Improved Survival in Chronic Myeloid Leukemia (CML) Since the Introductin of Imatinib Therapy - A Single Institution Historical Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2750-2750
Author(s):  
Hun Lee ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Blastic Phase ◽  
Group A ◽  
The Impact ◽  
Over Time

Abstract Abstract 2750 Background: Outcome of CML since introduction of imatinib therapy has improved. Aims: analyze improvement of CML outcome in different phases. Study Group: A total of 1,569 patients with CML referred since 1965, within 1 month from diagnosis, were reviewed and used to identify phase-specific prognostic factors: 1,148 chronic, 175 accelerated, 246 blastic. Results: The median survival was 8.9 years in chronic, 4.8 years in accelerated, and 6 months in blastic phase. In chronic phase, the 8-year survival was ≤ 15% before 1983, 42–65% from 1983 to 2000, and 87% since 2001 (Figure 1). Survival was worse in older patients (p=0.004), but less significant since 2001 (p=0.07). Survival by Sokal risk was significantly different before 2001 (p<0.001), but not since 2001 (p=0.4). In accelerated phase, survival improved over time (p<0.001); the 8-year survival in patients treated since 2001 was 75% (Figure 2). Survival by age was not different in years < 2001 (p=0.09), but was better since 2001 in patients ≤ 70 years (p=0.004). Multivariate analysis derived adverse factors since 2001: older age (p=0.049), increased marrow blasts (p=0.03). In blastic phase, the median survival improved over time (p<0.001), although it is only 7 months since 2001. Conclusions: Survival in CML significantly improved significantly since 2001, particularly so in chronic and accelerated phases. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in chronic phase, and accentuated the impact of age in accelerated and blastic phases. Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

scholarly journals Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 1981-1987 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Single Institution ◽  
Historical Experience ◽  
Blastic Phase ◽  
The Impact ◽  
Over Time

Abstract A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.

Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3290-3290 ◽  
Author(s):  
Alex Bazeos ◽  
Jamshid Khorashad ◽  
François-Xavier Mahon ◽  
Lina L Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses ◽  
Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C&gt;T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or &gt;90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p&lt;0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

Different Definitions of Progression-Free Survival (PFS) and Event-Free Survival (EFS) May Result In Perceived but Not Real Differences In Long-Term Outcome When Comparing Trials In Chronic Myeloid Leukemia (CML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 672-672
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Jianqin Shan ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Patient Choice ◽  
Imatinib Therapy ◽  
Free Survival ◽  
Blastic Phase ◽  
Resistance Loss ◽  
Frontline Therapy

Abstract Abstract 672 Background The favorable results of second generation tyrosine kinase inhibitors (TKIs; nilotinib, dasatinib) in frontline therapy of Philadelphia chromosome (Ph) positive-CML may establish them as new standards in frontline therapy. This depends on the maturing data with the long-term endpoints of PFS and EFS. Different definitions are used to define “progression” and “event” in different studies. This may result in perceived but not real differences in outcomes with various TKIs when comparing trials. In addition, multi-institutional sponsored trial designs may compound the variable definitions: 1) patients taken off study for occurrences other than the defined “progression” or “event” (eg toxicity, intolerance, other) are censored at the time they are off therapy and not coded for progression/event/death once they are off TKI; and 2) such studies have limited capacities to follow up patients for progression/event after they are off drug therapy for more than 30–60 days. Single institutional studies have a potential advantage of continuing to monitor patients for progression/events after they are off the particular protocol TKI. Study Aim To analyze the impact of differences in the definitions of PFS and EFS used in the IRIS, ENEST-nd, DASISION, and M.D. Anderson (MDACC) trials on outcome, when these definitions are applied to patients with newly diagnosed CML treated with TKIs on MDACC studies. Patients and Methods 435 patients (July 2000-April 2010) with early chronic phase Ph-positive CML treated with imatinib (n=281), nilotinib (n=78), and dasatinib (n=76)were analyzed for outcome using different definitions. Definitions were: 1) PFS- ENEST: progression = accelerated or blastic phase (AP-BP) on nilotinib/imatinib therapy + CML related death on nilotinib/imatinib therapy or within 30 days off therapy; 2) EFS-IRIS: event = progression to AP-BP on imatinib + death of any cause on imatinib + loss of CHR or major CG response; 3) PFS-DASISION: progression = EFS-IRIS definition + WBC increase to more than 20; deaths are coded on dasatinib and within 60 days off dasatinib; 4) EFS MDACC: event = progression to AP-BP + loss of major CG response +resistance/loss of CHR/lack of achievement of response by ELN criteria + off for toxicity + death from any cause on or off therapy (if not counted prior to death as progression/event). Results The median follow-up is 67 months (2-116). Of the 435 patients treated, 312 (72%) remain on TKI therapy; 123 (28%) were taken off for the following reasons: resistance/loss of response n = 33; blastic phase on TKI therapy n=6; intolerance/toxicity n= 29; other causes n = 55. Reasons off for the latter 55 patients are: lost to follow – up (n=14); non-compliance (n=11); financial issues (n=8): intercurrent illness (n=7); patient choice (n=5); referral to SCT in chronic phase (n=2); and death from non-CML cause (n=8: 1 complications of surgery, 2 old age, 1 CHF, 1 pneumonia, 2 car accident/suicide, 1 cardiac infarction). So far, 33 patients (7.6%) have died; 8 while on TKI therapy (none from CML; detailed earlier); 2 within 60 days off TKIs (1 AML, 1 renal cancer); and 23 off TKIs for > 60 days. Deaths in the latter 23 were from: 10 post resistance/relapse/BP (accounted for as event/resistance at time off TKI); 10 taken off for toxicity/intolerance (censored at time off; 8 deaths later from CML, 1 post SCT, 1 unknown); 4 off for other illness/non-compliance/lost to FU/pt choice (3 deaths later from CML; 1 from other). Thus, of the 33 deaths, only 19 (8 deaths on TKI + 2 deaths within 60 days + 9 off for resistance/relapse/BP) would be counted as progression/events on the IRIS/ENEST/DASISION studies while 14 would be censored at time off TKI. Based on these 4 definitions, the number of progression/events were: PFS-ENEST 26 progressions; EFS-IRIS 40 events; PFS-DASISION 43 progression/events; EFS-MDACC 76 events. The corresponding 5-year PFS EFS rates were 93%, 90%, 89%, and 81%. (Figure) Conclusions With the importance of EFS and PFS in determining whether new TKIs are better than imatinib in frontline therapy, precise and common definitions of these endpoints across randomized clinical trials and single institutional trials are needed. Randomized multi-institutional trials may not collect accurately all events after patients are off TKI therapy for 30–60 days. Disclosures: Kantarjian: Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. O'Brien:Novartis: Research Funding; BMS: Research Funding. Kadia:Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy.

Acquisition Of Compound BCR-ABL1 Alleles As A Mechanism Of Resistance To Ponatinib In Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 853-853
Author(s):  
Don L Gibbons ◽  
Sabrina Pricl ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermeglia ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
The Impact ◽  
In Cells

Abstract BACKGROUND Ponatinib targets the inactive conformation of the ABL1 kinase and avoids interacting with the side chain of the mutated 315 residue. In vitro, ponatinib inhibits all single-point BCR-ABL1 mutations. Yet, a significant proportion of patients with chronic myeloid leukemia in chronic phase (CML–CP) do not respond to ponatinib and a subset loses their response during the course of treatment. The mechanisms of resistance to ponatinib are currently not well characterized. OBJECTIVE To determine the impact of compound BCR-ABL1 mutations (polymutants) on the activity of ponatinib. METHODS BCR-ABL1 mutational status was determined in 70 pts with CML-CP post imatinib failure and during dasatinib therapy by DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. Free energy of binding (DGbind) for the unmutated and all mutant BCR-ABL1 kinase/inhibitor complexes were obtained using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methodology. Single and polymutant BCR-ABL1 alleles obtained by direct mutagenesis and their expression was forced into Ba/F3 cells by electroporation by the pMX/eGFP-BCR-ABL1 expression vector using the Amaxa System. RESULTS After imatinib failure, 125 ABL1 kinase domain mutations at 113 amino acid positions were detected in 61/70 (87%) pts, including 38 (54%) with mutations in ≥20% of sequenced clones. Mutations conferring resistance to >1µM imatinib were detected in 30 (43%) pts. Polymutant BCR-ABL1 alleles were detected in 29/70 (41%) pts. These patients received dasatinib for a median of 19 mos (range, 2-52), during which dasatinib-resistant mutations were detected in 10/32 (31%) assessable cases (5 with T315I). Polymutants were present in 16/32 (50%) pts (all of them dead in blast phase). The proportion of clones carrying unmutated BCR-ABL1 was markedly lower in patients who only achieved a minor or no cytogenetic response compared to those achieving a major cytogenetic response (p=0.0001), suggesting exhaustion of unmutated clones and expansion of mutant (and polymutant) clones linked to clinical dasatinib resistance. Then, we performed 3D structural analyses to determine the thermodynamic impact of 21 BCR-ABL1 mutants (11 single and 10 double mutants) in the ability of ponatinib to bind the kinase domain (Table). Most single mutants did not result in high ponatinib resistance (except for E255K, IC50=8.8nM; DGbind=-10.99±0.01). However, the association of any 2 of 3 point mutants (T315I, F317L, V299L) in a dual polymutant produced highly resistant BCR-ABL1 proteins that exhibited fold change values from 19 to 40, compared to the unmutated protein, with T315I/F359V displaying the highest resistance (IC50=61nM; DGbind=-10.23±0.03 kcal/mol), unveiling a mechanism of escape to ponatinib. In Ba/F3-based assays, ponatinib (but not imatinib or dasatinib) was active against Ba/F3-BCR-ABL1T315I cells. Polymutants exhibited very high ponatinib resistance (10-fold higher than that of cells carrying BCR-ABL1T315I). As predicted in silico, BCR-ABL1T315I/F359V was the most resistant polymutant tested. Cell growth inhibition was coupled with CrkL and STAT5 phosphorylation inhibition. Ponatinib, while suppressing STAT5 phosphorylation, could not suppress CrkL phosphorylation in cells expressing the BCR-ABL1T315I/F359V polymutant kinase, even at 100 nM (50-fold the IC50 required to inhibit BCR-ABL1T315I). CONCLUSIONS Polymutants are very frequent in pt samples after TKI failure (particularly after sequential TKI therapy) and tend to induce high ponatinib resistance. Our in silico platform predicted very accurately TKI sensitivity in cells carrying different BCR-ABL1 mutations, which makes it clinically applicable for matching specific mutations to the most effective TKI. Some polymutants require ponatinib concentrations not clinically reachable, thus representing a mechanism of escape to ponatinib therapy through selection and expansion of refractory clones. Disclosures: Talpaz: ariad: Research Funding. Cortes:Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Quintas-Cardama:ariad: Consultancy.

Outcome of patients of CML in AP and BC with imatinib: A retrospective analysis of patients from India

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17531-17531
Author(s):  
H. Menon ◽  
S. S. Hingmire ◽  
R. Bharath ◽  
K. Jain ◽  
N. Ghadyalpatil ◽  
...  
Keyword(s):  
Median Survival ◽  
Median Duration ◽  
Single Agent ◽  
Active Agent ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Advanced Phase ◽  
The Impact

17531 Background: Imatinib is a very active agent in advanced phase CML. The present study assesses the impact of Imatinib therapy on the outcome of Indian patients with CML in Accelerated Phase (AP) and Blast Crisis (BC). Methods: Patients of CML in AP or BC who were treated with Imatinib based therapy between 2001 and 2006 were analyzed retrospectively. Results: A total of 65 patients who received Imatinib based treatment for CML in AP or BC were analyzed. Thirty eight (58.46 %) patients diagnosed in chronic phase (CP) were initiated on Imatinib based treatment at time of progression to AP or BC. The remaining 27 (41.53 %) patients had AP or BC of CML at initial diagnosis. At the time of start of Imatinib treatment 36 (55.38 %) patients had AP and 29 (44.61 %) were in BC. Imatinib as a single agent was used in 41 (63.07 %) patients (27 in AP and 14 in BC) and in combination with oral 6-MP and Etoposide was used in 24 (36.92 %) patients (14 in AP and 10 in BC). Hematological response (HR) was seen in 64.61% (42 out of 65) patients, complete HR in 32 (49.23 %) and partial HR in 10 (15.38 %). Cytogenetic response (CR) was noted in 21 (32.31%) patients (Complete -10, Partial -9, and Minor - 2). Twenty eight (43.07%) patients remained progression free (HR+CR in 16 and only HR in 12 patients) till the last date of follow up (median duration of follow-up was 17 months).For the whole group (n=65) the overall survival from the diagnosis of AP or BC after commencing Imatinib treatment was 65.3%, 51.6% and 34.4% at 1, 2 and 3 years respectively. The median survival was 25 months. The median survival and OS at 1 year, as expected, was significantly better for patients in AP (36 months, 77.4 %) as compared to those in BC (11 months, 48.2%)(p=0.004) and both were much longer than previously reported with non-Imatinib therapy. Outcome in patients with AP or BC was not significantly improved by addition of 6-MP and Etoposide. Temporary discontinuation of Imatinb for grade III/IV toxicity was done in 27 (41.53 %) patients for a median duration of 28 days. Conclusions: Imatinib has improved the outcome of patients with advanced phase CML. Our data also documents this in patients from India. However, Imatinib needs to be studied with newer combinations to achieve long term disease control in patients with CML, particularly those in BC. No significant financial relationships to disclose.

scholarly journals HIF-1α Promotes Cbfbeta-SMMHC-Induced Acute Myeloid Leukemia Development

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1559-1559
Author(s):  
Benedikt W. Pelzer ◽  
Anita Hollenbeck ◽  
Stefanie Weber ◽  
Bertram Opalka ◽  
Lucio H. Castilla ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cellular Growth ◽  
Free Survival ◽  
Kaplan Meier ◽  
Leukemia Development ◽  
The Impact ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) develops by the acquisition of genomic alterations which initiate different pathways leading to full-blown malignancy. The type of genomic driver alteration governs AML biology and clinical disease course. Translocations involving the core-binding factor (CBF) complex such as t(8:21) and inv(16) represent distinct subgroups of AML genomic drivers. However, additional factors promoting CBF AML leukemogenesis remain largely unknown. Due to the hypoxic nature of the bone marrow the activation of the ubiquitous hypoxia-sensing pathway via HIF-1a might promote CBF leukemogenesis. Nevertheless, in different AML models HIF proteins were recently considered as oncogenic drivers and also as tumor suppressors. Therefore, we here aimed to clarify the role of HIF-1a in CBF AML. Initially, we investigated the impact of hypoxia-sensing pathway activation on the growth of the CBF AML cell lines Kasumi-1 [t(8:21)] and ME-1 [inv(16)]. Kasumi-1 cells showed increased growth after 24 as well as 48 hours at 3% compared to 21% oxygen conditions. In contrast, ME-1 cellular growth was not altered by hypoxic culture conditions. Next, we genetically modified the HIF-1a pathway in the CBF AML leukemogenesis context with a previously established conditional inv(16) mouse model (Cbfb+/56M). These mice express the Cbfbeta-SMMHC oncoprotein upon Cre-mediated recombination. In preliminary studies we could show neither vav-iCre mediated Hif-1a gain- nor loss-of-function altered steady-state hematopoiesis, which was recently confirmed by others (Milica Vukovic et al., Blood 2016). We proceeded by crossing conditional inv(16) with conditional mice overexpressing a HIF-1a variant (LSL-HIF1dPA) being insensitive to oxygen-dependent degradation. The conditional inv(16) and HIF1dPA alleles were simultaneously activated using the ubiquitous hematopoietic vav-iCre transgene. Strikingly, we observed accelerated leukemia development in inv16;HIF1dPA mice compared to inv(16) mice without genetic HIF-1a pathway alterations (median survival 68 vs. 116 days; Figure 1). In a complementary approach we crossed the vavi-Cre conditional inv(16) system into a conditional Hif-1a knock-out (KO) background [inv(16);Hif-1aKO mice]. Here we observed significantly delayed leukemia onset in inv(16);Hif-1aKO mice compared to inv(16) control mice (median survival 223 vs. 116 days; Figure 1). The gross leukemic phenotype with high peripheral leukocyte count, splenomegaly and liver infiltration did not differ between the groups. Finally, we analyzed deletion of the conditional Hif-1aKO allele of leukemic inv(16);Hif-1aKO mice and observed complete recombination resulting in a Hif-1a null constellation. Thus, AML in inv(16);Hif-1aKO mice did not develop from clones which evaded vav-iCre mediated Hif-1a deletion. In conclusion, HIF-1a represents a critical factor promoting murine inv(16) leukemogenesis and it will be worthwhile studying the impact of genetic or pharmacologic HIF-1a alteration in established inv(16) leukemia. Figure 1 Kaplan-Meier curves of leukemia-free survival in control [Cre-negative littermates; n=55], inv(16) [n=31], inv(16);HIF1dPA [n=17] and inv(16);Hif-1aKO [n=18] mice. Figure 1. Kaplan-Meier curves of leukemia-free survival in control [Cre-negative littermates; n=55], inv(16) [n=31], inv(16);HIF1dPA [n=17] and inv(16);Hif-1aKO [n=18] mice. Disclosures Dührsen: Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Göthert:Proteros: Consultancy; Ariad Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria.

Prognostic Factors in Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors- Single Center Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2210-2210 ◽  
Author(s):  
Kajetana Foryciarz ◽  
Tomasz Sacha ◽  
Izabela Florek ◽  
Sylwia Czekalska ◽  
Magdalena Zawada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Population Based ◽  
Molecular Response ◽  
First Line

Abstract Abstract 2210 Poster Board II-187 Background: Imatinib mesylate (IM), a targeted inhibitor of the BCR-ABL tyrosine kinase, is widely used to treat chronic myeloid leukemia (CML). However, considerable number of patients fails to achieve or loose complete cytogenetic response (CCyR) or major molecular response (MMR). The mechanisms of failure in the majority of cases are unknown. Identification of patients who may subsequently fail to respond to imatinib would provide a considerable aid to clinical management. Few long-term retrospective population-based data on the outcome of these patients are available. Aims: To identify prognostic factors that can predict failure of treatment with tyrosine kinase inhibitors (TKI), and to optimise CML therapy after first line TKI failure. Patients and methods: The retrospective population-based analysis included 138 patients (68 females, 70 males, median age 47 yrs) in early chronic phase (ECP) (n=63), late chronic phase (LCP) (n=60) or accelerated phase (AP) (n=15) of CML. All enrolled patients were treated with IM 400mg/day for CP or 600 mg/day for AP as a first line TKI. Patients were monitored for cytogenetic and molecular response every 6 and 3 months respectively using conventional cytogenetic on bone marrow and quantitative PCR (RQ-PCR) on peripheral blood. Results of RQ-PCR were expressed as a ratio of BCR-ABL/ABL% [IS]. Definitions of CCyR, MMR as well as CP and AP were consistent with European LeukemiaNet recommendations. The analyzed factors included: time to complete hematologic remission (CHR), time to CCyR, time to MMR and additional cytogenetic abnormalities in Ph positive cells [ACA Ph(+)] during first line IM treatment and % of CCyR and MMR during second line TKI treatment. To estimate probability of CCyR and MMR cumulative incidence analysis was used. Cytogenetic and molecular progression free survival (PFS) was estimated by Kaplan-Meier analysis. Results: Probability of CCyR for the analyzed group was 55%, 60% and 62% after 12, 18 and 24 months of treatment with IM respectively. Probability of cytogenetic PFS was 92%, 83%, 81% and 76% in 12, 18, 24 and 36 months respectively. There was observed statistically significant correlation between probability of achievement of CCyR, MMR and the following: time to CHR, time to imatinib introduction, phase of the disease and ACA Ph(+). No correlation between probability of CCyR, MMR and age, sex, Sokal and Hasford risk factors was observed. 1) Early CHR in up to 8 weeks after diagnosis (dx) predicted CCyR and MMR achievement irrespective of treatment schedule to CHR (p<0,0001) (Fig 1.). 2) Early IM introduction up to 4 months since dx increased probability of CCyR and MMR in 12 and 18 months respectively (p<0,0001). 3) Patients in LCP were significantly less likely to obtain CCyR and MMR comparing to ECP and results in this group were similar to AP patients (p=0,0004) (Fig. 2). 4) Early CCyR up to 6 months after starting IM increased probability of MMR (p<0,0001). 5) ACA Ph(+) were confirmed as an adverse prognostic factor regarding to achieving (p=0,005) and maintaining (p=0,01) of CCyR. 6) Treatment with higher dose of IM predicted better outcome when ACA Ph(+) at diagnosis and/or at least 10% of blasts in bone marrow or peripheral blood at dx were considered as AP criteria. 7) Among patients after IM failure those treated with 2G TKI were more likely to achieve and maintain CCyR (52%) than those with escalation of IM (24%) (p=0,02). Conclusions: These data suggest need of 1) therapy intensification from the very moment of diagnosis, 2) early achievement of CHR, 3) early IM introduction (<4 months from dx in analysed population), 4) the precise defining of AP with rigid criteria may result in better outcome. 5) Relative risk (Sokal and Hasford) relationship with treatment results seems to be not sufficient when IM is introduced after a long time since diagnosis. 5) Treatment switch to 2G TKI but not imatinib escalation after first line IM treatment failure is proposed to be an optimal treatment standard. Disclosures: Foryciarz: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Sacha:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Florek:BMS: Research Funding; Novartis: Research Funding. Czekalska:BMS: Research Funding; Novartis: Research Funding. Zawada:Novartis: Research Funding; BMS: Research Funding. Skotnicki:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Prevalence of Sars-Cov-2 Infection in Patients with Chronic Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Simone Claudiani ◽  
Carolina Rosadas ◽  
Myra McClure ◽  
Maryam Khan ◽  
Richard S. Tedder ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Asian Indian ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Solid Cancer ◽  
Acute Limb Ischemia ◽  
Serological Testing ◽  
The Impact

Background: The new SARS-CoV-2-induced disease (COVID-19) pandemic has represented a huge challenge for the health systems and has been responsible for almost 700.000 deaths worldwide as of 1st August 2020. Older age, male sex, comorbidities, ethnicity and socioeconomic factorsare risk factors for severe COVID-19. While the direct effect of solid cancer on the COVID-19 outcome has been investigated and is still debated, limited information is available on the impact of an underlying hematological malignancy on the risk of contracting SARS-CoV-2, the clinical presentation and the outcome of the infection. We report on the prevalence of SARS-CoV-2 infection in a large cohort of patients (pts) with chronic myeloid leukemia (CML). Methods: We retrospectively investigated the exposure to SARS-CoV-2 through serological testing in a single centre cohort of CML pts. Of more than 600 pts on active follow-up, we have screened 161 pts between 1st June and 27th July 2020. At each consultation, we recorded any exposure to or symptoms of SARS-CoV-2 infection in the preceding 6 months. The Imperial Hybrid DABA, a two-step double antigen binding assay (DABA) for the detection and measurement of total antibody directed to the receptor binding domain (RBD) of SARS-CoV-2 was used for analysis. The cut-off (CO) for positivity is established by adding 0.1 to the average of optical density (OD) obtained for the negative controls. A sample-OD/cut-off (S/CO) value ≥ 1 is considered reactive. Results: 161 CML pts in chronic phase underwent serological testing (median age 54 years (18-92), male n=94). Twenty pts were off TKI (post-alloSCT, n=12; in treatment free remission n=6; pregnancy=1 and intolerance n=1) and 141 were on active treatment (imatinib [n=41], dasatinib [n=38], nilotinib [n=23], bosutinib [n=21], asciminib [n=11], ponatinib [n=6] and K0706 [n=1]). The ethnic distribution was White (n=119), Asian-Indian (n= 24), Asian-Chinese (n=3), Black (n=9), Arab (n=5), Mixed Asian-White (n=1). Eighteen pts (11.2%) have tested positive (Table 1). Thirty-eight pts (23.6%) reported symptoms compatible with COVID-19 of whom 12 (31.6%) were DABA positive. Six of 123 (4.9%) asymptomatic pts also tested positive. The time from onset of symptoms to the date of testing were similar in both seropositive (105 days, range 56-180) and seronegative pts (100 days, range 21-205). The median S/CO ratio was 9.9 (1-23.3) in the symptomatic and 1.5 (1.2-21.4) in the asymptomatic pts. Among the 18 positive pts, the median age at symptom presentation was 54 years (38-75) and 12 were males. The median time from CML diagnosis was 7.6 years (0.2-20) and two pts were post-alloSCT. Ethnicity was White, Asian-Indian, Black in 8 (44.4%), 6 (33%) and 4 (22.2%), respectively. In 15 pts (83.3%) symptoms were absent or mild, moderate in 2 and severe in one patient 2 years post-alloSCT on continuing immunosuppression for GvHD. Only 2/18 had PCR tests for SARS-CoV-2 at the time of infection and both were positive. Of the 16 pts not tested for antigen, 2 had been in close contact with a family member with a PCR-confirmed SARS-CoV-2 infection. In the mild cases, the most frequent symptoms were fever (n=7) and cough (n=6), followed by fatigue (n=2), myalgia (n=2) and anosmia (n=2). One patient presented only with acute limb ischemia, derived from thrombus in the superficial femoral artery. One patient had radiological features of COVID-19 pneumonia, but did not require hospitalization. The only patient with severe COVID-19 developed pneumonia requiring CPAP, was refractory to tocilizumab (anti-IL6), but recovered after starting ruxolitinib (JAK2-inhibitor). The median time to complete resolution of symptoms was 21 days (7-56). Conclusions: The prevalence of infection in our CML pts is similar to that of the overall population, which suggests that they are capable of mounting appropriate antibody response against SARS-CoV-2. Importantly, in seropositive pts symptoms were mild. Of note is the higher prevalence in the BAME community and underlines the potential role of socioeconomic factors in disease transmission. Expansion of this CML cohort and serial antibody testing in seropositive patients will provide further information regarding prevalence and durability of serological responses. Disclosures Milojkovic: Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

scholarly journals Dynamic Personalized Assessment in Patients with Chronic Myeloid Leukemia in Chronic Phase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3026-3026
Author(s):  
Koji Sasaki ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Marina Y. Konopleva ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Longitudinal Data ◽  
Dose Reduction ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Joint Model ◽  
Front Line ◽  
Genetics Research ◽  
The Impact

Abstract Introduction Tyrosine kinase inhibitors (TKI) have improved survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). There is a growing interest in treatment discontinuation after achieving sustained MR4.5. Over the course of therapy patients dose reduction of their TKI or switch to another TKI for various reasons. Multivariate joint models for dynamic personalized assessment incorporate survival and longitudinal data of multiple repeated measurements. Such models can handle longitudinal data of BCR-ABL levels over time as well as the dose of each TKI in every clinic encounter. The aim of this study is to evaluate the impact of dose adjustments and TKI switch on the achievement of sustained MR4.5. Methods From July 2000 to January 2017, 646 patients who enrolled in frontline TKI trials (imatinib 400 mg/day, 73 patients; imatinib 800 mg/day, 208 patients; nilotinib 800 mg/day, 148 patients; dasatinib 100 mg/day, 150 patients; dasatinib 50 mg/day, 16 patients; ponatinib 45 mg/day, 43 patients; ponatinib 30 mg, 8 patients) including 10,623 clinical visits to verify the dose of TKI, and 8,319 measurements of BCR-ABL by reverse transcriptase polymerase chain reaction. Sustained MR4.5 was defined as at least 2-year duration of MR4.5. Multivariate joint modeling with multiple longitudinal measurements was performed for dynamic personalized assessment with the combination of Cox proportional hazard model with generalized linear mixed models. For the estimation of parameters of the joint model, a Bayesian approach was used with Markov Chain Monte Carlo methods. The dose of each TKI, and the BCR-ABL/ABL ratio were considered as time-dependent covariates in the generalized linear mixed model. The dose of each TKI was handled as numeric values which enabled to accommodate treatment effect of dose-reduced TKI and alternative TKI after front-line TKI failure throughout different clinical trials. Results Overall median follow-up was 105 months (range, 0.3-213.4); imatinib 400 mg/day, 193 months; imatinib 800 mg/day, 166 months; nilotinib 800 mg/day, 81 months; dasatinib 100 mg/day, 79 months; dasatinib 50 mg/day, 10 months; ponatinib 45 mg/day, 48 months; ponatinib 30 mg/day, 40 months. A total of 334 patients (52%) achieved sustained MR4.5; median time to sustained MR4.5 was 44 months (95% confidence interval, 30.3-56.1). The trajectories of BCR-ABL levels (Figure 1A) and the dose of TKI are shown (imatinib, Figure 1B; dasatinib, Figure 1C; nilotinib, Figure 1D; ponatinib, Figure 1E). Multivariate joint model identified the daily dose of imatinib (p <0.001; hazard ratio [HR], 1.0017; 95% credible interval [CI], 1.0006-1.0028), dasatinib (p <0.001; HR, 1.0153; 95% CI, 1.0078-1.0237), nilotinib (p <0.001; HR, 1.0017; 95% CI, 1.0006-1.0028), ponatinib (p <0.001; HR, 1.0243; 95% CI, 1.0036-1.0471) as prognostic factors for the achievement of sustained MR4.5. An example of dynamic personalized assessment for the guidance of dose reduction and alternative TKI was shown in Figure 1F. Hypothetical Patient #1 was treated with front-line dasatinib 100 mg/day. At 6.24 months of dasatinib 100 mg/day, BCR-ABL1/ABL1 ratio was 0.18 % on the international scale. Assuming Patient #1 developed refractory pleural effusion not controlled with steroid and diuretics, expected cumulative rate of sustained MR4.5 at dasatinib 80 mg/day, dasatinib 50 mg/day, dasatinib 20 mg/day, nilotinib 300 mg/day, ponatinib 15 mg/day, imatinib 400 mg/day were calculated in Figure 1F. Dynamic personalized assessment by multivariate joint model estimated sustained MR4.5 at 5 years of TKI therapy after the suggested treatment options as follows; dasatinib 80 mg/day, 41% (95% CI, 31.0-55.8); dasatinib 50 mg/day, 29% (95% CI, 18.9-41.7); dasatinib 20 mg/day, 20%, (10.8-32.5); nilotinib 300 mg/day, 37% (95% CI, 28.8-45.6); imatinib 400 mg/day, 28% (19.0-37.1); ponatinib 15 mg/day, 22% (95% CI, 13.0-32.5). Conclusion Dynamic personalized assessment of TKI dose reduction and alternative TKI selection optimizes treatment decision at the time of TKI failure in patients with CML-CP. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Daver:Otsuka: Consultancy; Kiromic: Research Funding; Sunesis: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; BMS: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Alexion: Consultancy; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding.

scholarly journals Clinical Outcomes of Patients with Primary Myelofibrosis in Japan: A Nationwide Survey over a 17-Year Study Period

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3126-3126
Author(s):  
Katsuto Takenaka ◽  
Kazuya Shimoda ◽  
Naoyuki Uchida ◽  
Taizo Shimomura ◽  
Koji Nagafuji ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Median Survival ◽  
Research Funding ◽  
Nationwide Survey ◽  
Primary Myelofibrosis ◽  
Survival Duration ◽  
Survival Prediction ◽  
Median Survival Duration ◽  
The Impact ◽  
Over Time

Abstract Backgrounds: Primary myelofibrosis (PMF) is associated with poor prognosis and a marked reduction in life expectancy, with median survival durations ranging from 3.5 to 6 years, according to previous studies with great variation. We conducted a 17-year nationwide survey (1999-2015) to elucidate the clinical outcomes of patients with PMF in Japan, and evaluated the change of survival duration over time. Patients and Methods: Questionnaires were sent annually to approximately 500 hematology departments of board-certified member institute of the Japanese Society of Hematology to collect data about clinical features and prognoses of patients with PMF. Newly diagnosed patients with PMF were enrolled in this study and were followed up annually to collect prognostic information. Approximately 50 patients were enrolled per year, yielding an eventual total of 780 patients with PMF that were included in a 17-year study period (1999-2015). Results: The median age at diagnosis was 66 years. At the time of the analysis, 374 enrolled patients (48%) had died after a median survival duration of 47 months (95% CI, 41-53 months). Of the patients for whom the final cause of death was known, infection (n = 89) and transformation into acute leukemia (n = 91) were the most frequent causes. The 3-year overall survival (OS) rate was 59% (95% CI, 55%-63%). Significant improvements in the 3-year OS rate were not observed during the 17-year period of analysis (p = 0.235)(Figure A). Among the proposed prognostic models for predicting the outcomes of PMF patients, the Dynamic International Prognostic Scoring System of PMF (DIPSS) plus model was the most feasible for our cohort. However, the calculated areas under ROC curves were 0.609, and only modest accuracy was observed in this regard. Forty-three patients (median age of 52 years; range, 24-66 years) received allogeneic hematopoietic stem cell transplantation (alloSCT) at a median of 343 days after diagnosis. The estimated median survival duration after first alloSCT was 134 months (range, 71 to not reached), with a 3-year OS rate of 84% (95% CI, 68%-93%). The median survival duration after diagnosis among patients who received alloSCT was 207 months (range, 105 to not reached), and this is significantly longer than that calculated for patients who did not receive alloSCT (median: 45 months; range, 38-49 months; p < 0.001)(Figure B). Ruxolitinib therapy was given to 47 patients, but did not have an impact on survival duration. Conclusions: The survival curves of patients diagnosed during different subperiods of our study period exhibited complete overlap, indicating a lack of improvement in survival duration over time. However, only alloSCT among current treatment modalities had an impact on the natural course of PMF. Regarding prognostic prediction, DIPSS plus was the optimal model for survival prediction even among Japanese patients with PMF. However, the ROC analysis indicated that the prognostic covariates in DIPSS plus were not sufficient, and additional information regarding gene mutation statuses (e.g., CALR and ASXL1) might be required to predict the precise outcomes of PMF patients. A long-term registration study is required for further evaluations of prognosis and the impact of treatments on survival. Figure Figure. Disclosures Shibayama: Novartis Pharma: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau. Ozawa:Sumitomo Dainippon Pharma Co. Ltd: Research Funding; Takara Bio Inc: Research Funding; Celgene Japan: Consultancy; JCR Pharmaceutical Inc: Consultancy.

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