Attempt to Discontinue Imatinib Following Interferon Alfa Pre-Treatment In Chronic Phase CML Patients Achieving Stable Complete Cytogentic Responses (CCyR)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4898-4898
Author(s):  
Izhar Hardan ◽  
Yulia Volchek ◽  
Tali Tohami ◽  
Ninette Amariglio ◽  
Luba Trakhtenbrot ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Interferon Alfa ◽  
Cytotoxic T Cell ◽  
Molecular Response ◽  
Molecular Remission ◽  
Line Therapy ◽  
Pre Treatment

Abstract Abstract 4898 Imatinib (IM) has been shown to induce sustained clinical responses and stable remissions resulting in improved survival in chronic phase (CP) CML patients (pts.). Currently the state of the art is life long continuation of IM therapy which raises issues like the emergence of drug resistance, long-term safety and tolerability, compliance and costs. Interferon Alfa (IFNα), which has anti-CML activity and may induce major cytogenetic responses (MCyR), has in contrast to IM, immunoregulatory properties including the induction of anti-CML cytotoxic T-cell activity. Moreover, in initial studies of IM discontinuation it seemed that previous IFNα exposure was beneficial for the maintenance of molecular remission after IM cessation. We, therefore, hypothesized that adding IFNα to IM prior to IM discontinuation will increase the proportion of pts. remaining in continuous molecular response. We report on the long term, median follow up of 40 months (range, 33–41), outcome of CP CML pts. who discontinued IM after the addition of IFNα. CP CML pts. in CCyR for ≥2 years on IM were included. Study pts. received a combination of PegIFN (Pegasys, Roche) (180 μg/week, sc) and IM (400 mg) for 9 months followed by 3 months of PegIFN monotherapy, and were followed up thereafter without any anti leukemia therapy. Twelve CP CML pts. were included, 9 males and 3 females. Median age was 50.5 years (range, 33–67). Disease duration was 67 (18-96) months. Eight of the pts. (67%) received IFNα prior to IM as first line therapy. Eight of the patients had a major molecular response (MMR), 2 were in complete molecular response (CMR) (of 48 and 10 months duration) and 2 had less than a MMR. Of the evaluable pts. only 1 had a BCR ABL KD mutation (E373D). IFNα dose had to be reduce to 90–135 μg/week, sc due to intolerance in 10/12 pts. Median duration of CCyR (n=12) and MMR (n=8) at the time of IM discontinuation was 47.5 (21-86) months and 19.5 (9-84) months, respectively. Cytogenetic relapse occurred in 8 pts. 8 (2-38) months after IM discontinuation. Loss of molecular responses could be detected in all 8 pts. during follow up, and prior to the cytogenetic relapse at 8 (1-25) months post IM discontinuation. An additional 1 pt. had a molecular relapse but has maintained his CCyR 20 months post IM discontinuation. IM (400 mg/day) was reintroduced in all 8 pts. with loss of CCyR and they all re-achieved a CCyR 3.5 (3-7) months after IM re initiation. Five of the 8 pts. (62%) achieved also a MMR at 5, 7, 8, 10, and 11 months post IM re- administration, respectively. After a median follow up of 40 (range 33–41) months, 4 of the 12 study pts. (33.3%) are in persistent molecular remission. These 4 pts. achieved a CMR (n=1) (of 10 months duration) or MMR (n=3) (of 8, 14 and 19 months, respectively) prior to IM discontinuation. Notably, 2 of these 4 pts. had IFNα exposure as front line therapy pre-IM initiation. In summary, only a minority of CML pts. with stable MMR or CMR have a long lasting remission and will not relapse following IM discontinuation. Pts. having a cytogenetic relapse after IM discontinuation respond to IM re-administration by re-achieving CCyR and mostly MMR. The role of IFNα pre treatment, as well as the depth of molecular response needed to be achieved pre-IM discontinuation, should be further evaluated in a well designed 2 arms controlled randomized studies. Disclosures: No relevant conflicts of interest to declare.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

scholarly journals Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4147-4147
Author(s):  
Hélène Deutsch ◽  
Andre Baruchel ◽  
Joelle Guilhot ◽  
Arnaud Petit ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Median Time ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Second Line Therapy ◽  
Blastic Crisis ◽  
Line Therapy ◽  
Phase Iv

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p<0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p<0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

Can Targeted Therapy for CML Still Learn From Transplant? Using Post-transplant RQ-PCR monitoring to Clarify the Importance of the Depth of Molecular Remission On the Risk of Subsequent Relapse.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2789-2789
Author(s):  
Frederick Pimm ◽  
Richard Szydlo ◽  
Letizia Foroni ◽  
Francesco Dazzi ◽  
Jaspal S Kaeda ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Unrelated Donor ◽  
Molecular Response ◽  
Molecular Remission ◽  
Post Transplant ◽  
Long Term Treatment ◽  
Risk Of Relapse

Abstract Abstract 2789 The use of tyrosine kinase inhibitors (TKI) in the management of chronic myeloid leukemia (CML) has dramatically improved survival, with some 80% of patients achieving a deep and durable molecular remission (MR). The current focus for these patients is the ability to withdraw long-term treatment and a number of ‘stopping’ studies have been initiated worldwide. Many of these approaches are derived from the French STIM study which showed that 40% of patients who had been real-time quantitative PCR (RT-qPCR) negative for BCR-ABL1 for two years could cease treatment without experiencing disease relapse. However, the RT-qPCR assay used in this study was particularly stringent with a sensitivity of 10−5, compatible with a five log reduction in BCR-ABL1 transcripts (MR5), and it is not clear that the same level of success will result from studies using MR4 and MR4.5 as the indication for treatment cessation. Furthermore, because of the lack of accuracy in RT-qPCR assays when the number of BCR-ABL1 transcripts approach zero, some laboratories report as undetectable, transcript numbers <6 or even <11. In order to investigate the importance of the depth of molecular response on the risk of subsequent disease recurrence, we studied the long-term follow-up of, and RT-qPCR results from, patients who received allogeneic stem cell transplantation as treatment for CML at a time when minimal residual disease detection was performed by RT-qPCR using ABL1 as the control gene. We analysed data from 180 patients transplanted from January 1998 onwards who received an allo-SCT from an HLA-identical sibling or a matched unrelated donor and who had survived for at least 6 months post-transplant with a consistent sequence of 5 or more RT-qPCR results from the time of transplant to the end of follow-up. Patients were assessed on the depth of their MR; 9 categories of ‘complete’ MR were defined based on BCR-ABL1 transcript threshold for negativity (BCR-ABL1=0, BCR-ABL1>0 but <6, BCR-ABL1>5 but <11) and control transcript number (CTN) (CTN>104 but <104.5, CTN>104.5 but <105, but CTN>105). We ranked these categories, firstly by BCR-ABL1 transcript threshold, defining negativity at a lower threshold as a deeper response, and then sub-ranked by CTN, defining a larger CTN as a deeper response. Of the 180 patients, 49 (27%) did not achieve ‘complete’ MR by any definition and for the 131 (73%) patients who did reach some degree of ‘complete’ MR, the median time from transplant to best molecular response was 8.7 months (range, 1.0–103 months). We defined relapse as progression to an RT-qPCR level that triggered the use of donor lymphocyte infusions i.e. BCR-ABL1/ABL ratio exceeded 0.02% in 3 samples, or exceeded 0.05% in 2 samples, or showed rising levels with the last 2 samples higher than 0.02%, or worse (loss of cytogenetic or haematological remission). The 2 year relapse incidence post SCT was 94% in the group who did not achieve any degree of ‘complete’ MR, 94% in the group who achieved MR with BCR-ABL1<11 and >0, CTN>104 (n=32, 17.8%), 55% in the group BCR-ABL1=0, CTN>104 and <104.5 (n=19, 11%), 26% in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47, 26%), and 6% in the group BCR-ABL1=0, CTN>105 (n=33, 18%) (p<0.0001). In multivariate analysis with adjustment for donor type, classifying the 33 patients who achieved BCR-ABL1=0, CTN>105 as the optimal molecular responders the relative risk of relapse was 90.1 in 49 patients who never achieved MR by any definition, (p<0.0001), 21.7 in the group BCR-ABL1<11 and >0, CTN>104 (n=32) (p<0.0001), 8.1 in the group BCR-ABL1=0, CTN>104 and<104.5 (n=19) (p<0.0001), and 2.11 in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47) (p=0.002). In conclusion, fewer detectable BCR-ABL1 transcripts with larger numbers of control transcripts, i.e. a deeper response, predict a lower risk of relapse in post-transplant survivors and may have important implications for the ability to stop long-term TKI therapy. Disclosures: No relevant conflicts of interest to declare.

A Sensitive Replicate RQ-PCR of BCR ABL Transcripts Suggests That A Large Portion of Long Term Post Allogeneic SCT CML Patients Are in Deep MR and May Therefore Be Cured From Their Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1690-1690
Author(s):  
Maya Koren-Michowitz ◽  
Avichai Shimoni ◽  
Filomena Daraio ◽  
Francesca Crasto ◽  
Roberta Lorenzatti ◽  
...  
Keyword(s):  
Median Time ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Disease Status ◽  
Molecular Response ◽  
Transcript Levels

Abstract Abstract 1690 RQ-PCR has become the major method for the follow up of CML pts in the tyrosine kinase inhibitor (TKI) era. In CML pts undergoing allogeneic SCT (Allo-SCT) it has been shown that successive increase in quantitative BCR ABL transcript levels is in correlation with the clinical outcome and may serve as an early sign of disease relapse and an indication for a therapeutic intervention such as the addition of a TKI or DLI. However, the sensitivity of current RQ-PCR methods which is limited to approximately 10−4 in the majority of routine clinical laboratories, do not allow for the detection of very low BCR ABL transcript levels, and therefore RQ-PCR negativity cannot be regarded as CMR in the majority of pts. Studies of replicate RQ-PCR (rRQ-PCR) have shown that the number of measurement repetitions is relevant in the detection of rare transcripts and rRQ-PCR was found to be more sensitive than conventional RQ-PCR in TKI treated CML pts. We evaluated the role of rRQ-PCR in the detection of MRD in a cohort of long term post Allo-SCT CML patients. Samples from 12 CML pts (M=7, F=5), median age 43 y, at a median time of 85 months after SCT (range 28–136) were tested. SCT was myeloablative (n=6) or with RIC (n=6), from a matched sibling (n=7) or a MUD (n=5), in first chronic phase (CP1) (n=8) or at a later phase (n=4). rRQ-PCR was done in 82 replicates using the same conditions of conventional RQ-PCR. Results of rRQ-PCR are given in Table 1. 75% of the patients had negative RQ-PCR in all 82 wells, while 3 patients had positive results in 1 (1.2%), 2 (2.4%) and 6 (7.3%) wells, respectively, which was above the background determined in normal PB samples (6/901 positive wells, 0.66%). The sensitivity of rRQ-PCR was 10−5.5 or higher in all patients. Negative rRQ-PCR result was not related to the phase at SCT (CP1 vs. others), conditioning regimen (myeloablative vs. RIC), donor type (sibling vs. MUD) or the presence of GVHD. Median time from diagnosis to SCT was borderline longer in patients with positive rRQ-PCR results (61 vs. 25 months, p=0.08). Higher sensitivity RQ-PCR methods are able to further define subgroups of post BMT CML pts and allow for a more accurate follow up of MRD. We will present update clinical data at 1 year after rRQ-PCR determination. Table 1. Results of rRQ-PCR. Patient number Disease status at SCT Conditioning Time from diagnosis to SCT (months) Time from SCT to rRQ-PCR (months) rRQ-PCR result BCR ABL/ABL1 (IS) Total quantity of ABL transcripts Level of MR 1 AP RIC 97 57 0 575034.8 MR5.5 2 CP2 MA 6 30 0.0000862 705622.3 3 CP2 MA 273 48 0.0007393 563237.5 4 CP1 RIC 4 52 0 997521.8 MR6 5 CP1 MA 16 34 0 555768.9 MR5.5 6 CP1 MA 39 30 0 700630.1 MR5.5 7 CP1 MA 6 40 0 874247.9 MR5.5 8 CP1 RIC 61 68 0.0000484 1067353 9 CP1 RIC 33 46 0 938046.4 MR5.5 10 CP1 RIC 18 58 0 1467748 MR6 11 AP RIC 6 28 0 776271.9 MR5.5 12 CP2 MA 3 23 0 860350.6 MR5.5 RIC reduced intensity conditioning; MA myeloablative conditioning; MR molecular response. 1 Average result of positive wells normalized to the international standard. PCR positive in 12, 63 and 24 wells of 82 tested. Disclosures: No relevant conflicts of interest to declare.

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was &lt;0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed &gt;2 fold rise from nadir to a level &gt;0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of &lt;600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) &gt;6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by &gt;6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P&lt;0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at &gt;6 to 12m and &gt;12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

Peptide-Vaccine Treatment Associated with TKI Therapy in Patients with CML Is Able to Induce Immunologic, Cytogenetic and Molecular Responses: a Single Center Experience with Long-Term Follow up.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2185-2185 ◽  
Author(s):  
Elisabetta Abruzzese ◽  
Malgorzata Monika Trawinska ◽  
Angela Coletta ◽  
Serena Zaza ◽  
Roberta Giovagnorio ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Treatment Plan ◽  
Peptide Vaccine ◽  
Chronic Phase ◽  
Intradermal Injection ◽  
Variable Degree ◽  
Molecular Remission ◽  
Number Of Patients

Abstract Abstract 2185 Poster Board II-162 Introduction: The main objective in the intent to “cure” chronic myeloid leukemia (CML) is to obtain complete cytogenetic remission (CCR) and molecular remission. Tyrosin kinase inhibitors (TKI) treated patients (pts) achieve CCR, but BCR-ABL transcripts can still be detectable, and complete molecular remission (CMR), intended as undetectable transcript, are rare. Moreover about 10% of up-front treated patients show resistance to Imatinib, that reaches 30% in late chronic phase, loss of response during treatment is not negligible, and treatment cannot be stopped. Thus the eradication of residual disease still appears a difficult goal for a TKI alone. An alternative approach to target the residual disease is an active specific immunotherapy. We associated TKI therapy and immunogenic peptides derived from the p210 b3a2 and b2a2 fusion protein (developed by M. Bocchia et al. University of Siena) in pts with chronic phase (CP) CML with stable disease in trying to obtain a specific immunologic activation able to induce a measurable clinical response. Patients population and methods: 17 pts (11 M:6 F) with CP CML, median age 55,5 (range 30-68) treated with Imatinib (16) or Dasatinib (1) were enrolled in the studies. All patients but one were in late chronic phase and had been treated with 2 (2 pts), 3 (11 pts) or >3 (4 pts) lines of therapies. Median time from diagnosis was 64.1(16-143) months, and patients were treated for a median of 30.8 months with TKI before peptide vaccination. 15 pts had b3a2 and 2 a b2a2 transcript. Pts presented with stable, measurable disease at cytogenetic or molecular level from at last 6 months. Vaccination included GM-CSF pre treatment and administration of 5 p210 b3a2 (CMLVAX100) or 1 b2a2 (CMLVAX25) derived peptides. Treatment plan consisted of an induction plan of 6 vaccinations every two weeks, followed by additional boosts every 3-6 months for responding patients. During vaccination, patients continued their conventional treatment with Imatinib/Dasatinib. Prior to vaccine all patients were tested with an intradermal injection of peptides (DTH) to evaluate their sensitivity to the CML antigens, and all of them resulted negative. Cytogenetics, FISH and molecular biology, peptide-specific immune responses (DTH, CD4+ proliferation, immunophenotype) were analyzed before and during treatment. Results: 15/17 pts are evaluable (2 patients had just completed the first 3 months and were not considered for their short follow up), and all patients but one showed a variable degree of response. All patients presented with some degree of DTH indicating the “recognition” of peptides by effector T cells (biologic response). 5/9 pts with positive cytogenetic (2-66% Ph+) reached CCR, and 3 also CMR, while 1 patient did not respond (the one with high tumor burden, 66% Ph+). 3/6 pts in CCR at time of vaccination reached CMR. The majority of responses were rapidly reached (after the induction) and were long lasting. After 69 month follow up 6/15 patients are still treated. Patients suspended vaccination due to: no response (1), lost CCR (5), progression (1), 2nd neoplasm (1), allergic reaction (1). One patient that reached CCR and MCR after vaccination stopped imatinib and was closely monitored thereafter. She is now treated with only vaccine boosts twice/year and still in CMR after 28 month. Specific immune response will be described. Conclusions: These data suggest that addition of b3a2 or b2a2-specific vaccine may have synergistc effect with TKI favouring reduction of residual disease and increasing the number of patients that reach CMR. A multicentric trial is ongoing through the GIMEMA CML study group, and a pilot study to stop TKI in long lasting CMR is in preparation. Disclosures: No relevant conflicts of interest to declare.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Outcome of Patients with CML Treated with Dasatinib or Nilotinib after Failure of Second Prior TKIs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2294-2294
Author(s):  
Antonella Russo Rossi ◽  
Massimo Breccia ◽  
Fausto Castagnetti ◽  
Luigiana Luciano ◽  
Antonella Gozzini ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Cell Uptake ◽  
Second Line ◽  
The Third ◽  
Line Therapy ◽  
Third Line ◽  
New Mutations

Abstract Abstract 2294 Background. The TKIs Nilotinib and Dasatinib offer additional therapeutic options for patients with CML who are resistant or intolerant to Imatinib. These agents, active against the majority of Imatinib resistant BCR-ABL mutated clones, have a different pattern of kinase target selectivity, pharmacokinetics parameters, cell uptake, efflux properties and adverse events profiles. Preliminary results suggest that some patients may respond to a second TKI used as third line therapy, but little is known about the long term benefit of such an approach.Aim of this collaborative Italian study was to verify the response (rate and duration) and the clinical outcome in patients with CML treated with a third TKI after sequential failure of the previous ones. Methods. We evaluated 66 patients with CML, resistant/intolerant to Imatinib and treated with Dasatinib or Nilotinib, then switched to a third- line TKI after treatment failure. Of these, 29 patients were treated with dasatinib after imatinib/nilotinib failure and 37 with nilotinib after imatinib/dasatinib failure. Patients were monitored with complete blood counts, cytogenetic analysis, bone marrow aspiration RT-PCR and mutational analysis. Results. A total of 66 patients (median age 63 years, range, 33–85 years) were treated with sequential TKIs; 40 (61%) patients had received interferon-a before starting Imatinib; 26 (39%) patients received imatinib as first line therapy. The median time on imatinib therapy was 47.5 months (range 4–101 months). At the start of nilotinib as second line, 27/29 (93%) patients were in CP, 1 (3.5%) in AP, and 1 (3.5%) in BP. 9 patients (31%) had developed mutations before starting treatment. The median time on second line TKI was 8 months (range 2–36 months). In the resistant patients 4 new mutations were identified (F359V in two patients, T315I, Y253H+F359V). At the start of dasatinib as second line, 33/37 (89.2%) patients were in CP, 4 (10.8%) in AP. 7 patients (18.9%) had developed mutations before starting treatment. The median time on second line TKI was 14 months (range 4–59 months).In the resistant patients 5 new mutations were identified (F137L in three pts, M318T, M244V+F317L). At the start of the third TKI, 60/66 (90.9%) patients were in CP, 5 (7.6%) in AP, and 1 (1.5%) in BP. Of these, 7 patients (18.9%) on dasatinib and 7 (24.1%) on nilotinib had mutations before starting treatment. The best response to the third line treatment with TKI was 10 (15.2%) MMR, 10 (15.2%) CCyR, 8 PcyR (12.1%), 5 (7.5%) mCyR, 24 (36.4%) CHR and 9 (13.6%) No Response (NR). In the dasatinib group, 9 (31%) patients discontinued treatment because of toxicity versus 17 (45.9%) patients in the nilotinib group.Two new mutations (F317L, E255V) emerged with dasatinib as third line therapy.After a median follow up of 13 months (range 2–37 months) 50 patients (48 CP, 2 AP) are continuing therapy (33 on nilotinib, 17 on dasatinib).Since the start of the third TKI, 61 patients (92.4%) are still alive for a median overall survival of 110 months (range 15–300) (52 CP, 7 AP, 2 NA); the 5 deaths (7.6%) were caused by disease progression and spread of the gene mutation T315I. Discussion. In our study, about one third of patients derived benefit from the use of three sequential TKIs; patients with better, longer response (28.7%) to third TKI were the same patients with a better response to the Imatinib and 2TKIs therapy. All these patients had taken interferon therapy before the Imatinib. In this subset of patients (good responders: CCyR and MMR) 5 patients developed mutations that were sensitive to the sequential treatment.The lack of a durable cytogenetic remission could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKI; a change of therapy resulted in an adequate response. In our series, patients with poor prognosis showed mutations not sensitive to the TKIs treatment. Conclusions. Although allogeneic SCT is the treatment of choice in all patients failing 2 TKIs who are suitable candidates for this approach, alternative strategies are required for ineligible patients. The use of a third TKI after failure of two previous TKIs induces response in some patients. Longer follow up of a larger series of patients is needed to determine the long term impact of the response. Disclosures: No relevant conflicts of interest to declare.

Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3438-3438
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Annual Rate ◽  
Molecular Response ◽  
Free Survival ◽  
Cumulative Rate ◽  
Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4499-4499
Author(s):  
Santiago del Castillo ◽  
Regina Garcia Delgado ◽  
Laura Entrena ◽  
Agustin M Hernandez ◽  
Arturo Campos ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Genetic Material ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Current State ◽  
Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

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