Abstract 5002
Janus kinases are critical components of cytokine signaling pathways that regulate hematopoiesis, growth, immunity, inflammation, and development. Oncogenic mutations of the ...non-receptor tyrosine kinase JAK2 are found in many Philadelphia chromosome negative myeloproliferative neoplasms. The V617F mutation in JAK2 occurs in 95% of patients with polycythemia vera, 50% of those with essential thrombocythemia and 50% of primary myelofibrosis patients. Preclinical results strongly support that JAK2 inhibitors could be effectively used in these three indications. Replacement of valine 617 with phenylalanine upregulates the tyrosine kinase activity of JAK2, causing constitutive activation of the JAK-STAT pathway and growth factor-independent cell proliferation. JAK2 has also been postulated to play an important role in BCR-ABL signal transduction. Therefore, inhibitors of the tyrosine kinase activity of JAK2 are under investigation as new therapy strategies for CMPNs. In this study the role of the novel JAK2 inhibitor, NVP-BSK805 (Novartis Pharmaceuticals), has been investigated in cells expressing either BCR-ABL or mutant JAK2. Possible synergistic effects between NVP-BSK805 and the already established tyrosine kinase inhibitors imatinib and nilotinib were assessed.
The in vitro activity of NVP-BSK805 was analyzed in 12 hematopoietic cell lines, including 7 BCR-ABL positive (K562, KCL22, KU812, Lama87, BV173, EM3, SUP-B15), 4 JAK2 mutated (CHRF288, SET2, UKE1, HEL), the T-cell leukemia cell line Jurkat, and the neuroendocrine colonic tumour line LCC-18. Concentration kinetics from 0 up to 25 μM were established using XTT proliferation assays and flow cytometry for measuring apoptosis. Protein levels of JAK2, phospho-JAK2, STAT5, phospho-STAT5 and BCR-ABL were analyzed using Western blotting. NVP-BSK805 was also tested in combination with imatinib and nilotinib. JAK2 was sequenced in all cell lines in order to detect possible mutations in the gene.
Of the JAK2 mutated cell lines tested, 3 of 4 (CHRF288, SET2, UKE1) showed a significant reduction of proliferation, as well as viability, compared to the other cell lines. CHRF288 responded best to NVP-BSK805 with an IC50 value of 0.22 ± 0.04 μM. UKE1 and SET2 had similar values of 0.35 ± 0.03 μM and 0.37 ± 0.05 μM. Interestingly, HEL (V617F positive) cells showed only an IC50 value (1.8 ± 0.17 μM) for NVP-BSK805, comparable with that of the non-mutated BCR-ABL positive cell lines (1.5 to 2.7 μM). LCC-18 showed the weakest response of all cell lines tested, with an IC50 value of 9.93 ± 0.202 μM. Each cell line responded to concentrations higher than 5 μM with a strong reduction of proliferation due to inhibition of various kinases. Combination of the JAK2 inhibitor with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL positive cell lines responded well to both CML therapeutic agents. Western blotting of proteins of the JAK-STAT pathway confirmed the results of the proliferation and apoptosis tests showing a strong reduction of phoshorylated STAT5 in CHRF288 cells after a 30 min incubation even with NVP-BSK805 concentrations as low as 0.01 μM. UKE-1 and SET-2 showed reduction of pSTAT5 from 0.1 μM. Levels of total STAT5 were not affected. In all the other cell lines no changes were detected in any of the proteins tested.
Here, we tested a novel JAK2 inhibitor in cells carrying the V617F mutation. Interestingly, not every cell line with the JAK2 V617F mutation showed a good response upon JAK2 inhibition, indicating that there are additional factors determining response. On the other hand, clinical trials with JAK inhibitors in myelofibrosis have shown responses in V617F-mutated and non-mutated patients, warranting further research to identify predictors of response. In BCR-ABL mutant cells not harbouring JAK2 mutations no significant inhibition of proliferation or apoptosis was detected following JAK2 inhibition, indicating that there are JAK2 independent signal transduction pathways of BCR-ABL to avoid apoptosis.
le Coutre:Novartis Pharmaceuticals: Honoraria, Research Funding.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The phase 3 LASOR trial is the only randomized trial that compares the effects of imatinib dose escalation with those of switching to nilotinib in pts with Philadelphia chromosome–positive (Ph+) ...CML-CP who experience suboptimal response to frontline imatinib. Suboptimal response has been associated with inferior long-term outcomes in several landmark analyses and was observed in 13% of pts randomized to the imatinib arm of ENESTnd by 12 mo (vs 4% in each nilotinib arm).
Adults (N = 191) with CML-CP with suboptimal CyR to frontline imatinib 400 mg once daily (QD) were randomized 1:1 to nilotinib 400 mg twice daily (BID; n = 96) or imatinib 600 mg QD (n = 95). Suboptimal CyR was defined according to 2009 European LeukemiaNet (ELN) criteria as: no CyR ≥ 3 to < 6 mo (Ph+ > 95%), no partial CyR (PCyR) ≥ 6 to < 12 mo (Ph+ 36%-95%), or no complete CyR (CCyR) ≥ 12 to <18 mo (Ph+ 1%-35%) after starting imatinib. All pts had complete hematologic response at study entry. The primary endpoint was CCyR (Ph+ 0%) at 6 mo after randomization. The key secondary endpoint was major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo. Crossover to the alternate treatment arm was allowed for pts who failed to achieve CCyR by 6 mo or had intolerance or loss of response at any time.
Baseline characteristics were well balanced between arms, with most pts entering study for not having PCyR at 6 mo or CCyR at 12 mo (Table). The primary endpoint, CCyR at 6 mo after randomization, was observed in 47 (49.0%) and 40 (42.1%) pts in the nilotinib and imatinib arms, respectively (P = .3844). Crossover was more common in pts randomized to the imatinib arm. Crossover occurred before the primary endpoint analysis at 6 mo in 6 pts in the nilotinib arm (5 for intolerance; 1 for lack of efficacy) and 15 pts in the imatinib arm (13 for intolerance; 1 for lack of efficacy; 1 for loss of response). Median time to crossover was 3.9 and 3.6 mo in the nilotinib and imatinib arms, respectively. None of the nilotinib pts who crossed over to imatinib vs 6 of the 15 imatinib pts who crossed over to nilotinib achieved CCyR at the primary analysis time point 6 mo after randomization. Ten pts in the nilotinib arm and 7 in the imatinib arm had neither samples evaluable for CyR at 6 mo nor had crossed over to the alternate treatment arm. Excluding these pts (evaluable population) and counting crossed-over pts as non-responders, 47 of 86 pts (54.7%) in the nilotinib arm and 34 of 88 (38.6%) in the imatinib arm achieved CCyR at 6 mo. Analyses of molecular response at 6 mo after randomization suggested higher rates in the nilotinib arm for BCR-ABLIS ≤ 1% (CCyR equivalent) and ≤ 0.1% (MMR) compared with the imatinib arm (52.1% vs 29.5% and 31.3% vs 11.6%, respectively). The safety profile for both drugs was consistent with prior reports of pts who switched therapy after inadequate responses to imatinib.
Patients with suboptimal CyR to imatinib (today classified by ELN as warning/failure) represent a significant unmet need in the treatment of CML-CP. This important study is the only randomized evaluation of imatinib dose escalation vs switch to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population. Although the primary endpoint was not met, sensitivity analyses accounting for crossover and more sensitive molecular monitoring demonstrated higher rates of response with switch to nilotinib vs imatinib dose escalation in pts with suboptimal response to frontline imatinib.
Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Teva: Consultancy, Research Funding. Bullorsky:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Sacha:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Owugah:Novartis Pharmaceuticals Corporation: Employment. Kumar Nidamarthy:NOVARTIS HEALTH CARE Pvt Ltd: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Piccolo:Novartis: Employment. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract 2028
A monosomal karyotype, as defined by the presence of two or more autosomal monosomies or a single autosomal monosomy in the presence of at least one structural chromosomal abnormalities ...(core binding factor abnormalities excluded), was shown to confer to a highly unfavorable prognosis in patients (patients) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) treated with conventional chemotherapy. Here, we investigated the prognostic impact of a monosomal karyotype on the outcome of patients with AML or MDS following allogeneic stem cell transplantation (alloSCT).
254 patients who underwent alloSCT at our center between 1994 and 2010 were retrospectively analyzed. 204 patients (80%) had AML (de novo AML: 167 patients, therapy-related AML (tAML), AML evolving from MDS: 37 patients) and were in CR1 (157 patients (77%) or CR>1 (47 patients (23%). 50 patients had MDS (RA/RCMD: 36 patients, RAEB-I: 7 patients, RAEB-II: 9 patients). Median age was 47 years (range: 17–72 years). 223 patients (88%) received peripheral blood stem cells (PBSCs), 31 patients (12%) received bone marrow (BM). Conditioning consisted of standard myeloablative conditioning (MAC) in 134 patients (53%), whereas 120 patients (47%) received reduced intensity conditioning (RIC). 13 patients (5%) had a core-binding factor leukemia (CBF group), 117 patients (46%) were cytogenetically normal (CN group), 79 patients (31%) had an unfavorable risk MK-negative karyotype (MK– group), 26 patients (10%) had a highly unfavorable MK-positive (MK+ group). In 19 patients (8%) the karyotype was unknown/not evaluable.
After a median follow-up of 51 months (range: 3–191 months) for the surviving patients, 134 patients (53%) are alive and in remission. Causes of death were relapse in 53 patients (21%) or NRM in 58 patients (23%). At 1, 3 or 5 years projected OS (DFS) was 70±6% (66±6%), 57±6% (56±6%) or 54±7% (54±7%). At 3 years patients in the MK+ group had a statistically significantly lower OS (DFS) of 29% (29%) as opposed to 52% (52%) in the MK– group, 68% (66%) in the CN group, or 67% (55%) in the CBF-group (p<0.001). Likewise, the probability or relapse was highest in the MK+ group (72%) as compared to the MK- group (37%), the CN group (24%), or the CBF group (14%) (OS: p=0.001, DFS: p=0.003). There was no statistically significant difference in non-relapse mortality between the four groups.
These data indicate that karyotypic abnormalities remain the most important prognostic factors predicting the outcome of patients with AML or MDS. In particular, the presence of a monosomal karyotype provides a strong negative prognostic prediction for these patients undergoing alloSCT. Therefore, our data suggest that these patients should be referred to alloSCT in CR (AML) or early stage disease (MDS).
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract 3470
Allogeneic stem cell transplantation (alloSCT) represents a curative treatment option for the post-remission therapy of patients with acute myeloid leukemia (AML) or myelodysplastic ...syndrome (MDS). The presence or absence of distinct karyotypic abnormalities has a substantial impact on the risk of relapse and overall outcome. In particular, complex, i.e. ≥3, chromosomal aberrations are associated with a poor outcome.
We retrospectively analyzed 91 patients (47 female, 44 male) with secondary AML or therapy-related AML (n=50; CR1: n=22, CR>1: n=2, no CR: n=24) or MDS (n=41; RA/RCMD: n=14, RAEB-1: n=11, RAEB-2: n=16) who underwent alloSCT at our center between 1995 and 2008. An intermediate-risk karyotype was present in 47 patients, whereas 38 patients had a poor-risk karyotype. Among those, 22 patients had aberrations of chromosome 5 and/or 7. 45 patients were treated with standard myeloablative conditioning (MAC) (12 Gy total body irradiation, 2×60 mg/kg cyclophosphamide) prior to alloSCT, whereas 46 patients received reduced intensity conditioning (RIC) (fludarabine 6×30 mg/m2, busulfan 2×4 mg/kg, anti-thymocyte globulin 4×10 mg/kg). 35 patients had a matched-related donor (MRD) and 37 or 13 patients had a matched-unrelated (MUD) or a mismatched-unrelated (MMUD) donor.
After a median follow-up of 58 (12-170) months, 42/91 patients (46%) are alive and in CR. 20/91 patients (22%) succumbed to relapse and 27/91 patients (30%) died from treatment-related mortality (TRM). Projected OS (DFS) at 1, 3, or 5 years was 60% (55%), 52% (53%), or 50% (48%) and TRM was 27%, 27%, or 31%. Patients with a poor-risk cytogenetic profile had a significantly lower DFS as compared to patients with an intermediate-risk cytogenetics, i.e. 57% versus 36% at 5 years (p=0.04). However, within the group of patients with a poor-risk karyotype, those with aberrations of chromosome 5 and/or 7 had significantly lower OS (30% versus 50% at 5 years; p=0.03), or DFS (26% versus 50%; p=0.01) as compared to patients with complex aberrations. In contrast, the OS of patients with complex chromosomal aberrations excluding those who have chromosome 5 and/or 7 aberrations had a similar OS, DFS, or probability of relapse as compared to patients with an intermediate risk karyotype. Of note, in this subgroup there was no statistically significant difference in OS or DFS between patients conditioned with either standard MAC or RIC. Likewise, there was no statistically significant difference between patients transplanted from a MRD or a MUD.
Taken together, these results indicate that the presence of a poor-risk karyotype has a substantial prognostic impact in patients with secondary AML, therapy-related AML or MDS undergoing alloSCT. In particular, patients with aberrations of chromosome 5 and/or 7 are highest risk of relapse. Nonetheless, a substantial proportion of these patients may achieve durable remissions following either standard or RIC-alloSCT.
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract only
7052^
Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. ...Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ≤ 0.1% BCR-ABL
IS
), MR
4
(≤ 0.01%
IS
), and MR
4.5
(≤ 0.0032%
IS
) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n = 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n = 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n = 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497. Table: see text
Abstract only
6512
Background: The BELA study compared the efficacy and safety of BOS (dual Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 pts with newly diagnosed CP CML ...were randomized to BOS 500 mg/d (n = 250) or IM 400 mg/d (n = 252) and stratified by Sokal risk group and geographic region. Efficacy analyses included all randomized pts (ITT); safety analyses included all treated pts (BOS, n = 248; IM, n = 251). Data described below are for ≥24 mo of follow-up; updated data for ≥30 mo of follow-up will be presented. Results: Median treatment duration was 27.5 mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving treatment. The primary reason for BOS discontinuation was a treatment-emergent adverse event (TEAE; 24% vs 7% with IM); the primary reason for IM discontinuation was disease progression (13% vs 4% with BOS). Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 79% for BOS and 80% for IM. Cumulative major molecular response (MMR) rates by 24 mo were 59% for BOS and 49% for IM (P = 0.019), including 16% and 12% of pts with complete molecular response (4.0-log sensitivity). On-treatment transformation to accelerated/blast phase occurred in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML progression); 24-mo Kaplan-Meier overall survival estimates were 97% (BOS) and 95% (IM). BOS was associated with higher incidences of gastrointestinal events than IM (diarrhea 70% vs 25%, vomiting 32% vs 16%; primarily transient), but lower incidences of edema (13% vs 40%) and musculoskeletal events (cramps 4% vs 22%, bone pain 4% vs 10%). Grade ≥3 TEAEs in ≥2% of BOS or IM pts were diarrhea (12% vs 1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade ≥3 lab abnormalities (≥15% of pts) with BOS and IM were neutropenia (10% vs 24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase (23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS was effective for newly diagnosed CP CML and had a distinct toxicity profile. With continued follow-up both on-treatment transformation to accelerated/blast phase and overall survival continue to favor BOS versus IM.
Abstract only
TPS6640
Background: Myelofibrosis (MF) can be primary in origin or can progress from polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). MF is characterized by cytopenias, ...reactive bone marrow fibrosis, splenomegaly, and constitutional symptoms including weight loss, fever, and night sweats. MF is associated with dysregulation of the Janus kinase pathway, irrespective of JAK2V617F mutation status. Recently, ruxolitinib (INCB018424) was approved for the treatment of MF on the basis of results from 2 phase 3 trials (COMFORT-I and -II). These trials demonstrated marked reductions in splenomegaly and symptom burden, and improvements in health-related quality of life (QoL) measures. Methods: JAK Inhibitor rUxolitinib in Myelofibrosis Patients (JUMP) is a global, phase 3b expanded access trial (NCT01493414) designed to assess the safety and efficacy of ruxolitinib in adult pts with PMF, PPV-MF or PET-MF who are treatment naïve, and are intolerant of, or had progressed on any prior therapy. Inclusion criteria: peripheral blast count of <10%, adequate liver and renal function and intermediate-2 or high risk MF according to IPSS criteria or intermediate-1 risk MF with palpable spleen length ≥ 5 cm. The primary endpoint is to assess the safety of ruxolitinib. Additional endpoints include the proportion of pts with a > 50% reduction in palpable spleen length, % change in white blood cell and platelet counts from baseline (BL), and change in packed red blood cell transfusion requirements. Changes from BL in QoL scores will be assessed using validated ECOG PS, FACT-Lymphoma, and FACIT instruments. Pts with a BL platelet count > 200,000/μL will receive oral ruxolitinib 20 mg BID; pts with a BL platelet count of 100,000/μL to 200,000/μL will receive 15 mg BID; dose modifications are permitted for safety and efficacy. Global enrollment is open and currently includes 277 pts. This is planned to be the largest study ever conducted in pts with MF. Table: see text
In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal ...response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension).
