scholarly journals Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1816-1816 ◽  
Author(s):  
Soo Young Choi ◽  
Sung-Eun Lee ◽  
Yun jeong Oh ◽  
Soo-Hyun Kim ◽  
Richard C. Woodman ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE. The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or intolerance to treatment were allowed to switch to other treatment. Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3). With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10). Up to now, all patients in three groups have maintained CCyR without progression or resistance. 10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD. Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614). Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia. Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. 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.

Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3775-3775 ◽  
Author(s):  
Soo-Young Choi ◽  
Sung-Eun Lee ◽  
Soo-Hyun Kim ◽  
Eun-Jung Jang ◽  
Jin-hwa Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
First Line

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

A Retrospective Real-Life Analysis of Chronic Myeloid Leukemia Patients in Suboptimal Response to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4446-4446
Author(s):  
Dario Ferrero ◽  
Elena Crisà ◽  
Marco Cerrano ◽  
Mario Boccadoro ◽  
Francesca Pirillo ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Standard Dose ◽  
Real Life ◽  
Significant Risk ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Significant Difference ◽  
Response Detection

Abstract Abstract 4446 Life expectancy of CML patients has greatly improved in tyrosine-kynase inhibitor (TKI) era, but still some questions remain about the management of suboptimal responders (SR) to imatinib standard dose. This group of patients appears to be heterogeneous, with significant differences in terms of event-free survival between cytogenetic SR and molecular SR (Alvarado et al, Cancer 2009) European Leukemia Net (ELN) recommendations did not clarify those differences and there isn't a clear agreement on SR: maintaining imatinib at standard or higher dose or switching to another TKI are all considered acceptable options (Baccarani et al, JCO 2009). We retrospectively analyzed 63 CML patients, diagnosed in chronic phase between 1988 and 2011, SR to imatinib 400 mg/d, treated according to the 3 different ELN options. Fifty-two patients received imatinib front line and 11 had been previously treated with an interferon based therapy. Sokal score, evaluable in 44 patients, was high in 7, intermediate in 24 and low in 12, respectively. Twenty-five patients were cytogenetic SR and 38 molecular SR. The median follow-up from diagnosis was 76 months (range 10–292). At suboptimal response detection 47 patients (74%) continued imatinib 400 mg/d (30 of them afterword switched to high dose imatinib or new TKI), 12 patients (19%) increased imatinib dose to 600 mg/d (7) or 800 mg/d (5) (8 of them later changed TKI) and only 4 patients switched immediately to new TKI. Twenty-three percent of the 47 patients who continued imatinib 400 mg/d obtained a stable complete cytogenetic response (CCyR) and major molecolar response (MMR) while 27% underwent to a failure. Globally thirty-tree SR patients increased imatinib dose, 36% at suboptimal response detection and 64% after a median of further 12 months of standard dose treatment (range 3–50): 48% of them obtained a durable CCyR and MMR. Twenty-six evaluable patients switched to new TKI (9 to nilotinib and 17 to dasatinib), 13 after high dose imatinib: 62% of the patients achieved a stable CCgR and MMR. Both high dose imatinib and new TKI were significantly more effective in achieving CCyR and MMR than maintaining imatinib 400 mg/d (p<0,05). Considering separately the subgroup of cytogenetic SR patients, a stable CcyR has been reached by 35% of patients continuing imatinib standard dose, by 50% of the patients who increased imatinib dose and by the totality of the patients treated with new TKI (option significantly superior to the other two, p<0,05). Among molecular SR, 26% of the patients obtained a stable MMR with imatinib 400 mg/d, 52% with imatinib 600 or 800 mg/d and 63% switching to new TKI. The difference was statistically significant between new TKI and imatinib 400 standard dose only (p<0,05). Cytogenetic SR maintained at imatinib 400 mg/d had a higher risk of event (defined as loss of hematologic or cytogenetic response or death) compared to molecular SR (40% vs 5%, p<0,01), although at the last follow-up, after a change in therapeutical strategy, no difference in response rate was detected between cytogenetic and molecular SR (68% vs 71%) in stable CCyR and MMR. Two patients progressed to accelerated phase (clonal evolution) but then obtained an optimal response after switching to new TKI; 2 patients died of unrelated disease. Among the 61 living patients, 71% was in MMR, 26% in CCyR only and 3% didn't reach CCyR (for these patients the efficacy of the therapeutic change is not evaluable yet). In our casistics cytogenetic SR had a higher risk of negative events than molecular SR, as reported in literature, although they obtained similar responses after changing therapeutic strategy. No clear advantage in maintaining imatinib 400 mg/d after suboptimal response was observed, since it led to a few optimal responses and was associated with a significant risk of treatment failure. Imatinib dose increment might represent a more reasonable option, at least for molecular SR. Considering the global casistic no significant difference in response rates were found between new TKI and high dose imatinib even if dasatinib and nilotinib showed a trend towards a superior efficacy in patients mostly unresponsive to the last option, suggesting that an earlier switch to new TKI might further increase the proportion of optimal responders. For cytogenetic SR the switch to new TKI brought better results than those obtained with high dose imatinib: therefore it seems to be the best choice in this subgroup of patients. Disclosures: No relevant conflicts of interest to declare.

The Persistence of p190 BCR-ABL Transcripts Is Associated with Lower Probability of Molecular Response to Imatinib in Early and Late Chronic Phase CML Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3282-3282
Author(s):  
Anna Garuti ◽  
Adalberto Ibatici ◽  
Gabriella Cirmena ◽  
Maurizio Miglino ◽  
Riccardo Varaldo ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Lower Probability ◽  
Molecular Response ◽  
Qrt Pcr ◽  
Complete Cytogenetic Response ◽  
Group 2 ◽  
Group 1

Abstract Background. It has been demonstrated that about 70% of patients with CML in chronic phase (CP) at diagnosis co-expressed p210 and p190 BCR/ABL transcripts, although at a much lower level (Blood1996;87:5213–17). In previous studies, the co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was considered as indicative of higher tumor burden. However, the clinical relevance of p190 BCR-ABL mRNA monitoring in CML pts under Imatinib on bone marrow (BM) samples is not known. Materials and Methods. BM samples were obtained from 83 pts with CP-CML treated with Imatinib at a daily oral dose ranging between 300–500mg. These included 192 samples from 43 pts with late CP-CML (post-IFN failure) and 140 samples from 40 pts with early CP-CML who received Imatinib as first line therapy. Median follow-up was 18 (3–58) and 39 (12–58) months for early and late CP-CML, respectively. As part of a diagnostic work-up, BM samples from each patient were assessed for expression of both p210 and p190 BCR/ABL levels by real-time quantitative reverse transcription PCR (QRT-PCR) using a TAQ-Man system (ABI Prism 7700 Perkin Elmer) for BCR-ABL and ABL genes. The median number of BM assessment was 3 (2–6) for early CP-CML and 4 (2–10) for late CP-CML. A major molecular response (MMR) was defined as BCR-ABL/ABL ratios less than 0.05%. A specific nested RT-PCR screening was assessed for detection of p210 (b2a2, b3a2) and p190 (e1a2) BCR-ABL transcripts to confirm the negative data of p210 and p190 in QRT-PCR. Results. A MMR was obtained in 20 pts (50%) and 20 pts (46%) in early and late CP-CML respectively. However, early CP-CML pts showed a significantly greater reduction in p210 BCR-ABL levels compared to late CP-CML after 12 months of Imatinib therapy (p=0.006), indicating a different kinetic of molecular response. Co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was 73% for early CP-CML, whereas it was not available for late CP-CML. To test whether the persistence of p190 BCR-ABL transcript was predictive of MMR, we divided CML pts in 2 groups, those with 0 or 1 p190 BCR-ABL positive samples (group 1) and those with 2 or more positive samples (group 2) during the follow-up. We found that CP-CML pts of the group 2 showed a significant lower probability to obtain MMR molecular response compared to pts of group 1 both for late and early CML patients respectively [17/24 (71%) vs 5/19 (26%) with p=0.0039)], [15/21 (71%) vs 6/18 (33%) with p=0.017)]. This correlation holds also for complete cytogenetic response (data not shown). Conclusions. In this study, approximately 50% of pts reached a MMR; half of them had undetectable values of p210 BCR-ABL transcripts. However, in a proportion of pts with complete cytogenetic response and low level of p210 BCR-ABL transcript, the expression of p190 is still detectable. The persistence of p190 signal despite the 2–3log fall in p210 BCR-ABL levels, may be of prognostic significance and may disclose unfolded concepts of biological relevance.

Imatinib Mesylate Dose Escalation Improves Disease Response in Chronic-Phase Chronic Myeloid Leukaemia Patients after Cytogenetic or Molecular Suboptimal Responses to Standard Doses of Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1052-1052 ◽  
Author(s):  
Delphine Rea ◽  
Gabriel Etienne ◽  
Selim Corm ◽  
Pascale Cony-Makhoul ◽  
Martine Gardembas ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Median Duration ◽  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Dose Increase

Abstract In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.

Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1499-1499
Author(s):  
Soo-Young Choi ◽  
Sung-Eun Lee ◽  
Yun Jeong Oh ◽  
Soo-Hyun Kim ◽  
Richard C. Woodman ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Advanced Disease ◽  
Residual Disease ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
First Line

Abstract Background In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line therapy. Methods Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results With a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). Conclusions These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

Atypical BCR-ABL Transcripts Chronic Myelogenous Leukemias Show Particular Features, and Their Classical Worse Prognosis Seems Abrogated by Imatinib Mesylate. A Retrospective Analysis of 22 Patients, on the Behalf of the French Intergroup of CML (Fi(ϕ)-LMC Group).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3285-3285
Author(s):  
Franck E. Nicolini ◽  
Nathalie Grardel ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
Agnès Buzyn ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Group 4 ◽  
Blastic Phase ◽  
Group 3 ◽  
Group 2 ◽  
Worse Prognosis ◽  
Group 1

Abstract Chronic Myelogenous Leukemia (CML) originates in the chromosome (Ph1), a reciprocal translocation, corresponding to the BCR-ABL fusion oncogene. A small proportion (1–2%) of CML patients show breakpoints falling outside of the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [either shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different BCR-ABL proteins. In this study, we retrospectively analysed the clinical characteristics and outcomes of cohorts of CML patients harbouring atypical transcripts in and treated with imatinib (IM). Twenty-two patients were analysed: 9 e1a2 [Group 1 (G1)], 4 e6a2 [Group 2 (G2)], 5 e19a2 [Group 3 (G3)], and 4 e8a2 [Group 4 (G4)] BCR-ABL transcripts. Two patients were in myeloid blastic phase at onset (1 in G1 and 1 in G2) and others in chronic phase. Age at diagnosis was significantly younger for e19a2 patients (39.5 years versus 64 for G1, 58.5 for G2, 72 for G3, p=0.005). Female patients were predominant for G1 (5F/3M), but not for other groups. All patients presented a classical Ph1 at karyotyping analysis at diagnosis, but 1 had a -7 (G1), 1 an additional t(11;16) with the Ph1 (G2), 1 a +8 (G3) and 1 a -Y (G3). The majority of patients presented typical CML features at diagnosis, however number of differences could be found: WBC counts were higher for e1a2 and e8a2 patients (74.2 109/l and 62.7 respectively vs 20.9 for G2, and 37.8 for G3, p&lt;0.03). A significant relative monocytosis was present for e1a2 patients (10% vs 4 (G2), 2.5 (G3), 5.5 (G4), p&lt;0.05), and a marked basophilia was present for e6a2 patients vs others (p&lt;0.0008). There was a trend for higher platelet counts in G3 vs others. Hasford and Sokal scores were somewhat comparable in all groups. Median follow-up since diagnosis was 24 months for G1, 10 for G2, 17 for G3 and 31 for G4. Only one patient received interferon for 7 months before IM (G1), all other patients did not receive any other treatment than hydroxyurea before IM. All patients were treated with IM alone initially at 400–600 mg/day. Median duration of IM was 18 months for G1, 9 for G2, 12 for G3, and 30 for G4. At time of analysis 1 pt in G2 and 1 patient in G3 died of progression (blastic phase), and the overall survival (OS) since IM start was better for e19a2 and e8a2 patients, but patients remain very few. However, these OS do not seem different from what has been observed for M-BCR transcripts (IRIS study). In conclusion, atypical BCR-ABL transcripts CMLs show particular diagnosis features, but their poor prognosis reputation seems abrogated by IM.

Evaluation of the Impact of Three Different Pre-Transplant Strategies On the Outcome of Myeloma Patients Candidates to High-Dose Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1223-1223
Author(s):  
Alessandro Corso ◽  
Silvia Mangiacavalli ◽  
Luciana Barbarano ◽  
Annalisa Citro ◽  
Paola Brasca ◽  
...  
Keyword(s):  
Patient Flow ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Oral Dexamethasone ◽  
Group 3 ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Abstract 1223 Poster Board I-245 Introduction This study aimed at evaluating the impact of three different pre-transplant therapies on the outcome of patients (pts) eligible for high-dose therapy. Methods two-hundred sixty eight newly diagnosed MM pts aged £65 years, Durie-Salmon stage III, II, or I in progression, were consecutively enrolled from 2000 to 2007 in three different protocols, with three different pre-transplant therapy: Group 1: (145 pts) 3 pulse-VAD cycles; Group 2: (67 pts) 3 pulse-VAD cycles plus 3 Thal-Dex cycles (thalidomide at the dose of 100 mg/day orally at bedtime, continuously for 3 months, oral dexamethasone at the dose of 20 mg on days 1-4 and 14-17 every 28 days); Group 3: (57pts) 4 Vel-Dex courses (Bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, 11; oral Dexamethasone 40 mg on days 1-4 and 8-11 every 3 weeks). After induction all pts received two DCEP-short cycles as mobilization (oral Dexamethasone 40 mg/day on days 1-4 + Cyclophosphamide 700 mg/m2/day i.v., Etoposide 100 mg/ m2/day i.v., cisPlatin 25 mg/m2/day for 2 days) with peripheral blood stem-cell (PBSC) collection prompted by G-CSF followed by one or two transplants (Tx) with melphalan 200 mg/m2 as conditioning regimen. Response was defined according to IMWG uniform criteria. Pts were considered responsive when obtaining at least a PR. Results pts in the three group were similar for age, gender, Ig type, ISS stage. A significant higher percentage of Durie and Salmon stages III was found in group 3 (83% vs 68% in group 1 and 67% in group 2, p=0.0002). The median follow-up was 46 (1-150) months for group 1, 43 (1-68) months for group 2, and 29.7 (1-79) months for group 3. At the time of this analysis in the three groups 51%, 65%, 90% of transplanted pts respectively were still alive, and progression after transplant was registered in 84%, 80%, 50% respectively. Patient flow before Tx was similar (p=0.45): 19% in group 1, 27% in group 2, 23% in group 3. In group 1, 2% of pts went off-study after VAD, and 17% after mobilization phase. In group 2, patient flow was equally distributed: 7% after pulse VAD, 10% after thal-dex, 9% after DCEP. In group 3, 12% of the pts went off-study after Vel-Dex, 11% after DCEP. Table 1 summarized responses. In group 3 (Vel-Dex) response was better along all protocol phases with respect to group 1 or 2 (p<0.00001). The number of responsive pts progressively increased from 87% after Vel-Dex (CR 31%), to 96% after transplant (CR 38%). Response rates of group 1 and 2 patients were not significantly different either after induction (p=0.6), after DCEP (p=0.5), and after Tx (p=0.65). On intention to treat basis, vel-dex induction produced a better, although not significant, PFS (34.6 months vs 29 in group 1 and 26.8 in group 2, p=0.56). OS were not statistically different among the three groups, event though the different follow-up could affect the analysis (median OS 110 in group 1, 66 months in group 2, and not reached in group 3, p=0.37). In multivariate analysis PFS was improved only by the achievement of CR (p=0.001). No significant difference was observed between VGPR or PR (p=0.43). Conclusion In this study, only CR not VGPR impacts on the outcome. Vel-Dex producing a significant high CR rate after TX (38%), seems to improve survival of MM patients candidate to high-dose therapy with respect to conventional pre-transplant strategies. Disclosures Morra: Roche:.

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.

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]

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