Chronic Myeloid Leukemia Pts Research Articles

Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

P694Evaluation of preclinical atherosclerosis in chronic myeloid patients continuously treated with tyrosine kinase inhibitors

Abstract In tyrosine kinase inhibitors (TKIs) era chronic myeloid leukemia (CML) became from fatal to well controlled chronic disease. Meanwhile it seems that some TKIs may have cardiovascular (CV) effects. The aim of the study was to assess signs of preclinical atherosclerosis (PA) on different TKIs in CML patients (pts). Patients and method In our study 126pts with CML obtained TKIs as any line at least 6mos were included. Males were 56 (44,5%). The median age was 52 (20–76)yrs. Pts with previous history of atherosclerotic CV events were excluded. There were 115 (91%), 61 (48%), 48 (38%), 12 (11%) pts ever obtained Imatinib (IMA), Nilotinib (NILO), Dasatinib (DASA) or Bosutinib (BOSU) with median treatment duration 22mos, 14mos, 16mos and 15,5mos, respectively. Median time since the first TKI was 48 mos. There are 79, 46, 12 pts obtained 2, 3 or 4 TKIs. To assess PA ankle-brachial index (ABI) and intima media thickness (IMT) were measured. To evaluate ABI Vascular Screening System VaSera VS-1500 was used. Normal values for ABI and IMT were >0,9 and ≤1,1. Results ABI was abnormally low in 14/108 (13%) evaluable pts. Previous TKIs of IMA, NILO, DASA and BOSU were in 12 (86%) and 87 (93%), 9 (64%) and 41 (43%), 5 (35%) and 29 (31%), 1 (7%) and 9 (10%) pts with or w/t low ABI. All NILO its were pretreated with IMA. Only 2 pts previously obtained other TKIs. Median time on NILO was 23 mos and 15mos in pts with or w/t abnormal ABI, respectively. Median age for pts with or w/t low ABI was 53 and 52 yrs. The proportion of male pts were lower in abnormal vs normal ABI group – 29% and 44%. In NILO group 2 pts were male and median age for all pts was 51yrs. IMT was evaluable in 86 pts. The median value of IMT was 0,8mm for all pts. It was abnormal in 12 (14%) pts with median thickness 1,3mm. All pts previously ever obtained IMA. NILO, DASA and BOSU were exposed in 5 (42%) and 33 (46%), 5 (42%) and 23 (31%), 1 (8%) and 7 (10%) pts with or w/t IMT abnormalities. The proportion of males was 4 (33%) and 34 (46%) among pts with or w/t abnormal IMT. Pts with high vs normal IMT were older with median age 64 vs 44yrs. TKIs2 were ever obtained in 13/14 (93%) and 11/12 (92%)pts with abnormal ABI and IMT< respectively. Both ABI and IMT were abnormal only in 4 pts. Heart SCORE was high and very high only in 18/80 (22,5%) pts. Median age for low vs high risk pts were much lower (40 vs 52yrs). There were no differences between treatment groups according to SCORE distribution. Overall 9/50 (18%) and 3/32 (9%), 5/38 (13%) and 3/28 (11%)pts on NILO and DASA, had abnormal ABI and IMT. Conclusion CML pts heavily pretreated with different TKIs were included In the study. The most pts with abnormal ABI and IMT have ever been obtaining TKIs2. Pts with NILO more frequently experienced low ABI. There were not significant differences among TKIs groups regarding heart SCORE or IMT. It seems that extended PA is low on TKIs including NILO in CML pts w/t previous SVEs. Acknowledgement/Funding Funded from government assignment

PF420 RESULTS OF A PROSPECTIVE MULTICENTER STUDY ON PRO‐ATHEROTHROMBOTIC EFFECT INDUCED BY TYROSINE‐KINASE INHIBITORS FOR FIRST‐LINE TREATMENT OF CML PTS (KIARO TRIAL)

Background:Tyrosine kinase inhibitors (TKI) revolutionized treatment and prognosis of chronic myeloid leukemia (CML), but some patients (pts) still suffer from potentially severe TKI‐related toxicity. Of particular relevance is cardiovascular (CV) toxicity, mostly associated to Nilotinib (NILO) and Ponatinib. In a previous retrospective, cross‐sectional, multicenter study we confirmed a higher CV risk for pts treated with NILO, particularly those harboring the unfavorable OLR1 genetic polymorphism and we found a NILO‐associated pro‐inflammatory/oxidative effect, with increased IL6/IL10 and TNFα/IL10 ratios and levels of oxidized LDL (oxLDL) compared to Imatinib (IMA). We here report clinical, genetic and serologic results of a prospective multicenter Italian trial including CML pts treated with any of current first‐line TKIs (IMA, NILO, DASA).Aims:(1) to assess CV toxicity in CML pts in which first‐line TKI choice was made according to current CV risk guidelines (2) to assess pts’ genetic predisposition to CV events (3) to confirm a pro‐oxidative/inflammatory effect induced by NILO during treatment.Methods:A clinical CV risk score (S) was calculated using the algorithm from the European SCORE project. Integrating clinical with genetic information from 12 Single Nucleotide Polymorphisms (SNPs) associated with CV risk (ANRIL, SORT1, MIA3, CXCL12, MRPS6, PHATCR1, WDR12, LDLR, MRAS, CYP17A1, OLR1, IL10) an integrated score (IS) was obtained. CV‐relevant clinical and biological parameters were collected at specific timepoints (diagnosis, +1, +3, +6, +12 months) together with blood samples for IL6, IL10, TNFα and oxLDL plasma levels assessment.Results:Between September 2013 and September 2018, 177 newly‐diagnosed CML pts starting either IMA, NILO or DASA treatment, entered this study. After a median follow‐up of 22.4 months (range: 35 days – 5.4 years), a CV event has occurred in 5 pts, with a median time to event of 15 months (range: 44 days – 31.4 months). This accounts for an incidence of 5.9 per 1000 patient‐year, superior to that of a general age‐ and sex‐matched population (3.85 per 1000 patient‐year, OR 3.27, 95%CI 2.16–4.63; p = 0.013). Pts treated with NILO had lower CV risk at diagnosis (S = 6.9 ± 2.8) compared to those treated with DASA (S = 8.1 ± 3.2; p = 0.042) or IMA (S = 9.9 ± 4.9; p = 0.019). Nonetheless, 3/57 (5.2%) NILO‐treated pts developed CV toxicity, as opposed to 1/83 (1.2%) IMA‐treated (HR 2.9, 95% CI 1.8–4.4; p = 0.021) and 0 out of 37 DASA‐treated pts. One CV event occurred in a patient treated with first‐line IMA 23 months after being switched to Bosutinib, and therefore was not attributed to IMA.Levels of anti‐inflammatory cytokine IL10 were higher after 6 and 12 months of IMA or DASA compared to NILO. Also IL6/IL10 and TNFα/IL10 ratios in IMA‐ and DASA‐treated pts were lower compared to NILO‐treated pts. Increased levels of oxidation marker oxLDL were observed after 12 months of NILO, but not during IMA or DASA treatment. The few CV events registered did not allow for any correlation between genetic polymorphisms and increased CV risk in our population.Summary/Conclusion:This study confirms a higher CV risk for pts treated with NILO, even in a contemporary setting where pts were carefully selected for having a low pre‐treatment CV risk. This may be a consequence of a NILO‐induced pro‐inflammatory/oxidative status, as shown by reduced levels of IL10 and increased levels of oxLDL in pts treated with NILO. A longer follow up is necessary to identify possible specific genetic polymorphisms conferring higher CV risk in this population of CML pts treated with TKI.image

S882 OPTIMIZATION OF TKI TREATMENT IN ELDERLY PATIENTS WITH PH+ CHRONIC MYELOID LEUKEMIA AND STABLE MR3.0 OR MR4.0: 1ST YEAR RESULTS OF THE ITALIAN MULTICENTRIC PHASE-III RANDOMIZED OPTKIMA STUDY

Background: Family planning is important in patients (pts) with chronic myeloid leukemia (CML) who can have a near normal lifespan in tyrosine kinase inhibitors (TKI) era. Management of CML on conceptions and pregnancies is not defined as cases are rare and data are scarce. To investigate this issue a multicenter retrospective and prospective observational study of conception/pregnancy in CML pts was initiated within the European LeukemiaNet (ELN) from February 2014 till present. All ELN centers and participants from other countries were invited and received the study's protocol which was adopted in agreement with specific national laws. Aims: The main goal was to describe CML pts in terms of pregnancy/conceptions management and outcome. Secondary goals included demographics, characteristics of CML, management during pregnancy, pregnancy outcomes and characteristics of children. Methods: Adult pts aged ≥18 years with Ph+ positive CML and pregnancy were included after signing a written informed consent. Data were collected either in the coordinating centers in Moscow (Russia) and Rome (Italy) followed by the analyses of the entire data set. A total 305 pregnancy cases in 234 CML female pts from 15 centers of 13 countries worldwide were analyzed (Table 1). Results: Chronic phase at diagnosis was in 217/221(98%) pts. In 50 (21%) pts CML was diagnosed during pregnancy, while 184 (67%) got pregnant after diagnosis. Median (Me) time from CML diagnosis to pregnancy was 59 months (range 1–203). The outcomes of 305 pregnancies were as follows: labor 234 (77%), induced abortion 42 (14%), spontaneous abortion 21 (7%) and ongoing pregnancy or unknown outcome 8 (2%). Labor at full term was in 141 (75%) of 187 cases fully reported (Table 2). Molecular response (MR) evaluations at the start of pregnancy were recorded in 249/305 cases. Deep MR (DMR or BCR-ABL≤0,01% IS), major MR (MMR or BCR-ABL≤0,1%> >0,01% IS), MR2 (BCR-ABL>0,1%> ≤1% IS) and no MR2 (BCR-ABL>1% IS) was observed in 80 (32%), 31 (12%), 32 (13%) and 106 (43%) cases respectively. In 182 (71%) of 257 pregnancies with known data pts conceived while on TKI: 77% under imatinib (IM) and 23% TKI 2nd/3rd generation. TKIs were usually stopped early in 1st trimester (4–5 week of gestation) when the pregnancy was discovered. In 82 pregnancies pts were treated during 2nd-3rd trimester, after placental formation, until labor with IM: 33 (40%) of cases), nilotinib (NIL): 8 (9%), interferon (IFN): 23 (28%, 1 PEG-IFN), hydroxyurea: 6 (7%). IM was used throughout pregnancy in 13 (16%). One case of leukaferesis was recorded. The number of born children in 226 fully reported labors was 233 (including twins). Congenital abnormalities were recorded in 4 (1,7%) cases as follows: polydactyly (1), hypospadias (1) and non-closed foramen ovale of interatrial septum (2). None of the abnormalities were severe or life threatening, relationship to TKI use was considered unlikely by physicians. Low birth weight was recorded in 13 children with IM or NIL exposure at late pregnancy. The follow-up of all children was uneventful, with Me age at follow-up of 5 years (range 2 months-17 years).Summary/Conclusion: Most pregnancies in CML female pts resulted in normal childbirth with no increased rate of birth abnormalities in spite of TKI use at conception even if treatments were mostly early stopped at implant (4–5 weeks). Different therapies were used during pregnancy when needed. The results in terms of conception/pregnancy may be valuable for the development of CML treatment schemes particularly considering the variety of disease status.

PS1187 ASSOCIATION OF CELLULAR IMMUNITY WITH MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA PATIENTS ON TYROSINE KINASE INHIBITORS THERAPY

Background:Chronic myeloid leukemia (CML) is considered to be one of the cancers most sensitive to immunological manipulation. The most recent goal in CML treatment tyrosine kinase inhibitors (TKIs) is to induce a durable deep molecular response (DMR; BCR‐ABL1 ≤ 0.01%) as a prelude to successful treatment‐free remission. The lack of overt relapse in such pts has been attributed to immunological control of CML, although its precise mechanisms are as yet unclear.Aims:The aim of the study was to assess the relative (%) and absolute counts (AC) of major lymphocytic populations in correlation with the molecular response in a large series of patients with CML on TKI therapy.Methods:A total of 171 consecutive patients with CML treated with TKIs were enrolled in the study ‐ 91 men and 80 women. Immunophenotypic analysis of major T/B/NK cell populations was performed by flow cytometry at diagnosis and in the course of the disease in parallel with the monitoring of the molecular response (MR) by quantitative PCR analysis using GeneXpert fully automated platform (n = 523 tests).Results:At diagnosis, significant lymphocytosis was detected in all CML pts (mean 8.7 ± 4.4 x109/l), due to higher % and AC of T‐cells (mean 79.4% ± 11.6%; 7.1 ± 4.2 x109/l) with normal CD4:CD8 ratio (Th:Tc). The AC of NK and CD19+ B‐cells were within or close to the reference ranges. After therapy was given, all lymphocytic populations demonstrated a decrease of AC. However, significant differences in major lymphocytic populations were observed between pts with hematological response to TKIs who had never achieved MR compared to those with DMR in terms of higher mean values of WBC counts (p = 0.009); % and AC of CD3+ T‐cells (mean 68.4% ± 11.9% vs 67.3% ± 11.7%; mean 1.6 ± 8.3x109/l vs 1.4 ± 5.5 x109/l, p = 0.000); % and AC of CD8+ T‐cells (mean 24.8% ± 8.0% vs 22.1% ± 7.3%; mean 0.6 ± 0.4x109/l vs 0.4 ± 0.2x109/l, p = 0.000) resulting in lower Th:Tc. Further, within the group of MR4.5log/MR5log, pts with undetectable BCR‐ABL1 transcripts demonstrated lower % of CD8+ T‐cells compared to BCR‐ABL1 positive cases (mean 20.9% ± 6.7% vs 23.2 ± 7.4%, p = 0.011). Pts with optimal MR according to ELN criteria were characterized with lower % of CD8+ (mean 22.4% ± 7.2% vs 26.1 ± 9.2%, p = 0.000) and CD3+ (mean 72.1% ± 12.6% vs 76.4% ± 11.5%, p = 0.001) T‐cells; higher % of CD19+ B‐cells (mean 11.8 ± 6.1% vs 8.8 ± 4.8%, p = 0.000) and Th:Tc ratio (p = 0.006).Summary/Conclusion:Our data demonstrated dynamics in lymphocyte counts with treatment of CML patients as well as the differences in the lymphocytic populations, and clearly in the cytotoxic cells, depending on the depth of the therapeutic response achieved, thus supporting the idea that, in addition to the specific inhibition of the hybrid BCR‐ABL oncoprotein by TKIs in CML pts, the cellular immunity may further play role in disease control.

PF422 THE LONG‐TERM TREATMENT RESULTS OF THE MULTICENTER EUTOS ELN POPULATION‐BASED STUDY (EUTOS‐PBS) IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN RUSSIAN FEDERATION

Background:The data of 2904 adult patients (pts) with newly diagnosed chronic myeloid leukemia (CML) from 20 European countries were included into the multicenter EUTOS ELN population‐based Study (EUTOS PBS) from 2008 to December 2012 (Hoffman V et al. 2016). Russia took part in the EUTOS PBS and included 6.8% of the total number of pts. The EUTOS PBS in Russian Federation was prolonged and the results were updated at a long‐term follow‐up.Aims:To evaluate the long‐term results of treatment in pts with newly diagnosed CML in EUTOS PBS in Russia.Methods:The analyzed cohort of 197 pts (18 years) with Ph’+ /BCR‐ABL1+CML diagnosed in period 10/01/2009 ‐ 31/12/2012 from 6 regions of Russia was included into EUTOS PBS. CML was diagnosed in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) in93,4%, 6% and 0,6%pts respectively. The ELTS low, intermediate and high score(n = 179)was in 86 (48%), 50 (28%) and 43 (24%) pts accordingly. Median (Me) age was 50 (18–82) years, the male/female ratio was equal. The overall survival (OS) considering CML phase, cumulative incidence (CI) of deaths depending on death reasons was analysed. The CI of complete cytogenetic response (CCyR) and major molecular response (MMR) was evaluated. All calculations were done using the SAS Version 9.4 package of procedures program.Results:Me follow‐up in the Russian part of EUTOS PBS was 69 (0,7 – 96) months (mo). Imatinib (IM) and 2ndgeneration tyrosine kinase inhibitors (TKI2) were used as 1stline therapy in 97% and 3% pts accordingly. The 5 years CI of CCyR and MMR at the 1stline TKI therapy was 83% and 67% accordingly. The switch to the 2ndand 3rdline of TKI2 therapy was in 22 (12%) of 193 pts, the main reason was IM failure.The OS by 5, 6 and 7 years was 80% (95% CI 72% ‐ 86%), 78% (95% CI 65% ‐ 80%) and 73% (95% CI 65% ‐ 80%) respectively in total cohort (p < 0,001). The OS of pts with low and high ELTS score was 88% and 56% (p < 0,0023) respectively by the 80 mo of follow‐up. The 5‐year OS in pts with AP+BC phase was 39%.In total 47 (23,8%) pts died during the whole observation period. The largest number of deaths was observed in the 1styear after the CML diagnosis: 17 (36%) of 47 cases. The death reasons were as follows: 1) progression of CML to AP/BC in 20 (43%) pts, 2) death in remission (pts with CCyR and /or MMR within 6 months before death) in 5 (11%) pts, 3) death without progression to AP/BC but with signs of leukemia and without CCyR in 22 (46%) patients. The 5 years CI of death from all reasons was 20%, CI of CML‐related and CML non‐related death at 5thyear was 18% and 11% respectively (figure1).Summary/Conclusion:In general, the results of therapy in CML pts of the Russian non‐selected population sample were comparable to the data of the whole European cohort. A higher proportion of pts with ELTS high ELTS scoreand a lower proportion of pts switched to 2nd/3rdline TKI therapy in comparison with Europe was identified. These issues could have an impact on the number of CML‐related deaths and their high proportion in the 1styear of therapy. Therefore, the early therapy interventions within the 1styear of therapy in CML pts are apparently important for the long‐term treatment results.image

PS1177 PROGNOSTIC FACTORS FOR MOLECULAR RELAPSE‐FREE SURVIVAL AFTER DISCONTINUATION OF TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA BASED ON RUSSIAN MULTICENTER PROSPECTIVE TRIAL (RU‐SKI)

Background:About 50% of chronic myeloid leukemia (CML) patients (pts) after TKI discontinuation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all pts re‐achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topicalAims:To define the prognostic factors for molecular relapse‐free survival after TKI discontinuation in Russian CML populationMethods:The base for the analysis was the Russian multicenter prospective study RU‐SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety‐eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR‐ABL<0.01%) for at least two years were enrolled. Pts with previous imatinib failure and treatment‐free remission (TFR) failure were eligible. The BCR‐ABL level was evaluated by RQ‐PCR according to the international scale (IS). The schedule of molecular tests was as follows: monthly during the first six months (mo) after TKI cessation, every two mo from six to 12 mo and every three mo thereafter. Treatment by the same TKI was resumed in case of MMR loss (BCR‐ABL>0.1%). We used the proportional hazards regression analysis to identify independently significant factors for molecular relapse‐free survival (MRFS). We categorized each independently significant factor into two groups, depending on the optimal cutoff level obtained by the minimum P‐value approach. We used the Kaplan‐Meier method for calculating the probability of MRFS and the log‐rank test for comparison.Results:One year MRFS in all group was 51%. MRFS rate in pts with history of previous TFR failure (n = 7) was 14%. We decided to exclude from multivariate analysis pts with history of previous TFR failure to identify significant factors for the first attempt of therapy cancellation. Baseline pts characteristics (1st stop, n = 91): male: 48%; median (Me) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second‐generation (2G) TKI in 28 (31%) pts. Me follow‐up time after TKI cessation was 24 mo (range 12 to 41). Probability of MRFS (1st stop) was 55% after 12 mo of follow‐up. We include in multivariate analysis the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors with p ≤0.05. Treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group were attributed to favorable factors for MRFS after the optimal cutoff level was obtained (fig.1). We have found that the duration of TKI therapy, and not the duration of DMR has an independent prognostic value for the Russian CML population. The lack of molecular monitoring data at early stages of the disease in long‐term treated pts cause to the 1st DMR detection bias. Indeed, a longer time to the 1st DMR was observed in pts with the longer duration of TKI therapy (fig.2).Summary/Conclusion:Patients with treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group and without history of previous TFR failure are more preferable for TKI discontinuationimage

PB2221 OVEREXPRESSION OF PRV1 GENE IN MYELOID NEOLASMS AND ASSOCIATION WITH OTHER MOELCUALR ABNORMALITIES

Background:The polycythemia rubra vera 1 gene(PRV1) gene encodes a cell surface glycoprotein that plays a role in neutrophil activation and transmigration. PRV1 overexpression was found in significant proportion of patients(pts) with BCR‐ABL1‐negative myeloproloferative neoplasms(MPN). In the pre‐JAK2 mutation era testing of PRV1expression was recommented to differentiate polycythemia vera(PV) and essential thrombocytemia(ET) from secondary erythrocytosis or thombocytosis, respectively. The available data concerning the incidence of PRV1 overexpression, as well as its association with JAK2 gene mutation status is highly variable.Aims:To determine the incidence of PRV1 overexpression in different myeloid neoplasms and its association with other molecular abnormalities.Methods:Overall 167 pts with MPN were included in this study:43 with ET; 30 – PV; 15 ‐ primary myelofibrosis(PMF); 22 ‐ unspecified MPN(uPMN), 53 ‐ chronic myeloid leukemia(CML), including 18 pts at diagnosis and 35 pts on therapy with TKI; 4 pts with chronic myelomonocytic leukemia(CMML). PRV1 expression level was evaluated by reverse‐transcription polymerase chain reaction(RT‐PCR), with co‐amplification of b‐actin RNA as an internal control using total RNA from peripheral blood mononuclear cells. Semi‐quantitative characterization of PRV1 expression was done using 3grade score system: negative (‐): no product of PRV1 amplification; moderately elevated expression (+): PRV1 product with lower intensity than b‐actin product; strong overexpression(++): product of PRV1 amplification with intensity equivalent or higher than that of the b‐actin. To determine the association of PRV1 expression with JAK2 mutation status PRV1 expression was assessed in serial dilutions of homozygous JAK2V617F RNA in JAK2 wild type RNA. The PRV1 expression was clearly visible in up to 25% JAK2V617F mutation load. All pts were tested for the presence of BCR‐ABL1, JAK2V617F, and some cases for CALR and/or MPL W515L/K mutations.Results:Overall, PRV1 overexpression was found in 80.5% of pts with MPN (Table 1): 83.6%(n = 36) in ET; 93.3%(n = 28) in PV; 73.3%(n = 11) in PMF; 61.1%(n = 11) in CML(including 1 pt with co‐expression of BCR‐ABL1 and JAK2V617F); 95.5%(n = 21) in uMPN. PRV1 overexpression was significantly associated with JAK2V617F (+) status in BCR‐ABL1(‐) MPN with frequency of ranging between 73.3% and 95.5%. Interestingly, 3 JAK2V617F (‐) pts with PMF and PRV1 overexpression were found positive for CALR(n = 2) or MPL(n = 1) mutations.It was found higher prevalence of pts with strong overexpression PRV1(++) ‐ 67.9%(n = 19) in PV, 71.4%(n = 15) in uMPN, 77.8%(n = 7/9) in CML, with highest value in PMF ‐ 81.8%(n = 9). In contrast, in ET only 58.3%(n = 21) were PRV1(++). In CMML 1 pt was PRV1(++) and the second was PRV1(+). Strong PRV1 expression clearly correlated with JAK2V617F mutation load: PRV1(++) was found 24/28(85.7%) of homozygous pts, compared to 20/46 (43.5%) in heterozygous pts and 21/38 (55.3%) in JAK2 V617F(‐) pts. In CML pts on TKI therapy, PRV1 overexpression was found in 6/35 (17.1%) ‐ cases without any molecular response.Summary/Conclusion:PRV1 overexpression was found in a significant proportion of pts with BCR‐ABL1‐pos and BCR‐ABL1‐neg MPN, with highest frequency in PV and lowest in CML. Despite the clear association of PRV1 overexpression and JAK2V617F status, overexpression was also found in the absence of mutation suggesting alternative underlying mechanisms of activation of PRV1.image

Compound BCR-ABL1 Kinase Domain Mutants: Prevalence, Spectrum and Correlation with Tyrosine Kinase Inhibitor Resistance in a Prospective Series of Philadelphia Chromosome-Positive Leukemia Patients Analyzed By Next Generation Sequencing

Compound BCR-ABL1 Kinase Domain Mutants: Prevalence, Spectrum and Correlation with Tyrosine Kinase Inhibitor Resistance in a Prospective Series of Philadelphia Chromosome-Positive Leukemia Patients Analyzed By Next Generation Sequencing

Kinetics of the Leukemic Clone in Patients with Chronic Myeloid Leukemia during Pregnancy

Kinetics of the Leukemic Clone in Patients with Chronic Myeloid Leukemia during Pregnancy

Quality of Life in Chronic Myeloid Leukemia Patients with Deep Molecular Response Who Stopped Therapy By Tyrosine Kinase Inhibitors: Interim Results of Russian Prospective Multicenter Trial RU-SKI

BackgroundIt is reasonable to incorporate quality of life (QoL) assessment into the comprehensive evaluation of treatment outcomes in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) who enter the treatment-free remission (TFR) phase and stop therapy by tyrosine kinase inhibitors (TKIs). QoL assessment was included into the design of Russian prospective multicenter trial RU-SKI along with the clinical outcomes evaluation.AimTo study QoL in chronic phase (CP) CML pts with DMR before stopping TKI treatment and during TFR observation.Materials and methodsThe study has been conducted within the clinical approbation supported by the Ministry of Health of RF. The CML CP pts with therapy by any TKI ≥ 3 years (yrs) and stable DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled. Pts who met these criteria and had previous resistance to any TKI were also eligible. TKIs were resumed in case of major molecular response loss (MMR, BCR-ABL>0,1%). The QoL questionnaires RAND SF-36 and EORTC QLQ C30 were filled out by the pts before stopping TKI treatment and at 1, 3, 6 and 12 months (mo) after treatment discontinuation. The comparison group consisted of healthy persons matched by age and gender to CML CP pts (n=97). The Mann-Whitney test, paired Wilcoxon test and Generalized Estimation Equations (GEE) with adjustment to age, gender, the risk group according to Sokal score and duration of TKI treatment were used for the statistical analysis.ResultsQoL assessment was performed in all 99 CML CP pts who were enrolled into the trial during a period from Aug 2015 till Dec 2017. The TKIs before treatment cessation were as follows: imatinib and second-generation (2G) TKIs were used in 69(70%) and 30(30%) pts accordingly. 2G TKIs were used in 9(30%) and in 21(70%) pts as 1st and 2nd line accordingly. Mean age was 47±14.5 yrs, 48.5% were males, 12.1% had high Sokal risk score. The physical functioning of CML pts before stopping TKI treatment compared to the healthy controls was significantly worse (p<0.05). Other QoL scales before stopping TKI treatment were slightly worse with no statistically significant difference compared to healthy controls (figure 1). MMR was lost in 45 pts, and was maintained in 54 pts, Me follow-up time after TKI stop was 14,9 mo (range 2,5-32). The significant improvement of role physical functioning and role emotional functioning was found (p<0.05) in pts who maintained stable MMR during 12 mo after TKI discontinuation. The Integral QoL Index increased from 0,58 to 0,72 (p<0,001) in these pts. The decreasing of nausea/vomiting, diarrhea, shortness of breath at different time points (p<0.05) during TFR was revealed (figure 2). The QoL and symptoms before TKI interruption and after reinitiating of TKIs in 45 pts who resumed treatment were similar. The Integral QoL Index before and after stopping TKI treatment was 0.62 vs 0.64 (p>0.05).ConclusionThe QoL in CML CP pts with DMR on TKI treatment is slightly worse and physical functioning is significantly lower as compared to healthy controls. The positive changes of the role functioning along with TKI treatment-related symptoms decrease were revealed in pts who maintained stable MMR during 12 mo of TFR. No changes in QoL and no new symptoms were found in pts who reinitiated treatment before and after TKIs interruption. The results of QoL assessment may contribute to optimization of the treatment strategies of CML patients with DMR. [Display omitted] DisclosuresChelysheva:Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures; Novartis: Other: provided consultations and performed lectures. Shukhov:Bristol Myers Squibb: Other: provided consultations and performed lectures ; Novartis: Other: provided consultations and performed lectures . Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Ionova:Takeda: Research Funding; BMS: Research Funding.

Imatinib Suspension and Validation (ISAV) Study: Final Results at 79 Months

Introduction. It is known that imatinib can be safely discontinued in patients (pts) with Chronic Myeloid Leukemia (CML) with minimal residual disease. Here we report an update of the Imatinib Suspension And Validation (ISAV) study at 79 months (mts) from study initiation to provide long term follow up data.Aims. The ISAV study aims to validate the capability of digital PCR (dPCR) to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR and to evaluate relapse rate, time to recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL).Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (chronic or accelerated phase) treated with imatinib for more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 mts, with a minimum of 3 Q-RT-PCR performed at their own sites. After discontinuation of imatinib therapy, Q-RT-PCR was performed monthly (mts 1-6), bimonthly for 36 mts and then every 6 mts for additional 2 years, to assess the maintenance of the molecular remission. The loss of molecular remission was defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. dPCR was performed at screening and at 36 mts for those pts who were still in remission. Patients' QoL during imatinib discontinuation/resumption was evaluated through the EORTC QLQ-C30 questionnaire.Results. The ISAV study enrolled 112 pts with a median follow-up time of 60.0 mts [95% CI: 59.6-60.6] for pts who do not relapsed; 66.1% of them completed the study as per protocol. The 58.9% of pts were male and 37.4% were aged 65 or older; median duration of imatinib treatment was 103.2 mts with median duration of CMR of 25.6 mts before imatinib discontinuation. At 79 mts from imatinib discontinuation, 56 pts of the 107 eligible ones relapsed and resumed imatinib with a relapse rate of 52.3% [95%CI: 20.4-32.6]; 69.6% of them relapsed in the first 9 mts. Of the 52 not-relapsed pts, 40 (76.9%) regained Q-RT-PCR positivity without losing MMR. In this latter group 2 pts experienced late relapses, at 30.6 and 45.5 mts respectively. A loss of CCyR occurred in 13 pts (23.6%): 10/13 CCyR losses were recovered, the remaining 3 were not assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.8 [95% CI: 1.0-2.0] mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse was evident. dPCR results before imatinib discontinuation showed that 23.4% of pts were positive and 76.6% negative at the time of discontinuation, with a Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.1 [95%CI: 0.99-1.22]. At 36 mts from imatinib discontinuation 80.4% [95%CI: 30.6-50.4] of the pts tested were positive in dPCR. Moreover, the results of dPCR performed at imatinib discontinuation and age together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation, particularly with regard to nausea, diarrhea, fatigue and insomnia (p<0.05). An inverse and transient trend toward increased pain emerged at mts 1 and 3.Conclusions. At 79 mts from the beginning of the study, 52.3% of pts relapsed, with 24% loosing CCyR. The majority of relapses occurred in the first 9 mts after discontinuation however late relapses were also observed, up to the 4th year. Therefore, pts who discontinue imatinib should be monitored for a long period of time, especially if they show positive PCR values after discontinuation. All relapsed pts including those who lost CCyR regained their original response after restarting TKI. Age <45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia. Disclosuresle Coutre:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Kim:Pfizer: Research Funding; BMS: Research Funding; Ilyang: Research Funding; Novartis: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

Prognostic Model of Successful Tyrosine Kinase Inhibitors Discontinuation Based on the Russian RU-SKI Multicenter Prospective Study

Background: A large number of tyrosine kinase inhibitors (TKI) discontinuation studies has shown that about 50% of chronic myeloid leukemia (CML) patients (pts) after TKI cessation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all patients re-achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topical.Aim: Develop a prognostic model for the better selection of CML patients for TKI discontinuation.Methods: The base for the training set was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR-ABL<0.01%) for at least two years were enrolled. Seven Pts with a previous history of unsuccessful treatment-free remission (TFR) were excluded from the analysis. The BCR-ABL level was evaluated by RQ-PCR according to the international scale (IS). The schedule of molecular tests was as follows: monthly during the first six months (mo) after TKI cessation, every two mo from six to 12 mo and every three mo thereafter. Treatment by the same TKI was resumed in case of MMR loss (BCR-ABL>0.1%). We used the Kaplan-Meier method for calculating the probability of TFR. Univariate analyses were performed using the log-rank test to identify prognostic factors for TFR. Variables found to be significant at the p<0.10 level were entered into a proportional hazards regression analysis. We categorized each independently significant factor into two groups, depending on the optimal cutoff level obtained by ROC analysis and the minimum P-value approach. The next step was a second multivariate analysis including categorized variables. A favorable factor from each variable was scored as 1, while the adverse factor was scored proportionally to the level of hazard ratio. The cumulative score for each patient was calculated. Patients were allocated to either a high or a low risk group concerning MMR loss after the cutoff level was determined by ROC analysis. The validation set included a series of 48 retrospective cases of discontinued patients selected according to RU-SKI inclusion criteria.Results: Baseline characteristics of the training set (n=91): male: 48%; median (Mе) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second-generation (2G) TKI in 28 (31%) pts. Me follow-up time after TKI cessation was 14 mo (range three to 36). Probability of TFR was 55% after 12 mo of follow-up. We analyzed the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Age, Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors and included in the survival prognostic model (Table 1). 73% (n=66) of pts scored 5.5 points or less and were assigned to the low risk group. The probability of TFR was 64% and 33% for the low risk and high risk groups, respectively (p=0.001) (Figure 1). Baseline characteristics of validation set (n=48): male: 36%; Ме age at TKI cessation 46 years (range 22 to 76); Me duration of TKI therapy six years (range 3.5 to 13.2); Me duration of DMR 2.8 years (range two to 10). Therapy before treatment stopped: imatinib in 31 (65%) pts, 2G TKI in 17 (35%) pts. Me follow-up time after TKI cessation was 36 mo (range six to 116). Probability of TFR was 47% after 30 mo of follow-up. In the validation set, 77% (n=37) of pts were assigned to the low risk group. The probability of TFR was 56% and 18% for the low risk and high risk groups, respectively (p=0.007) (Figure 2).Conclusion: RU-SKI prognostic model is effective in prediction of successful TFR and can be used for better selection of CML pts for TKI discontinuation. [Display omitted] DisclosuresShukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Novartis: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

Comparative Monitoring of Minimal Residual Disease (MRD) By RT-Quantitative (RT-qPCR) and Digital PCR (dPCR) in Ph+ Chronic Myeloid Leukemia (CML) Patients Treated with TKIs for Recognition of Stable Deep Molecular Response (DMR) and Identification of Best Candidates to TKIs Treatment Discontinuation

Current therapy of CML with tyrosine kinase inhibitors (TKIs) aims to achieve a Major Molecular Response to avoid the disease progression to blastic phase and, possibly, a Deep Molecular Response (DMR), to gain the opportunity for TKIs discontinuation and Treatment Free Remission (TFR). However, TFR strategies are not yet optimized, as well as the criteria for patients (pts) selection to TKI discontinuation are not well defined. The patient9s CML prognostic score, the duration of TKI treatment and "stable" DMR before discontinuation and the levels of DMR are still matters of debate. Due to its intrinsic limitations, RT-qPCR cannot be considered as an optimal tool for a precise detection of minimal BCR-ABL1 transcript levels and DMR monitoring. The digital PCR (dPCR) has emerged as a more sensitive and accurate method to detect and monitor the BCR-ABL1 minimal residual disease (MRD). This study focused on the BCR-ABL1 RT-q/dPCR comparative monitoring in CML pts treated with TKIs and with durable DMR (≥ 2 years), as conventionally assessed by RT-qPCR, before the enrollment. The aim was to evaluate the reliability and the efficiency of dPCR, as compared to RT-qPCR, for a better identification of "stable" DMR and for a better selection of the candidates for treatment discontinuation. 118 CML pts with durable DMR were enrolled and 493 peripheral blood samples were comparatively analyzed by both RT-qPCR, according to the last International Guidelines, and dPCR (QS3D Digital PCR System). RT-qPCR results were assessed as BCR-ABL1 %IS. dPCR results were assessed as number of BCR-ABL1 copies/□l of reaction and the molecular response was categorized as □ 0.468 or Starting from the first RTq/dPCR comparative assessment, the 118 pts were monitored every 3/4 months for at least 3 time points. Grouping the 118 pts according to the RT-qPCR molecular results at the enrolment, 50 cases (42%) resulted in the MR4.0group and 68 (58%) in the MR 4.5-MR5.0 group. No significant differences were observed between these 2 groups in terms of clinical and hematological characteristics. At the same time, the 118 pts were divided in 2 groups based on the comparative dPCR molecular results, according to the above mentioned cut-off value: 29 (25%) and 89 (75%) cases had dPCR values □ and □0.468 BCR-ABL1 copies/□l, respectively. No significant clinical differences were observed between these 2 groups. Out of these 118 pts, 87 (74%) discontinued the TKI treatment and 24 (28%) of them lost the DMR after a median time of 3 months (range 1-30). Based on dPCR, 23/87 (26%) and 64/87 (74%) had dPCR □ 0.468 and In order to reach a better recognition of stable DMR, which is strictly related with the probability to achieve and maintain TFR after TKIs discontinuation, we comparatively analyzed, by RTq/dPCR, the course of MRD during the follow up period. In the case of monitoring by RT-qPCR, a wide oscillation of the molecular responses was observed and they tended to be superimposable both in the group of pts with MR4.0 and in those with MR4.5 and 5.0. In the case of monitoring by dPCR, the values assessed at the enrolment and during the follow up revealed the capability of the dPCR to measure different and heterogeneous numbers of BCR-ABL1 copies in each pts. Moreover, the pts with a dPCR below the cut-off value of 0.468, at enrolment, were maintaining values (median 0,175; range 0-1,863), significantly lower (p This retrospective study show that the dPCR is more accurate and sensitive than conventional RT-qPCR for detecting and monitoring the BCR-ABL1 molecular levels and potentially able to improve the recognition of the stable DMR and selection of the candidates to TKI treatment discontinuation. Disclosures Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Gaidano:Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Rossi:Teva: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Honoraria; Sanofi: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Membership on an entity9s Board of Directors or advisory committees; Sandoz: Honoraria; Jazz: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria; Amgen: Membership on an entity9s Board of Directors or advisory committees. Gobbi:Novartis: Consultancy; Ariad: Membership on an entity9s Board of Directors or advisory committees; Pfister: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Consultancy; Celgene: Membership on an entity9s Board of Directors or advisory committees. Voso:Celgene: Research Funding, Speakers Bureau. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy.

Frontline Treatment with Dasatinib in Very Elderly Patients (> 75 Years) with Chronic Myeloid Leukemia: Is It Feasible?

Dasatinib (DAS) has been licensed for first line treatment of patients (pts) with Chronic Myeloid Leukemia (CML): however, in the current clinical practice, DAS is often considered too toxic for the treatment of elderly CML patient. In particular, no data are available in very elderly CML pts as to toxicity and efficacy. To address this issue, we evaluated a “real-life” cohort of 39 CML pts in chronic phase aged > 75 years and treated with frontline DAS in 20 Italian Centers from 6/2012 to 10/2017.Main clinical features at diagnosis are reported in the Table 1. Overall, 23/39 pts (58.9%) had ≥ 2 comorbidities requiring concomitant therapies: according to ECOG scale, performance status at baseline was 0 - 1 in 34 pts (87.2%) and 2 in 5 pts (12.8%). Median interval from diagnosis to DAS therapy was 0.8 months (IQR 0.5 - 1.4). Daily DAS starting dose was 100 mg in 30 pts (76.9%), 80 mg in 1 pts (2.6%) and 50 mg in 8 pts (20.5%), respectively.All pts were evaluable for toxicity and efficacy; on the whole, grade 3/4 hematological and extra-hematological toxicities were detected in 6 (15.4%) and 11 (28.2%) pts, respectively. DAS therapy was permanently discontinued in 9 pts (23.0%) due to toxicity (3 pts in the first 12-month period of treatment and 6 beyond).Pleural effusions of all WHO grades occurred in 12 pts (30.7%) after a median period of DAS treatment of 16.3 months (IQR 2.2 - 31.8): in 4 of them pleural effusion occurred during the first 6-month period of treatment.Overall, 36/39 patients (92.3%) achieved at any time complete cytogenetic response (CCyR), 30/39 (76.9%) major molecular response (MR 3.0) and 16/39 (41.0%) deep molecular response (MR 4.0/4.5). Only 1 patient (2.6%) evolved in a blastic phase after 13 months from DAS initiation.After a median period of 27.8 months (IQR 19.1 - 37.5), 5 patients died (1 from blastic phase and 4 from unrelated causes): cumulative event-free survival and overall survival at 36 months were 63.2% (95%CI 45.2 - 81.2) and 85.3% (95%CI 73.3 - 97.3), respectively (Figures 1 and 2).In conclusion, these data indicate that DAS therapy may have a role also in the treatment of patients aged > 75 years, being effective as in younger subjects and having an acceptable safety profile. DisclosuresGugliotta:Novartis: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria.

Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs

Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs

Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts).AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts.METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events.RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%.The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y.SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. DisclosuresGugliotta:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted

The SETD2 protein is a histone methyltransferase that specifically catalyzes the trimethylation of Lysine 36 on histone H3 (H3K36me3). SETD2/H3K36me3 are implicated in transcript elongation and splicing, DNA repair, chromosome segregation. SETD2 gene deletions and/or mutations (mostly frameshift or nonsense) have been reported in solid tumors (clear cell renal cell carcinoma, bladder cancer, lung cancer, melanoma, endometrial cancer) and in acute leukemias.Using a Western Blotting (WB) approach to screen for SETD2 protein expression and for H3K36me3 levels in a relatively large cohort of 80 advanced-phase chronic myeloid leukemia (CML) patients (pts), we could detect reduced or null SETD2 and H3K36me3 in 86% of pts as compared to a pool of healthy donors and to chronic phase (CP) pts at diagnosis who achieved optimal responses to TKI, but neither mutations/deletions nor transcriptional down-regulation were the underlying causes. Inhibition of proteasome-mediated degradation in primary cells from pts with undetectable SETD2 restored H3K36me3 and led to accumulation of hyper-ubiquitinated SETD2, suggesting that a functional protein is produced but rapidly degraded. Moreover, proteasome inhibition was found to induce apoptosis and to reduce clonogenic growth. In K562 cells (SETD2/H3K36me3low), co-immunoprecipitation (co-IP) performed before and after proteasome inhibition showed accumulation of the hyper-ubiquitinated form of SETD2 bound to MDM2. MDM2 inhibition by SP-141 resulted in cytostatic effects and restored SETD2 expression and activity. Superimposable results were achieved by siRNA-mediated silencing of MDM2, suggesting that MDM2 is implicated in SETD2 reduced stability. Co-IP also showed that SETD2 interacts with Aurora Kinase A a Ser-Thr kinase frequently overexpressed in CML. We found that Aurora Kinase A phosphorylates SETD2, and both pharmacological inhibition by Danusertib and siRNA-mediated silencing rescued SETD2 expression and activity.Next, to investigate whether SETD2/H3K36me3 loss may contribute to genetic instability, LAMA 84 (SETD2/H3K36Me3high) and K562 (SETD2/H3K36me3low) cells were studied by WB and immunofluorescence (IF) to assess phosphorylated histone 2A.X (γH2AX) and Rad51 foci in steady state conditions and after sub-lethal DNA damage by UV exposure. The same studies were performed after SETD2 silencing for 3 months. Cells with low or silenced SETD2 had significantly higher levels of γH2AX and were unable to induce homologous recombination (HR) repair after DNA damage. Clonogenic assays performed in LAMA 84 cells before and after SETD2 silencing, in K562 (SETD2/H3K36me3low) and in imatinib-resistant (IM-R) K562 cells which have lost SETD2 expression and activity, suggested that reduction of clonogenic growth after proteasomal or MDM2 inhibition is strictly dependent on SETD2 expression and functional status (Figure 1A).First and second generation proteasome inhibitors (bortezomib, carfilzomib and ixazomib) inhibited the clonogenic potential of the mononuclear cell fraction from both CP (n=2) and blast crisis (BC) (n=4) CML pts at subnanomolar concentrations, with the extent of anti-tumor activity clearly anti-correlated with SETD2 expression and H3K36me3 levels: pts with lower SETD2 expression showed lower LD50 when compared with pts with higher SETD2 expression and H3K36me3 levels (Figure 1B). Similarly, clonogenic assays performed by administrating increasing doses of SP-141 (from 0.25 to 1.25 µM) suggested that MDM2 specific inhibition had more significant effects in BC-CML pts showing low SETD2 levels and activity as compared to BC-CML pts showing intermediate SETD2 levels and activity and to CP CML pts.In conclusion, phosphorylation by Aurora Kinase A and ubiquitination by MDM2 contribute to SETD2 non-genomic loss of function in advanced-phase CML. Loss of SETD2/H3K36me3 is associated with increased DNA damage and impaired HR repair. Restoring physiological H3K36me3 levels may help improve the outcome of this critical subset of pts.Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma). [Display omitted] DisclosuresCastagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Novartis: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria. Abruzzese:Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Martinelli:Ariad/incyte: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Consultancy. Cavo:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy.

Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

Social Parameters Are Independent Predictors for Survival in Chronic Myeloid Leukemia

Introduction and data: Social and demographic personal data are important to be included in analysis and interpretation of results of any population studies in oncology. But it looks like social status is underestimated as cofounder for survival of patients with chronic myeloid leukemia (CML). The aim of this study was to check the prognostic value of social parameters like marital status and education level in comparison with standard risk factors. Russian CML Registry include more than 10 thousand patients (pts) data. In the analysis 8326 CML pts in chronic phase (CP) with first line TKI therapy were included: 91% of pts were treated by Imatinib and 9% by other TKIs. Mean age was 49years, 4607 f/ 3705 m. Me of follow-up-4.24years. Overall survival(OS) was estimated starting the diagnosis date, event was death from any reason, date of last contact was censored for alive pts. Survival analysis was performed by SAS procedures. Results:Firstly, we perform one-way survival analysis and estimate OS depending upon the 3 parameters Sokal Score, Marital Status and Education. There are high significant dependences OS on all three factors as shown on picture 1 (OS estimates depending on values of: 1A) Sokal score (low, intermediate, high), 1B) Marital Status (married, single, widowed/divorced), 1C) Education (low/secondary, higher). Marital Status and Education are correlated with Sokal Score (corresponding Pearson's coefficients are 0.19 and 0.12, p<0.0001). This association is caused by age but is not so strong. Than we have estimate OS in each Sokal's risk groups (picture 2. OS estimates depending on Marital Status (single, married - blue line, widowed/divorced - green line) in different Sokal's risk groups: 2A) - low, 2B) - intermediate, 2C) - high). OS estimates depending on Education (picture 3; (low/secondary red line, higher- blue line) in different Sokal's risk groups: 3A) low, 3B) intermediate, 3C) high. And we see that Marital Status and Education are predictive in each risk group but the most influent in high risk group. Marital Status and Education are correlated with other impotent cofounder- age. It should be checked in additional multi factor analysis we plan to do. We also run the proportional risk regression Cox's model on this data. Hazard ratio (HR) and significance (Px2) for included parameters are following: Sokal score - HR=1.59, Px2<0.0001; Education- HR=1.76, Px2<0.0001; Marital Status- HR=1.40, Px2<0.0006. Conclusions: The social and demographic personal data should be included in any analysis of CML population data. Marital Status and Educationare obviously associated with adherence behavior of CML patients and must influent on longitude therapy output. The highly education level is favorable factor, widowed/divorced marital status is unfavorable factor for OS prognosis. [Display omitted] DisclosuresKulikov:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.