Introduction FLT3-ITD (Internal tandem duplication) and FLT3-TKD (tyrosine kinase domain, D835) mutations are frequently seen in AML; FLT3-ITDs are associated with inferior survival. Development of FLT3-TKD mutation during FLT3 inhibitor-therapy is seen in up to 22% of patients and associated with FLT3 tyrosine kinase inhibitor (TKI) treatment failure (Cancer 2014). Crenolanib besylate is an orally bioavailable TKI with activity against both FLT3-ITD and FLT3-TKD mutations. We evaluated the clinical efficacy of crenolanib in relapsed/refractory AML pts with activating FLT3 mutations. Methods This was a single center phase II open label study of crenolanib administered at 200 mg/m2/day three times a day continuously in 28 day cycles. FLT3 mutated pts (either FT3-ITD or FLT3-TKD) with primary AML, therapy-related AML and AML following an antecedent hematological disorder were included. Pts were ≥18 years of age with ECOG PS of 0-2. Pts with CNS disease were excluded. Pts relapsing post-allogeneic stem cell transplant could be included if they were >30 days post-transplant. 38 pts enrolled in 2 parallel cohorts of which 34 were evaluable, 13 in cohort A (FLT3 TKI-naïve) and 21 in cohort B (progressed on prior FLT3 TKI). Results Median age was 61 (30 – 87). Patients had undergone a median of 3.5 prior therapies (range 1 – 8); 38% of pts had diploid and 23% complex cytogenetics. Among patients with available information, NPM1 mutation was identified in 62% (10/16) and DNMT3A in 57% (8/14). Median baseline marrow blast % was 58% (7 – 97%). Of cohort B patients, prior therapy was sorafenib in 57%, quizartinib in 14%, PLX3397 in 5% and midostaurin in 10%. 9% and 5% had received 2 and 3 FLT3 TKIs, respectively. 10 enrolled patients had progressed post-transplant (SCT) (3 allogeneic in cohort A; 6 allogeneic, 1 autologous in cohort B). Median duration of study therapy was 9 wks (range 5 – 24), 2 pts remain on study. Reasons for study cessation were disease progression in 66%, no response in 16%, toxicity in 6%, clinical deterioration due to other co-morbidities in 6%, 3% lost to follow up and 3% to receive SCT. At a median follow up of 14 weeks (wks), ORR was 47%: 12% achieved complete response with incomplete count recovery (CRi), 32% hematological improvement (Hi) (85% of them with >50% decrease in blast count) and 3% morphologic leukemia-free state (MLFS). 21% had progressive disease and 32% no response. The median event-free survival (EFS) was 8 wks and overall survival (OS) was 19 wks for the whole cohort. The response by cohort was: Table FLT3 TKI naïve Prior FLT3 Therapy Response % CRi 23 5 MLFS 8 0 Hi 31 33 NR 31 33 PD 8 29 Median OS 55 wks 13 wks (p=0.027) Median EFS 13 wks 7 wks (p<0.001) Pts achieving marrow response (CRi and MLFS) had superior EFS (median 22 wks vs 8 wks for non-responders, p=0.003), with a trend toward superior OS for the marrow responders (median 55 weeks versus 15 wks, p=0.166). 2 of the 4 pts with FLT3-TKD in cohort A responded (CRi, Hi). Among pts with both mutations, 1/1 pt in cohort A achieved CRi and 5/6 pts in cohort B achieved Hi. EFS and OS were not influenced by complex cytogenetics, number of prior therapies or the presence of NPM1 or DNMT3A mutations. OS and EFS were, for patients with ITD (19 wks; 7 wks), D835 (6 wks; 8 wks) or both FLT3 mutations (12 wks; 9 wks), p=0.908; 0.391 respectively. The main grade 3 toxicities were GI side effects (abdominal pain and nausea). There was no death attributed to treatment related toxicity. Conclusions Crenolanib is a well-tolerated FLT3 TKI with clinical efficacy in heavily pre-treated, relapsed/refractory FLT3 mutated AML patients. The superior results in FLT3 inhibitor-naïve patients suggests that on-target FLT3 inhibition is likely primarily responsible for drug efficacy. Combination therapy (e.g., with chemotherapy or hypomethylating agents) could potentially provide additive efficacy in both treatment-naïve and relapsed/refractory pts. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes. Thus, to minimize GVHD and maximize GVL we selectively activated and expanded stem-cell donor-derived T cells that were reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, NY-ESO-1). Products were successfully generated from 29 HCT donors, and they demonstrated multi-leukemia antigen specificity (mLSTs). In contrast to DLIs, mLSTs selectively recognized and killed leukemia-antigen-pulsed cells with no activity against recipient-derived normal cells in vitro. We have now administered escalating doses of these mLSTs (0.5-10x107 cells/m2) to 25 trial enrollees with AML/MDS after HCT, 17 of whom were at high risk for relapse and 8 of whom had relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD up to a dose of 10x107 cells/m2. We observed anti-leukemia effects in vivo that translated into not yet reached median LFS and OS at 1.9 years of follow-up among survivors, evidence of sustained immune pressure and objective responses in the active disease cohort (1 CR and 1 PR). In conclusion, mLSTs are safe and promising for the prevention or treatment of AML/MDS following HCT.
Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12–142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3–96.9 weeks) and median event-free survival was 5 weeks (range 1.7–21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.
Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.
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