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We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.

Introduction Duration of treatment with tyrosine kinase inhibitors (TKI) is an important favorable prognostic factor for treatment-free remission (TFR) and deep molecular response (DMR) in patients (pts) with chronic myeloid leukemia (CML). Aim To analyze the impact of first-line treatment duration with imatinib and 2G TKI on molecular relapse-free survival (MRFS) in CML pts with sustained DMR. Patients and methods In total, 174 CML pts in chronic phase with ≥3 years treatment duration and sustained DMR (MR4-MR5, BCR-ABL IS 0.1%). Median (Me) age of pts was 43 (range 21-86) years; 39% were males. Me TKI treatment duration was 86 months (IQR 57-125 mo), Me DMR duration was 45 (IQR 29-66 mo). Imatinib, 2G TKI in first-line and 2G TKI in second-line were discontinued in 116 (66.7%), 15(8.6%) (11 nilotinib, 3 dasatinib, 1 bosutinib) and 43 (24.7%) (34 nilotinib, 9 dasatinib) pts respectively. Results Me follow-up time after treatment cessation was 33 months (range 1-133). MRFS at 6, 12, 24 and 36 months was 62% (CI: 55-70%), 53% (CI: 45-60%), 50% (CI: 42-57%) and 48% (CI: 40-56%) respectively. Treatment duration and MR4.5 vs MR4 were significant for MRFS both in univariate (p=0.009 and p=0.015) and multivariate analysis (p=0.017 and p=0.037). No difference in 36 months MRFS was observed for imatinib (47% (CI: 42-60%)), first-line 2G TKI (59% (CI: 33-84%) p=0.58) and second-line 2G TKI (47% (CI: 32-63%) p=0.97) groups. However, significantly shorter treatment duration was observed in first-line 2G TKI group (Me=44 mo (IQR 40-52 mo)) vs imatinib (Me=93 mo (IQR 69-127 mo)), p Conclusion The 2G TKI as a first-line seem to be an effective option to reduce the treatment duration before TFR in CML pts although MRFS rate was not significantly improved in our study.

Abstract 4432 Background: The incidence of chronic myeloid leukemia (CML), reported from some population based registries, varies significantly. CML is known as age-dependent disease, so population age structure may strongly influent on the data. For international comparisons several systems for age-standardization are using in epidemiological studies. We conducted our retrospective study to reveal differences in CML incidence rates on the basis of calculation – crude or age-adjusted according to different population standards in St. Petersburg and Leningrad region. Methods: In 2005 the database of Ph- and/or bcr-abl- positive CML patients (pts) was conducted in St. Petersburg and Leningrad region. Since then the data from all newly diagnosed CML patients were included prospectively on population basis. The database was updated at least bi-annually. The data were obtained from hematologists, as general practitioners and private physicians are not licensed to treat oncohematological disorders. The data were double checked from the list of Imatinib distribution (the only drug reimbursed for first line treatment). To calculate crude CML incidence rate we use the data of the general census of the population in Russia in 2010 (the whole population of our region is 6596434 with population in age 15 and above 5821133). For age-adjusted CML incidence rate we use three of currently existing standards: The Segi (“World”), The Scandinavian (“European”) and the WHO standard (based on world average population between 2000–2025). Results: There are 258 (242 in chronic, 9 in accelerated and 7 in blastic phases) CML adult (15 years and above) pts, registered during 2006–2011. The median age is 53 years (48,5 and 55,5 years for men and women respectively). Sokal score was evaluable in 209 pts. It is low in 37%, intermediate in 35% and high in 28% pts. The crude CML incidence rate is slightly higher in men than in women with ratio 1,2:1. Mean annual crude CML incidence rate was 0,65 per 100 000 whole population of Saint Petersburg and Leningrad region, but it was 0,74 in adult population (15 years old and above). Mean annual CML incidence rates in the same age groups were slightly higher in all three standardized systems: 0,94 in Segi, 0,84 in Scandinavian and 0,88 in WHO standard populations. CML incidence rates in all age groups are presented in the table 1. CML incidence rate was lowest in young pts. It was unexpectedly very low in senior pts. CML incidence rates nearly for all age groups were slightly higher in St. Petersburg than in the Leningrad region. The majority of pts (98%) were treated with Imatinib (93% first or second line) or other tyrosine kinase inhibitors (5% first line-in international clinical trials, 18% after Imatinib failure or intolerance). Stem cell transplantation was performed only in 8/258 (3%) pts. Only 25235 (7,5%) evaluable pts progressed from chronic to advanced phases. Only 29/258 (11%) pts dead mostly due to CML (21 CML related deaths were reported). Estimated 5 years overall survival is 91,5%. Mean annual overall CML pts death rate was 1,9% (mean annual death rate between 2006–2010 in whole population of our region was 1,6%). Mean pts accumulated very fast - annual CML prevalence increasing rate between 2005–2011 was more than 14% (Picture 1). Conclusions: CML incidence both crude and age-adjusted in our population based registry is nearly the same in young and middle age, but much lower in senior (65 years and above) pts groups in comparison with published data from other registries which probably represents peculiarities of health system rather than real incidence. In the tyrosine kinase inhibitors era CML patients death rate is very low (nearly the same as in whole population) and CML pts is accumulated very fast in our region. Disclosures: No relevant conflicts of interest to declare.

Abstract 4452 Imatinib (IM) is now used world-wide as a first line chronic myeloid leukemia (CML) treatment. Although some time lack may exist between diagnosis and IM treatment. Earlier (Blood 2009, 114: Abstract 4278) we have shown that in CML chronic phase (CP) pts with very long history of the disease(more than five years)the pretreatment by Busulfan was the adverse prognostic factor on Imatinib therapy. Now we extend our study by a population of pts recently and for rather short time pretreated by busulfan. Aim. To investigate the effect of busulfan pretreatment on survival and responses to imatinib in CML pts in late CML CP. Materials and methods. In retrospective study 85 pts with CML CP from St-Petersburg, Leningrad region (Russian Federation) and several Ukrainian centers were included. The main inclusion criteria were: CML late CP (the duration of the disease more than 6 mos before IM start), IM therapy in routine clinical practice at least 12 months. The median time of IM therapy was 42,9 mos (12–97 mos), the median age of pts at the IM start was 49,5 years (19–83), male/female ratio 31/54. 23 patients were pretreated with busulfan (the study group) and 62 were not (control group). These groups were equal by age, sex, the median time from diagnosis to the IM start (28,3 mos in the study group and 23,9 in the control group), Sokal risk groups. Median time of busulfan pretreatment was 3,9 mos (1–62 mos). Statistical analysis was performed with SPSS 17. Results. In the whole group of patients frequency of complete cytogenetic response (CCyR) was 60% (51/85), estimated overall survival (OS) by 5 years from IM start was 87% (death rate 7% - 6/85). In the study group CCyR rate was significantly lower, than in the control group: 34,8% (8/23) and 69,35% (43/62), respectively, p=0,038. Estimated OS by 5 years was 72% (death rate 17% - 4/23) for busulfan-pretreated pts and 95% (death rate 3% - 2/62) for the control group, p Interestingly, that in the group of shortly busulfan-pretreated pts (the duration of pretreatment ≤6 mos), the lower CCyR rate has also been observed – 31% (4/13), although all other parameters were seemed equal to the control group (median time before IM start 28,3 mos). Conclusion. The pretreatment with busulfan impaired negatively the efficacy of imatinib treatment in CML late CP patients. Even short pretreatment (less than 6 mos) had adverse effect on CCyR. The mechanism is unclear. Busulfan pretreatment before imatinib therapy should not be used. Disclosures: No relevant conflicts of interest to declare.

Abstract 4476 At present, the main goal of chronic myeloid leukemia (CML) therapy is to obtain complete cytogenetic response (CCyR) which is strongly associated with patient's survival. The second main factor for good prognosis after CCyR achievement is its stability. The aim of this study was to reveal factors, influencing the stability of CCyR in CML chronic phase (CML-CP) patients on Imatinib (IM) therapy in routine clinical practice. Patients and methods: In patients database of St-Petersburg and Leningrad region there are 235 CML-CP patients, who received IM for 12 months or more. Eligibility criteria for analysis were as follow: IM start dosage 400 mg/day, CCyR, which was confirmed by at least 2 consecutive cytogenetic analysis with 0% Ph+ cells in at least 20 metaphases. Patients in CCyR with IM therapy interruptions more than 3 months were censored at the date of last cytogenetic analysis. Results: 115 patients from our database were found to eligible for analysis. The median age at the diagnosis was 48 years (16-76 years). Male/female ratio was 50/65. The median time from diagnosis to IM treatment was 7 months (0.1-108 months), 55 patients begun the IM treatment in early CML-CP (≤ 6 months since diagnosis). 64, 38 and 13 patients had low, intermediate and high Sokal scores respectively. There were no differences between patients in early and late CML-CP. 56 (48,7%) patients before IM were treated with interferon. The median observation time on IM treatment was 56 months (16-88 months). Overall estimated probability of CCyR loss was 16%, rate 12.1% (14/115). In 10 patients CCyR was lost within major CyR. The estimated overall survival (all causes of death) was 78% (death rate 4.3% (5/115)), and only 1 death was CML-related. The probability of CCyR loss was not depend on previous interferon therapy and was equal in both groups -16%. The rate of CCyR loss was 15.3% (9/59) vs 8.9% (5/56) in pts with or without interferon pretreatment respectively. Sokal scores also didn't influence CCyR stability: CCyR loss rates were 10.9% (7/64), 13.2% (5/38), 15.4% (2/13) for low, intermediate and high risks, respectively (p>0.1). Probabilities of CCyR loss in different ages groups were similar: 13% (rate 8% (4/50)) vs 18% (rate 15.4% (10/65)) in patients older and younger than 50 years old, respectively (p>0.1). CCyR loss was less frequent in early CML-CP 10% (rate 3.6% (2/55)) then in late CML-CP 21% (20% (12/60)), p=0.032. For more thoroughly analysis, patients in late CML-CP were divided in subgroups related to duration of CML before IM initiation: >6 and ≤12 months, >12 and ≤60 and more than 60 months. Probabilities of CCyR loss in this groups were 22% (rate 20% (3/15)), 27% (rate 25.7% (9/35)) and 0% (rate 0% (0/10)), respectively (p Among patients, who lost CCyR, only 2/14 (14%) patients progressed to blast crisis. One of them was treated with chemotherapy followed by allo-SCT. At present, he is still alive in CCyR and complete molecular response. Another patient with blast transformation was treated by high dose IM with chemotherapy. There is no response and patient died due to progressive disease. From other patients: CCyR was re-obtained in 7 patients - in 5 patients on IM (2 pts on the same dose and 3 pts after IM dose escalation) and in 2 pts on second generation TKIs. One patient after IM dose escalation is not yet evaluable. Other 3 patients didn't respond either high dose IM or second generation TKIs, but are still alive in CML-CP. One patient lost from follow up. Conclusions: Patients in CML-CP with CCyR has very good prognosis. Very few patients progressed and dead during several years. There are two factors, which influence the probability of CCyR loss: initiation of IM in early CP and CCyR in first year of treatment are favorable to good prognosis for CCyR durability. Disclosures: No relevant conflicts of interest to declare.

Abstract 4288 Resistance to imatinib could be overcome by new generations of TKIs. Data about the efficacy of second line TKI treatment may help to create a system for prognosing the duration of 2nd line TKI treatment and time of switching from second line TKI treatment to hematopoietic stem cell transplantation. The aim of the study was to evaluate the results of 2nd line TKI treatment in patients resistant or intolerant to imatinib. Patients and methods 44 resistant and 3 intolerant to imatinib pts were included. Cytogenetics with G-banding and PCR with sequencing were performed for evaluation the response and mutations. There were 39, 7 and 1 pts in CP, AP and BP respectively, Patients were treated by three different ATP-pocket inhibitors. The follow-up on 2nd line TKIs was 0.9-48mons (Median - 15.9 mons), median follow-up from diagnosis was 73,9 mons. In prognosis analysis (CHR, cytogenetics, Sokal) intolerant patients were not included. Results Probability of overall survival from diagnosis by 10 years was 85%. Probability of survival from the start of TKI2 by 4 y -90%. There were no differences in survival in pts with primary and secondary resistance, in CP and AP. Patients with low and intermediate Sokal risk did better than patients with high risk (p=0.014, Fig. 1.). 8 pts had T315I mutation when studied on second line TKI therapy. Achievement of CCyR was 50% (58% when T3151 patients were excluded), it was higher in low+intermediate in comparison with high risk pts (60% vs 30%, p=0.091), in CP than in AP (56% vs 20%,p=0.07), in patients with CHR at switching than in those without CHR (72% vs 18%, p=0.014). We failed to find any differences in CCyR achievement in pts with different best cytogenetic response on imatinib (complete, major, minor, minimal responses, absence of cytogenetic response). MCyR depended on the type of resistance - it was higher in secondary, than in primary resistant pts (80% vs 45%,p=0.06, Fig2). Probability of MCCyR loss was 20%, all of them appear during the first year of treatment. It was higher in AP than in CP (40% vs 12%,P=0.04). Probability of 4 years PFS was high - 75%, also without differences in primary vs secondary resistance and even in AP vs CP. Conclusion Second line TKI treatment is very efficacious in imatinib resistant pts. The effect depended on the type of resistance and phase of the disease, CHR at the moment of switching to 2nd line treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract 4278 Imatinib(IM) has become the “gold standard” for the treatment of CML CP. In clinical trials the majority of pts obtain complete hematologic (CHR) and complete cytogenetic (CCyR) responses. The aim of the study was to evaluate the results of treatment by IM in CML CP pts in general practice (outside clinical trials). Patients and methods There are 335 pts with CML in databases in Saint-Petersburg and Leningrad region. Most of them (283/335-84,5%) are ever treated with IM. Disease phases at the time of the start of IM therapy by ELN (from 268/283 evaluable pts) and MDACC (from 256/283 evaluable pts) criteria were: CP – 232 and 215, AP – 28 and 33, BP - 8 and 8 respectively. All 232 pts in CML CP (by ELN criteria) treated since 2001 by IM were included in the study. Before IM 91/232(39%), 114/232(49%) and 17/232 (7,3%) pts were pretreated by hydroxyurea, interferon-alfa with or without hydroxyurea and busulfan. 12/335(4%) pts were undergone alloSCT(6 alive, 6 dead due to progression or TRM) There were 134/232(58%) pts in early (duration before Im ≤ 12 mos) and 98/232(42%) pts in late CP (> 12 mos). In early and late CP, there were 49/123 and 50/89, 40/123 and 23/89, 34/123 and 16/89 evaluable pts with low, intermediate and high Socal score respectively. The predominance of low Sokal score in late CP pts could to be related to survival benefit before imatinib.. The median time before Im for the whole group, for early and late CP pts were 7,4 mos(from 7 days to 132 mons), 1,8 mons (form 7 days to 12 mons) and 39 mons (from 12,1 mos to 132 mos) respectively. Median time of Im therapy was 33 mos (1 - 75 mos) in whole group, 24mons (1 - 73mos) in early and 34mos(2 - 75mos) in late CP pts respectivel Results Estimated overall survival by 6 years was 94,2% in whole group, 97% and 87% in early and late CP pts resp. Only 14/228(6,1%) of evaluable patients died due to CML: 4/130(3%) in early and 10/98(10,2%) in late CP group. 4 pts, resistant to IM, were transplanted: 1 in early CP and 3 in BP. Deathes were due to TRM or disease progression. CHR was achieved by 3 mons in most cases: 82/110(74,5%) and 36/64(56%) pt, in early and late CP, resp. Patients (39 in hole group, 12 in early and 27 in late CP) with CHR before IM were excluded from these analyses. The probability of CCyR by 6 years was 98% in early CP and 82% in late CP (p=0.002). The rate of CCyR was 75% 80/107) vs 31% (14/75) in patients with or without CHR by 3 mons (p=0.00). The same differences were found in early and late CP. CCyR in patients with CHR before IM was the same as in patients with newly obtained CHR by 3 mons on IM. Thereafter we have divided group of pts with late CP according to its duration before IM (very early - Achievement of CCyR was higher in pts in very early(69.1%) and early –late(68.2%) than in very late group(34.6%)(p=0.09) Further subdivisions of the period of 6-60 mos did not reveal any differences. Moreover, when we deleted the patients pretreated with busulfan, the differences were found only between early and early-late phases. We have separately analyzed very late group, it appeared that pretreatment with busulfan severely decreases CCyR (22% vs 81% in with (12 pts) or without (7 pts) busulfan pretreatment, p=0,002. Probably, patients in very late CP is a specific group of patients with preformed very good prognosis. Clonal evolution before treatment (8 pts in early CP and 7 in late CP) did not influence CCyR achievement. The probability of progression to AP/BP was slightly higher in late (6%) than in early CP (3%) (p=0.05). The appearance of clonal evolution was higher in late than in early CP (p=0,0002). Progression to AP/BP was 1% vs 11% in pts with or without CHR by 3 mos resp. (p=0.003). Conclusions Imatinib is efficacious drug in general hematological practice with very high probability of overall survival, CCyR and low risk of progression to AP/BP. CHR is an early and very important predictor for further successful treatment. Achievement of CCyR strongly depends on CHR by 3 mons. Patients with CHR before imatinib have similar CCyR in patients with CHR by 3 mons on imatinib. Pretreatment period predispose patients to clonal evolution on imatinib treatment. Busulfan pretreatment severely decreases probability of CCyR. Disclosures: No relevant conflicts of interest to declare.