary refractory to induction chemotherapy and 13 received sorafenib in first (n=11) or second (n=2) relapse. Eight of 18 patients relapsed after SCT and were treated with sorafenib. One patient was treated for steadily increasing Flt3-ITD copy numbers, that is, in molecular relapse after SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 98 days (range, 16-425 days). All patients achieved a hematological response (HR) characterized by complete (n=17) or near complete peripheral blast clearance (n=2). Of the 18 patients the documented best response to sorafenib were: HR in 9 cases, bone marrow response (HR and blast reduction in marrow) in 4 cases, complete remission (normalization of peripheral blood counts and bone marrow blasts < 5%) in one case and complete molecular remission (molecular negativity for Flt3-ITD) in 4 patients. After a median treatment duration of 180 days (range, 82-270 days) 7 of the 18 (39%) patients developed clinical sorafenib resistance: two of eight (25%) of the SCT-group and 5 of 10 (50%) of the non-SCT group. Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant side effects, observed in 13 patients. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: Sorafenib monotherapy has significant clinical activity in Flt3-ITD positive relapsed and refractory AML and may be particularly effective in the context of allo-immunotherapy where 3 CMR could be seen. Disclosures: Enghofer: Bayer Schering Pharma: Employment. Off Label Use: sorafenib, used to treat Flt3-ITD positive AML patients.

Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3314-3314 ◽  
Author(s):  
Stephan Metzelder ◽  
Anemone Finck ◽  
Martin Fey ◽  
Sebastian Scholl ◽  
Matthias Kröger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Growth Factor ◽  
Side Effects ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Allogenic Stem Cell Transplantation ◽  
Acute Myeloid

Abstract Abstract 3314 Introduction: The FLT3-internal tandem duplication is the most frequent genetic aberration in normal karyotype acute myeloid leukemia (NK-AML) and associated with a poor prognosis. Patients with FLT3-ITD positive AML relapsing after allogenic stem cell transplantation (allo-SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 receptor tyrosine kinase, and, at low nanomolar concentrations also the mutated variant of FLT3, FLT3-ITD. Sorafenib also inhibits Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). We have previously reported that sorafenib monotherapy is effective in relapsed FLT3-ITD positive AML (Metzelder et al., Blood 2009; Metzelder et al., ASH 2009, poster #2060). Here we significantly extend these compassionate use experiences by reporting on clinical response details from 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 60 centers in Germany, Singapore and the United States, where FLT3-ITD-positive patients had been treated with sorafenib monotherapy. 26 centers returned information on therapy details of 55 patients. These included data on age, FAB-classification, karyotype, FLT3-ITD molecular testing, type and duration of response to prior therapy and to sorafenib, sorafenib dosing and tolerability. 16 patients were excluded from further analysis because of FLT3-ITD negativity or application of chemotherapy concomitant to sorafenib. Results: There were 39 evaluable patients (20 male, 19 female), grouped into i) primary refractory patients (PR-P) (n=11), receiving one (n=5) or two cycles (n=6) of chemotherapy before commencing sorafenib, ii) relapsing patients (REL-P) (n=12) with hematological recurrence after between one and four cycles of prior chemotherapy, syngenic, or autologous SCT, and iii) patients relapsing after allogenic SCT (SCT-P) (n=16). One patient was treated first line with sorafenib. One patient was treated before and after allo-SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 71 days (range, 13 to 270) for PR-P, 76 days (range, 9 to 160 days) for REL-P, and 76 days (range, 20 to 489 days) for SCT-P. All reported patients in this cohort responded to sorafenib. In the PR-P group, there were 6 hematological remissions (HR), characterized by complete (n=4) or near complete peripheral blast clearance (n=2), 4 complete remissions (bone marrow blasts < 5% with (CR) or without (CRp) normalization of peripheral blood counts) and one complete molecular remission (CMR, molecular negativity for FLT3-ITD). Six of these 11 PR-P underwent allo-SCT after responding to sorafenib induction. In the REL-P group there was one patient with a partial blast clearance (PR), 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. In the SCT-P group there were 3PR, 2HR, 7 BMR and 4 CMR. Notably, the median time to treatment failure due to frank clinical sorafenib resistance was 119 days for PR-P and REL-P, but was not reached in the SCT-P group. This difference was statistically significant (p-value 0.0217). Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant but manageable side effects. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: This analysis on a large cohort of 39 FLT3-ITD positive patients confirms our previous reports on the remarkable clinical activity of sorafenib monotherapy in FLT3-ITD positive AML. Evidence is accumulating that sorafenib may be particularly effective in the context of allo-SCT, where long-term responses were seen. Disclosures: No relevant conflicts of interest to declare.

Evidence of increased angiogenesis in patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 309-313 ◽  
Author(s):  
Jerry W. Hussong ◽  
George M. Rodgers ◽  
Paul J. Shami
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Inhibition Of Angiogenesis ◽  
Novel Strategy ◽  
Von Willebrand ◽  
Endothelial Growth Factor ◽  
Acute Myeloid

Abstract Angiogenesis plays a key role in solid tumor growth. The purpose of this work was to study angiogenesis in acute myeloid leukemia (AML). We stained bone marrow samples from 20 adult patients with untreated AML and 20 normal controls using endothelial cell markers (ULEX-E and von Willebrand factor [vWF]). The number of vessels per millimeter length of bone marrow core biopsy specimen was scored by light microscopy. Using ULEX-E staining, AML marrows had (average ± SEM) 8.3 ± 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had 4.3 ± 1.8 vessels/mm (range, 1.6-7.9). A similar difference was noted using vWF staining (8.6 ± 3.0 vessels/mm vs 4.9 ± 2.2 vessels/mm in AML vs normal bone marrows, respectively). The differences between the numbers of vessels/mm in AML and normal marrows were highly significant (P &lt; .0001 for both ULEX-E and vWF staining). When analyzed by FAB category, there was no difference in the average number of vessels/mm among the different subgroups of AML. Using reverse transcriptase polymerase chain reaction, we observed that the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML cells from untreated patients expressed mRNA for vascular endothelial growth factor (VEGF). Both cell lines as well as all fresh AML isolates tested expressed VEGF protein. Basic fibroblast growth factor was expressed only in HL-60 cells and in only 3 of 4 fresh AML samples. These observations suggest that angiogenesis may play a role in the pathogenesis of AML. Inhibition of angiogenesis could constitute a novel strategy for the treatment of AML. (Blood. 2000;95:309-313).

scholarly journals Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia

2019 ◽  
Vol 21 (1) ◽  
pp. 164 ◽  
Author(s):  
Thomas Cluzeau ◽  
Nathan Furstoss ◽  
Coline Savy ◽  
Wejdane El Manaa ◽  
Marwa Zerhouni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Myelodysplastic Syndrome ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Significant Proportion ◽  
Acute Myeloid

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.

scholarly journals Serum Epidermal Growth Factor Receptor and p53 in Patients with Acute Myeloid Leukemia

2019 ◽  
Vol 87 (June) ◽  
pp. 1363-1369
Author(s):  
MADONNA M. EL-TOUKHY, M.B.B.Ch. HEBA A.M. MORAD, M.D. ◽  
HOSSAM A. HODIB, M.D. WAEL F. MOHAMED FARRAG, M.D.
Keyword(s):  
Acute Myeloid Leukemia ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Acute Myeloid

Evidence of increased angiogenesis in patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 309-313 ◽  
Author(s):  
Jerry W. Hussong ◽  
George M. Rodgers ◽  
Paul J. Shami
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Inhibition Of Angiogenesis ◽  
Novel Strategy ◽  
Von Willebrand ◽  
Endothelial Growth Factor ◽  
Acute Myeloid

Angiogenesis plays a key role in solid tumor growth. The purpose of this work was to study angiogenesis in acute myeloid leukemia (AML). We stained bone marrow samples from 20 adult patients with untreated AML and 20 normal controls using endothelial cell markers (ULEX-E and von Willebrand factor [vWF]). The number of vessels per millimeter length of bone marrow core biopsy specimen was scored by light microscopy. Using ULEX-E staining, AML marrows had (average ± SEM) 8.3 ± 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had 4.3 ± 1.8 vessels/mm (range, 1.6-7.9). A similar difference was noted using vWF staining (8.6 ± 3.0 vessels/mm vs 4.9 ± 2.2 vessels/mm in AML vs normal bone marrows, respectively). The differences between the numbers of vessels/mm in AML and normal marrows were highly significant (P < .0001 for both ULEX-E and vWF staining). When analyzed by FAB category, there was no difference in the average number of vessels/mm among the different subgroups of AML. Using reverse transcriptase polymerase chain reaction, we observed that the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML cells from untreated patients expressed mRNA for vascular endothelial growth factor (VEGF). Both cell lines as well as all fresh AML isolates tested expressed VEGF protein. Basic fibroblast growth factor was expressed only in HL-60 cells and in only 3 of 4 fresh AML samples. These observations suggest that angiogenesis may play a role in the pathogenesis of AML. Inhibition of angiogenesis could constitute a novel strategy for the treatment of AML. (Blood. 2000;95:309-313).

scholarly journals Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis

2017 ◽  
Vol 8 (9) ◽  
pp. 245-261 ◽  
Author(s):  
Molly M. Gallogly ◽  
Hillard M. Lazarus ◽  
Brenda W. Cooper
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Resistance Mutations ◽  
Acute Myeloid

The development of FLT3-targeted inhibitors represents an important paradigm shift in the management of patients with highly aggressive fms-like tyrosine kinase 3-mutated (FLT3-mut) acute myeloid leukemia (AML). Midostaurin is an orally administered type III tyrosine kinase inhibitor which in addition to FLT3 inhibits c-kit, platelet-derived growth factor receptors, src, and vascular endothelial growth factor receptor. Midostaurin is the first FLT3 inhibitor that has been shown to significantly improve survival in younger patients with FLT3-mut AML when given in combination with standard cytotoxic chemotherapy based on the recently completed RATIFY study. Its role for maintenance therapy after allogeneic transplantation and use in combination with hypomethylating agents for older patients with FLT3-mut has not yet been defined. Midostaurin also has recently been shown to have significant activity in systemic mastocytosis and related disorders due to its inhibitory effect on c-kit bearing a D816V mutation. Activation of downstream pathways in both of these myeloid malignancies likely plays an important role in the development of resistance, and strategies to inhibit these downstream targets may be synergistic. Incorporating patient factors and tumor characteristics, such as FLT3 mutant to wild-type allele ratios and resistance mutations, likely will be important in the optimization of midostaurin and other FLT3 inhibitors in the treatment of myeloid neoplasms.

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