scholarly journals Imatinib Suspension and Validation (ISAV) Study: Final Results at 79 Months

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 461-461 ◽  
Author(s):  
Silvia Mori ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
Ester Pungolino ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Median Duration ◽  
Research Funding ◽  
Well Being ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission ◽  
The Impact ◽  
Risk Of Relapse

Abstract Introduction. It is known that imatinib can be safely discontinued in patients (pts) with Chronic Myeloid Leukemia (CML) with minimal residual disease. Here we report an update of the Imatinib Suspension And Validation (ISAV) study at 79 months (mts) from study initiation to provide long term follow up data. Aims. The ISAV study aims to validate the capability of digital PCR (dPCR) to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR and to evaluate relapse rate, time to recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL). Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (chronic or accelerated phase) treated with imatinib for more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 mts, with a minimum of 3 Q-RT-PCR performed at their own sites. After discontinuation of imatinib therapy, Q-RT-PCR was performed monthly (mts 1-6), bimonthly for 36 mts and then every 6 mts for additional 2 years, to assess the maintenance of the molecular remission. The loss of molecular remission was defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. dPCR was performed at screening and at 36 mts for those pts who were still in remission. Patients' QoL during imatinib discontinuation/resumption was evaluated through the EORTC QLQ-C30 questionnaire. Results. The ISAV study enrolled 112 pts with a median follow-up time of 60.0 mts [95% CI: 59.6-60.6] for pts who do not relapsed; 66.1% of them completed the study as per protocol. The 58.9% of pts were male and 37.4% were aged 65 or older; median duration of imatinib treatment was 103.2 mts with median duration of CMR of 25.6 mts before imatinib discontinuation. At 79 mts from imatinib discontinuation, 56 pts of the 107 eligible ones relapsed and resumed imatinib with a relapse rate of 52.3% [95%CI: 20.4-32.6]; 69.6% of them relapsed in the first 9 mts. Of the 52 not-relapsed pts, 40 (76.9%) regained Q-RT-PCR positivity without losing MMR. In this latter group 2 pts experienced late relapses, at 30.6 and 45.5 mts respectively. A loss of CCyR occurred in 13 pts (23.6%): 10/13 CCyR losses were recovered, the remaining 3 were not assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.8 [95% CI: 1.0-2.0] mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse was evident. dPCR results before imatinib discontinuation showed that 23.4% of pts were positive and 76.6% negative at the time of discontinuation, with a Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.1 [95%CI: 0.99-1.22]. At 36 mts from imatinib discontinuation 80.4% [95%CI: 30.6-50.4] of the pts tested were positive in dPCR. Moreover, the results of dPCR performed at imatinib discontinuation and age together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation, particularly with regard to nausea, diarrhea, fatigue and insomnia (p<0.05). An inverse and transient trend toward increased pain emerged at mts 1 and 3. Conclusions. At 79 mts from the beginning of the study, 52.3% of pts relapsed, with 24% loosing CCyR. The majority of relapses occurred in the first 9 mts after discontinuation however late relapses were also observed, up to the 4th year. Therefore, pts who discontinue imatinib should be monitored for a long period of time, especially if they show positive PCR values after discontinuation. All relapsed pts including those who lost CCyR regained their original response after restarting TKI. Age <45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia. Disclosures le Coutre: Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Kim:Pfizer: Research Funding; BMS: Research Funding; Ilyang: Research Funding; Novartis: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

Imatinib Suspension and Validation (ISAV) Study: Results at 24 Months

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2775-2775 ◽  
Author(s):  
Silvia Mori ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
Ester Pungolino ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Median Duration ◽  
Research Funding ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Advisory Committees ◽  
Risk Of Relapse

Abstract Introduction. A substantial proportion of patients (pts) affected by Chronic Myeloid Leukemia (CML) achieve complete negativity in Q-RT-PCR. In this situation, as already demonstrated in other STOP trials, it is possible to safely discontinue imatinib treatment but it is still not clear how to discriminate subjects who will relapse. In fact even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been developed. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated. Aims. The ISAV study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results and to evaluate relapse rate and timing of recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL). Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples were obtained for dPCR and the pts discontinued imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients' QoL during imatinib discontinuation/resumption is evaluated through the EORTC QLQ-C30 questionnaire. Results. The study enrolled 112 pts with a median follow-up (FUP) time of 28.0 mts [95% CI: 25.5-30.1]. The 59.3% of pts were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.7 mts before imatinib discontinuation. The cumulative probability of survival is 97.8% [95% CI: 91.4-99.5]. dPCR results showed that 23.1% of pts were positive and 75.9% negative, with a significant Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.112 [95% CI: 1.009-1.225]. At 24 mts from imatinib discontinuation, 53 pts (49.1%, 95% CI: 39.3-58.9) of the 108 eligible pts relapsed and resumed imatinib; 73.6% of them relapsed in the first 9 mts and the last relapse occurred 21.8 mts after imatinib discontinuation. A loss of CCyR occurred in 13 pts (34.2% of those tested): 10/13 CCyR losses were recovered, the remaining 3 were not assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 55 not-relapsed pts, 42 (38.9% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 2.9 mts [95% CI: 2.0-3.1] in the relapsed pts and 4.5 mts [95% CI: 2.9-6.9] in pts who developed only PCR positivity. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse is evident. Moreover, age and dPCR results together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation and in particular nausea, diarrhea and fatigue (p<0.01). An inverse and transient trend toward increased pain emerged at mts 1 and 3. Conclusions. At 45 mts from the beginning of the study, with a median FUP of 28.0 mts, 49.1% of pts relapsed; the majority of relapses developed in the first 9 mts after imatinib discontinuation. Age < 45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia. Disclosures Abruzzese: BMS, Novartis, Pfizer, Ariad: Consultancy. Assouline:BMS: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. D'Emilio:Celgene: Research Funding. Dong-Wook:ll-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals The Risk of Relapse in CML Patients Who Discontinued imatinib Can Be Predicted Based on Patients Age and the Results of dPCR Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 813-813 ◽  
Author(s):  
Silvia Mori ◽  
Elisabetta Vagge ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Median Time ◽  
Median Duration ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Risk Of Relapse

Abstract Introduction. Chronic myeloid leukemia (CML) patients (pts) treated with imatinib first line achieve complete cytogenetic response (CCyR) in > 70% of cases and major molecular response (MMR) in 18-58%. These pts have a life expectancy similar to the general population. However even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been recently developed (Goh HG et al., 2011). dPCR corresponds to a 100 fold increase in sensitivity as compared to Q-RT-PCR. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated. Aims. The Imatinib Suspension And Validation (ISAV) study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results. Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible for this study. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples are obtained for dPCR and the pts discontinue imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is evaluated through the EORTC – C30 Quality of Life questionnaire. Results. The enrolment in ISAV began in November 2011 and ended in July 2013. The study enrolled 112 pts: Italy 69.6%, Germany 21.4%, Canada 5.3%, Spain 2.6% and Israel 0.9%. Among the 112 pts, 59.3% were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.8 mts before imatinib discontinuation. To date, the median follow-up (FUP) time is 16.6 mts [95% CI: 14.9-18.2]. Forty-seven pts (43.5%, 95% CI: 34.0-53.4) of the 108 eligible pts relapsed and resumed imatinib; 38/47 (80.9%) of them relapsed in the first 9 mts and the last relapse occurred 19.6 mts after imatinib discontinuation. A loss of CCyR occurred in 11 pts (23.4%): 10/11 CCyR losses were recovered; 1 patient withdrew the consent shortly after obtaining a partial cytogenetic response. No case of CML progression was observed. After the resumption of imatinib the median time to either MMR or CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 61 not-relapsed pts, 43 (39.8% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 3.6 mts [95% CI: 3.0-4.8] and the range of duration of Q-RT-PCR positivity (below 0.1%) was between 5.7 and 29.2 mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR or duration of CMR was identified. An inverse relationship between pts age and risk of relapse is evident: 90% of pts < 45 years relapsed vs 37.5% in the class ≥ 45 - < 65 years and 27.5% of pts ≥ 65 years, p(χ2)<0.0001. dPCR results showed that 23.4% of pts were positive and 76.6% negative, with a dPCR Negative Predictive Value (NPV) of 63.4% (Tab.1) and a significant NPV ratio (dPCR/Q-RT-PCR) of 1.131 [95% CI: 1.032-1.239]. Age and dPCR results predicted the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (30.6%; Fig.1). Conclusions. After 32 mts from the beginning of the study, with a median FUP of 16.6 mts, 43.5% of pts relapsed; the majority of relapses developed in the first 9 months after imatinib discontinuation. Age < 45 years and dPCR positivity are significantly associated with relapses. Funded by Regione Lombardia. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Validation of Digital-PCR Analysis through Programmed imatinib Interruption in Q-RT-PCR Negative Chronic Myeloid Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4040-4040
Author(s):  
Silvia Mori ◽  
Elisabetta Vagge ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Diagnostic Method ◽  
Digital Pcr ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission

Abstract Introduction Imatinib induces complete cytogenetic response (CCyR) in up to 80% of chronic myeloid leukemia (CML) patients (pts) and major molecular response (MMR) in 33-60% of them. These patients enjoy life expectancy similar to general population. However even undetectable BCR-ABL may not equate to eradication of the disease because the sensitivity of the standard diagnostic method, the Q-RT-PCR, is limited. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, corresponding to a 100 times increased sensitivity as compared to conventional Q-RT-PCR, was developed (Goh HG et al., Leuk Lymphoma 52(5): 896-904. 2011). Therefore dPCR, assessing with more sensitivity the presence of minimal residual disease, could potentially identify pts in whom CML is eradicated. The Imatinib Suspension And Validation (ISAV) study is aimed at assessing the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results. Methods This study involves 15 sites, 10 in Italy and 5 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. In this study CML patients (Chronic Phase or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 months, with a minimum of 3 Q-RT-PCR performed in their own centers. After signing the informed consent, pts were tested for dPCR and discontinued imatinib therapy. They are being monitored by standard Q-RT-PCR for 36 months to assess the maintenance of the molecular remission. At the end of this period, a peripheral blood sample for dPCR analysis will be obtained from those pts who will still have undetectable BCR-ABL transcripts by Q-RT-PCR, to verify CML eradication. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is being evaluated trough the EORTC – C30 Quality of Life questionnaire. Results The enrollment in the ISAV study began in November 2011 and ended in June 2013. The study enrolled 112 pts: Italy 69.6%, Berlin 21.4%, Montreal 5.3%, Zaragoza 2.6% and Tel Hashomer 0.9%. Sixty-one percent of the pts were male and 38% were aged 65 or older; median duration of imatinib treatment is 102 months with median duration of CMR of 32 months before imatinib discontinuation. To date, the median follow-up (FUP) time is 4.6 months [95% CI: 4.1-5.8] and 92 pts out of 112 (82%) had at least one Q-RT-PCR performed after imatinib discontinuation. The following analysis is restricted to 48 pts with a minimum of 6 months of FUP. Of these 48 pts, 20 remained Q-RT-PCR negative (42%, 95% CI:29-56%, median duration of negativity after imatinib discontinuation: 10.3 months). Nineteen pts (40%, 95% CI:27-53%) relapsed and resumed imatinib. All relapses occurred in the first 10 months and all but 3 of them in the first 6 months. A loss of CCyR happened in 5 pts out of 19 (26%): 1 pt regained CCyR after 3 months of re-treatment and is now in CMR, 1 pt died shortly after the diagnosis of relapse because of lung adenocarcinoma and 3 pts are now being monitored after imatinib resumption. No case of progression of CML was observed. After the resumption of imatinib the median time to either MMR or CMR, whichever came first, was 2.1 [95% CI: 0.9-5.8] months. Finally, nine pts (18%, 95% CI:10-31%) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity in this group of pts was 2.92 months (range 1-5 months), and the range of duration of Q-RT-PCR positivity (below 0.1%) is between 2 and 14 months. No significant correlation between relapse and previous duration of imatinib treatment, time to CCyR or duration of CMR was present. Patients previously treated with interferon showed a trend toward lower risk of relapse which is not significant so far. Finally, 19% of pts complained of musculoskeletal/articular pain after imatinib discontinuation. Conclusions After 21 months from the beginning of the study with a median follow-up of 4.6 months, 40% of pts relapsed; the majority of relapses happened in the first 6 months after imatinib discontinuation. The correlation of dPCR results with clinical outcomes will be presented at the meeting. Disclosures: le Coutre: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Research Funding. Gozzini:Novartis: Consultancy; Bristol Myers Squibb: Consultancy.

Molecular Remission to Imatinib in Patients with Chronic Myeloid Leukaemia (CML) Is Less Durable Compared to Patients after Allografting.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 276-276
Author(s):  
Thoralf Lange ◽  
Thomas Bumm ◽  
Marc Mueller ◽  
Sandra Otto ◽  
Haifa K. Al-Ali ◽  
...  
Keyword(s):  
Nested Pcr ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Standard Dose ◽  
Healthy Individuals ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Conventional Cytogenetics ◽  
Risk Of Relapse

Abstract Objectives: Patients with CML who achieve molecular remission (MR, defined as a RT-PCR negativity for BCR-ABL transcripts) after myeloablative stem cell transplantation (SCT) have a low risk of relapse, and the majority may be cured. The frequency of MR on imatinib varies greatly and the durability of these responses has not been reported. To investigate if MR after SCT and on imatinib are equally stable, we directly compared two cohorts of patients treated with imatinib or SCT, respectively, from the time of their first negative RT-PCR result. Patients and Methods: One hundred and forty-four CML patients in chronic (n=104) or accelerated phase (n=40) treated with standard dose imatinib were routinely monitored by conventional cytogenetics, quantitative RT-PCR (qPCR) and conventional nested PCR in case of negative qPCR results. Nineteen patients (13.2%) had at least 1 negative nested PCR. To assess the level of residual disease in patients with a single negative RT-PCR result, 10 replicate reactions were performed, each corresponding to &gt; 106 white bone marrow cells. Thirty-six samples (median 3, range 1–4) from patients in MR on imatinib and 45 samples (median 2, range 1–3) from patients in MR after SCT were available. Twenty samples from healthy individuals were tested as controls. Results: The first negative result was noted after a median of 16.8 months (range 11.5–36.1) of imatinib therapy and 6.6 months (range 4.7–9.5) after SCT, respectively. The projected risk of molecular relapse at 12 months after the first negative RT-PCR result was 83% in patients on imatinib but only 20% in patients after SCT (P = 0.0001). Only two patients on imatinib remained in molecular remission at 13.8 and 16.6 months. While none of the patients with molecular relapse after allograft lost CCyR, one patient on imatinib progressed to cytogenetic relapse. The replicate assay was positive in 18/36 samples (50%) from patients on imatinib, 8/46 (17.4%) after allografting and 4/20 (20%) from healthy individuals. These differences were significant between patients on imatinib and after allografting (P = 0.003) and between patients on imatinib and healthy individuals (P = 0.005), but not between patients after allografting and healthy individuals (P = 0.9). Negativity by replicate testing was more stable in patients after allografting, although, even in these patients, positive replicate reactions continued to occur with longer follow-up. Conclusion: Imatinib-induced MR is usually not durable, in contrast to MR after transplant. Consistent with this, the level of residual disease in samples negative by single nested PCR is higher in patients on imatinib compared to patients after SCT. These results suggest that disease eradication with imatinib monotherapy may be rare. Patients on imatinib followed by PCR should be made aware of the fact that a single negative test does not have the same significance as in patients after SCT.

Imatinib at Weekly Dosage May Induce and Maintain Haematologic and Molecular Remission in Chronic Eosinophilic Leukemia Harbouring FIP1L1-PDGFRA Fusion Gene- An Extended Follow-up Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1755-1755
Author(s):  
Grzegorz Helbig ◽  
Malgorzata Calbecka ◽  
Justyna Gajkowska ◽  
Andrzej Moskwa ◽  
Alina Urbanowicz ◽  
...  
Keyword(s):  
Median Time ◽  
Fusion Gene ◽  
Hypereosinophilic Syndrome ◽  
Imatinib Treatment ◽  
Weekly Dose ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Chronic Eosinophilic Leukemia ◽  
Weekly Dosage

Abstract Background. A small proportion of patients with hypereosinophilic syndrome (HES) demonstrate the presence of an interstitial deletion in chromosome 4 leading to the creation of the imatinib-responsive fusion gene- FIP1L1-PDGFRA (F/P). Recently, we showed that a single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukemia (CEL) with detectable F/P transcript. Here, we present data from 12 patients CEL and HES, 11 of which were F/P positive, who achieved a rapid complete haematologic remission (CHR) with daily imatinib treatment and remission was then maintained with a weekly imatinib schedule. Design and methods. Twelve patients, 11 out of 12 with detectable F/P were treated with imatinib at the initial doses varies between 100–400mg. There were 10 male and 2 female with a median age of 57 years (19–80). Median time to start imatinib was 23 months (1–204 months). The imatinib dose was de-escalated while patients remained in haematologic remission. As a response maintenance, once weekly imatinib was established in all cases. Results. All studied patients achieved a complete haematologic remission (CHR) and 100% of cases with detectable F/P fusion gene before imatinib, demonstrated a molecular remission determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The breakpoints occured within exon 12 of PDGFRA whereas breakpoints dispersed across the FIP1L1 locus occuring between exons 10 and 13. Median time to achieve CHR was 13 days (4–90), and median time to molecular remission was 9 months (4–24). As a remission maintenance, imatinib doses were set at 100mg weekly in 9 pts and 200mg weekly in 3. With a median follow-up of 21 months (8–49 months) all pts remain in CHR. The FIP1L1-PDGFRA is undetectable in 11 patients by RT-PCR. Conclusions. Imatinib at weekly dosage may induce and maintain remission in patient with CEL expressing F/P fusion gene. This strategy appears to be safe and cost savings.

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.

Long-Term Molecular Results Of The Gimema VEL-03-096 Trial: Molecular Remission Achievement and Loss Are Major Outcome Predictors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2077-2077
Author(s):  
Simone Ferrero ◽  
Marco Ladetto ◽  
Daniela Drandi ◽  
Federica Cavallo ◽  
Elisa Genuardi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Salvage Treatment ◽  
Clinical Relapse ◽  
Molecular Remission ◽  
Advisory Committees ◽  
Risk Of Relapse

Abstract Background and aims The extensive use of new drugs in multiple myeloma (MM) allowed the achievement of unprecedented levels of cytoreduction and major advantages in survival rates, though almost all patients still relapse after a successful treatment. PCR-based minimal residual disease (MRD) studies are powerful prognostic tools, able to indentify patients at high risk of relapse. Thus, there is a growing interest in MRD to modulate therapy also in MM, as already happens in other lymphoid neoplasms. However available reports have a too short follow-up to be conclusive. In particular some points need to be addressed: 1) which is the long-term outcome of patients achieving molecular remission (MR) in the absence of further treatment? 2) What is the prognostic impact of MR loss? 3) How long is the window between MR loss and clinical relapse? These issues have been addressed based on the mature results of the GIMEMA VEL-03-096 trial [EudraCT Number 2004-000531-28], which currently has a median follow-up (mFU) of 93 months. Patients and methods Inclusion criteria and treatment schedule have been already reported [Ladetto et al., J Clin Oncol 2010]. MRD was assessed on bone marrow at diagnosis, study entry, after two VTD courses, at the end of treatment and then every six months up to clinical relapse. Patients underwent MRD detection using both qualitative nested PCR and Real Time Quantitative (RQ)-PCR, employing immunoglobulin heavy chain-derived patient specific primers, as described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000; van der Velden et al., Leukemia 2007]. MR was defined as negative MRD results by nested-PCR or less than 1EE-04 by RQ-PCR. Loss of MR was defined as an increase of MRD levels of at least one log in consecutive samples at whenever timepoint. For survival analysis duration of response (DOR), progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) rates were used, as detailed in IMWG criteria [Rajkumar et al., Blood 2011]. Results Thirty-nine patients were enrolled. So far 27 serological progressions, 22 clinical relapses needing salvage treatment and 12 deaths (two non-MM-related) were observed. Median PFS was 60 months, median TNT 67 months and OS at mFU was 64%. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. Currently, 26 MR and 11 MR losses have been registered. The achievement of MR was strongly associated with a better outcome, in terms of median DOR (62 vs 9 months, p<0.001), PFS (67 vs 22 months, p<0.001), TNT (108 vs 30 months, p<0.001) and resulted significant for OS, too (72% vs 48% at mFU, p=0.04, Figure 1A-B). Moreover, patients with ongoing MR, MR loss or not achieving MR at all showed increasing risk of relapse, respectively (DOR not reached vs 38 vs 9 months, PFS 92 vs 63 vs 22 months, TNT not reached vs 72 vs 30 months, each p<0.001, Figure 2). Interestingly, the time lag between MR loss and clinical relapse for patients achieving and then loosing MR was comparable to that between end of consolidation and clinical relapse for patients never obtaining MR (TNT 19 vs 11 months p=0.34). Finally, analyzing the relationship between MR achievement, MR loss and need for a salvage treatment, of the 26 patients who obtained MR only 11 (42%) received a retreatment at a median time of 42 months (range: 22-87 months). Of these 11 clinical relapses, 7 were anticipated by a molecular relapse (64%), occurring at a median time of 9 months (range: 2-39 months). The 4 relapses not anticipated by MR loss occurred in cases with inadequate follow-up sampling or at least two years after the end of the planned molecular follow-up. Conclusions Besides confirming the strong prognostic value of PCR-based MRD monitoring in MM, our long-term results indicate the following: 1) the 42 months TNT of patients achieving MR underlines the excellent disease control of MM patients once obtained MR; 2) the occurrence of MR loss heralds relapse, with a TNT from MR loss comparable to TNT of patients not achieving MR; 3) there is a 9 months lag between MR loss and need for salvage treatment. These observations will have increasing relevance considering that ongoing methodological developments will allow effective MRD monitoring in the vast majority of MM patients. Disclosures: Off Label Use: Bortezomib and thalidomide as post-transplant consolidation during first-line treatment of multiple myeloma. Ladetto:Celgene: Research Funding, Speakers Bureau; Jannsen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Cavallo:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Caravita:Celgene: Honoraria, Research Funding; Jannsen Cilag: Honoraria. Guglielmelli:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Expectations, Prefitting Counseling, and Hearing Aid Outcome

2009 ◽  
Vol 20 (05) ◽  
pp. 320-334 ◽  
Author(s):  
Gabrielle H. Saunders ◽  
M Samantha Lewis ◽  
Anna Forsline
Keyword(s):  
Hearing Aids ◽  
Hearing Aid ◽  
Well Being ◽  
Fine Tuning ◽  
Initial Contact ◽  
High Expectations ◽  
Digital Hearing Aids ◽  
The Impact ◽  
Unrealistic Expectations

Background: Data suggest that having high expectations about hearing aids results in better overall outcome. However, some have postulated that excessively high expectations will result in disappointment and thus poor outcome. It has been suggested that counseling patients with unrealistic expectations about hearing aids prior to fitting may be beneficial. Data, however, are mixed as to the effectiveness of such counseling, in terms of both changes in expectations and final outcome. Purpose: The primary purpose of this study was to determine whether supplementing prefitting counseling with demonstration of real-world listening can (1) alter expectations of new hearing aid users and (2) increase satisfaction over verbal-only counseling. Secondary goals of the study were to examine (1) the relationship between prefitting expectations and postfitting outcome, and (2) the effect of hearing aid fine-tuning on hearing aid outcome. Research Design: Sixty new hearing aid users were fitted binaurally with Beltone Oria behind-the-ear digital hearing aids. Forty participants received prefitting counseling and demonstration of listening situations with the Beltone AVE™ (Audio Verification Environment) system; 20 received prefitting counseling without a demonstration of listening situations. Hearing aid expectations were measured at initial contact and following prefitting counseling. Reported hearing aid outcome was measured after eight to ten weeks of hearing aid use. Study Sample: Sixty new hearing aid users aged between 55 and 81 years with symmetrical sensorineural hearing loss. Intervention: Participants were randomly assigned to one of three experimental groups, between which the prefitting counseling and follow-up differed: Group 1 received prefitting counseling in combination with demonstration of listening situations. Additionally, if the participant had complaints about sound quality at the follow-up visit, the hearing aids were fine-tuned using the Beltone AVE system. Group 2 received prefitting counseling in combination with demonstration of listening situations with the Beltone AVE system, but no fine-tuning was provided at follow-up. Group 3 received prefitting hearing aid counseling that did not include demonstration of listening, and the hearing aids were not fine-tuned at the follow-up appointment. Results: The results showed that prefitting hearing aid counseling had small but significant effects on expectations. The two forms of counseling did not differ in their effectiveness at changing expectations; however, anecdotally, we learned from many participants that that they enjoyed listening to the auditory demonstrations and that they found them to be an interesting listening exercise. The data also show that positive expectations result in more positive outcome and that hearing aid fine-tuning is beneficial to the user. Conclusions: We conclude that prefitting counseling can be advantageous to hearing aid outcome and recommend the addition of prefitting counseling to address expectations associated with quality of life and self-image. The data emphasize the need to address unrealistic expectations prior to fitting hearing aids cautiously, so as not to decrease expectations to the extent of discouraging and demotivating the patient. Data also show that positive expectations regarding the impact hearing aids will have on psychosocial well-being are important for successful hearing aid outcome.

scholarly journals P–070 Evaluation of SARS-CoV–2 in human semen and effect on total sperm number: A prospective observational study

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Best ◽  
M Kuchakulla ◽  
K Khodamoradi ◽  
T Lima ◽  
F Frech ◽  
...  
Keyword(s):  
Semen Analysis ◽  
Epidemiological Data ◽  
Semen Parameters ◽  
Human Semen ◽  
Sperm Number ◽  
Rt Pcr ◽  
Sperm Analysis ◽  
Reproductive Techniques ◽  
The Impact

Abstract Study question Is the SARS-CoV–2 virus present in human semen and what is the impact on semen parameters following an infection? Summary answer SARS-CoV–2 infection, though not detected in semen of recovered men, can affect TSN in ejaculate in the acute setting. What is known already Early epidemiological data has suggested that the primary mode of transmission is through respiratory droplets, but the presence of SARS-CoV–2 has been identified in other bodily fluids such as feces, urine, and semen. Study design, size, duration We prospectively recruited thirty men diagnosed with acute SARS-CoV–2 infection using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of pharyngeal swab specimens. Thirty semen samples from recovered men were obtained 11–64 days after testing positive for SAR-CoV–2 infection. The median duration between positive SAR-CoV–2 test and semen collection was 37 days (IQR=23). Participants/materials, setting, methods Semen samples were collected from each individual using mailed kits. Follow-up semen samples were done with mailed kits or in-person in office setting. Semen analysis and PCR was performed after samples were received. Main results and the role of chance The median total sperm number (TSN) in ejaculate was 12.5 million (IQR=53.1). When compared with age-matched SARS-CoV–2(-) men, TSN was lower among SARS-CoV–2(+) men (p = 0.0024). Five men completed a follow-up sperm analysis (median 3 months) and had a median TSN of 18 million (IQR=21.6). No RNA was detected by means of RT-PCR in the semen in 16 samples tested. Limitations, reasons for caution First, most of the semen samples came from non-severe men of whom were in the recovery stage and lacked symptoms. Additionally, our sample size was relatively small and overnight mail-in semen analysis kits were used during the acute phase of infection to minimize contact with positive subjects. Wider implications of the findings: Our findings suggest extremely low risk of viral transmission during sexual contact and assisted reproductive techniques, although further data need to be obtained. The impact on TSC in recovered men from SARS-CoV–2 infection is concerning, nevertheless long-term follow-up of these men is critical to determine the nadir of TSC. Trial registration number 20200401

scholarly journals The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4359-4359
Author(s):  
Koji Sasaki ◽  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Rita Assi ◽  
Kiran Naqvi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Risk Of Death ◽  
Genetics Research ◽  
The Impact ◽  
Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

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