scholarly journals Real Life Long-Term Survival Analysis in Patients with Chronic Myeloid Leukemia Treated with Tkis in Spain

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3074-3074
Author(s):  
Luis Felipe Casado Montero ◽  
Valentin Garcia Gutierrez ◽  
Pilar Giraldo ◽  
Manuel Perez-Encinas ◽  
Raquel de Paz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Term Survival ◽  
Probability Of Survival ◽  
Ifn Alpha ◽  
Sequential Treatments

Abstract Introduction: TKIs introduction in the treatment of chronic myeloid leukemia (CML) has offered an outstanding improvement in prognosis, especially in survival. Data about TKIs were obtained from clinical trials but little is known about their translation to real life. In addition, clinical trials are mainly based on efficacy analysis to just one line of therapy, rather than treatment sequences (due to failure or intolerance). Objectives: To analyze the long-term survival of patients outside clinical trials in response to TKI treatment, describing the pattern of sequential treatments the patients actually received. Patients and methods: CML patients in first chronic phase, treated with TKIs (imatinib, nilotinib, dasatinib) either as monotherapy or in sequence, outside clinical trials. The setting was a multicentric, hospital-based registry. Survival and their potentially associated variables were studied. Results: Demographics, risk and treatment distribution: 696 patients (423 men, 273 women) with a median age at diagnosis of 41y (14-94y) were included with a follow up of 85±7 months (m) from diagnosis, 78±6.6 m from first treatment, and 69±6 m from first TKIs; 106 patients (15%) were over 70y. The risk distributions were as follows: Sokal: low (L) 48%, intermediate (I) 38% and high (H) 13%; Euro score: L 51%, I 45% and H 4%; EUTOS L: 91% and H 9%; EUTOS LT: L 68%, I 25% and H 7%. Treatment groups were the following: Group 1: IFN alpha and then imatinib or 2¼ GTKIs (176 patients); Group 2: imatinib only (340 patients); Group 3: imatinib and then nilotinib, dasatinib or both due to failure or intolerance (131 patients) and Group 4: 2¼GTKIs in first line (49 patients). Survival: Estimated survival by 10 years was 80%. Ninety-one patients have died (27 due to unknown reasons, 33 due to progression or BMT, 7 due to second neoplasias and 21 due to cardiac or neurological disease). Variables associated with survival: In the univariate survival analyses (log rank test) either from diagnosis, first therapy or first TKIs, the Sokal, Eutos, Euro and EUTOS LT scores as well as age over 70y were the only statistically significant variables associated with survival.(figure 1). In the multivariate analysis (Cox model), only Sokal and Eutos LT scores, and age over 70y were independent variables. Patients older than 70 years at diagnosis had a 50% probability of survival by 8 years. It is worth mentioning that, although the probability of overall survival from diagnosis was higher in the group receiving imatinib after IFN alpha, this difference was not seen when measuring the probability of survival after the first treatment o first TKI. This is probably explained by the higher proportion of low-risk score in patients having had previous IFN. Whereas the cause of death was progression in half of the patients aged equal or less than 70 years, in patients older than 70 years, two third of the deaths were not related to progression of CML. Conclusions: 1.These results show that the probability of survival by 10 years is roughly 80%, and extend the findings of our previous work showing that this probability is not different across different sequential treatments (imatinib before IFN, alone or switched to 2»GTKis due to intolerance o failure)(1). This fact emphasizes the rescue potential of available TKI therapies. 2. We have validated for the first time the Eutos LT score in real life population. 3. Patients over 70 years have shorter survival due to reasons different than progression, opening an interesting field of research, and a non-negligible room of improvement. Figure 1 (1)Casado LF, et al Cancer Med. 2015 Mar 10. Figure 1. (1)Casado LF, et al Cancer Med. 2015 Mar 10. Disclosures Casado Montero: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Steegmann:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

scholarly journals Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3211-3219 ◽  
Author(s):  
W Arcese ◽  
JM Goldman ◽  
E D'Arcangelo ◽  
A Schattenberg ◽  
A Nardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Actuarial Survival ◽  
Term Survival ◽  
Probability Of Survival ◽  
Ifn Therapy

We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.

scholarly journals Asciminib in Real-Life Clinical Practice, Safety and Efficacy Profile in Chronic Myeloid Leukemia Pretreated Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2563-2563
Author(s):  
Lucía Pérez-Lamas ◽  
Alejandro Luna ◽  
Concepcion Boque ◽  
Pilar Giraldo ◽  
Blanca Xicoy ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Previous Response ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Efficacy Profile

Abstract Introduction: asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that potently inhibits aberrant kinase activity of the BCR-ABL1 oncoprotein via allosteric binding. asciminib has shown high efficacy profile in heavily pretreated Chronic Myeloid Leukemia (CML) patients with an adequate safety profile in phase I and III clinical trials. However, data from the use of asciminib in real life setting are still scarce. Methods: We gathered real-life retrospective data from 49 patients with BCR-ABL1 positive CML treated with asciminib (mean dose: 40 mg twice daily) between October 2018 and July 2021 at 33 institutions. The indication of asciminib was made according to the criterion of the attending physician and the drug was granted by Novartis under a controlled access program. Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % IS in all centers. Treatment responses were calculated with the patients at risk at each specific time points. For the event free survival (EFS), the events were treatment discontinuation due to any reason, progression or death. Data collection followed the local regulations for observational studies. Results: Median time on asciminib was 11,69 months for the entire cohort. Patients' characteristics are displayed on Table 1. Most patients were heavily pretreated with at least 3 prior TKI lines in 45 patients (91,83%), 18 of them receiving prior Ponatinib. Switch to asciminib occurred due to intolerance in 32 patients and due to resistance in the remaining 17. Fifteen patients (30,61%) harbored mutations in BCR-ABL1 (3 with a T315 mutation). Regarding efficacy (Table 2), probability of reaching or maintaining previous responses were 94%, 45% and 21% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Considering probabilities of improving previous response, rates were 40%, 42% and 33% for the same parameters. Probabilities to obtain CCyR and MMR in resistant and intolerant patients were 29% (4/14) vs 55% (6/11) and 27% (4/15) vs 52% (11/21), respectively. Amid the patients previously treated with Ponatinib, probabilities of reaching or maintaining previous response were 53% (9/17) and 35% (6/17) for CCyR and MMR respectively, and 30% (3/10), 23% (3/13) displayed improvement of response. Regarding responses in patients with mutations, 39% (5/13) achieved or maintained CCyR and 31% (4/13) MMR; whereas 20% (2/10) and 18% (2/11) improved such responses. Of the three patients with T315I mutation, one discontinued due to progression to advanced stages, and the rest maintained the previous response. With a median follow-up of 11,69 months, the estimated EFS was 80% (figure 1). In terms of safety (Table 3), the most frequent extra-hematological adverse events (AE) were: fatigue (16,2%), joint pain (13,5%) and nausea (8,1%), most of them grade 1-2. Grade 3-4 AE were observed in 10% of patient (fatigue (2), cholestasis enzyme elevation (1), hypertension (1), pancreatitis (1) and pericardial effusion (1)). Thrombocytopenia was shown as the most frequent AE (16,3%), with 6% of patients suffering from grade 3-4. Dose reduction was required in 15 patients (30,6%). After a median follow up of 51 weeks, 73,5% of the patients remained on treatment. Only fourteen patients discontinued treatment due to progression or loss of efficacy, whereas 6% of patients discontinuing treatment due to intolerance. Conclusions: The results presented are in line with the data obtained in clinical trials, positioning asciminib as a potential safe and efficacious treatment for CML patients with failure to several TKI lines. Figure 1 Figure 1. Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; Celgene/Bristol-Myers-Squibb,: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding.

scholarly journals Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3211-3219 ◽  
Author(s):  
W Arcese ◽  
JM Goldman ◽  
E D'Arcangelo ◽  
A Schattenberg ◽  
A Nardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Actuarial Survival ◽  
Term Survival ◽  
Probability Of Survival ◽  
Ifn Therapy

Abstract We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.

Uncommon long-term survival in a patient with chronic myeloid leukemia

2009 ◽  
pp. 1-2
Author(s):  
Fabio Stagno ◽  
Paolo Vigneri ◽  
Vittorio Del Fabro ◽  
Stefania Stella ◽  
Salvatore Berretta ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Term Survival ◽  
Long Term Survival

scholarly journals Translation of the Philadelphia chromosome into therapy for CML

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4808-4817 ◽  
Author(s):  
Brian J. Druker
Keyword(s):  
Cancer Research ◽  
Clinical Trials ◽  
Myeloid Leukemia ◽  
Therapeutic Agent ◽  
Philadelphia Chromosome ◽  
Hematologic Malignancies ◽  
Successful Development ◽  
Term Survival ◽  
Abl Tyrosine Kinase

AbstractThroughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy. These range from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease. The successful development of imatinib as a therapeutic agent for CML can be attributed directly to decades of scientific discoveries. These discoveries determined that the BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib, with imatinib significantly improving the long-term survival of patients with CML. Continuing in this tradition of scientific discoveries leading to improved therapies, the understanding of resistance to imatinib has rapidly led to strategies to circumvent resistance. Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers.

scholarly journals How to manage CML patients with comorbidities

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 237-242
Author(s):  
Jorge Cortes
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Health Condition ◽  
Close Monitoring ◽  
Optimal Outcome ◽  
Term Survival ◽  
Holistic Management

Abstract Patients with chronic myeloid leukemia (CML) often have comorbidities, at an incidence that might be higher than in the general population. Because of the favorable outcome of most patients with CML treated with tyrosine kinase inhibitors (TKIs), a greater number of comorbidities might be the most significant adverse feature for long-term survival. The presence of comorbidities may also affect the risk of developing adverse events with TKIs. This effect is perhaps best exemplified by the risk of developing arterio-occlusive events, which is greatest for patients who have other risk factors for such events, with the risk increasing with higher numbers of comorbidities. The coexistence of comorbidities in patients with CML not only may affect TKI selection but also demands close monitoring of the overall health condition of the patient to optimize safety and provide the opportunity for an optimal outcome to such patients. With optimal, holistic management of leukemia and all other conditions afflicting them, patients with CML and comorbidities may aim for a near-normal life expectancy, just as the more select patients enrolled in clinical trials now enjoy.

scholarly journals Long-term survival estimates for imatinib versus interferon-? plus low-dose cytarabine for patients with newly diagnosed chronic-phase chronic myeloid leukemia

Cancer ◽  
2004 ◽  
Vol 101 (11) ◽  
pp. 2584-2592 ◽  
Author(s):  
Kevin J. Anstrom ◽  
Shelby D. Reed ◽  
Andrew S. Allen ◽  
G. Alastair Glendenning ◽  
Kevin A. Schulman
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Long Term Survival ◽  
Low Dose Cytarabine

Baseline Characteristics Of Patients With Chronic Myeloid Leukemia In a Prospective Observational Study (SIMPLICITY)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4026-4026 ◽  
Author(s):  
Jorge E. Cortes ◽  
Rüdiger Hehlmann ◽  
Carlo Gambacorti-Passerini ◽  
Stuart Goldberg ◽  
H. Jean Khoury ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Clinical Research ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
First Line ◽  
Historical Cohort ◽  
Prospective Cohorts

Abstract Background Oral BCR-ABL tyrosine kinase inhibitors (TKIs), including imatinib (IM), dasatinib (DAS) and nilotinib (NIL), have improved survival in chronic-phase chronic myeloid leukemia (CP-CML). Few data are available that compare TKIs in daily clinical practice across multiple regions. Methods SIMPLICITY is an ongoing observational cohort study of adult patients with newly diagnosed CP-CML receiving first-line treatment with IM, DAS or NIL in the USA and Europe (Eu) outside of clinical trials (NCT01244750). The primary objective is to assess effectiveness of these TKIs in clinical practice. The study includes three ‘prospective’ cohorts of patients treated with IM, DAS or NIL since 2010 (the study opened after first-line approval of all three TKIs) and a ‘historical’ cohort treated with IM since 2008. Preliminary baseline demographics are presented for prospective cohorts. Results 860 prospective patients (Eu: 32%, USA: 68%) were enrolled through June 20, 2013, receiving IM (n=399), DAS (n=229) or NIL (n=232). Median age at initiation of first-line TKI was 56 years, with significant differences in pairwise comparisons between DAS and IM and NIL and IM (Table). Demographics were consistent across cohorts. Only 30% of patients had Hasford or Sokal scores recorded. ECOG performance status (PS) was available in 54% of patients. The number of baseline comorbidities per patient (mean: 3.2 + 2.7) was balanced across cohorts; 51% of patients presented with ≥3 comorbidities. Patients in the IM cohort had a higher prevalence of gastrointestinal comorbidities (P=.006 and .007 for DAS vs IM and NIL vs IM, respectively), and the NIL cohort had a higher prevalence of musculoskeletal comorbidities than the DAS cohort (P=.015). The proportions of patients with cardiovascular comorbidities were 38%, 36% and 42% in the DAS, NIL and IM cohorts, respectively, consisting primarily of hypertension (31%) and hyperlipidemia (17%) (P>.05 across cohorts). Coronary artery disease was present in 9%, cardiac arrhythmias in 6%, myocardial infarction in 3% and peripheral arterial disease in 2% of patients. The proportion of patients with diabetes was 10%. Clinicians reported effectiveness as the most common reason for TKI selection; familiarity and cost were also cited as reasons for IM selection (P<.001 vs DAS and NIL). Comorbidities were not drivers of TKI selection in this analysis. Conclusions This is the first report from the prospective cohorts of SIMPLICITY. Demographics were consistent across cohorts. Overall, the SIMPLICITY population is older with potentially more comorbidities than patients enrolled in first-line clinical trials with restrictive inclusion criteria (NEJM 2003 348 994; NEJM 2010 362 2260; NEJM 2010 362 2251). Initial TKI selection does not appear to be driven by baseline comorbidity, rather by perceived effectiveness, cost and familiarity. Hasford/Sokal scores were not recorded in the majority of patients prior to starting first-line TKI therapy. Outcomes data are being collected across cohorts that will inform about a multi-region population treated outside clinical trials. Disclosures: Cortes: Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Hehlmann:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Oncology: Honoraria, Research Funding, Speakers Bureau; Ariad: Honoraria, Research Funding, Speakers Bureau. Khoury:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Teva: Honoraria. Mauro:Novartis Oncology: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Paquette:Ariad: Consultancy; Incyte: Consultancy, Honoraria; Novartis: Consultancy. Foreman:ICON Clinical Research: Employment, My employer ICON Clinical Research receives research funding from pharmaceutical companies including manufacturers of CML drugs Other. Mohamed:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Hirji:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment.

Significance of Peri-Transplant Dynamics of Minimal Residual Disease (MRD) in Adults with Acute Myeloid Leukemia (AML) in Morphological Remission Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 173-173
Author(s):  
Yi Zhou ◽  
Daisuke Araki ◽  
Megan Othus ◽  
Jerald P. Radich ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Before And After ◽  
Minimal Residual

Abstract Background: Numerous studies from others and our institution have demonstrated that the presence of minimal residual disease (MRD), detected at the time of hematopoietic cell transplantation (HCT), is strongly and independently associated with increased relapse risk and short survival in adults with acute myeloid leukemia (AML) undergoing myeloablative allogeneic HCT in morphologic complete remission (CR). In contrast, very little information is available regarding the prognostic significance of peri-transplant MRD dynamics in these patients. Since bone marrow staging studies with multiparameter flow cytometric (MFC) assessment for MRD are routinely obtained not only before but also at approximately day +28 following transplantation at our institution, we here retrospectively studied the relationship between peri-HCT MRD dynamics and post-transplant outcomes in a large patient cohort. We asked whether persistence or disappearance of MRD might identify cohorts of patients in whom post-transplant therapy was particularly indicated or unnecessary. Patients and Methods: AML patients ³18 years of age were eligible for this retrospective analysis if they were in first or second morphologic CR or CR with incomplete blood count recovery (CRi) irrespective of the presence of MRD, underwent allogeneic HCT with myeloablative conditioning between 2006 and 2014, received peripheral blood or bone marrow as stem cell source, and had pre-HCT bone marrow staging studies available that included 10-color MFC assessments for MRD. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow; any level of residual disease was considered MRDpos. We considered post-HCT MRD assessments in patients in whom bone marrow re-staging with MFC MRD analysis were obtained 28±7 days after transplantation. For this analysis, the primary endpoint of interest was overall survival, which was estimated using the Kaplan-Meier method. Results: 311 patients were identified and included in this study. Consistent with our previous analyses, patients with MRD at the time of HCT (MRDpos; n=76) had significantly shorter survival than MRDneg patients (n=234; estimated 3 year post-HCT survival: 26% [95% confidence interval: 17-37%) vs. 73% [66-78%], P <0.001). 310 patients survived at least 21 days following transplantation; for 279 of these (89.7%), post-HCT MRD assessments were obtained at day +28±7 and available for analysis. 214 patients (76.7%) had no MFC evidence of MRD before and after HCT (MRDneg/MRDneg), 2 (0.7%) were MRDneg/MRDpos, 49 (17.6%) were MRDpos/MRDneg, and 14 (5.0%) were MRDpos/MRDpos. Of the 65 patients who had detectable MRD either before and/or after transplantation, 58 had decreasing levels of MRD (MRDdecr) over the peri-HCT period, whereas 7 patients had increasing MRD levels (MRDincr) around the time of transplantation. As depicted in Figure 1, MRDneg/MRDneg patients had excellent long-term outcomes (survival at 3 years after day +28 MRD assessment: 76% [69-82%]), whereas both MRDneg/MRDpos patients died within 70 days after the day +28 MRD assessment. Interestingly, for patients who were MRDpos before transplantation, outcomes were relatively poor regardless of whether or not they had persistent MRD around day +28 after transplantation (MRDpos/MRDneg patients: 23% [12-36%]; for MRDpos/MRDpos patients: 19% [4-44%]). However, long-term survival was only observed among MRDdecr patients (at 3 years after day +28 MRD assessment: 24% [14-37%]), whereas all MRDincr patients died a median of 97 (range: 15-808) days following the post-HCT MRD assessment (Figure 2). Conclusion: Patients who have no evidence of MRD before and after HCT have excellent long-term outcomes. In contrast, patients who are MRDpos before transplantation have poor survival expectations regardless of whether or not they clear MRD within the first 28 days after transplantation, but long-term survival is only found among some patients with decreasing MRD levels over the peri-transplant period. This finding suggests that patients who are MRDpos at the time of HCT should be considered for pre-emptive therapeutic strategies given their high risk of disease recurrence regardless of the day +28 MRD information. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Radich: Incyte: Consultancy; Ariad: Consultancy; Gilliad: Consultancy; Novartis: Consultancy, Research Funding. Walter:Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy; Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding.

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