Busulfan Induces Hematologic and Molecular Responses in Polycythemia Vera (PV) Refractory to Multiple Drugs

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5068-5068
Author(s):  
Emil Tom Kuriakose ◽  
Stefani Gjoni ◽  
Y. Lynn Wang ◽  
Amy Jones ◽  
Nicholas C.P. Cross ◽  
...  
Keyword(s):  
Response Time ◽  
Polycythemia Vera ◽  
Phase Iii ◽  
Molecular Response ◽  
Low Doses ◽  
Molecular Responses ◽  
Hematologic Response ◽  
Significant Difference ◽  
Multiple Drugs

Abstract Abstract 5068 Busulfan, a highly effective and established drug in polycythemia vera (PV), produces lasting clinical and hematologic responses. Its use as a first and second line therapy for PV recently diminished owing to largely unsubstantiated concerns of increased leukemogenicity. However, in a pivotal phase III trial of busulfan vs. P32 conducted by the EORTC in patients with PV, busulfan sustained long term clinical and hematologic responses as well as superior 10 year overall survival (70% vs. 55%). Toxicity was minimal and a low incidence of acute leukemia was reported (1% at 8 years). Accordingly, we treated 5 PV patients with busulfan, 4 of whom were refractory to multiple drugs including hydroxyurea (HU), pegylated interferon alfa-2a (pIFN), imatinib, dasatinib, and anagrelide. Clinical and hematologic response was graded according to PVSG criteria and molecular response according to ELN criteria. JAK2V617F allele burdens were determined by pyrosequencing, which quantifies mutant alleles more than 5%. If negative by pyrosequencing, we used an ARMS-PCR assay with a sensitivity of 0. 1%. Phlebotomy was performed to maintain the hematocrit (Hct) less than 45% for men and 42% for women. Treatment with busulfan was discontinued if patients experienced adverse side effects and/or had platelet counts less than 100, 000/mL while in clinical remission. All 5 patients had complete hematologic responses (CHR) within 3 months of starting busulfan (table 1). Molecular responses (MR) were: 1 complete (CMR) after 6 months, 1 partial (PMR) after 6 months, and 3 with no response (NMR) after 3, 7, and 60 months of treatment respectively. The 2 patients who had MR were homozygous for JAK2V617F, and the 3 who did not were heterozygous. Treatment was discontinued in the patient with CHR and CMR after 7 months due to thrombocytopenia; the patient has since maintained CHR and CMR for 3 years off treatment. The remaining 4 patients have maintained CHR on low doses of busulfan (table 1). No adverse events were observed over a median treatment duration of 15 months (range: 3–60 months). The significant difference in molecular response between patients with homozygous and heterozygous JAK2 mutations receiving similar doses of busulfan is noteworthy. This suggests a susceptibility of homozygous JAK2V617F clones to busulfan, but not to other drugs including HU, IFNa, and anagrelide. In summary, our 5 patients with multidrug refractory PV had rapid and sustained hematologic responses to busulfan at low doses, with favorable short and long term toxicity profiles. Two JAK2V617F homozygous patients had the best MR. Our findings indicate the effectiveness of a safe, relatively inexpensive drug in inducing clinical outcomes not significantly different from that of costly drugs, such as JAK2 inhibitors. In addition, the high rates of MR we observed in patients with homozygous JAK2 mutations warrant further study of busulfan with respect to this parameter. Table 1: Demographics and treatment results of 5 patients treated with busulfan for PV Patient Age (yr)-Sex (M/F) Prior treatments-duration (yr) Busulfan dose Adverse effects Duration of tx (months) Hematologic response/time to response (months) Molecular response/time to response (months) Pre-busulfan JAK2 allele burden 1 75-F HU-2 yr 4mg daily thrombocytopenia 7 CHR/3 CMR/6 100% 2 70-F HU+anagrelide-1yr Imatinib-2yr Dasatinib-3 yr IFNa-1 yr 2mg 3 times a week None 15 CHR/1 PMR/6 85% 3 84-F HU-2 yr Dasatinib- 3yr Imatinib-1yr 2mg 4 times a week None 18 CHR/3 None 27% 4 81-M HU-5 yr 2mg daily None 3 CHR/2 None 23% 5 81-F None 2mg 3 times a week None 60 CHR/3 None 45% 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 <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 >2 fold rise from nadir to a level >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 <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) >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 >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<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 >6 to 12m and >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

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 ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 340-340 ◽  
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.

Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3784-3784 ◽  
Author(s):  
Kiran Naqvi ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Frontline Therapy

Abstract Abstract 3784 Background: TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim: To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods: We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results: Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies. Conclusion: New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

Early Responses At 3 Months and 12 Months After Starting Imatinib As Predictive Factors For The Achievement Of Deep MR In Japanese CML Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2744-2744
Author(s):  
Masayoshi Masuko ◽  
Tatsuo Furukawa ◽  
Tadashi Koike ◽  
Kazue Takai ◽  
Koichi Nagai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Predictive Factors ◽  
Study Group ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Observation Study ◽  
Molecular Responses ◽  
Optimal Response ◽  
Prior Therapy ◽  
Significant Difference

Abstract Background and Purpose Imatinib therapy shows excellent efficacy for chronic myeloid leukemia (CML) patients. The five-year overall survival of chronic-phase CML patients treated with imatinib can be expected to reach over 90%. Now, the goal of therapy has become the achievement of therapy-free remission (TFR) for most patients. However, predictive markers for achieving deep molecular response (MR) or TFR are yet to be elucidated. The recently published European LeukemiaNet recommendations 2013, which are mostly based on Caucasian studies, show the importance of an early response at 3 months or 12 months after starting imatinib treatment to assess optimal response. Using the registry of our study group, we assessed whether early cytogenetic or molecular responses at 3 months and 12 months after starting imatinib are associated with the achievement of deep MR or long-term outcome in Japanese CML patients. Patients and Method We reviewed 135 CML patients in the registry of our study group. Imatinib was started between December 2001 and June 2008. We retrospectively analyzed 92 CML patients (35 patients with prior therapy before imatinib) who could be assessed for partial cytogenetic response (PCyR: Ph<35% or bcr/abl transcript <10%) at 3 months after starting imatinib treatment, and 81 patients (25 patients with prior therapy before imatinib) who could be assessed for major molecular response (MMR: bcr/abl transcript <10% or 300 copies/μg) at 12 months in our multicenter observation study group. The clinical data was reviewed in August 2010. We excluded patients who had been switched from imatinib to a second tyrosine kinase inhibitor (TKI) before August 2010. We compared overall survival and the cumulative achievement of deep MR (negative bcr/abl transcript by PCR or the TMA-HPA method) between patients with and without PCyR at 3 months, also between patients with and without MMR at 12 months. The probability of overall survival and the cumulative incidence of deep MR were calculated by the Kaplan-Meier method and compared by the log-rank statistic. Results Seventy-six out of 92 patients (82.6%) achieved PCyR at 3 months. Forty out of 81 patients (49.3%) achieved MMR at 12 months. The patients with PCyR at 3 months showed significantly better overall survival (p=0.004) and higher cumulative achievement of deep MR (p=0.009) than the patients without PCyR. Overall survival between the patients with and without MMR at 12 months did not show a significant difference (p=0.06). However, the patients with MMR at 12 months showed significantly higher cumulative achievement of deep MR (p<0.001) than the patients without MMR. Conclusion Early cytogenetic and molecular responses at 3 months and 12 months after starting imatinib are also predictive factors for good prognosis and the achievement of deep MR in a registry of Japanese patients. Our data confirm the criteria of optimal response in European LeukemiaNet recommendations 2013 was appropriated for Japanese CML patients in practical setting. Disclosures: No relevant conflicts of interest to declare.

Predictive Value Of Early Molecular Responses In Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Imatinib In First-Line Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4941-4941
Author(s):  
Katia B. Pagnano ◽  
Bruna Vergilio ◽  
Eliana C M Miranda ◽  
Marcia Torresan Delamain ◽  
Maria Helena De Almeida ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
First Line ◽  
Molecular Responses ◽  
Advanced Phase ◽  
Significant Difference ◽  
The Impact

Abstract Several studies demonstrated the prognostic significance of an early molecular response in chronic myeloid leukemia (CML) patients (pts) treated with imatinib in first line or other tyrosine kinase inhibitors. Aims: The aim of this study was to evaluate the impact of early molecular responses, at 3 and 6 months after treatment with imatinib in CML pts and correlate these responses with CCR, MMR, overall survival (OS) and event free survival (EFS). Patients and Methods Between February 2006 and June 2012, 95  adult pts with newly diagnosed CML in chronic phase (CP) received imatinib 400mg/daily. CP was defined using WHO 2008 criteria. All pts received a short course of hydroxiurea until imatinib was available. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Statistical analysis: OS was measured from imatinib start until date of death or last visit. An event was defined as death from any cause. EFS was measured from imatinib start until the first event (loss of complete hematological response (CHR); complete cytogenetic response (CCR), progression to advanced phase, death or imatinib discontinuation) or last visit. OS and EFS rates were calculated using Kaplan-Meier method and log-rank test to compare its curves. The MMR probabilities according to molecular responses at 3 and 6 months were calculated by c2 method and cumulative incidence, considering as competitive event death or progression, before the event. Results 95 pts were analyzed, 57 (60%) male, with a median age of 47 years (17-79); Sokal score: high, intermediate and low was 30, 38.6 and 31.4% respectively; EUTOS scores was 81.5% low and 18.5% high. The median time from diagnosis until imatinib therapy was 1 month (0-5) and the follow-up was 39 month (3-89). Responses: 88% achieved CHR; 50% CCR and 53% MMR. One patient progressed to advanced phase during follow-up, while on imatinib treatment. 21 (22%) pts discontinued imatinib due to intolerance (47.6%); resistance (42.9%), death (4.8%) and Allo-HSCT (4.8%). At 3 months from the start of therapy, 30/64 (46.8%) achieved CCR, 15/64 (23.4%) partial cytogenetic response and 20/64 (31.2%) less than partial; by RQ-PCR, 72.3% (68/94) achieved at 3 months BCR-ABL transcripts ≤10% and 27.7% (26/94) > 10%. At 6 months 55.2% (48/87) had BCR-ABL transcripts ≤ 1% and 44.8% (39/87) >1%. The OS was 97% (95%CI: 95-99%) and EFS 63% (95%CI: 52-75%).There was no significant difference in OS and EFS in pts with RQ-PCR > 10% vs ≤ 10% at 3 months (figure 1), but pts with BCR-ABL transcripts > 10 and >1-10% at 6 months had an inferior EFS in comparison with pts with  BCR-ABL transcripts ≤ 1%  (41%,50%,89% respectively - p= 0.005), (figure 2). The CI showed that CCR pts at 3 months reached MMR earlier at 24 month (54% vs 18%, p=0.03), as well as CCR pts at 6 months, albeit no significance statistically (52% vs 37%, p= 0.16). For RQ-PCR at 3 months, pts with BCR-ABL transcripts 0-1% had a probability of 88% to achieve MMR, 1-10% had 52% and >10% 42%, p< 0.0001 (figure 3). In conclusion, our results show that early molecular responses are predictive of achieving MMR and BCR-ABL transcripts <1% at 6 months is predictive of EFS in CP-CML treated with imatinib. Disclosures: No relevant conflicts of interest to declare.

Final Results from PROUD-PV a Randomized Controlled Phase 3 Trial Comparing Ropeginterferon Alfa-2b to Hydroxyurea in Polycythemia Vera Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 475-475 ◽  
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Aleksander Skotnicki ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Research Funding ◽  
Thrombotic Event ◽  
Phase Iii ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Phase Iii Trial ◽  
Allele Burden ◽  
Randomized Controlled

Abstract Background: Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients. Study design: Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naïve to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy. Results: 257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naïve to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500µg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits). This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%. Conclusions: This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Georgiev:Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.

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 Long Term Outcome of Chronic Phase Chronic Myeloid Leukemia (CP CML) Patients (pts) from the French Spirit Study Comparing Imatinib (IM) 400 Mg to Higher Dose Imatinib or Combination with Peg-interferonα2a (PegIFN) or Cytarabine (Ara-C) : A Trial of the FI LMC (France intergroupe de la leucemie myéloïde chronique)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1793-1793 ◽  
Author(s):  
Francois Guilhot ◽  
Francoise Rigal-Huguet ◽  
Joelle Guilhot ◽  
Agnès Guerci-Bresler ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Prospective Trial ◽  
Surrogate Marker ◽  
Chronic Phase ◽  
Phase Iii ◽  
Molecular Response ◽  
Vascular Events ◽  
Long Term Outcome ◽  
Molecular Responses

Abstract Although they produce high rate of molecular response second generation tyrosine kinase inhibitors or imatinib cannot eradicate CML primitive progenitors. Interferon has been shown to modulate gene expression, inhibits leukemic cell growth and induces an immunomodulatory response. In vitro studies support the use of combination of IM plus interferon. We designed a phase III randomised multicenter open-label prospective trial comparing IM 400 mg/d (n=223) with 3 experimental arms: IM 600 mg/d (n=171), IM 400 mg/d combined to s/c Peg-IFN2a (90 µg/wk) (n=221) and IM 400 mg/d combined to s/c Ara-C, (20 mg/m2/d, d15-28 of 28-day cycles)(n=172). Pts were allocated at a 1.1.1.1 ratio, stratified by Sokal risk groups. Molecular assessments were centralised, blinded and calculated according to the international standardised ratio (IS) As of December 31st 2010, date for closing accrual, 787 pts have been included. We first demonstrated that the addition of PegIFN increased the molecular responses. The planned molecular analysis after 1 year based on the outcome of 636 pts resulted in a highly significant superiority of MR4 (≤0.01 % Bcr-Abl/Abl on IS) of the combination IM 400mg-PegIFN (Preudhomme et al. N Engl J Med, 2010). The protocol was also amended after the demonstration that a lower dose of PegIFN (45 µg/week) resulted in less toxicity and similar molecular responses as compared with 90 µg/week. Of interest, a 3-months BCR-ABL transcript level of ≤10% IS was associated with PFS (Accelerated phase, blast crisis, deaths) and time to progression (TTP) improvement overall. However, results which were observed with the addition of PegIFN or an increased dose of IM frontline do not confirm the relevance of the 10% BCR-ABL cut-off level as a strong surrogate marker for progression. After a median observation time of 60 months, 5-year overall survival (OS) was 94%, and 5-year PFS was 93%. Overall 70 pts died because of blastic (n=24) or accelerated phases (n = 1). Out of the 35 pts who progressed to AP and BC, 11 are alive. A blastic phase was recorded in 27 pts (myeloid 20, lymphoid 6, biphenotypic 1), of these 4 are alive (2 myeloid, 2 lymphoid). Main causes of deaths in CP (n = 46) were infections (IM 400 n=4,IM 600 n=0, IM PegIFN n=4, IM Ara-c n=0 ), vascular events (IM 400 n=1,IM 600 n=2,IM PegIFN n=1, IM Ara-c n=1) malignancies (IM 400 n=3, IM 600 n=2 ,IM PegIFN n=4, IM Ara-c n=7 ). In addition, the following causes of death were recorded: suicide (n=2), GVHD (n=2), miscellaneous (n=13). Cumulative incidence of progression, PFS and OS by arms are shown in the table: Table 1 IM 400 (n = 223) IM 600 (n = 171) IM PegIFN (n = 221) IM Ara-c (n 172) Cumulative incidence of progression (p: 0.43)(a) N progressions 11 11 7 6 N competing events (deaths in CP) 9 7 15 15 At 60 months % (95%CI) 5% (3-8) 5% (3-9) 2% (1-4) 4% (2-8) PFS (p:0.92)(b) N (progressions and deaths) 20 18 22 21 At 60 months 93% 93% 94% 91% (95%CI) (89-96) (88-96) (90-97) (85-94) OS (p: 0.64)(b) N (deaths) 15 16 19 20 At 60 months 95% 94% 95% 91% (95%CI) (91-98) (89-97) (91-97) (86-95) Gray’s test Log-rank test Conclusions:The French SPIRIT trial demonstrated that the combination of imatinib with Peg-IFNα2a was associated with deeper molecular responses at 12 months and was able to counteract the risk of early progression in newly diagnosed CML-CP patients. The dose of 45µg/week is well tolerated and sufficient for achieving molecular responses and should be used in further trials. The risk of progression to blastic or accelerated phase, although currently non-significant, is lower with this combination. An update of outcomes will be presented. Disclosures Maloisel: Hospira: Consultancy; Sandoz: Research Funding; Pfizer: Research Funding. Gardembas:BMS: Honoraria. Legros:Novartis, BMS: Honoraria.

Meta-analysis of gender effect for first-line chronomodulated 5-fluorouracil-leucovorin-oxaliplatin (ChronoFLO) compared with FOLFOX or constant infusion (conventional delivery, CONV) against metastatic colorectal cancer (MCC) in three international controlled phase III randomized trials (RT)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4112-4112 ◽  
Author(s):  
F. Levi ◽  
P. Innominato ◽  
A. Poncet ◽  
T. Moreau ◽  
S. Iacobelli ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Constant Infusion ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Significant Difference

4112 Background: Gender predicted for the most effective schedule in a RT of ChronoFLO vs CONV against MCC: overall survival (OS) was significantly increased in men on chronoFLO vs FOLFOX, whereas the reverse was found in women (Giacchetti, JCO 2006). Methods: To assess the relevance of gender for patient (pt) outcome, meta-analysis was performed on individual pt data (IPD) from 3 RT in 845 MCC pts treated with chronoFLO vs CONV (346 F, 499 M at 36 centers in 1990–2002)(Lévi, JNCI 1994; Lancet 1997). Data bases were merged and updated at 9 y after inclusion of the 1st pt. Main prognostic factors were comparable in each RT according to gender and treatment arm (median age: 61y; PS=0, 46% pts; liver M, 85% pts; liver involvement >25%, 41% pts; lung M, 37% pts; CEA>10, 56% pts). Results: No significant difference was found according to delivery schedule or gender in the whole population for Response Rate (RR), Progression-Free Survival (PFS) and OS. However, men on chronoFLO had highest RR, longest PFS and OS. PFS and OS were highest in women on CONV ( Table ). The rate of complete macroscopic resections of liver metastases (R0+R1) was 12.5% in men on chronoFLO vs 7.8–8.5% in men on CONV or in women on either schedule. A complete histologic response of liver metastases was documented in 2.1% of the men on chronoFLO vs 0–1.1% in the other groups. The relative risk of an earlier death in men vs women was 0.76 [95% CL, 0.91 to 0.94] on chronoFLO and 1.24 [0.99 to 1.56] on CONV. Conclusions: This IPD meta-analysis of 3 RT in MCC with a minimum follow up of 5 years confirms that men benefit from chronoFLO as compared to CONV delivery, with regard to long term outcome and medico-surgical strategy. ChronoFLO should be preferred to conventional oxaliplatin-5-FU-LV schedules in men with MCC. Support: ARTBC Internationale, P. Brousse Hospital, Villejuif, France. [Table: see text] No significant financial relationships to disclose.

Impact of p16 status on the QOL effects of chemoradiation for locally advanced oropharynx cancer: Results of TROG 02.02.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5571-5571 ◽  
Author(s):  
Jolie Ringash ◽  
Richard Fisher ◽  
Lester J. Peters ◽  
Brian O'Sullivan ◽  
Andy Trotti ◽  
...  
Keyword(s):  
Oropharyngeal Cancer ◽  
Locally Advanced ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
Ecog Ps ◽  
The Impact ◽  
Subsequent Time Point

5571 Background: We report the impact of p16 status on quality of life (QOL) for patients with stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oropharynx (OPC) treated with concurrent chemoradiotherapy in a large international phase III trial (TROG 02.02/HeadSTART). Methods: The 861 patients accrued received definitive radiotherapy (RT) (70 Gy/7 weeks) concurrently with 3 cycles of either cisplatin (100mg/m2) or cisplatin (75 mg/m2) plus tirapazamine (290 mg/m2/day) by random assignment, as previously described. QOL was measured with the FACT-H&N at baseline, 2,6,12, 23 and 38 months. No significant difference in overall or subscale QOL score change from baseline was observed between arms at any subsequent time point; results for the oropharynx subgroup by p16 status are reported for both treatment arms combined. Results: Of 853 eligible participants, 465 had OPC, for whom p16 status could be determined in 206. Of 179 who received adequate RT (≥ 60 Gy, no major deviations) and completed baseline QOL, 104 were p16+ and 79 were p16-. p16+ patients had better baseline ECOG PS, lower T-category, higher N-category, were younger and were less likely to be current smokers. Baseline mean FACT-H&N score was statistically and clinically significantly better in p16+ patients (111 vs. 102, p=0.001). The drop in QOL from baseline to 2 months was more severe in p16+ cases (-20.4 vs -9.1, p=0.001), resulting in an equalization of 2 month scores (p16+: 90.6, p16-: 93.6, p=0.16). At 6 and 12 months post-treatment, no difference in score changes from baseline by p16 status was seen (6 mo, p16+: -6.2, p16 -:-1.2, p=0.22; 12 mo, p16 +: -0.3, p16 -: +2.0, p=0.82). Conclusions: p16 associated oropharyngeal cancer has been shown to be a distinct entity with different demographic features. In our study, such patients exhibited better baseline QOL and a more severe drop immediately after treatment, but did not differ in long-term QOL response to the effects of aggressive concurrent chemoradiation. Given the favorable prognosis of p16-associated oropharyngeal cancer, efforts to reduce the QOL burden of treatment are warranted.

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