Low-Burden TP53 Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2 Status

Abstract Myeloproliferative neoplasms (MPN) are characterized by abnormal proliferation of myeloid lineages and a tendency toward leukemic transformation. Inactivation of tumor suppressor TP53 has been repeatedly associated with MPN transformation into secondary acute myeloid leukemia (sAML), but no fully expanded TP53 mutated clones in chronic phase of MPN were reported. The link between TP53 mutations and widely used cytoreductive treatment by hydroxyurea (HU) still remains controversial. To which extent TP53 mutations represent a risk of disease progression is not known. We aimed to search for low-burden TP53 mutated subclones in chronic-phase-MPN patients and to correlate presence of these clones with therapy, disease course, and other clinical features. In total we analyzed 220 patients by ultra-deep next generation sequencing (NGS). We detected TP53 mutations in 39 (18 %) patients with variant allelic frequency of 0.1-16.3 % at the first examination. The analysis of 136 patients treated with hydroxyurea or other drugs (anagrelide (ANA), interferon α (IFN)) for more than 4 years, as well as a group of 84 patients untreated by cytoreductive drugs, showed that TP53 mutations occurrence in chronic phase is independent of hydroxyurea use, disease type, and JAK2/CALR/MPL status. Mutations were found in 17/72 (24 %) HU treated patients, in 11/64 (17 %) patients treated by other drugs, and in 11/84 (13 %) untreated patients. Median size of mutated clones was 0.5 % and was not influenced by previous treatment. In 10 patients we found more than one mutation. In patients harboring TP53 mutations, retrospective samples were examined if available to explore the clonal evolution of TP53 mutated clones. The respective TP53 mutations were found in 13/20 cases analyzed; out of them, in 4 cases the mutation was found even in a diagnostic sample. Follow-up samples were examined in 28 patients with TP53 mutations and the mutation burden changed during the monitored time in majority of patients; however, the expansion into dominant clone was observed in one patient only. When all data from retrospective and prospective analyses taken together (30 patients), the median follow-up was 7.2 years. TP53 mutation burden tended to increase in 14 patients. In 6 patients the mutation burden remained stable and in 4 patients it fluctuated. In 6 patients the mutated clone size decreased; out of them in 2 originally very low-burden mutations (0.2 %) were not detectable in samples taken 15 and 3.4 years later. We did not observe any correlations of different patterns in TP53 mutation changes with therapy or other clinical characteristics (disease type, driver mutation, time from diagnosis, treatment response). Further, we assessed the TP53 mutation impact on overall survival and leukemic transformation. The mutations did not negatively affect disease progression or overall survival either from diagnosis or from mutation identification. sAML developed in 2 patients with TP53 mutations 17.9 (treated with IFN) and 8.3 (treated with HU) years from diagnosis. In the latter patient, the sAML developed from a different clone as it was TP53-wt, JAK2-wt, although 2 TP53 mutated clones within JAK2 mutated clone were detected in chronic phase. On the other hand, we have observed another interesting case where the TP53 mutation burden grew rapidly from 10 % up to nearly 100 % during the follow-up. In contrast to published data, this patient did not show any clinical signs of disease progression for 2 years after the expansion and died of MPN unrelated cause. In summary, using highly sensitive method we showed that low-burden TP53 mutations are present in MPN chronic phase. Neither their presence nor their size is associated with previous therapy and has impact on overall survival or leukemic transformation. Monitoring of TP53 mutations during the disease course showed that their clonal development is rather variable; nevertheless, TP53 minor mutations may represent a pool for future clonal evolution. Supported by MZ CR-RVO (FNBr, 65269705), MUNI/A/1028/2015, H2020 692298, MZO AZV 15-31834A, 15-30015A, MEYS LQ1601 and LM2015064. Disclosures Gisslinger: Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v116.21.3438.3438 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3438-3438

Author(s):

Naveen Pemmaraju ◽

Hagop Kantarjian ◽

Susan O'Brien ◽

Srdan Verstovsek ◽

Elias Jabbour ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Chronic Phase ◽

Annual Rate ◽

Molecular Response ◽

Free Survival ◽

Cumulative Rate ◽

Prospective Trials

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

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Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients

Blood ◽

10.1182/blood.v118.21.2445.2445 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2445-2445

Author(s):

Annika Dufour ◽

Stefan K Bohlander ◽

Evelyn Zellmeier ◽

Gudrun Mellert ◽

Karsten Spiekermann ◽

...

Keyword(s):

Disease Progression ◽

Research Funding ◽

Tp53 Mutation ◽

Lymphocytic Leukemia ◽

Dominant Negative ◽

Tp53 Mutations ◽

Mutational Status ◽

Igvh Mutational Status ◽

Binet Stage ◽

Previously Treated

Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

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Molecular and Cytogenetic Response After 3 Months of Imatinib Treatment Is Predictive for the Risk of Disease Progression and Death in Newly Diagnosed Chronic Myeloid Leukemia Patients – a Follow-up Analysis of the German CML Study IV

Blood ◽

10.1182/blood.v118.21.783.783 ◽

2011 ◽

Vol 118 (21) ◽

pp. 783-783 ◽

Cited By ~ 4

Author(s):

Benjamin Hanfstein ◽

Martin C. Müller ◽

Philipp Erben ◽

Michael Lauseker ◽

Susanne Saussele ◽

...

Keyword(s):

Overall Survival ◽

Disease Progression ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Cytogenetic Response ◽

Imatinib Treatment ◽

Risk Of Disease ◽

Equity Ownership

Abstract Abstract 783FN2 Introduction: The advent of second generation tyrosine kinase inhibitors (TKI) in the front line treatment setting of chronic myeloid leukemia (CML) has tightened the evaluation of imatinib response. Early assessment of response markers might identify slow responders harboring a BCR-ABL positive clone with an inferior susceptibility to tyrosine kinase inhibition. This group of patients could benefit from an early dose escalation or a change of treatment to a second generation TKI thus avoiding the risk of disease progression. Therefore we sought to evaluate the impact of molecular and cytogenetic response levels after 3 months of imatinib treatment on the further course of disease. Patients and methods: A total of 1,340 patients (median age 52 years, range 16–88, 40% female) were included into the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg/d (n=381), imatinib 800 mg/d (n=399) and combinations of standard dose imatinib with interferon alpha (n=402) and low-dose cytarabine (n=158). Median follow-up was 4.7 years (range 0–9). Molecular response after 3 months was assessed in 743 patients, cytogenetic response in 498 patients. The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABL IS). Only patients expressing typical BCR-ABL transcripts (b2a2, b3a2, b2a2 and b3a2) were considered. Cytogenetic response was determined by conventional metaphase analysis. Disease progression was defined by the incidence of accelerated phase, blastic phase or death from any reason. A landmark analysis was performed for progression free survival (PFS) and overall survival (OS). Results: Disease progression was observed in 149 patients (11.1%), 127 patients died (9.5%). After 3 months of treatment the median BCR-ABL IS was 2.6% (0-100), the median proportion of Philadelphia chromosome positive metaphases (Ph+) was 8% (0-100). The BCR-ABL landmarks of 1% and 10% after 3 months of imatinib both proved to discriminate significantly for PFS and OS: BCR-ABL IS <1% (n=233) vs. ≥1% (n=486), p=0.041 for PFS, p=0.048 for OS; BCR-ABL IS <10% (n=524) vs. ≥10% (n=195), p=0.004 for PFS and p=0.001 for OS. A stratification in 3 risk groups according to the achievement of a BCR-ABL IS of <1%, 1–10% and >10% after 3 months resulted in a significant difference between the poor risk group (>10%, n=195) and the intermediate risk group (1-10%, n=291): p=0.038 for PFS and p=0.012 for OS. The difference between the intermediate risk group and the good risk group (<1%, n=233) was not significant. The five year survival probability was 97%, 94% and 87% for the good, intermediate and poor risk group, respectively. Cytogenetic response landmarks after 3 months of imatinib were also predictive for PFS and OS: Ph+ ≤35% (n=362) vs. Ph+ >35% (n=123), p=0.022 for PFS, p=0.043 for OS; Ph+ ≤65% (n=401) vs. Ph+ >65% (n=84), p=0.004 for PFS and p=0.011 for OS. A 3 group stratification did not reach statistical significance. Conclusions: The achievement of molecular and cytogenetic response landmarks after 3 months of imatinib treatment is predictive for long term progression free and overall survival. At 3 months a BCR-ABL IS of 10% or more is associated with a 5-year overall survival of 87% suggesting an early change of treatment, whereas a BCR-ABL IS of 1% or less indicates a favorable 5-year overall survival of 97%. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

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Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3785.3785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3785-3785 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Carlo Gambacorti-Passerini ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

David Marin ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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The Level of Residual CLL Objectively Predicts the Outcome of Patients Following FCR-Based Therapy with Sequential Benefits per Log Depletion and Improved Post-Treatment Monitoring

Blood ◽

10.1182/blood.v126.23.1717.1717 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1717-1717 ◽

Cited By ~ 2

Author(s):

Andy C Rawstron ◽

Dena Cohen ◽

Ruth Mary De Tute ◽

Lucy McParland ◽

Laura Collett ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Disease Progression ◽

Survival Benefit ◽

Research Funding ◽

Residual Disease ◽

Independent Predictor ◽

Log Reduction ◽

End Of Treatment

Abstract BACKGROUND: Minimal residual disease (MRD) in CLL is an independent predictor of progression-free and overall survival after chemo-immunotherapy. Data from the DCLLSG trials indicate that a high, intermediate and low risk of disease progression is seen in patients with >1%, 0.01-1%, or <0.01% MRD respectively. The survival benefit per log reduction is informative in other disorders and may be a more informative measure for comparing different treatments. AIM: To apply the ERIC consensus 1-tube multiparameter MRD strategy prospectively in two UK clinical trials of FCR-based treatment (ADMIRE and ARCTIC) to determine the survival benefit per log depletion. METHODS: The level of residual disease was determined using multi-parameter flow cytometry according to the ERIC consensus protocol with a limit of quantification of 10-4 / 0.01% or better on 415 patients at 3 months after end of treatment. RESULTS: The level of MRD at end of treatment was a powerful predictor of PFS and OS independent of age, stage, IWCLL response, FISH and IGHV mutation status. Per log reduction in CLL level, the hazard of disease progression decreased by 33% (95%CI 27-38%) and the hazard of dying decreased by 22% (95%CI 13-29%). Although there were statistically significant improvements per log reduction, the DCLLSG 2-log model showed more meaningful differences in outcome over the period of follow-up. The median PFS for patients with >1% vs. 0.01-1% vs <0.01% BM MRD was 24 months vs. 48 months vs. not reached (NR, 82% progression-free at 48 months, figure 1a) respectively and the median OS was 49 months vs. NR (78% alive at 48M) vs. NR (85% alive at 48M) respectively. Median PFS and OS for all patients achieving a PR or worse was 41M and 51M respectively indicating that the presence of >1% MRD predicts equivalent or worse outcome than a clinical PR. PB MRD analysis at 18 months after randomisation (~1 year after treatment) was also strongly predictive of outcome: 98% of patients with <0.01% PB CLL at the 18M timepoint remain alive and treatment-free for the subsequent year (Figure 1b). CONCLUSIONS: Prospective enumeration of MRD using the ERIC consensus 1-tube multiparameter protocol confirms that MRD at end of treatment is a powerful independent predictor of progression-free and overall survival. Post-treatment follow-up using peripheral blood MRD could be more informative than clinic assessments because patients with <0.01%MRD are highly unlikely to require treatment within the following year while in patients with ≥0.01%MRD the rate of disease progression can be accurately predicted. Patients with >1% MRD at end of treatment in the peripheral blood have a similar outcome to those with a clinical PR and a bone marrow assessment is not informative in these cases. The level of MRD is highly informative with sequential improvements in outcome per log depletion. The DCLLSG 2-log categorisation (>1%, 0.01-1%, or <0.01%) is simple and effective for discriminating patients with PFS of <2yrs vs. >6yrs. Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to <2yrs PFS and <0.01% MRD predicting >5yrs median PFS Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to <2yrs PFS and <0.01% MRD predicting >5yrs median PFS Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Disclosures Rawstron: BD Biosciences: Patents & Royalties; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding. Gregory:Celgene: Honoraria; Janssen: Honoraria. Hillmen:Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Research Funding.

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Ponatinib in Combination with FLAG-IDA Chemotherapy for Blast-Phase Chronic Myeloid Leukemia: Final Results of the Seamless Phase I/II Dose-Finding UK Trials Acceleration Programme (TAP) Matchpoint Trial

Blood ◽

10.1182/blood-2021-147972 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 312-312

Author(s):

Mhairi Copland ◽

Daniel Slade ◽

Graham McIlroy ◽

Gillian Horne ◽

Jennifer Byrne ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Chronic Phase ◽

Optimal Dose ◽

High Dose Chemotherapy ◽

Dose Finding ◽

High Dose ◽

Blast Phase

Abstract Background Outcomes for patients with blast-phase chronic myeloid leukaemia (BP-CML) are extremely poor, and allogeneic stem cell transplantation (alloSCT) represents the only opportunity for cure. Crucially, long-term survival post-transplant depends on first attaining a return to chronic phase though salvage treatment. Novel strategies that improve response and can optimise transplant outcomes are therefore required. In the era of tyrosine kinase inhibitors (TKIs), BP-CML has become an orphan disease. Consequently, the prospective trials needed to guide clinical practice are rarely attempted. We now report the final results of the prospective MATCHPOINT trial which uses an innovative EffTox design to investigate the activity and tolerability of the TKI ponatinib in combination with high-dose chemotherapy, to improve remission status and transplant outcomes in BP-CML. Methods and patients Between March 2015 and April 2018, 17 patients were recruited through the UK Trials Acceleration Programme to this dose-finding, seamless phase I/II trial of daily ponatinib combined with fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (PON-FLAG-IDA) salvage therapy. We employed EffTox, an advanced Bayesian method to simultaneously consider response to treatment (efficacy) and dose-limiting toxicity (DLT) in all treated patients, providing a single measure of clinical utility, which then informed the subsequent dose level recommendation. The primary objective was to determine the optimal dose of ponatinib, in combination with chemotherapy, as determined by the EffTox model. The primary outcomes were attainment of a second chronic phase and occurrence of a DLT. Secondary outcomes investigated the toxicity of combination therapy, alloSCT outcomes, and survival. The median follow-up of trial patients is 41 months. Results Nine patients completed one cycle of PON-FLAG-IDA, a further eight patients completed both planned cycles. Using an EffTox analysis, the optimal dose of ponatinib was determined as 30mg once daily. Eleven patients achieved a return to chronic phase and four experienced a DLT, fulfilling the pre-specified criteria for clinically relevant efficacy and toxicity. After PON-FLAG-IDA salvage, eight patients attained complete cytogenetic response and five major molecular response (MMR). The most common grade 3-4 non-hematologic toxicities were febrile neutropenia (29% of patients), lung infection (24%), fever (18%) and hypocalcaemia (18%). Three patients experienced treatment-related mortality. Twelve patients proceeded to alloSCT, of whom seven are alive after median 36 months post-transplant follow-up. Only one of the five patients achieving MMR relapsed post-alloSCT, neither of the other relapsing patients achieved a second chronic phase pre-transplant. Median overall survival (OS) of the whole cohort was 12 months (95% confidence interval 6 months to non-calculable), median OS of patients undergoing alloSCT has not been reached. Conclusions Ponatinib has shown that it can be safely combined with high-dose chemotherapy to achieve a return to chronic phase in patients with BP-CML, and represents an effective novel treatment strategy in this high-risk population. Responding patients subsequently undergoing alloSCT can benefit from long-term disease-free survival. The EffTox method enabled very efficient data usage from this high-risk patient population, and is a model for investigating novel therapies in other ultra-orphan cancers. Figure: Overall survival of the MATCHPOINT cohort Figure 1 Figure 1. Disclosures Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Byrne: Incyte: Honoraria. Rothwell: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Brock: Eli Lily: Honoraria; Invex Therapeutics: Honoraria; Merck: Honoraria; Roche: Honoraria; AstraZeneca: Current holder of individual stocks in a privately-held company; GSK: Current holder of individual stocks in a privately-held company. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Clark: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Milojkovic: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Ponatinib for the treatment of blast-phase CML

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Imatinib in Very Elderly (> 75 years) CML Patients: Are Low-Doses (<400 mg daily) Enough?

Blood ◽

10.1182/blood.v118.21.2770.2770 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2770-2770 ◽

Cited By ~ 1

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Dario Ferrero ◽

Francesco Cavazzini ◽

Malgorzata Monika Trawinska ◽

...

Keyword(s):

Overall Survival ◽

Disease Progression ◽

Median Time ◽

Standard Dose ◽

Chronic Phase ◽

Published Data ◽

Very Elderly ◽

Group 2 ◽

Lost To Follow Up

Abstract Abstract 2770 In the “real world” of clinical practice, often physicians choose to treat very elderly CML patients with imatinib (IM) at lower than standard (400 mg/day) dose, but there are no published data on the results. To highlight this issue, we retrospectively revised 200 > 75 years old CML patients in chronic phase treated with IM 29 haematological Italian Institutions. We compared 58 patients (29%) who received low-dose IM (≤ 300 mg/day) according to physician decision (LD group) with the remaining 142 patients (71%) who received standard dose IM (SD group). In the SD group, there were 73 males and 69 females with a median age at IM start of 77.9 years (IR 76.0–80.3), Sokal Risk at diagnosis was low in 3 patients, intermediate in 86, high in 39 and not evaluable in 12. Two or more concomitant diseases requiring specific treatments were present in 93/142 patients (65.4%), with 85 patients (59.8%) taking 3 or more concomitant drugs. Twenty-seven patients (19.0%) were in late chronic phase (≥ 12 months from diagnosis before starting IM); on the whole, median time from diagnosis to IM was 1.1 months (IR 0.5–3.0). In the LD group, there were 31 males and 27 females with a median age of 80.2 years (IR 77.9–84.5) at IM start, Sokal Risk at diagnosis was intermediate in 34 patients, high in 17 and not evaluable in 7. Two or more concomitant diseases requiring specific treatments were present in 43/58 patients (74.1%), with 43 patients (74.1%) taking 3 or more concomitant drugs. Fifteen patients (25.8%) were in late chronic phase; on the whole, median time from diagnosis to IM was 1.8 months (IR 0.7–10.4). Starting dose of IM was 300 mg/day in 44 patients (75.8%) and < 300 mg/day in 14 patients (24.2%). According to CTC-AE, grade 3–4 hematological and extra-hematological toxicities were observed in 29 (20.4%) and 30 (21.1%) patients in the SD group compared with 10 (17.2%) and 14 (24.1%) patients in the LD group, respectively. Overall, 63 patients in the SD group (44.3%) required a dose reduction compared to 13 (22.4%) in the LD group (p=0.004): eleven (7.7%) patients in the SD group discontinued IM for toxicity compared to 13 (22.4%) in the LD group (p=0.004). Response to IM in the 2 groups is detailed in the table.SD groupLD grouppN° patients evaluable for response13656Early discontinuation8 (5.8%)8 (14.3%)0.054Resistant disease3 (2.2%)1 (1.8%)0.859Complete haematological response only24 (17.6%)12 (21.4%)0.527Partial cytogenetic response9 (6.6%)6 (10.7%)0.329Complete cytogenetic response92 (67.6%)29 (51.8%)0.052Major molecular response69 (50.7%)17 (30.3%)0.012 After a median follow-up of 33.7 months (IR 18.1–64.7), in the SD group 35 patients died (5 from disease progression and 30 from unrelated causes), 5 patients were lost to follow-up and 102 are still alive: in the LD group, 15 patients died (3 from disease progression and 12 from unrelated causes), 3 patients were lost to follow-up and 40 are still alive. In the SD group, 2-year and 5-year overall survival were 93.2% (CI95% 88.6–97.2) and 65.7% (CI95% 55.0–76.3), respectively; in the LD group, 2-year and 5-year overall survival were 89.7% (CI95% 80.4–98.9) and 67.0% (CI95% 49.6–84.4), respectively. In conclusion, in very elderly CML patients even reduced IM dose appears to be safe and effective enough to achieve sustained cytogenetic and molecular responses with prolonged overall survival. Therefore, also very elderly patients with co-morbidities should have this chance of cure without no upper age limit. Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

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Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Blood ◽

10.1182/blood.v118.21.455.455 ◽

2011 ◽

Vol 118 (21) ◽

pp. 455-455 ◽

Cited By ~ 2

Author(s):

Jorge E Cortes ◽

Anish Maru ◽

Carmino Antonio Antonio De Souza ◽

François Guilhot ◽

Ladan Duvillie ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Primary Reason ◽

Newly Diagnosed ◽

Function Test ◽

Grade 3

Abstract Abstract 455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

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Second-Line Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: An 8-Year Update

Blood ◽

10.1182/blood.v130.suppl_1.900.900 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 900-900

Author(s):

Tim H. Brümmendorf ◽

Carlo Gambacorti-Passerini ◽

Dong-Wook Kim ◽

Yeow Tee Goh ◽

Iryna Dyagil ◽

...

Keyword(s):

Disease Progression ◽

Research Funding ◽

Chronic Phase ◽

Study Drug ◽

Cytogenetic Response ◽

Second Line ◽

Kaplan Meier ◽

Imatinib Resistant ◽

Dose Reductions

Abstract Bosutinib is an orally active, dual SRC/ABL tyrosine kinase inhibitor (TKI) approved for treating adult patients with chronic phase, accelerated phase (AP), or blast phase (BP) Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. In an open-label, phase 1/2 study (NCT00261846), second-line bosutinib demonstrated durable hematologic and cytogenetic responses and good tolerability in patients with Ph+ CP CML who were imatinib resistant (IM-R) or imatinib intolerant (IM-I) (Cortes, Am J Hematol, 2016). Here we report a 96-month update of this study and its ongoing extension study (NCT01903733). Adult patients with Ph+ CP CML who were resistant or intolerant to first-line imatinib were included in this analysis. 195 IM-R and 89 IM-I patients received bosutinib starting at 500 mg/d. Median age (range) was 53 yr (18-91 yr), time from CML diagnosis was 3.7 yr (0.1-15.1 yr), treatment duration was 25.6 mo (0.2-133 mo), and follow-up duration was 53.7 mo (0.5-133 mo). Bosutinib dose was increased to 600 mg/d in 13% of patients. For the last enrolled IM-R and IM-I patients, time from first dose of bosutinib to data cutoff was 96.5 mo and 94.2 mo, respectively. At 8 yr, 26% of patients were still receiving bosutinib. Major cytogenetic response (MCyR) was achieved by 60% of patients in both groups (Table). Median duration of MCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining MCyR at 8 yr was 60% (IM-R) and 75% (IM-I). Complete cytogenetic response (CCyR) was achieved by 49% (IM-R) and 51% (IM-I) of patients. Median duration CCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining CCyR at 8 yr was 57% (IM-R) and 69% (IM-I) of patients. On-treatment transformation to accelerated phase or blast phase occurred in 7% (IM-R) and 2% (IM-I) of patients with no new events since the 5-yr follow-up. The cumulative incidence of on-treatment progression or death at 8 yr was 28% (IM-R) and 11% (IM-I), respectively (Table). Overall survival at 8 yr on study was 75% for the IM-R group and 87% for the IM-I group. Dose delays due to adverse events (AEs) occurred in 133 (68%) and 76 (85%) of IM-R and IM-I patients, resulting in median cumulative treatment delays of 25 d and 27 d, respectively. Dose reductions due to AEs occurred in 93 (48%) and 54 (61%) of IM-R and IM-I patients, respectively. Median cumulative duration of dose reduction was 357 d and 267 d, and median time to dose reduction was 49 d and 54 d in the IM-R and IM-I cohorts, respectively. By 8 yr, treatment was discontinued in 141 (72%) and 69 (78%) of IM-R and IM-I patients, respectively. The most common reasons for discontinuation were disease progression (23%) and AEs (16%) in the IM-R cohort, and AEs (42%) and patient request (13%) in the IM-I cohort. In the IM-R cohort, the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (4%), increased ALT (2%), and diarrhea (2%). In the IM-I cohort the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (11%), neutropenia (5%), increased ALT (3%), and rash (3%). Among the 40 patients (21%) in the IM-R cohort who died on study, the most frequent reasons for death were disease progression (12%) and AEs unrelated to study drug (7%). For the 11 patients (12%) in the IM-I cohort who died on study, the most frequent reasons were disease progression (7%) and unknown (3%). No patients died due to an AE related to study drug and 13 patients (5%) died within 30 days of last dose. Five subjects died since the 5-yr follow-up; 3 within 30 days of last dose. These long-term (8-yr) data are consistent with previous findings associating second-line bosutinib therapy with similar rates of durable major cytogenetic responses in the majority of patients with imatinib-resistant and imatinib-intolerant CP CML. Most AEs could be managed through temporary treatment interruptions and dose reductions. Disclosures Brümmendorf: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gambacorti-Passerini: BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Pagnano: Roche: Speakers Bureau; Amgen: Consultancy; Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy. Aguiar: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Cortes: Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

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TP53 Mutations and Outcome After Fludarabine and Cyclophosphamide (FC) or FC Plus Rituximab (FCR) in the CLL8 Trial of the GCLLSG.

Blood ◽

10.1182/blood.v114.22.1267.1267 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1267-1267 ◽

Cited By ~ 6

Author(s):

Thorsten Zenz ◽

Patrick Hoth ◽

Raymonde Busch ◽

Hanne Helfrich ◽

Dirk Winkler ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Research Funding ◽

Tp53 Mutation ◽

Statistical Significance ◽

Response Rates ◽

Genetic Profile ◽

Reference Laboratory ◽

Tp53 Mutations ◽

Molecular Systems

Abstract Abstract 1267 Poster Board I-289 The international multicenter randomized CLL8 trial evaluated 1st line treatment with FC or FCR in 817 CLL patients. Analysis of TP53 mutation status by a re-sequencing chip (Amplichip, Roche Molecular Systems) and confirmatory direct DNA sequencing were performed in a central reference laboratory. Samples were available for 628 (76.9%) patients and this cohort was representative of the full trial population regarding other baseline prognostic factors and demographics. Outcome was analyzed for subgroups defined by genetic parameters in univariate and multivariate analyses. The incidence of the TP53 mutations was 11.9% (71/628; 41 in FC arm, 30 in FCR arm). Forty-two of 51 patients (82.4%) with 17p deletion had a TP53 mutation. 5% of patients without 17p deletion (28/553) had a TP53 mutation. Patients with TP53 mutation showed lower complete response (CR) and overall response (OR) rates as compared to the group without TP53 mutation (6.9 vs. 36.4% and 62.1% vs. 95.3% (p<.01)). Lower response rates were observed for the TP53 mutation groups in both arms (FC and FCR): CR (3.2% and 11.1%), CR+PR (51.6% and 74.1%). Response rates for patients without TP53 mutation were 24.2% (CR (FC)) and 92.2% ORR (FC) vs. 47.8 (CR FCR arm) and 98.2% (ORR FCR). Median progression free survival (PFS) was significantly shorter for patients with TP53 mutations (12.4 months vs. 45 months) (HR: 4.4 (3.29-5.87) p<0.001). Median PFS was similar for the TP53 mutated subgroup in both treatment arms (FC 12.1 / FCR 15.4 months; HR 0.53 (0.31-0.9) p=0.19). PFS for the patients without TP53 mutations was 35.1 months in the FC arm and 51.9 months in the FCR arm (HR: 0.58 (0.45-0.75) p<0.001). Patients with TP53 mutation showed a median OS of 39.3 months whereas median OS was not reached in all other patients (HR 6.01 (4.08-8.87) p<0.001). Comparing OS separately for the treatment arms in the groups defined by presence or absence of TP53 mutation showed a slightly better outcome for the FCR arm for both subsets, although the comparison did not reach statistical significance (TP53 mutations HR: 0.64 (0.33-1.2) p=0.19; no TP53 mutation HR: 0.68 (0.43-1.2) p=0.09) (Fig. 1). Multivariate analysis was performed by Cox regression including age, stage, treatment arms, IGHV status, genomic aberrations and TP53 mutation. Regarding PFS (n=567), independent prognostic factors were 17p- (HR: 3.6; p<.001), TP53 mutation (HR: 2.2; p<.001), unmutated IGHV (HR: 1.7, p<.001), age (HR: 1.4; p<.001), and FCR treatment (HR: 0.52; p<.001). Regarding OS (n=580), 17p- (HR: 3.5; p<.001), TP53 mutation (HR: 2.6: p<.001), unmutated IGHV (HR: 1.6; p=.035), and FCR treatment (HR: 0.6; p=0.019) were identified as independent factors. In conclusion, 17p deletion and TP53 mutation remain powerful prognostic markers after 1st line FC and FCR treatment in CLL. When considering the genetic profile and treatment in a multivariate model, FCR improves PFS and OS compared to FC in CLL. TP53 mutations are associated with poor response and survival independent of 17p deletion. Fig. 1 Overall survival of patients in the CLL8 trial based on treatment arm and presence / absence of TP53 mutation. Fig. 1. Overall survival of patients in the CLL8 trial based on treatment arm and presence / absence of TP53 mutation. Disclosures Zenz: Roche: Honoraria. Patten:Roche Molecular Systems: Employment. Truong:Roche Molecular Systems: Employment. Wu:Roche Molecular Systems: Employment. Fingerle-Rowson:Roche: Honoraria. Fischer:Roche: Travel reimbursment. Fink:Roche: Travel reimbursment. Jäger:Roche: Honoraria, Research Funding. Böttcher:Roche: Research Funding. Kneba:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wenger:Roche: Employment. Mendila:Roche: Employment. Hallek:Roche: Consultancy, Research Funding. Döhner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

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