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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 165-165 ◽  
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.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4035-4035 ◽  
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 (&gt;4 log reduction on imatinib therapy for &gt;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 &gt; 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.

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1578-1578 ◽  
Author(s):  
Franck E. Nicolini ◽  
Gabriel Etienne ◽  
Viviane Dubruille ◽  
Lydia Roy ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
Log Reduction

Abstract Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

scholarly journals For Patients with Sustained MR4-MR4.5, Less Frequent Molecular Monitoring during the First 12 Months after Tyrosine Kinase Inhibitor Cessation Is Viable for Timely Detection of Loss of MMR

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1890-1890
Author(s):  
Naranie Shanmuganathan ◽  
Susan Branford ◽  
Jodi Braley ◽  
Devendra Hiwase ◽  
David T. Yeung ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Monitoring Strategy ◽  
Molecular Monitoring ◽  
Advisory Committees

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukaemia (CML) patients in stable deep molecular response leads to treatment-free remission (TFR) in approximately 50% of cases. In most studies, monthly PCRs was performed for 12 months followed by 2-3 monthly testing thereafter. Around 80% of molecular relapses occur within the first 6 months after TKI cessation. The current recommendation for TKI recommencement is a single BCR-ABL1 value ≥0.1% IS (International scale), indicating loss of major molecular response (MMR). Not all institutions can offer monthly PCR monitoring due to financial constraints, particularly relevant in developing countries. For some patients, remaining on TKI is a cheaper alternative. Aim: To assess the safety of less frequent BCR-ABL1 monitoring for detection of loss of MMR for CML patients attempting TFR. Methods: We monitored 85 patients who ceased TKI with the aim of achieving TFR. Patients had a minimum of 24 months of sustained MR4 (n=3) or MR4.5 (n=82) prior to TKI cessation. At the time of TKI cessation, 64 patients were on imatinib (75%), 17 on nilotinib (20%) and 4 on dasatinib (5%). Forty of the patients were enrolled in the TWISTER study where the criteria for TKI recommencement was loss of MMR or 2 consecutively rising BCR-ABL1 positive values. The remaining patients were on a registry study and the trigger for TKI recommencement was loss of MMR. Results: TKI recommencement occurred in 49 of 85 patients. Median time to TKI recommencement was 4 months (range 2-28 months) at a median BCR-ABL1 value of 0.27% on the International Scale (IS), range 0.002-24% IS. Thirty-six of the 49 patients (73%) lost MMR prior to TKI recommencement; the median time to loss of MMR was 3 months (range 1 to 10 months). One patient lost MMR within the first month. Figure A demonstrates the time to loss of MMR in the 36 patients with PCR values ≥ 0.1%. Eighteen of the 36 patients (50%) lost MMR by the 3 month BCR-ABL1 assessment and 35 of 36 patients (97%) lost MMR by 6 months. The latest loss of MMR was at 10 months. Fourteen patients recommenced TKI at a BCR-ABL1 value of >1% and 1 recommenced at a value >10%. Clinician delay in TKI recommencement of 1 month resulted in a BCR-ABL1 rise from 0.84% to 24% with associated loss of complete hematological response. We propose monthly BCR-ABL1 testing between 2 and 6 months post TKI cessation followed by 2 monthly testing. Detection of a BCR-ABL1 value of ≥0.1% would trigger TKI recommencement. In the presence of a rising BCR-ABL1, which remains ≤0.1%, monthly monitoring should ensue in order to avoid hematological relapse. If this strategy were employed in this cohort of patients, only 1 patient would have had the trigger for TKI recommencement delayed by 1 month (estimated BCR-ABL1 at recommencement ~2.5%). This patient had loss of MMR in the first month post TKI cessation. If this molecular monitoring strategy was applied to patients in our cohort who had not lost MMR at TKI recommencement, we estimate that 1 other patient would have had TKI recommencement delayed by 1 month based on the average BCR-ABL1 doubling time of 1 log per month. A proportion of patients maintain low levels of BCR-ABL1 after TKI cessation and do not lose MMR. There were 2 such patients in our cohort. Conclusion: The critical time for molecular monitoring to trigger TKI recommencement is the first 6 months. A monthly monitoring strategy beginning 2 months after cessation would capture the majority of patients at loss of MMR. The data suggest that after 6 months, 2-monthly monitoring could follow. Monthly BCR-ABL1 testing can be re-introduced in the event of a positive result in those that ceased TKI with undetectable BCR-ABL1 or if there is a BCR-ABL1 result higher than the cessation value. This approach would reduce BCR-ABL1 testing by approximately 33% in the majority of cases while minimizing hematological relapse. Therefore this strategy would reduce the cost and inconvenience of molecular monitoring for a trial of TKI cessation, making the option of TFR available to some patients for whom it is otherwise not feasible. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yeung:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group.

scholarly journals Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5700-5700
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Maire Okoniewski ◽  
Osama Diab ◽  
Siddhartha Ganguly ◽  
Al-Ola Abdallah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Standard Of Care ◽  
Advisory Board ◽  
Advisory Committees ◽  
Fda Approval ◽  
Novel Drugs ◽  
Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

scholarly journals Does Addition of Rituximab (R) to BEAM Conditioning Improve Outcomes of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 785-785
Author(s):  
Deepa Jagadeesh ◽  
Navneet S. Majhail ◽  
He Yizeng ◽  
Kwang Woo Ahn ◽  
Carlos Litovich ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Older Age ◽  
Disease Stage ◽  
Karnofsky Performance Score ◽  
Advisory Committees ◽  
Significant Difference ◽  
The Impact

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P&lt;0.001), not being in CR at auto-HCT (HR 1.67, 95% CI 1.39-2.07; P&lt;0.001) and presence of ECitF (HR 1.52, 95% CI 0.54-3.26; P&lt;0.001). Older age (HR 2.26, 95% CI 1.48-3.45; P&lt;0.0002) and not being in CR at auto-HCT (HR 1.78, CI 1.47-2.14; P&lt;0.0001) were also associated with inferior PFS. There was no significant difference in the 100-day cumulative incidence of bacterial, viral or fungal infections between the two cohorts. Disease relapse was the main cause of death in both BEAM and R-BEAM cohorts (66% vs 55%). Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.

scholarly journals Differences in Presentation and Survival Outcomes for African American Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5647-5647 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
African American ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Significant Difference

Abstract Background : Though the incidence of MM is two- to threefold higher in the African American (AA) population compared to Caucasians, reported long term outcomes are less favorable presumably due to inequities in access to healthcare. Little is known about the biology or disease presentation among AAs. We have conducted a retrospective analysis of our institutional data of 1000 patients treated with RVD induction therapy, specifically assessing differences in presentation, disease biology, and outcomes in AA patients. Methods: A total of 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Of the 1000 patients included in the analysis, 564 (56.4%) of patients were white (W), and 339 (33.9%) were AA, consistent with the demographic representation of the state of GA and our institutional referral population. Median age of this cohort was 61 years (range 16-83), 57 for AA patients (range, 24-83) compared to 62 (range, 16-81) in white patients, suggesting the onset is earlier among AA which has been previously reported in population based studies. Other notable characteristics include: 42.5%M/57.5% F for AA cohort and 61.7%M/38.3%F for white cohort. In regard to stage, AA: 73.9% stage I/II, 26.1% stage III; W: 77.1% stage I/II, 22.9% stage III, showing no difference in prognostic staging at presentation. There was no statistically significant difference in the presenting labs between AA and whites except for hemoglobin, with more AA patients presenting with Hgb≤9.9 g/dL (45.7% AA vs 32.5% W, p <.0001). In terms of prevalence of high-risk cytogenetics, there was no significant difference between the two cohorts in: complex karyotype 16% white/14.4% AA; t(14;16) 2.4% W/2.8% AA; t(4;14) 4.7% W/5.0% AA; t(11;14) 11.7% W/15.9% AA; or del1p 6.5%W/7.8%AA. However, there were significant differences found in the rates of: amp 1q 19.2% W/10.6% AA, (p<.0001), del13 28.3% W/19.6% AA (p=.003), and del17p 11.7% W/7.2% AA (p=.019), all three significantly less frequent in AAs. Median time to transplant for the entire cohort was 5 months (range, 1-124), and median time to best response was 3 months (range, 0-39). There was no significant difference in the number of patients who underwent ASCT (84% W vs 82% AA, p=.241), nor in ≥VGPR rates post-induction and 100 days post-ASCT: 69.9% W vs 64.5% AA (p=.056) and 88.1% W vs 86.7% in AA patients (p=.317), respectively. Median PFS for the entire cohort was 63 months, 62 months (54-69.9) for white patients versus 65 months (53-76.9) for AA patients (p=0.403). At a median follow up of 38 months, median OS has not yet been reached. Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction, with one-third of the patients representing the AA population. In our dataset, AAs are diagnosed 5 years younger, with lower hemoglobin at presentation and lower rates of amp1q, del13 and del17p when compared to whites. When offered the same induction regimen and opportunity for ASCT, AAs tend to experience the same survival benefits as their white counterparts. The lack of significant difference in PFS or OS suggests standardization and improved access to care could lead to better long-term outcomes in the AA population. Disclosures Hofmeister: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3980-3980
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Post-Transplant Cyclophosphamide in Acute Leukemia Patients Receiving More Than 5/10 HLA-Mismatched Allogeneic Stem Cell Transplantation: A Study on Behalf of the ALWP of the EBMT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3890-3890
Author(s):  
Michele Wieczorek ◽  
Myriam Labopin ◽  
Luca Castagna ◽  
Eolia Brissot ◽  
Gerard Socié ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
Free Survival

Abstract Background Post-transplant cyclophosphamide (PTCy) is a powerful strategy to prevent occurrence of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Initially developed in the setting of haploidentical HSCT, PTCy has been increasingly used for fully HLA-matched transplants with favorable results. The purpose of this retrospective multi-center study is to evaluate PTCy-based GvHD prevention for patients with acute leukemia receiving a traditionally prohibitive highly mismatched HSCT and to describe their outcome. Methods This is a registry-based study employing the data set of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT). We retrospectively assessed the outcome of adult patients with acute myeloid or lymphoblastic leukemia (AML/ALL), transplanted between 2010 and 2020 with grafts from HLA-mismatched donors with more than 5/10 mismatches using PTCy-based GvHD prophylaxis. Results The study cohort consisted of 59 patients, with a median time of follow up of 20 (95% CI, 14-39) months. The median age was 47 (range, 18-69) years. Forty-four patients had a diagnosis of AML, 14 of ALL and one case of mixed phenotype acute leukemia. At time of transplant, 39 (66%) were in first or second complete remission, 4 (7%) were in later remission and 16 (27%) had active, relapsed or refractory, disease. Conditioning regimens were myeloablative for 54% of cases and peripheral blood was the preferred source of stem cells (64%). All donors were related. Most patients (85%) received a 4/10 HLA-matched transplant, the most commonly mismatched loci were C and DQB1, often with a double mismatch involving the same locus. Two cases of fully mismatched donors were also recorded. PTCy was always associated with other immunosuppressive treatments, especially with the standard combination of calcineurin inhibitors and mycophenolate mofetil. In only 8 cases in vivo T-cell depletion was realized with anti-thymocyte globulin. A large proportion of patients (86%) attained engraftment with a median time of 19 (range, 11-37) days. Only 8 patients did not reach engraftment and all of them died of infection or disease relapse in the first one-hundred days (range, 6-99) after HSCT. Thirty-three patients (58%) did not present any sign of acute GvHD (aGvHD). Cumulative incidence of grade II-IV and grade III-IV aGvHD at day 180 were 30.3% and 14.3%, respectively. At 2 years, the cumulative incidence of chronic GvHD (cGvHD) was 21%, and 7% for extensive cGvHD. Twenty-four patients died during the study period, mostly because of leukemia progression (n=13, 54%), infectious complications (n=6, 25%) and interstitial pneumonia (n=2, 8%). Other causes of death were hemorrhage, GvHD, and another non HSCT-related that accounted for one case (4%) each. At 2 years, the overall survival (OS), leukemia-free survival (LFS), and a GVHD and relapse free survival (GRFS) were 56%, 54% and 47% respectively. Rates of relapse incidence and non-relapse mortality were 28% and 19%, respectively. Conclusion According to this preliminary data overview, transplantation in a highly mismatched framework is possible, without unfavorable OS, LFS and GVHD rates. Despite the important limitation of the retrospective non-controlled nature of this analysis, these findings suggest that PTCy-based strategies could help overcome the barrier of HLA-matching and configure a new setting of transplantation, encouraging more in-depth investigations. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Gilead: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Astellas: Honoraria.

Towards DNA-Based Monitoring of Therapy In Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2284-2284
Author(s):  
Alexander A. Morley ◽  
Paul Bartley ◽  
David Ross ◽  
Sue Latham ◽  
Brad Budgen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Leukemic Cell ◽  
Cell Number ◽  
Molecular Response ◽  
Specific Primers ◽  
Advisory Committees ◽  
Significant Difference ◽  
The Difference

Abstract Abstract 2284 Monitoring of CML is conventionally performed by RT-qPCR but the use of RNA as the starting material leads to a number of disadvantages, which include propensity of RNA to degradation, a low level of endogenous BCR-ABL transcripts, requirement for reverse transcription, somewhat complex laboratory standardisation, and uncertain relationship between transcript level and leukemic cell number. The use of genomic DNA to quantify BCR-ABL sequences would overcome these disadvantages but it presents 2 major problems - the need to determine the breakpoint sequence for each patient and the need to synthesise and test specific primers for each patient. We developed a simple and rapid method for isolating the BCR-ABL sequence which involved a primary highly multiplexed PCR to amplify across the breakpoint and 2 subsequent PCRs using specially designed primers to eliminate the non-specific material produced in the primary PCR. The need to develop primers specific for each patient was bypassed by synthesising a library comprising 11 pairs (to enable nested PCR) of forward BCR primers and 493 pairs of reverse ABL primers which were all tested to ensure efficient amplification. Minimal residual disease (MRD) was quantified by a one round qPCR if the level was anticipated to be > 10-3, by nested qPCR if the level was anticipated to be < 10-4, and by one or both methods if the level was anticipated to be in the range 10-3 – 10-4. Quantification involved use of a standard curve comprised of various dilutions of diagnosis DNA and amplification was measured using a Taqman hydrolysis probe directed to the BCR region of the BCR-ABL sequence. MRD levels quantified by RT-qPCR were also available for 75 of the 79 samples. To date, 217 MRD estimations have been performed by DNA-qPCR on 79 samples obtained from 30 patients during treatment. MRD was quantified down to approximately 10-6. There was a highly significant correlation (p < 0.001) between the results of DNA-qPCR and RT-qPCR for the 54 samples in which MRD was quantified by both methods. MRD was quantified by DNA-PCR but was not detected by RT-qPCR in another 15 samples and was not detected by either technique in a further 6 samples. There were no samples in which MRD was detected by RT-qPCR but not by DNA-qPCR. Overall, the MRD result was significantly lower (p < 0.01) by a mean of 0.38 log units (2.4 fold) when quantified by RT-qPCR as compared to when quantified by DNA-qPCR. Replicate DNA-qPCR estimations on the same sample showed that the SD of a single estimation was 0.25 log units (95% CI = 3.2 × result to 0.31 × result) and there was no significant difference between a one-round qPCR and a nested qPCR for the 14 samples estimated by both methods. Analysis of the difference between the RT-qPCR result and the DNA-qPCR result for each sample drawn from an individual patient showed systematic differences between patients which were almost certainly attributable to differences in BCR-ABL expression. The Figure shows the difference between the RT-qPCR result and the DNA-qPCR result for the 17 patients for whom two or more samples had been quantified by both techniques. Each point refers to an individual sample. Some patients e.g. the 3 on the left of the Figure, appeared to be high expressors and other patients e.g. the 2 on the right, appeared to be low expressors. The level of expression differed from the mean by up to approximately 1 log unit (10 fold). Conclusions 1. DNA-qPCR provides MRD results which are broadly comparable to RT-qPCR results when MRD is > 10-4. 2. DNA-qPCR is more analytically sensitive than RT-qPCR by up to 2 log units. This may become increasingly important as more patients achieve complete molecular response as defined by RT-qPCR. 3. DNA-qPCR provides a more accurate measure of leukemic cell number than RT-qPCR as it is not influenced by the level of BCR-ABL expression. 4. DNA-qPCR is more expensive than RT-qPCR owing to the requirement for determining the breakpoint sequence and obtaining specific primers. However this initial expense can be amortised if multiple MRD estimations are performed during the course of monitoring –if this is the case then the extra cost/assay is minimal. Disclosures: Morley: Monoquant P/L: Equity Ownership, Research Funding. Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes: Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding.

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