Analysis of sex-based differences in clinical and molecular responses to ischemia reperfusion after lung transplantation

Abstract Background Sex and hormones influence immune responses to ischemia reperfusion (IR) and could, therefore, cause sex-related differences in lung transplantation (LTx) outcomes. We compared men’s and women’s clinical and molecular responses to post-LTx IR. Methods In 203 LTx patients, we used the 2016 International Society for Heart and Lung Transplantation guidelines to score primary graft dysfunction (PGD). In a subgroup of 40 patients with blood samples collected before LTx (T0) and 6, 24, 48 (T48), and 72 h (T72) after lung reperfusion, molecular response to IR was examined through serial analysis of circulating cytokine expression. Results After adjustment, women had less grade 3 PGD than men at T48, but not at T72. PGD grade decreased from T0 to T72 more often in women than men. The evolution of PGD (the difference in mean PGD between T72 and T0) was greater in men. However, the evolution of IL-2, IL-7, IL-17a, and basic fibroblast growth factor levels was more often sustained throughout the 72 h in women. In the full cohort, we noted no sex differences in secondary clinical outcomes, but women had significantly lower peak lactate levels than men across the 72 h. Conclusions Men and women differ in the evolution of PGD and cytokine secretion after LTx: Women have a more sustained proinflammatory response than men despite a greater reduction in PGD over time. This interaction between cytokine and PGD responses warrants investigation. Additionally, there may be important sex-related differences that could be used to tailor treatment during or after transplantation.

Download Full-text

Significant Higher Rates of Undetectable Molecular Residual Disease and Molecular Responses with Pegylated Form of Interferon a2a in Combination with Imatinib (IM) for the Treatment of Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukaemia (CML) Patients (pts): Confirmatory Results at 18 Months of Part 1 of the Spirit Phase III Randomized Trial of the French CML Group (FI LMC).

Blood ◽

10.1182/blood.v114.22.340.340 ◽

2009 ◽

Vol 114 (22) ◽

pp. 340-340 ◽

Cited By ~ 14

Author(s):

François Guilhot ◽

Claude Preudhomme ◽

Joelle Guilhot ◽

Francois-Xavier Mahon ◽

Franck Emmanuel Nicolini ◽

...

Keyword(s):

Interim Analysis ◽

Residual Disease ◽

Prospective Trial ◽

Phase Iii ◽

First Year ◽

Combination Regimen ◽

Molecular Response ◽

Median Dose ◽

Molecular Responses ◽

Grade 3

Abstract Abstract 340 Background: IM 400 mg daily is the front-line treatment of CP CML, but provides only 50% major molecular responses (MMR) at 18 months (Mo). Aims: we designed a phase III randomized multicenter open-label prospective trial comparing IM 400 mg/d (n=159) with 3 experimental arms: IM 600 mg/d (n=160), IM 400 mg/d combined to s/c cytarabine (Ara-C), (20 mg/m2/d, d15-28 of 28-day cycles)(n=158) and IM 400 mg/d combined to s/c Peg-IFN2a (90 μg/wk) (n=159). Methods: Pts were allocated at a 1.1.1.1 ratio, stratified by Sokal risk groups. Molecular assessments were centralized, blinded and calculated according to the international standardized scale (IS). The purpose of this trial was to first determine whether higher doses of IM or combining IM with interferon or Ara-C would result in higher rates of molecular responses and if so, in better survival. Thus the trial was designed to be conducted according to 2 parts. During the part 1, the increased dose of IM or a combination regimen would be considered as promising at 1 year, if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability A planned interim analysis of 636 pts based on an optimal molecular response (OMR = BCR-ABL/ABL ratio ≤ 0.01) (α=0.85%, β=10%) at 1 year has suggested the superiority of the combination of Peg-IFN2a and imatinib (ASH 2008). We now report the 18 months update of this planned interim analysis of part 1 of the trial. Results: Pts of the part 1 were recruited between 9/2003 and 10/2007, median age 51 yrs (18-82), 62% males; Sokal score was low 37%, intermediate 39% and high risk 24%. Median follow-up was 42 Mo. (range 18-73) for alive patients. MMR, OMR and undectable molecular residual disease (UMRD) rates are described in Table 1. During the first year of treatment the median dose of IM was 400 mg for the 3 arms including IM 400 and 590 mg for IM 600; the median dose for Peg IFN2a was 54 μg per week (range11-166) and was 24mg per day (range 10-40) for Ara-C. Overall, 45% of the pts discontinued Peg-IFN2a during the first 12 months. Of interest, duration of treatment with Peg-IFN2a had an impact on responses. In pts who have been treated less than 4 months as compare to more than 12 months, rate of MMR, OMR and UMRD increased from 48% to 82%, 23% to 49% and 8% to 20% respectively. Grade 3/4 neutropenia and/or thrombocytopenia occurred during the first year in 8% IM-400, in 14% IM-600, in 41% IM-Ara-C and in 40% IM-PegIFN arms respectively. No significant infection rates were observed between the 4 arms. Grade 3/4 non-haematological toxicities occurred in 19% IM-400 (oedemas, muscle cramps), in 30% IM-600, in 27% IM-Ara-C (diarrhoea) and in 31% IM-PegIFN pts (skin rashes, asthenia). Conclusions: Based on these results and as recommended by the Independent Data and Ethics Monitoring Board, the CML French Group (FI-LMC) stopped accrual into the IM 600mg and IM 400mg + Ara-C arms and is currently continuing with IM 400 mg as control arm and the combination IM400mg + Peg-IFN2a as best experimental arm. This second part of the trial aims to confirm if achieving significant higher molecular responses will translate into a better event free and overall survival. Disclosures: Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria.

Download Full-text

Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽

10.1182/blood.v120.21.694.694 ◽

2012 ◽

Vol 120 (21) ◽

pp. 694-694 ◽

Cited By ~ 2

Author(s):

Timothy P. Hughes ◽

Jeffrey H. Lipton ◽

Nelson Spector ◽

Brian Leber ◽

Ricardo Pasquini ◽

...

Keyword(s):

Board Of Directors ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Molecular Response ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6535 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6535-6535 ◽

Cited By ~ 16

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]

Download Full-text

Correlation Between Treatment Outcomes, Baseline Characteristics and Molecular Responses in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Essential Thrombocythemia

Blood ◽

10.1182/blood.v128.22.1929.1929 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1929-1929

Author(s):

Claire N. Harrison ◽

Adam Mead ◽

Sonia Fox ◽

Anesh Panchal ◽

Christina Yap ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Research Funding ◽

Advisory Board ◽

Symptom Improvement ◽

Separate Analysis ◽

Molecular Response ◽

Molecular Responses ◽

Early Satiety ◽

Patient Reported ◽

Grade 3

Abstract MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in essential thrombocythemia (ET) patients with resistance/intolerance to Hydroxycarbamide (HC) per European LeukemiaNet (ELN) criteria. Primary outcome was rate of complete hematological response (CHR) within 1 year (ELN criteria); secondary outcomes included partial HR, safety, thrombosis, hemorrhage, progression free survival (including transformation), molecular response (MR), symptom & quality of life (QOL) assessment. We present new data concerning molecular, symptom & clinical responses. Patients were stratified by JAK2V617F status, patient-reported symptoms & QOL determined using EQ5D, MDASI & MPN Symptom Assessment Form (MPN10), & compared using linear mixed models of post-baseline scores through month 12 adjusting for baseline; response was defined as ≥50% reduction in MPN10 total symptom score (TSS). JAK2/CALR/MPL allele burdens were assessed at baseline & 4 monthly. 110 patients were eligible for the modified ITT analysis, 58 (52%) & 52 (48%) in RUX & BAT arms respectively, comprising 44 males, 66 females, mean age 64.2ys, & resistant (24.5%), intolerant (51.8%) or both (22.7%) to HC. CHR was achieved in 27 (46.6%) of RUX patients vs 23 (44.2%) BAT patients (χ2 test p= 0.81). PHR occurred in 26 (44.8%) & 27 (51.9%) of RUX & BAT treated respectively. Grade 3 or 4 anemia occurred in 19% & 0% for RUX arm vs 0% (both grades) for BAT arm, grade 3 or 4 thrombocytopenia in 5.2% & 1.7% of RUX vs 0% (both grades) of BAT patients respectively. Grade 3 or 4 infections occurred in 10.3% of RUX patients vs 3.6% BAT arm. 9 RUX treated patients had 10 thrombotic events & 1 RUX patient a hemorrhage; vs 5 thrombotic & 5 hemorrhagic events in BAT patients (adjusted following central review). Transformations to post-ET MF occurred in 8 RUX vs 3 BAT treated patients, 1 RUX patient developed AML. 2 non-treatment related deaths occurred in each arm. Mean MPN-10 TSS & individual symptoms of early satiety & itching during the first 12 months were all significantly lower for RUX vs BAT (all p<0.05). Patients who achieved CHR had significantly better TSS, fatigue, inactivity, concentration problems, & MDASI symptom interference (all p<0.05) at baseline vs those without; however, scores during treatment did not appear to differ between CHR & non CHR groups after adjusting for these baseline differences. Allele burden during study & MRs (per ELN-IWG criteria Barosi Blood 2013) are shown in Table 1. Assays for JAK2 V617F were performed independently in 3 centres using qPCR (Guy's), TSCA NGS (Oxford) & amplicon-based NGS (Salisbury) & revealed Mean (range): JAK2 (Guy's): 33.2 (0.1-94.6), N=52; JAK2 (Oxford): 38.0 (0.5-92.2), N=52; JAK2 (Sal): 38.3 (0-90.0), N=50 (limited to JAK2 positive only). With Interclass Correlation Coefficient as follows ICC (Guy's v Oxford): 0.92 (95% CI 0.86-0.95) ICC (Guy's v Sal): 0.92 (95% CI 0.86-0.95) ICC (Oxford v Sal): 0.997 (95% CI 0.994-0.998). Notably MRs (n=5) only occurred with RUX treatment. There was no pattern of MR or progression with C/PHR or transformation, but 1 patient who transformed to PET MF had a complete MR. In a separate analysis baseline symptoms & QOL were not associated with JAK2, CALR, nor MPL status. Within RUX, baseline symptoms & QOL did not predict MR; however, fatigue, early satiety & abdominal discomfort (all p<0.05, Table 1) were significantly lower among those with MR vs not during treatment with a descriptively higher symptom response rate (2/4 [50%] vs 9/30 [30%]). Three non pre-specified multivariate analyses were performed to assess baseline factors influencing CHR (modelled for: treatment received, HC resistance or intolerance, white cell count, platelets, Hb & JAK2/CALR status); occurrence of ≥ grade 3 anemia or thrombocytopenia (modelled for: Hb (≥ 100g/dl) JAK2/CALR status); & transformation to PET-MF (modelled for: treatment, Hb ≤100g/dl). Only baseline Hb ≤100g/dl was significant for grade 3+ anemia (OR [95% CI]=0.17 [0.04, 0.72]), & PET-MF only occurred in patients with baseline WBC <10x109/L. This updated analysis shows that HC resistant/intolerant ET is clinically & molecularly diverse. We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies. Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression events. Disclosures Harrison: Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Aliman:Novartis: Other: Institutional funding and grant for international conference. . Chen:Novartis: Other: Advisory Board. Coppell:Novartis: Other: Travel, accommodation and conference attendance. Knapper:ONO pharmaceuticals: Research Funding; Novartis: Honoraria, Other: Travel and expenses for international conferences. Ali:Novartis: Honoraria, Other: Conference sponsorship, advisory board meetings. Hamblin:Novartis: Other: Advisory Board. Dueck:Bayer: Honoraria. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. McMullin:Novartis: Honoraria, Speakers Bureau.

Download Full-text

Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7053 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7053-7053

Author(s):

Nelson Spector ◽

Brian Leber ◽

Jeffrey Howard Lipton ◽

Carmino De Souza ◽

Beatriz Moiraghi ◽

...

Keyword(s):

Residual Disease ◽

Blast Crisis ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Molecular Responses ◽

The Difference ◽

Treatment Free Remission

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

Download Full-text

Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v120.21.1676.1676 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1676-1676 ◽

Cited By ~ 13

Author(s):

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Surapol Issaragrisil ◽

Richard E Clark ◽

Josy Reiffers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

The Impact

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID; n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Download Full-text

Nilotinib-Associated Molecular Responses Achieved in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients with a Suboptimal Molecular Response to Imatinib.

Blood ◽

10.1182/blood.v114.22.2206.2206 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2206-2206

Author(s):

Allen S. Yang ◽

Anand Jillella ◽

Carole B. Miller ◽

Luke P. Akard ◽

Daniel J. DeAngelo ◽

...

Keyword(s):

Research Funding ◽

Molecular Response ◽

Imatinib Treatment ◽

Molecular Responses ◽

Transcript Levels ◽

Log Reduction ◽

Group 2 ◽

Grade 3 ◽

The Impact ◽

Group 1

Abstract Abstract 2206 Poster Board II-183 Background Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to imatinib. The achievement of a major molecular response (MMR), defined as a 3 log reduction of the Bcr-Abl transcript level from the baseline mean, is a favorable prognostic factor for the disease at any time point. This multi-center, open-label study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in patients who have achieved complete cytogenetic response but have demonstrated a suboptimal molecular response to imatinib. Methods This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP patients (n=160) who achieve CCyR but have a suboptimal molecular response to imatinib defined either as: (Group 1) treated > 1 year with imatinib, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1 log increase in Bcr-Abl transcript levels regardless of the imatinib treatment duration. At study entry, patients are treated with nilotinib 300 mg b.i.d. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 months on treatment with nilotinib. Since there is a paucity of efficacy data published for suboptimal responders to imatinib, this preliminary analysis was performed on a small cohort of patients enrolled as of the data cut-off date of July 21, 2009. Results 11 CML-CP suboptimal molecular responding patients have been treated with a median of 2.6 months on nilotinib. One patient entered the study as a Group 2 patient and ten entered into Group 1. 1 patient was deemed ineligible due to lack of evidence of CCyR at baseline. The remaining 10 entered the trial with a baseline CCyR. Prior to enrollment, patients were treated with at least 400mg QD imatinib; the mean dose of prior imatinib treatment was 463 mg/day (range 377 – 573 mg/day). The median duration of prior imatinib treatment was 39.5 months (range 14.0-106.4 mo). 1 patient was previously treated with interferon. 8 patients have been treated for >3 months. Out of these 8 patients, 2 have been treated for > 6 months and 1 patient has been treated for > 9 months. Aside from these 8 patients, another 3 did not yet reach end of Month 3 at the time of analysis. Six out of 8 evaluable patients (75%) achieved MMR; 4 patients after three months on nilotinib, 1 patient after 4.5 months on nilotinib (measured at end of study), and 1 patient after 9 months on nilotinib. Overall, patients achieved a median log reduction of PCR transcript levels of 3.1 (range 2.1-4.5) from the standardized baseline (based on the IS) at the end of Month 3. 4 out of 11 patients were dose reduced for nilotinib related adverse events (AEs). No grade 4 AEs were reported. 1 patient experienced a grade 3 headache and two cases of grade 3 elevated ALT were reported. Brief dose interruptions were sufficient to manage most AEs. The median dose intensity was 600 (range 400-600 mg/day). No patients discontinued from the study due to an AE as of the data cut-off date. No patients who experienced QTcF changes had differences >34 msec from baseline. No QTcF prolongation >500 msec was observed. Conclusions Nilotinib treatment results in high rates of molecular response in CML-CP patients with suboptimal molecular responses to imatinib. 75% of the evaluable patients who switched to nilotinib achieved MMR at the time of analysis, and all evaluable patients achieved a median > 3 log reduction of PCR transcripts from the standardized baseline within 3 months of starting therapy. No patients were discontinued due to AEs. Outcomes for additional patients enrolled and longer term follow-up will become available. Disclosures: Yang: Bristol Myers Squibb: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Esai: Speakers Bureau; Therepi: Equity Ownership. Off Label Use: Nilotinib for suboptimal responders to imatinib therapy. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Akard:Novartis: Consultancy, Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Speakers Bureau. Goldberg:Novartis Pharmaceuticals: Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Download Full-text

Pegylated Interferon-α 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study.

Blood ◽

10.1182/blood.v120.21.166.166 ◽

2012 ◽

Vol 120 (21) ◽

pp. 166-166 ◽

Cited By ~ 3

Author(s):

Franck E. Nicolini ◽

Gabriel Etienne ◽

Viviane Dubruille ◽

Lydia Roy ◽

Françoise Huguet ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Chronic Phase ◽

Pegylated Interferon ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Front Line ◽

Molecular Responses ◽

Line Therapy ◽

Grade 3

Abstract Abstract 166 Background Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia (CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010). Aims Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28). Methods In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %. Results In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia. Conclusion The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.

Download Full-text

Dasatinib Treatment Induces Fast and Deep Responses In Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients In Chronic Phase: Clinical Results From a Randomized Phase 2 Study (NordCML006)

Blood ◽

10.1182/blood.v122.21.4032.4032 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4032-4032 ◽

Cited By ~ 1

Author(s):

Henrik Hjorth-Hansen ◽

Johan Richter ◽

Leif Stenke ◽

Hans Ehrencrona ◽

Bjørn Tore Gjertsen ◽

...

Keyword(s):

Research Funding ◽

Chronic Phase ◽

Clinical Results ◽

Molecular Response ◽

Newly Diagnosed ◽

Therapy Discontinuation ◽

Src Tyrosine Kinase ◽

Molecular Responses ◽

Treatment Responses ◽

The Difference

Abstract Background Dasatinib is a potent BCR-ABL1 and SRC tyrosine kinase inhibitor, which in vitro is more effective against progenitor and putative leukemia stem cells than imatinib. This may translate into deeper molecular responses in vivo. Methods We randomized (1:1) 46 newly diagnosed CML patients to receive dasatinib 100 mg or imatinib 400 mg once daily. The primary endpoint of our study was treatment response in stem and progenitor cell fractions (Mustjoki et al, Leukemia 2013). We here summarize the clinical results of the study after a 24-month follow-up focusing on toxicity and standard response evaluation by quantitative BCR-ABL1 PCR and cytogenetics (NCT00852566 www.ClinicalTrials.gov). Results Both imatinib and dasatinib treated patients fared well with deeper and faster treatment responses than what has been reported in the registration studies. By karyotyping, dasatinib induced a faster response by 3 months (median of 5% of Ph+ cells in imatinib group vs. 0% in dasatinib group, p=0.01, n=21 in each group), but already by 12 months the difference disappeared, as all evaluable patients were in complete cytogenetic remission. The rate of molecular response MR3.0 was already at the 3 months time-point better in the dasatinib group (36% vs 8%, p=0.02; see Table), but within 18 months imatinib patients caught up the difference. In contrast, the achievement of deeper therapy responses, MR4.0 and MR4.5, was clearly different between the groups and increased over 24 months. After 18 months 64% and 71% of imatinib- and dasatinib-treated patients had achieved MR3.0 (p=0.59), while the MR4.0 rates were 23% and 62% (p=0.009) and MR4.5 rates 4% and 41% (0.003) (see Table below). The difference in median transcript levels was approximately 1 log (>10-fold difference) in all time-points after 3 months of therapy (see Table below). A total of 7 patients (30%) in both groups discontinued assigned treatment. Main drug-related toxicities were as expected. Dasatinib-induced serosal inflammation (pleural/pericardial effusions) was more frequent than in registration studies (6 patients, 27%). In 4 patients (18%) this led to therapy discontinuation, despite of drug interruption and dose reductions. In the imatinib group 3 patients discontinued due to drug-related toxicity (liver toxicity, rash and severe hypogammaglobulinemia with recurrent infections). Disease progression occurred in one dasatinib-treated patient (cytogenetic progression with the appearance of V299L mutation at month 9) and two imatinib-treated patients (blastic transformation at month 2 and molecular progression at month 18). The patient in blast phase has been transplanted and is currently in molecular remission. No CML-related deaths occurred, but one patient died from lung cancer. Interpretation Dasatinib induced faster and deeper molecular responses than imatinib and overall responses were better in both groups than in the registration studies. Relatively high rate of serosal toxicity was observed among the dasatinib-treated patients, but this had no adverse effect on response. Upcoming studies will show if the deeper treatment responses induced by dasatinib therapy translate into increased probability of successful therapy discontinuation. Disclosures: Hjorth-Hansen: Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Travel Other; Merck: Research Funding. Richter:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Consultancy, Honoraria, Travel, Travel Other. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Mustjoki:Novartis: Honoraria; BMS: Honoraria, Research Funding.

Download Full-text