Akin, Cem

Abstract Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Abstract Dasatinib is approved as a second line therapy (Rx) for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia, as it targets Bcr/Abl tyrosine kinase. Due to its activity against other kinases, like KIT and PDGFR, we conducted a Phase II study of dasatinib in patients with Ph-negative acute and chronic myeloid diseases. Sixty-eight patients were treated at the starting dose of 70mg PO BID (9 patients with SM received 140mg as a single dose daily); 4 weeks=1 cycle. All patients were assessed for response and toxicity (no Grade 4 toxicity was observed). The results by disease type are detailed. Systemic mastocytosis: 33 patients were treated (18 indolent, 9 aggressive, 6 with associated hematologic malignancy); median age 57 years (29–74); 14 were males, all PDGFRA−; # prior Rx 1 (0–4), 16 not previously treated; median # cycles 4 (1–20). Two achieved CR: one SM-MF (JAK2 V617F+, complex cytogenetics) and one SM-HES; both c-KIT mutation negative, low tryptase, anemic, failed erythropoietin, and had abnormal WBC differential. SM-MF patient progressed to AML after 8 months on Rx and died, and SM-HES is still in CR after 18+ months. Nine patients had improvement in symptoms related to SM, lasting from 3–18+ months. Nineteen Grade 3 toxicities were observed; dose was reduced to −1 level in 15, and to −2 level in 5 patients. Acute myeloid leukemia: 9 patients were treated; median age 70 years (51–91); 7 were males, 4 had abnormal cytogenetics; # prior Rx 2 (0–3); median # cycles 1 (1–18). CR was observed in an 80y old male with trisomy 8, previously treated with 3+7 chemotherapy with short CR. He relapsed on dasatinib Rx after 60 weeks. Eight patients had no response (4 stopped Rx within first month). Six Grade 3 toxicities were observed. Myelodysplastic syndrome/chronic myelomonocytic leukemia: 6 patients were treated (3+3); median age 68 years (51–75); 4 were males, 1 with abnormal cytogenetics; # prior Rx 1.5 (0–5); median # cycles 1 (1–2). No responses were observed (2 stopped Rx within first month); one Grade 3 toxicity was observed. Hypereosinophilic syndrome/chronic eosinophilic leukemia: 8 patients were treated (5+3); median age 58 years (23–75); 5 were males, 3 had abnormal cytogenetics, all PDGFRA-; # prior Rx 1.5 (0–3); median # cycles 3 (1–17). One female patient with HES achieved CR (previously Rx with gleevec without response). She relapsed after 58 weeks while off Rx due to toxicity. Other patients did not respond (1 stopped Rx within first month); 5 Grade 3 toxicities were observed. Polycythemia vera: one patient was treated; 50yr old female, with no prior Rx, had no response after 3 months of dasatinib Rx. Chronic idiopathic myelofibrosis: 11 patients were treated; median age 63 years (47–77); 10 were males, 2 had abnormal cytogenetics; # prior Rx 2 (0–7); median # cycles 6 (1–9). No responses were observed (1 stopped Rx within first month); 4 Grade 3 toxicities were observed. Conclusion: Dasatinib is active in systemic mastocytosis (overall response rate 33%). Updated clinical and molecular results will be presented.

Abstract Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of <12 months – became long-term survivors after alloHCT. In summary, our results support development of a prospective alloHCT study, with the aim to optimize therapy and to improve overall outcome in advanced SM. Based on our pilot study, alloHCT should also be considered in practice for eligible and fit patients with SM-AHNMD (if treatment of AHNMD component needs alloHCT or SM component is aggressive), rapidly progressing ASM, MCL and MML when a suitable HLA-matched sibling donor or URD is available. Disclosures: Vercellotti: Sangart Inc.: Research Funding; Seattle Genetics: Research Funding. Akin:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding.

AbstractBackgroundAlthough the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P < 0.0001). Low‐ vs high‐risk OS at 2 years was 89% vs 51% (P < 0.0001).ConclusionsI‐CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low‐risk I‐CBFit score).

PurposeAdvanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.Patients and MethodsIn a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).ResultsResponses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.ConclusionAlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

AbstractMastocytosis is an emerging differential diagnosis in patients with more or less specific mediator‐related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator‐related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25–30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of ‘occult’ mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow‐up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.

Abstract Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

Abstract Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene. Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.

Abstract Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.