ALBERT

Description: Abstract 2214 Poster Board II-191 Imatinib (IM), nilotinib and dasatinib are remarkably effective as single-agent treatments for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known on their potential impact on the immune system and to date no human in vivo data are available. Data from in vitro and animal studies on the effects of IM on the immune response have been contradictory ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. In addition few data are available to assess potential immunomodulatory effects of the second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib. Dasatinib has inhibitory activity against a broader range of protein kinases than imatinib including the Src family kinases Lck and Fyn, both of which are associated with T-cell receptor primary signal transduction pathways. Dasatinib may also inhibit B cell signaling through the Lyn pathway which may have potential implications for immunotherapeutic strategies. An understanding of the effects of different TKIs on the immune response will have implications for the development of immunotherapeutic strategies. The aim of this study was to prospectively analyze humoral and cellular immune responses to vaccination against influenza virus (Flu) and Pneumococcus in CP-CML patients treated with IM, dasatinib or nilotinib compared to healthy controls. Fifty CP-CML patients on standard dose TKIs (IM, n=22; dasatinib, n=15; nilotinib, n=13) and 15 healthy controls were vaccinated against Flu (Inflenza vaccine Ph. Eur. 2008/2009, CSL biotherapies) and pneumococcus (Pneumovax II, Sanofi Pasteur MSD). Samples were taken pre and at 1 and 3 months post-vaccination. Titers of IgM and IgG anti-pneumococcal were determined using ELISA technology. A positive response was defined as an IgM serum titer 〉100 U/ml at 1 month; IgG response was considered positive for IgG 〉200 U/ml at 1 or 3 months. To investigate possible correlation between B cell subsets and the pneumococcal humoral response we evaluated IgM memory B cells (CD19+ CD27+ IgMhigh IgDlow) and switched memory B cell (CD19+ CD27+ IgM- IgD-) subsets using flow cytometry. We analyzed the immunological T-cell response to influenza virus both quantitatively and qualitatively using flow cytometry for intracellular TNF-α, IFN-gamma and IL2 and the cytotoxicity marker CD107a. A response was considered positive if there was a minimum of 0.10% Flu-specific TNF-α producing T-cells and the percentage of antigen-specific TNF-α producing T-cells was 2-fold or higher compared to pre-vaccination level. Preliminary results on 28 patients and 11 healthy controls have been analyzed thus far. Significantly fewer patients on TKIs mounted an anti-pneumococcal IgM response (IgM serum titer 〉 100 U/ml) compared to healthy controls (9/28 versus 8/11, p=0.033). An anti-pneumococcal IgM response was detected in 20%, 37.5% and 40% of CML patients on dasatinib, nilotinib and IM respectively, and in 73% of the healthy controls. Moreover, patients on TKI had significantly lower levels of anti-pneumococcal IgM at 1 month compared to healthy controls (median, 84.5 U/ml, range 5 to 200 vs 200 U/ml, range 15 to 200, p=0.006). At 1 month the median levels of IgM in patients on dasatinib, nilotinib and IM were 55 U/ml (range, 12 to 172), 87 U/ml (range, 8-138) and 90 U/ml (range, 5 to 200) respectively. We have so far analyzed CD8 and CD4 T cell responses to Flu vaccination in 15 patients on TKI and 5 healthy controls. Prior to vaccination, T cell responses against Flu were detected in 4/15 patients on TKI and 1/5 healthy controls, indicating pre-existing memory T cell responses to Flu. In these subjects the T-cell response to Flu did not increase significantly after vaccination and as such the response was defined as negative. A significant T-cell response to Flu was seen in 7/15 patients on TKI (median 0.28% TNF-α+CD4+ T cells, range 0.10–2.25%) and in 3/5 healthy control (median 0.79% TNF-α+CD4+T cells, range 0.12–1.34%). These preliminary results suggest that in patients with CML on TKIs the IgM B cell response to vaccination with Pneumovax is significantly impaired compared to healthy controls. We have as yet not detected a significant difference in T-cell response following vaccination with Flu in CML patients on TKIs compared to healthy controls. We are in the process of analyzing the remaining samples. Disclosures: Marin: Novartis: Consultancy, Research Funding.

Description: Abstract 1229 Poster Board I-251 Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment for the non-elderly multiple myeloma (MM) patients. Relapses invariably occur and therefore reinduction therapy followed by ASCT is often considered. We retrospectively analysed the results of second ASCT after relapse and re-induction and assessed the effect of bortezomib therapy prior to second ASCT. We included 177 MM patients who relapsed after the initial melphalan 140-200mg/m2 ASCT and treated in a single institution from July 1994 to April 2009. Patients who received melphalan/TBI conditioning, planned upfront tandem transplants, allogeneic SCT, palliation only or who suffered early death or death in remission were excluded from our analysis. The patients were divided into 4 groups based on the type of salvage treatment. Group 1 included 96 patients with median age 59.6 years (range 31.16 – 73.5) at the time of progression who were salvaged with treatment modalities other than a second ASCT or bortezomib. Group 2 received bortezomib based salvage but not a second ASCT and included 31 patients aged 61.7 years (49.3 – 72.9), group 3 included 28 patients aged 58.6 years (31.1 – 70.6) who were treated with a second ASCT and no bortezomib, and finally group 4 included 22 patients aged 59.1 years (32.6 – 70.6) who were treated with bortezomib and second ASCT. For the transplanted patients, the conditioning consisted of melphalan 140-200mg/m2. Bortezomib was given at standard doses (1.3mg/m2 at days 1,4,8, and 11) plus dexamethasone 20mg same and next day of bortezomib injection for 3 to 4 21-day cycles. Survival was estimated from the time of progression after the initial transplant. Univariate analysis showed longer survival for the transplanted patients (median 41.2 and 60.9 months for groups 3 and 4, 15.2 and 29.8 months for groups 1 and 2 respectively, Log Rank p=0.003). In multivariate Cox analysis the type of salvage treatment retained significance (p=0.013, OR 2.75, 95%CI 1.23 – 6.16). When patients treated with a second ASCT (groups 3 and 4) were analysed separately, the difference in survival between groups did not reach significance (p=0.32). Multivariate analysis showed longer survival if complete remission (CR) or near CR (nCR) had been achieved with the first ASCT (p=0.05, OR 6.4 95%CI 1.7 – 23.19) and if disease progression had occurred at least 12 months after the initial ASCT (p65 years, reduced melphalan dose (12 months following the initial ASCT is the most significant prognostic factor of PFS and survival after the second ASCT. Bortezomib based induction is suggested to improve CR and nCR rates after the first ASCT, however its use prior to second ASCT does not appear to produce longer PFS or survival. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 68 Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting TKI therapy strongly predicts for the achievement of cytogenetic and molecular responses and for PFS and OS. In particular, we have shown that CML patients treated with imatinib who at 3 months have a transcript level lower than 9.8% on the international scale or lower than 1.67% at 6 months fare significantly better. We have also shown that the molecular assessment made at 3 months on imatinib therapy is a better predictor of the prognosis of patients than the analysis of BCR-ABL1 transcripts at 6 months. Here we investigate whether it is possible to improve the prognostic accuracy of early measurement of the transcript level by combining the 3 and 6 month results. Between June 2000 and December 2010 282 consecutive adult patients with CML in CP seen at our institution received imatinib 400 mg daily as first line therapy. The median follow-up was 69 months (range 17–131). During follow-up 118 patients discontinued imatinib and received nilotinib (n=37), dasatinib (n=72) or an allogeneic stem cell transplant (n=9). BCR-ABL1 transcripts were measured in the blood at 6 to 12 week intervals using RQ-PCR and results were expressed as percent ratios relative to an ABL1 internal control with original laboratory values converted to the international scale. Two hundred and seventy-four patients were still alive in chronic phase and receiving imatinib at 6 months. We classified these patients according to their transcript levels at 3 months (lower or higher than 9.8%) and 6 months (lower or higher than 1.67%). 181 (66%) patients had low transcripts both at 3 and 6 months; these patients had an excellent outcome with a OS of 93.5% and a 100% cumulative incidence (CI) of CCyR. Fifty-seven (21%) of the patients had high transcript levels on both occasions; these patients had a significantly worse outcome than the previous cohort, namely an OS of 55.6% (p

Description: In multiple myeloma (MM), a malignancy of the bone marrow plasma cells (BMPC), hyperdiploidy (HY) and oncogene over-expression via chromosomal translocation [including CCND1- t(11;14), MAF- t(14;16), MMSET-t(4;14)] are the primary myeloma initiating events (MIE) that drive distinct transcriptional programs. These are further shaped by secondary SNV and CNV events. This genetic heterogeneity converges, in most cases, to a functionally dichotomous state of CCND1 or CCND2 overexpression. The molecular mechanisms underlying each of the distinct myelomagenic transcriptomes and the CCND1 vs CCND2 dichotomy have not been defined. To address these questions, we obtained highly purified BMPC from 3 healthy donors and 30 MM patients (HY: 15; CCND1: 4; MMSET: 5; MAF: 2; other: 4), either at diagnosis or relapse, and mapped their chromatin accessibility and transcriptome profiles by ATAC-seq and RNA-seq, respectively. In total, we obtained ~300K regions with accessible chromatin in either MM or normal PC. Overall chromatin accessibility increased in myeloma compared to normal PC, particularly in MAF- and MMSET-translocated subtypes. Analysis of combined ATAC-seq/RNA-seq by Multi-Omics Factor Analysis (MOFA) resulted in a clearer samples distinction than either ATAC-seq or RNA-seq alone, with altered chromatin accessibility accounting for more of the variance than expression. Of the top five identified factors, the top two (one transcriptome driven, one accessibility driven) distinguished normal from MM samples, whilst two more separated MMSET, MAF and CCND1 subgroups. Ninety seven, 157, 256 and 348 overexpressed genes in the CCND1, HY, MMSET and MAF subgroups, respectively, were predicted to be regulated by differentially accessible enhancers. Twenty percent (165/858) of these genes were overexpressed in 〉1 subgroup suggesting a process of chromatin accessibility-based convergence evolution. Enrichment analysis suggested direct or indirect involvement of Polycomb and chromatin remodellers; significant enrichment was also found for genes involved in neurogenesis. ATAC-seq footprinting predicted binding sites for 250 expressed transcription factors (TFs), 116 of which displayed higher binding frequency in myeloma than in normal PC and included both known (e.g., XBP1, RELA, IRF4, PRDM1) and potentially novel regulators of myeloma biology (e.g., CXXC1 and NFE2L1). The remaining 134 TF were predicted to be present in at least one MM subgroup, but absent in normal PC. Amongst them, as expected, MAF was active in the MMSET- and more so in the MAF-translocated subgroups. DepMap database analysis suggested myeloma cell dependency on 181/250 TF (CRISPR/Cas9 CERES score 〈 -0.1 in 〉3/14 MMCL analysed). In dissecting the regulatory basis of CCND2 vs CCND1 dichotomy, one MOFA factor completely separated MAF from CCND1 samples, placing extreme opposite weights on the expression of CCND2 and CCND1 respectively. Interestingly, the same factor identified open-chromatin clusters upstream of CCND2 and linked them to its over-expression. These clusters were also open in the MMSET group and in CCND2-expressing HY samples. Conversely, no accessibility was detected in the CCND1 group, the CCND1-expressing HY samples or in normal PCs. Further, super-enhancer calling using the H3K27ac histone mark in MAF-translocated JJN3 cells identified the region of interest as a bona fide super-enhancer. Chromatin long range interactions, as assessed by Capture-HiC, demonstrated high frequency interactions of the CCND2 promoter with the constituent elements of the putative super-enhancer. Experimental validation using a CRISPR/Cas9i system confirmed the functional role of all 4 super-enhancer constituents tested in the regulation of CCND2 expression, while TF footprinting predicted MAF binding to the super-enhancer in MAF-translocated PC. In conclusion, we show that distinct oncogenic transcriptomes in MM are underpinned by extensive chromatin changes, accompanied by TF activity 're-wiring' that does not necessarily require transcriptional deregulation of the TF themselves. We identify novel, non-oncogene TF dependencies that suggest therapeutic opportunities in MM and we discover and characterise the critical super-enhancer that drives overexpression of the CCND2 oncogene in MM. Disclosures Auner: Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy; Karyopharm: Consultancy. Hatjiharissi:Janssen: Honoraria. Caputo:GSK: Research Funding. Karadimitris:GSK: Research Funding.

Description: Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of “current CCyR-survival” (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ABL1 transcript ratio of ≤ 10% and had significantly superior overall survival (91.3% vs 72.1%, P = .02), event-free survival (49.3% vs 13.0%, P 〈 .001), and c-CCyRS (67.2% vs 11.2%, P = .0001) compared with the 33 patients with ratios 〉 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intention-to-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.

Description: Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 605 Variations in RTQ-PCR estimations of BCR-ABL1 transcript numbers between laboratories have resulted in recognised difficulties in interpreting results and have led to a global effort of harmonisation via an international reporting scale (IS). Currently this is achieved in a limited number of laboratories worldwide by exchange of samples and will hopefully be replaced by the production of internationally accredited reference reagents. Differences in the limits of sensitivity of assays in different laboratories pose particular problems in the definition and interpretation of molecular negativity, so-called complete molecular remission (CMR), leading some investigators to suggest distinctions between assays capable of detecting 4, 4.5 and 5 log reductions in tumour load and introducing the terms CMR4, CMR4.5 and CMR5. These definitions take on particular relevance when designing studies of de-escalation and/or stopping tyrosine kinase inhibitor (TKI) therapy. In the French STIM trial, criteria for stopping were relatively stringent in that patients were required to have at least 5 results of RTQ-PCR negativity in their local laboratory sustained over at least 2 years and confirmed on one further occasion in the centralised laboratory. Negative results of BCR–ABL 1 amplification were reported only if the RNA was of good quality and quantity (50 000 copies of normal ABL1). Subsequently several groups are designing similar studies. As our ability to stop treatment must in large part be determined by the level of residual disease at the time of cessation, it is important to have robust definitions of CMR. We maintain a comprehensive database of all our CML patients on TKI. For chronic phase this database now contains 521 patients (273 [52%] male) of median age 48 yrs (range 13–86). 212 patients received interferon prior to TKI therapy. The median follow up for surviving patients is 76 mths (range15-137). 88 (37 [42%] male) of these patients have achieved RTQ-PCR molecular negativity on more than one occasion and prompted us to identify the proportion that would satisfy entry criteria for a stopping study and hence the natural history of RTQ-PCR results in such patients. Confirmed complete molecular response (cCMR) was defined as two consecutive samples with no detectable transcripts at least 4 weeks apart with an ABL1 control 〉40,000 copies (median ABL1 control in the CMR samples was 84,000 copies). 64 patients met our criteria for cCMR, the remaining 24 patients had at least two negative results but never consecutively. 56 patients achieved cCMR on their first line TKI (imatinib in all but 2). Times from diagnosis to MMR and cCMR in this cohort were a median of 24 (range 3–77) and 46 mths (range 5–118) respectively. The median time from MMR to cCMR was 26 mths (range 0–89). Excluding 8 patients in whom follow-up since cCMR is less than 24 months the median duration from cCMR is 53 mths (range 24–113), Only one patient has subsequently lost MMR confirming the excellent prognosis of this cohort. However, only 10 patients (21%) have sustained RTQ-PCR negativity over a 2 year period that would deem them eligible for a STIM-equivalent study. If we were to define a less stringent CMR4.5 as a BCR-ABL ratio of 0.0032 in the international scale the number of eligible patients increases to 18/48 (37.5%). If we applied CMR4.5 to the 24 patients without consecutive RTQ-PCR results a further 3 patients would meet the criteria for a stopping study, total 21/88 (24%). In conclusion the numbers of patients eligible for stopping studies confined to sustained cCMR is relatively few although we cannot exclude the possibility that some patients were not entirely compliant. Although not proven, reducing the stringency of the definition of CMR is likely to lead to higher relapse rates in subsequent stopping studies than in the original STIM trial. This must be considered when interpreting the results of first-line second generation TKI where the rates of achievement of MMR and CMR may be higher than with imatinib. In these studies CMR may not be synonymous with a 50% chance of discontinuing treatment permanently and future studies might more appropriately consider strategies of de-escalation rather than cessation. Disclosures: Apperley: Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria.

Description: Abstract 3753 The tyrosine kinase inhibitors (TKIs) imatinib (IM), nilotinib (NIL) and dasatinib (DAS) are remarkably effective as single-agent therapy for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known of their potential impact on the immune response. No human in vivo studies to assess how these molecular-targeted drugs affect immune function in patients are available and data from in vitro and animal studies with imatinib have been contradictory, ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. Furthermore, although the immunomodulatory effects of TKIs on T cells, NK cells and dendritic cells have been explored in vitro, little is known of their potential impact on B cells. To characterize the in vivo immunomodulatory effects of TKIs, 51 patients with CP-CML in complete cytogenetic response (CCyR) on standard dose IM (n=26), DAS (n=14) or NIL (n=12) and 28 adult controls were recruited during two influenza seasons (2008 and 2009). Patients and controls were concomitantly immunized with an influenza vaccine (Ph. Eur. 2008/2009 or Ph. Eur. 2009/2010, CSL Biotherapies) and with the 23-valent polysaccharide pneumococcal vaccine (Pneumovax II; Sanofi Pasteur MSD). Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from patients and donors prior to vaccination and T and B responses to vaccination were assessed at 4 weeks and at 2–3 months post-immunization. T-cell responses to influenza vaccine were analyzed quantitatively and qualitatively using flow cytometry and intracellular cytokine assay for TNF-α, IFN-γ, IL-2 and the cytotoxicity marker CD107a. Serum titers of IgM and IgG pneumococcal antibodies were determined by ELISA. Analysis of B cell subsets was performed using flow cytometry and correlated with the pneumococcal IgM and IgG humoral response. Following vaccination, Flu-specific T cells were detected in 24/51 (47.0%) patients on TKI and 15/24 (62.5%) healthy controls (p=0.16). Polyfunctional T-cell responses (defined as the production of 2 or more cytokines or one cytokine and the cytotoxic marker CD107a) were induced in 6/10 evaluable patients and 4/8 normal controls (p=1.0). T-cell independent humoral responses to vaccination were assessed in 45 patients and 12 healthy controls by measuring pneumococcal IgM titers. Four weeks postimmunization, 11/12 (92%) controls achieved IgM pneumococcal Ab titers 〉80 U/ml compared to only 23/45 (53%) CML patients on TKI (p=0.010). The pneumococcal IgM titers were significantly lower in patients with CML on TKI compared to healthy controls (median, 89.0 U/ml, range 5–200 vs 200 U/ml, range 58–200, p=0.0006), suggesting that CML patients on TKI have impaired IgM responses to vaccination. To further characterize the humoral immune response to Pneumovax, we stratified CML patients based on their pneumococcal IgM titers. We found a significantly lower percentage of IgM memory B cell subset in CML patients who failed to mount a significant pneumococcal IgM response compared to patients who achieved a pneumococcal IgM response (median, 6.25% vs 16.4%, p=0.0059) and healthy controls (median, 6.25% vs 14.3%, p=0.0086). Furthermore, we found a significant correlation between anti-pneumococcal IgM titers and IgM memory B cell percentage (Spearman rank correlation test, r=0.61, p

Description: Imatinib is remarkably effective in treating patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) but somewhat less effective in treating patients who have previously received interferon-alfa (IFN), most of whom can be classified as being in ‘late CP’. For such patients who have failed IFN, a proportion achieve complete cytogenetic responses (CCyR) and subsequently major molecular responses (MMolR) on imatinib, but the durability of these responses is not yet established. We analyzed long-term outcomes for 216 consecutive CML-CP patients who started on imatinib after failing IFN at our institution. Their Sokal risk score was ‘low’ in 58 (27%) patients, ‘intermediate’ in 75 (35%) and ‘high’ in 83 (38%). At the time of starting imatinib 73 (34%) patients were IFN intolerant, 40 (18%) were hematologically resistant to IFN and 103 (48%) were cytogenetically resistant; of this last group 58 (27%) had primary resistance and 45 (21%) secondary resistance. The median interval between diagnosis and start of imatinib was 38 months (range 6 to 217). Ninety-two patients (42.6%; 95CI, 36.0–49.5%) achieved CCyR during follow-up; the estimated cumulative incidence of CCyR at 5 years was 46.8% (95CI 40.0–53.7%). Forty-five patients (20.8%; 95CI, 15.6–26.9%) achieved a MMolR; the estimated cumulative incidence of MMolR at 5 years was 23.7% (95CI 16.6–32.8%). The independent factors predicting achievement of MMolR were prior response to interferon and favorable Sokal category: the relative risks (RR) for achievement of a MMolR response were 3.34 for patients with secondary cytogenetic resistance to IFN (p〈 0.0001) and 0.5 and 0.2 for the Sokal intermediate and high risk groups respectively (p=0.012). For the 45 patients who achieved a MMolR the median follow-up was 68 months (range, 32–85 months); 24 (53%) patients achieved a 4-log reduction in the BCR-ABL transcript level, and in 10 (22%) cases the transcripts became undetectable. By intention-to-treat analysis the estimated progression-free survival (PFS, defined as loss of complete hematologic response or progression to advanced phase) for this group at 72 months was 100%. At latest follow-up 7 patients (16%) had lost their MMolR but only 2 (4%) of these had lost their CCyR. When comparing those 45 patients with 76 CML-CP patients who received front-line imatinib and achieved a MMolR (out of 207 patients at our institution), we found no differences in terms of cumulative loss of CCyR (p=0.60) or of MMolR (p= 0.94), suggesting a comparable durability of the responses in these two patient groups. In conclusion, although patients who receive imatinib in late CP generally fare worse than patients starting imatinib soon after diagnosis, patients in the two groups who achieve a MMolR have equivalent outcomes.

Description: The majority of patients with chronic myeloid leukemia in chronic phase gain substantial benefit from imatinib but some fail to respond or lose their initial response. In 2006, the European LeukemiaNet published recommendations designed to help identify patients responding poorly to imatinib. Patients were evaluated at 3, 6, 12, and 18 months and some were classified as “failure” or “suboptimal responders.” We analyzed outcomes for 224 patients with chronic myeloid leukemia in chronic phase treated in a single institution to validate these recommendations. Patients were followed for a median of 46.1 months. At each time point, patients classified as “failure” showed significantly worse survival, progression-free survival, and cytogenetic response than other patients; for example, based on the assessment at 12 months, the 5-year survival was 87.1% versus 95.1% (P = .02), progression-free survival 76.% versus 90% (P = .002), and complete cytogenetic response rate 26.7% versus 94.1% (P 〈 .001). Similarly, the criteria for “suboptimal response” at 6 and 12 months identified patients destined to fare badly, although criteria at 18 months were less useful. The predictive value of some other individual criteria varied. In general, the LeukemiaNet criteria have useful predictive value, but a case could now be made for combining the categories “failure” and “suboptimal response.”