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

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.

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

Blood ◽

10.1182/blood.v124.21.813.813 ◽

2014 ◽

Vol 124 (21) ◽

pp. 813-813 ◽

Cited By ~ 2

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.

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

Blood ◽

10.1182/blood-2018-99-112982 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 461-461 ◽

Cited By ~ 5

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.

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Switching to Nilotinib Are Associated with Deeper Molecular Responses in Chronic Myeloid Leukemia with Persistent Residual Disease on Long-Term Imatinib Therapy: STAT1 Trial in Japan

Blood ◽

10.1182/blood.v126.23.4032.4032 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4032-4032

Author(s):

Chiaki Nakaseko ◽

Naoto Takahashi ◽

Kaichi Nishiwaki ◽

Hitoshi Ogasawara ◽

Hisashi Wakita

Keyword(s):

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Residual Disease ◽

T Cell Subsets ◽

Imatinib Therapy ◽

Imatinib Treatment ◽

Advisory Committees ◽

Molecular Responses

Abstract Introduction: Nilotinib is a second-generation TKI that exhibits significant efficacy as first- or second-line treatment in patients with CML. Superior rates of deeper molecular responses were achieved with nilotinib vs. imatinib in patients newly diagnosed with CML in chronic phase in the ENESTnd trial. In addition, the 24-month analysis of the ENESTcmr study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of MR4.5 by 24-month vs. remaining on imatinib (42.9% on nilotinib vs. 20.8% on imatinib). Although our CMR study revealed that ABCG2 421C/A genotype was an independent predictor of CMR in imatinib-treated CML patients (Shinohara et al, Haematologica, 2013), a relationship between ABCG2 421C/Agenotypes and CMR rate has not been observed in CML-CP patients treated with Nilotinib until now. The purpose of this study is to evaluate the efficacy of nilotinib in patients with CML-CP who have achieved a MMR with imatinib. In addition, the correlation of deeper molecular responses with clinical, immunological, and pharmacokinetic parameters in CML-CP patients was evaluated. Methods: Patients with CML-CP who had achieved MMR but still had persistent BCR-ABL positivity by RQ-PCR on imatinib were eligible. Nilotinib will be taken twice daily (600 mg/day) for 2 years. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was written by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with ClinicalTrials.gov (number UMIN000005903). The primary objective of this multicenter phase II, single arm, open-label clinical study was to identify the MR4.5 rate at 24 months after the initiation of nilotinib treatment. The molecular response was evaluated according to the International Scale RQ-PCR upon study entry and every 3 months thereafter. Nilotinib trough concentrations were determined using high-performance liquid chromatography.Genotyping of SLC22A1 (156T>C, 480G>C, 1022C>T, and 1222A>G), ABCB1 3435T>C, ABCG2 421C>A, and the *6, *27 and *28 alleles of UGT1A1 were performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Flow cytometry-based analysis of peripheral blood T cell subsets was performed using a whole blood lysis technique. Results: Between July 2011 and December 2012, 80 Japanese patients were recruited, and 74 patients were evaluated in the study. The median age was 54.5 years. The ratio of men to women was 52:22. The median duration of imatinib treatment was 62.5 months (range, 13.3-131.1 months). All patients showed MMR at the time of entry into the study and the median time to MMR on imatinib therapy was 20.2 months (range, 4.6-92.1 months). The median duration of treatment was 17.9 months (range, 0.5-25.1 months) for nilotinib 300 mg twice daily. Dose reduction and interruption were seen 17.1% and 18.4% in safety data set (N=76), respectively. The patients achieving deeper molecular responses increased over time (Figure1). The rates of MR4 in the evaluable patients were 69% and 73% at 12 and 24 months, respectively, and the rates of MR4.5 were 28% and 49% at 12 and 24 months, respective. Comparison of the clinical backgrounds, pharmacokinetic, pharmacogenomic, and immunological parameters (NK cells, NK activity, and cytokines) in patients with MR4.5 at 24 months (n=33) and without (n=41) is performed. Age, sex, Sokal risk score, prior IFN therapy, duration of imatinib treatment and time to MMR were not significant predictive factors for achieving MR4.5 at 24 months. The mean nilotinib plasma trough concentration was not significantly different in both groups either (Table1). However, the frequency of patients with ABCG2 421A allele was significantly higher in patients with MR4.5 than without (OR 7.056, 95%CI 2.040-24.406, P =0.002). This finding suggested that the ABCG2 421A allele was associated with a higher intracellular retention and therefore, higher nilotinib exposure than the wild-type genotype. Conclusion: We confirmed that switching to nilotinib led to deeper molecular responses in CML patients with persistent residual disease on long-term imatinib therapy. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Nakaseko: Otsuka: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Masis: Consultancy; Astellas: Speakers Bureau; Sysmex: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees. Nishiwaki:Novartis: Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood.v122.21.2077.2077 ◽

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.

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Early Molecular Response and Female Sex Strongly Predict Achievement of Stable Undetectable BCR-ABL1, a Criterion for Imatinib Discontinuation in Patients with CML

Blood ◽

10.1182/blood.v120.21.165.165 ◽

2012 ◽

Vol 120 (21) ◽

pp. 165-165 ◽

Cited By ~ 4

Author(s):

Susan Branford ◽

David Ross ◽

Jodi Prime ◽

Chani Field ◽

Haley Altamura ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Imatinib Therapy ◽

Cumulative Probability ◽

Molecular Response ◽

Advisory Committees ◽

Significant Difference

Abstract Abstract 165 Introduction. The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients. Despite good responses to imatinib for most patients, treatment related side effects remain problematic and can affect quality of life. Studies have demonstrated that a proportion of carefully selected patients can sustain response after imatinib discontinuation. The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive RQ-PCR assay. The criteria for patient selection in the French Stop Imatinib (STIM) and Australian CML8 (TWISTER) imatinib discontinuation trials included stable undetectable BCR-ABL1 transcripts for at least 24 months with a PCR sensitivity of 5 and 4.5 log, respectively. The probability of continued remission after discontinuation for imatinib treated patients without prior interferon-α therapy was approximately 33%. It is not known how many imatinib treated patients will eventually meet these PCR criteria for a discontinuation trial. Aims. We aimed to determine 1) the cumulative probability of achieving the PCR criteria for imatinib discontinuation as defined in the CML8 study, and 2) factors that predicted its achievement. Method. The molecular response of 415 de-novo CML patients in chronic phase enrolled in consecutive clinical trials of imatinib since July 2000 was examined. The assigned daily imatinib dose was 400 mg for 90 patients, 600 mg for 202 patients and 800 mg for 123 patients. Molecular data were included until imatinib cessation or last follow-up. The minimum time since commencing imatinib was 30 months and the median time on imatinib was 45 months, range 3 to 136. The CML8 PCR criteria for imatinib discontinuation were confirmed undetectable BCR-ABL1 transcripts at a sensitivity of 4.5 log that remained undetectable on all PCR tests for at least 24 months while on imatinib therapy. In the current analysis the CML8 PCR discontinuation criteria are defined as ‘stable UMR4.5'. Results. At 8 years of imatinib therapy the cumulative incidence of stable UMR4.5 was 43%, Figure A. Patients were divided into groups according to the time to a confirmed major molecular response (MMR): by 3, 6, 12 or 18 months. There was a significant difference in stable UMR4.5, P<.001, Figure B. The cumulative incidence of stable UMR4.5 was more than 60% for all patients who achieved MMR by 12 months and only 16% for patients with MMR between 12 and 18 months. The time to a confirmed MMR influenced the time to reach a stable UMR4.5 after achieving MMR. Considering only patients who achieved stable UMR4.5, patients achieving MMR by 3 months took a further 39 months (median) to achieve stable UMR4.5. For those with MMR by 6 months and 12 months, the median month to a stable UMR4.5 was 50 and 76 months after MMR, P<.001. This suggests slower dynamics of BCR-ABL1 decline with delayed time to MMR. 52 patients achieved MMR after 18 months and none achieved a stable UMR4.5 by 8 years: median time to MMR was 27 months, range 21–87. Factors at the time of commencing imatinib (baseline) were examined for their association with stable UMR4.5; Sokal risk, age, sex, assigned imatinib dose and baseline BCR-ABL1 value, as well as the 3 month BCR-ABL1 value. Quantitative factors were categorized into groups, with cut-offs set at the median for age and quartiles for the baseline BCR-ABL1 value. By univariate analysis the only baseline factor that predicted for higher cumulative incidence of stable UMR4.5 at 8 years was female versus male, 68% versus 30%, P<.001, Figure C. During imatinib therapy females had significantly lower median BCR-ABL1 values at every assessment up to 42 months. The 3 month BCR-ABL1 value also predicted stable UMR4.5, P<.001, Figure D. Baseline and 3 month factors were entered into a multivariate analysis. The 3 month BCR-ABL1 value and sex were independent predictors of stable UMR4.5, P=.004 and P=.005, respectively. Conclusion. The time to achieve an MMR, sex and the 3 month BCR-ABL1 value predicted stable undetectable BCR-ABL1 while on imatinib. Lower BCR-ABL1 values and higher rates of stable UMR4.5 in females could be related to better drug adherence or biological differences. Further studies are indicated. Early MMR led to early achievement of the discontinuation criteria. The findings justify the focus on early achievement of MMR as a strategy to maximize recruitment to discontinuation studies. Disclosures: Branford: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy. Ross:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Yeung:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding.

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Around 70% of Japanese CML Patients Could Stop Imatinib According to a-STIM Criteria: The JALSG-STIM213 Study

Blood ◽

10.1182/blood.v126.23.4035.4035 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4035-4035 ◽

Cited By ~ 3

Author(s):

Naoto Takahashi ◽

Tetsuzo Tauchi ◽

Kunio Kitamura ◽

Koichi Miyamura ◽

Yoshio Saburi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Imatinib Therapy ◽

Molecular Response ◽

Imatinib Treatment ◽

Advisory Committees ◽

Molecular Responses ◽

Chugai Pharmaceutical ◽

Significant Difference

Abstract Introduction: Imatinib have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. Recently, treatment free remission (TFR) is one of the goals in CML treatment, and some prospective trials suggest that imatinib therapy may be safely discontinued in CML patients with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013, Rousselot JCO 2014). The purpose of this study was to confirm TFR in Japanese CML patients and to define prognostic biomarkers of successful TFR after stopping imatinib. Methods: Japanese CML patients on imatinib treatment in confirmed deeper molecular response (DMR) for at least two year (>4 log reduction on imatinib therapy for >24 months confirmed by four consecutive PCR tests) and under imatinib treatment for at least 3 years were eligible. Patients treated with other tyrosine kinase inhibitors or who received stem cell transplantations were excluded. MR4.5 was confirmed at the beginning of this study using Ipsogen BCR-ABL1 M-BCR IS-PCR kit in a central laboratory (Sysmex, Kobe, Japan). Primary endpoint was the major molecular remission (MMR) rate at 12 months after stopping imatinib. Molecular recurrence of CML was defined as loss of MMR according to A-STIM criteria (Rousselot JCO 2014). Results: From November 2013 to March 2014, 77 CML patients in chronic phase from 26 institutions were enrolled in this study. Nine were excluded (consent withdrawal n=1, not eligible n=8). Of the eligible 68 patients, 38.2% were female. Median age was 55.0 years (range, 23 to 84), and 13.2% and 16.2 % were high-risk according to EUTOS and Sokal Scores. Thirteen patients were treated with interferon prior to imatinib therapy. Median duration of imatinib treatment was 8 years (range, 3-12 years). The duration of imatinib treatment was less than 5 years in 12%, 5-8 years in 34% and > 8 years in 54% of pts. Time to MMR was 11.5 months (25%-75%, 7.5-22.7 months) and time to DMR (not detected by PCR) was 30.6 months (25%-75%, 17.6-59.9 months). Among the 68 patients, 46 patients (67.6%, 95%CI: [56.5% to 78.8%]) remained without molecular recurrence the first 12 months according to A-STIM criteria, defined as loss of MMR. Moreover, 43 patients (63.2%, 95%CI: [51.8% to 74.7%]) remained without molecular recurrence the first 12 months according to STIM criteria, defined as two consecutive loss of MR4.5 with 1 log increase. On the other hand, 22 patients who lost MMR were treated again with imatinib and all patients achieved MMR within 6 months. Time to 2nd MMR was 40 days. Although there was a trend for a better TFR rate for patients treated longer with Imatinib (Figure 1), no significant difference could be observed for molecular relapse within 12 months according to clinical characteristics including age, sex, Sokal risk score, prior IFN, and time to MMR/DMR (Table 1). Ten patients (15%) showed "withdrawal syndrome" which is transitory musculoskeletal pain within several weeks after imatinib discontinuation, and all patients except one recovered without any treatments. Conclusion: According to the A-STIM criteria, around 70% of patients with deep and sustained molecular responses could safely stop imatinib. TFR in this prospective Japanese clinical study was higher than previously reported, probably because there were much more patients who treated with imatinib for longer duration than previous studies. We will report prognostic factors in the exploratory research of JALSG-STIM213 study including T/NK-cell profiling in peripheral blood, BIM deletion polymorphism, and ABCG2 421C/A polymorphism at this ASH meeting. Table 1. Table 1. Figure 1. Figure 1. Disclosures Takahashi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Astellas: Speakers Bureau; Masis: Consultancy; Sysmex: Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Hatta:CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Celgene K.K.: Honoraria. Usuki:Fuji Film RI Pharma: Other: personal fees; Fujimoto Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Shionogi: Other: personal fees; MSD: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Astellas: Research Funding; Chugai Pharmaceutical: Other: personal fees; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Novartis: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Shire: Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other. Kobayashi:Gilead Sciences: Research Funding. Naoe:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Pfizer Inc.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Celgene K.K.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽

10.1182/blood-2020-139253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 51-52

Author(s):

Sung-Eun Lee ◽

Joon Seong Park ◽

Young Rok Do ◽

Sung-Hyun Kim ◽

Dae Young Zang ◽

...

Keyword(s):

Prospective Study ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Close Monitoring ◽

Advisory Committees ◽

Deep Molecular Response ◽

Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

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Older Age and Increased Neutrophil-to-Lymphocyte Ratio (NLR) Are Predictors of Mortality in a Multiethnic Urban Cohort of Hematologic Neoplasms and COVID-19 Patients

Blood ◽

10.1182/blood-2020-138842 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Angelica D'Aiello ◽

Sumaira Zareef ◽

Kith Pradhan ◽

Amanda Lombardo ◽

Fariha Khatun ◽

...

Keyword(s):

Cancer Treatment ◽

Board Of Directors ◽

Median Time ◽

Lymphocyte Count ◽

Research Funding ◽

Hematologic Neoplasms ◽

Private Company ◽

Advisory Committees ◽

Treatment Status ◽

Race Ethnicity

Introduction: We sought to compare outcomes among patients with hematologic neoplasms diagnosed with COVID-19 infection in a multiethnic urban academic medical center. Methods: A retrospective analysis of patients with hematologic neoplasms diagnosed with COVID-19 from March 17th to June 8th2020 was conducted. Subjects included were censored at last point of contact. Variables collected included age, gender, race/ethnicity, hematologic diagnosis, cancer treatment status, baseline and follow-up COVID-19 testing, neutrophil count, and lymphocyte count at time of diagnosis. Associations between hematologic diagnosis, cancer treatment status, age, gender, race/ethnicity, neutrophil-to-lymphocyte ratio (NLR), and overall survival (OS) were assessed using the Kaplan-Meier method with logrank test. Results: A total of 102 subjects with hematologic neoplasms and COVID-19 infection treated in Montefiore Health system were identified (Table 1). Thirty-nine (38%) subjects were undergoing active treatment, including 17 (16%) receiving conventional chemotherapy agents, 12 (12%) targeted therapy, and 10 (10%) combination therapy. Of those subjects, twenty (50%) experienced delay or discontinuation of treatment due to COVID-19 infection. Four subjects (4%) showed persistent infection by PCR at median duration of 25.1 days after initial diagnosis. Ten subjects (9.8%) showed clearance of the virus by PCR with median time-to-clearance of 51.8 days. Of 9 subjects with serologic testing, 8 tested positive for COVID-19 IgG antibody at median time of 62 days after initial COVID-19 diagnosis. Forty-seven (47%) subjects expired as a result of COVID-19 disease at the time of analysis. Disease type, treatment status, race/ethnicity, age, and gender showed no significant association with mortality. Patients older than 70 had worse outcomes than the younger population (p = 0.0082). Median neutrophil and lymphocyte count at time of diagnosis was 4500 and 900, respectively. NLR greater than 9 was associated with worse survival when compared to NLR less than 9 (p=0.0067). Conclusions: COVID-19 infection has adverse effects on patients with hematological neoplasms. Subjects older than 70 years had a significantly worse prognosis. Notably, subjects actively being treated with chemotherapy did not have worse outcomes than those not being treated in our cohort, supporting the notion than active COVID-19 infection per se should not result in treatment delays. In addition, high NLR correlates with worsened survival, suggesting that this could be a potential prognostic factor for COVID-19 mortality in the hematologic neoplasms population. Disclosures Steidl: Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Research Funding; Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:stelexis: Current equity holder in private company; BMS: Consultancy, Research Funding; Medpacto: Research Funding; Janssen: Research Funding; acceleron: Consultancy, Honoraria.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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