Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Is It Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2571-2571
Author(s):  
Daisuke Araki ◽  
Brent L Wood ◽  
Megan Othus ◽  
Jerald P. Radich ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Treatment Algorithms ◽  
Free Survival ◽  
Hazard Ratios ◽  
Minimal Residual ◽  
Active Disease

Abstract Background: Treatment algorithms for allogeneic hematopoietic cell transplantation (HCT) typically consider patients with acute myeloid leukemia (AML) in morphologic complete remission (CR) separately from those with active disease (i.e. ≥5% marrow blasts by morphology), implying distinct outcomes for these two groups. However, it is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcomes for patients in morphologic CR. This well established effect of pre-HCT MRD prompted us to compare outcomes in patients in MRDpos CR to those with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and Methods: We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry (MFC) on bone marrow aspirates in all patients. 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. Results: Three hundred and eleven patients (87%) were in morphologic CR at the time of transplantation, with 76 (21%) in MRDpos CR and 235 (66%) in MRDneg CR. 48 patients (13%) had active disease (7 untreated newly diagnosed AML, 16 untreated relapsed AML, and 25 refractory or relapsed AML who failed salvage therapies). Patients with MRDpos CR or active AML more often had adverse-risk cytogenetics (P=0.001) and secondary leukemias (P<0.001) than MRDneg CR patients. Patients with active AML also more often had incomplete blood count recovery before HCT than patients in morphologic CR (P<0.001). Three-year relapse estimates were 67% in MRDpos morphologic CR patients and 65% in patients with active AML, contrasted to 22% in MRDneg CR patients. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment for age, cytogenetic risk, type of AML (de novo vs. secondary AML), pre-HCT karyotype (normalized vs. not), and pre-HCT peripheral blood counts (recovered vs. not), MRDneg CR status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared to being in MRDpos morphologic CR or having active disease, with very similar outcomes between the latter two groups. Specifically, compared to MRDneg CR patients, the hazard ratios (95% confidence interval) for MRDpos CR patients and those with active disease were 3.68 (2.51-5.40) and 4.39 (2.56-7.53) (both P <0.001) for overall survival; for progression-free survival, corresponding hazard ratios were 4.37 (3.02-6.30) and 5.29 (3.18-8.80) (both P <0.001), whereas for risk of relapse, these estimates were 4.16 (2.68-6.44) and 4.86 (2.49-9.49) (both P <0.001), respectively. Conclusion: Outcomes for adults transplanted with morphologically detectable disease closely resemble those of MRDpos CR patients, with a cumulative relapse risk of ~65% and survival estimates of 20-25% at 3 years. This similarity held up after accounting for numerous other prognostic covariates. The resemblance in outcomes between patients with MRDpos morphologic CR and those with active disease at the time of HCT support the use of treatment algorithms that use MRD-based rather than morphology-based disease assessments. Disclosures Radich: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy. Walter:AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Pfizer, Inc.: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

scholarly journals Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease–Based Definition of Complete Remission?

2016 ◽  
Vol 34 (4) ◽  
pp. 329-336 ◽  
Author(s):  
Daisuke Araki ◽  
Brent L. Wood ◽  
Megan Othus ◽  
Jerald P. Radich ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Treatment Algorithms ◽  
Remission Status ◽  
Minimal Residual ◽  
Active Disease ◽  
Acute Myeloid

Purpose Patients with acute myeloid leukemia (AML) who are in morphologic complete remission are typically considered separately from patients with active disease (ie, ≥ 5% marrow blasts by morphology) in treatment algorithms for allogeneic hematopoietic cell transplantation (HCT), which implies distinct outcomes for these two groups. It is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcome for those patients in morphologic remission. This effect of pre-HCT MRD prompted us to compare outcomes in consecutive patients in MRD-positive remission with patients with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and Methods We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry on bone marrow aspirates in all patients. Any level of residual disease was considered to be MRD positive. Results Three-year relapse estimates were 67% in 76 patients in MRD-positive morphologic remission and 65% in 48 patients with active AML compared with 22% in 235 patients in MRD-negative remission. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment, MRD-negative remission status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared with MRD-positive morphologic remission status or having active disease, with similar outcomes between the latter two groups. Conclusion The similarities in outcomes between patients in MRD-positive morphologic remission and those with active disease at the time of HCT support the use of treatment algorithms that use MRD- rather than morphology-based disease assessments.

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.

In the Era of Bortezomib-Based Chemotherapy the Presence of Minimal Residual Disease Predicts Progression Free Survival after Autologous Hematopoietic Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5493-5493
Author(s):  
Robert F Cornell ◽  
Jade E Jones ◽  
Claudio A. Mosse ◽  
Heidi Chen ◽  
Laura Dugger ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Free Survival ◽  
Kaplan Meier ◽  
Minimal Residual

Abstract Background: Retrospective studies have shown that achieving minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) is predictive of outcomes in multiple myeloma (MM). Modern induction therapies including bortezomib (V), lenalidomide (R) followed by autologous hematopoietic cell transplant (AHCT) have resulted in substantial improvements in progression free survival (PFS) and overall survival (OS). The impact of bortezomib-based therapy on end of induction chemotherapy MRD status and post-AHCT MRD status is not well defined. We designed a prospective clinical trial (NCT01215344) to study the incidence of MRD negativity at end of induction and following AHCT, and its association with PFS and OS. Patients and Methods: Twenty patients with newly diagnosed, symptomatic MM were enrolled. They received four cycles of VRd induction therapy followed by AHCT. Dose modifications of VRd were controlled during the clinical trial. MRD status by MFC was evaluated at the end of induction chemotherapy and at day 100 post-AHCT. The MFC cut-off to determine MRD negativity was defined as 10-4. Outcomes analyzed included MM disease status, PFS and OS. Results: Three cohorts of patients were identified; patients achieving MRD negative status at the end of induction (cohort 1, 50%), those achieving MRD negative status only after AHCT (cohort 2, 15%) and patients never achieving MRD negative status (cohort 3, 35%). All patients achieving MRD negative status at the end of induction remained MRD negative post-AHCT. There were no significant differences in median age, renal function, disease stage, cytogenetic risk and maintenance chemotherapy post-AHCT between cohorts. The table summarizes characteristics of these cohorts. Patients who never achieved MRD negative status after AHCT had significantly shorter PFS (cohort 3) compared with patients who achieved MRD negative status (cohorts 1 and 2, p=0.008) (figure). The median PFS for cohort 3 was 2.64 years and not yet reached for the other cohorts. There were no significant differences in OS. Median follow-up for survivors was 2.53 years (range, 0.73-4.04). Conclusions: In this study, bortezomib-based therapy resulted in half of patients achieving MRD negative status with induction chemotherapy alone. AHCT improved the depth of response with 30% of patients who were MRD positive after induction therapy converting to MRD negativity following AHCT. Achieving a negative MRD state, pre- and at D100 post-AHCT resulted in improved PFS. These findings were independent of molecular cytogenetics or ISS stage. MRD positive status at day 100 post-AHCT is highly predictive of earlier disease progression, and may help identify patients for alternative management approaches. Delay of AHCT may be considered as a potential management option for patients with MRD negative status at the end of induction therapy, as being studied in the IFM DFCI study (NCT01208662). As some patients with MRD positive disease at the end of induction therapy become MRD negative with AHCT, these patients may benefit from AHCT and this population warrants further investigation. Table. Descriptive analysis Cohort 1 MRD -/- (%) (n=10) Cohort 2 MRD +/- (%) (n=3) Cohort 3 MRD +/+ (%) (n=7) Test Statistic Median Age 55 54 60 0.31 ISS Stage III 40 33 14 0.52 DS Stage III 89 67 60 0.14 Median Serum creatinine 0.90 0.60 0.88 0.10 Serum M-spike 2.0 1.9 2.1 0.80 Bone marrow plasma cells 14 44 14 0.18 Cytogenetics 0.37 Standard risk 40 0 57 Intermediate risk 50 67 43 High risk 10 33 0 Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Disclosures Cornell: Prothena: Research Funding. Jagasia:Takeda Inc: Research Funding.

Phase II Study of the Frontline Hyper-CVAD in Combination with Ofatumumab for Adult Patients (pts) with CD-20 Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1295-1295 ◽  
Author(s):  
Koji Sasaki ◽  
Paul B. Koller ◽  
Hagop M. Kantarjian ◽  
Deborah A Thomas ◽  
Maria R. Khouri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Multiple Organ Failure ◽  
Research Funding ◽  
De Novo ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Multiple Organ ◽  
Free Survival ◽  
Minimal Residual

Abstract Background: The hyper-CVAD regimen is an effective frontline regimen for de novo adult ALL. Expression of CD20 was identified as an adverse prognostic factor, associated with a higher incidence of relapse, lower 3-year complete remission duration (CRD) and lower 3-year overall survival (OS) rate. The addition of rituximab to the hyper-CVAD regimen in pts with CD20-positive ALL (≥20% expression by multicolor flow cytometry - FCI) improved outcome with 3-year CRD and OS rates by 68% and 65%, respectively. Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro. Ofatumumab's safety and efficacy has been proven in chronic lymphocytic leukemia. Therefore a combination of the hyper-CVAD regimen and ofatumumab may be associated with better response rates, higher 3-year CRD and overall survival rates. Methods: Pts with newly diagnosed ALL and pts who received one prior course of chemotherapy received 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); ofatumumab was given on courses 1 and 3, and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8); ofatumumab was given on courses 2 and 4. This treatment would be followed by POMP (6-mercaptopurine, MTX, VCR, prednisone) maintenance therapy for approximately 30 months, interrupted by intensifications months 6, 7 and 18, 19 with MTX/Pegylated asparaginase and hyper-CVAD-ofatumumab. Central nervous system prophylaxis with MTX and ara-C was administered. When indicated local radiotherapy was administered in patients with bulky mediastinal disease Results: To date 37 pts with de novo ALL and 4 pts in complete remission (CR) previously treated (2 with prior cycle of hyper-CVAD, 1 post fludarabine-cytarabine based regimen, 1 with cyclophosphamide and dexamethasone) have received a median of 6 cycles (1-8) of therapy. Median age is 46 years (32-71). Median WBC at diagnosis was 5.4 x 109/L (1 -202 x 109/L). CD20 expression above 20% was found in 27 pts (66%), between 10 and 20% in 3 (7%) and below 10% in 11 (27%). 2 pts (5%) had concomitant CNS disease at diagnosis. Among the 34 pts with evaluable baseline cytogenetic analysis, 20 (49%) were abnormal. All but one pt (97%) achieved a CR after cycle 1 (4 pts were in CR at the start); 1 pt died of septic shock and multiple organ failure at day 21 of cycle 1. Thirty-eight (95%) pts achieved minimal residual disease (MRD) negativity as assessed by FCI; of whom 23 (64%) achieved MRD negativity after induction. Ten (27%) pts did not receive the full 8 planned courses of induction-consolidation; 16 (43%) pts are receiving maintenance in CR; 4 (11%) pts finished all treatment; 5 (%) pts were referred to allogeneic stem cell transplantation due to multiple cytogenetic abnormalities and delay in achieving negative MRD. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days after induction chemotherapy, respectively. Grade ≥ 3 toxicity included increase of LFT's in 13 pts (32%), increase of bilirubin in 7 (17%), nausea/vomiting in 4 (10%), mucositis in 3 (7%), neuropathy in 3 (7%), and thrombotic events in 1 (2%). Febrile neutropenia episodes during induction and consolidation cycles were reported at rates of 67% and 89%, respectively. With a median follow up of 15 months (1-45), 35 pts are alive; 6 pts relapsed and one had molecular relapse only. Six pts died: 1 at C1D22 of sepsis and intracranial bleed; 1 at C3D17 of sepsis and multiple organ failure; 1 at maintenance C16D35 of sepsis; 1 of relapse post ASCT; 1 post salvage therapy for minimal residual disease relapse; 1 of progressive disease after relapse. The 2-year PFS and OS rates were 68% and 87% respectively. Conclusion: The combination of hyper-CVAD with ofatumumab is safe and highly effective in pts with CD20-positive ALL. Table 1. Patient characteristics and outcome N (%)/Median [range] N=41 Age (yrs) 44 [22-71] Sex Male 25 (61) Female 16 (39) PS 0-1 38 (93) 2-3 3 (7) WBC (x 109/L) 5.4 [0.7-201.7] CNS disease positivity 2 (5) CD20 + (%) 1-10 9 (22) 10-20 3 (7) >20 27 (66) Pos 2 (5) CG Diploid 14 (34) Abnormal 20 (49) IM/ND 7 (17) Response CR 37/38 (97) CR after induction 37/38 (97) MRD at CR 23/36 (64) MRD overall 38/40 (95) Early death 1 (3) Figure 1. Progression-free survival and overall survival Figure 1. Progression-free survival and overall survival Disclosures Cortes: Teva: Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Verstovsek:Incyte Corporation: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Minimal Residual Disease (MRD) Status in FCR-Treated CLL Patients at the End of Treatment Influences Progression Free Survival (PFS), Results of the Ctrial-IE (ICORG) 07-01/ CLL Ireland Study, with Mutational Analysis Providing Additional Insight

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3237-3237
Author(s):  
Niamh Appleby ◽  
Fiona M Quinn ◽  
David O'Brien ◽  
Smyth Liam ◽  
Johanna Kelly ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Minimal Residual ◽  
First Line Treatment

Abstract Fludarabine, cyclophosphamide and rituximab (FCR) therapy results in a complete remission (CR) rate of 72% and a median progression free survival (PFS) of 80 months in non-del (17P) CLL1. Achieving an MRD negative (MRD-ve) CR after completing therapy is an early surrogate marker for overall survival (OS) and PFS2. Specific genetic CLL subtypes determined by fluorescent in-situ hybridisation (FISH) analysis, immunoglobulin mutation IgVH, NOTCH1 and SF3B1 status determine response to chemotherapy3,4. We completed a multi-centre prospective study between 2008 and 2012, with a median follow up of 62.6 months using MRD status to determine length of therapy. Patients who achieved an MRD-veCR after 4 courses of FCR received no further therapy and the remaining patients completed 6 cycles of FCR. MRD status was tracked 6 monthly in patients who became MRD-veuntil MRD was detected. The genetic subtype was also analysed but did not influence treatment. Fifty-two patients {35M;17F, median age 61years (range 37-73)} were enrolled. Forty-six patients completed the MRD assessment after 4 cycles. Eleven patients discontinued assigned FCR therapy for the following reasons: prolonged cytopenia (4); non-compliance (1); autoimmune haemolytic anaemia (2); renal impairment (1); pleural effusion (1); not recorded (2). Eighteen (34.6%) patients achieved an MRD-veCR after 4 cycles and a further11 after 6cycles resulting in 29/52 (55.8%) MRD-veCRs in total. The median PFS was 72.3 months (95% Confidence Interval 61.3-84.1 months) and the median OS has not been reached. Patients who attained an MRD-veversusMRD+vestatus had a prolonged PFS (81.1 vs 46.2 months, p<0.0002). No difference in PFS was observed between patients reaching an MRD-veCR after 4 versus 6 cycles (median PFS81.1 vs 84.1 months,p=0.29). FISH results were available for 48 patients; del(13q) in 16/48 (33%), del(11q) in 15/48 (31%) no abnormality in 12/48 (25%), trisomy 12 in 4 (8%) and other abnormality in 1 patient. The IgVH status was unfavourable in 34/52 (65%), SF3B1 mutations were detected in 5/51 (9.8%) and NOTCH1 mutations in 10/52(19.2%) patients respectively, comparable to published studies of first-line treatment in CLL3,4. The median PFS for patients with good risk IgVH was not reached. Del(11q) did not impact on PFS (median PFS 66.5 vs 78.9 months, p=0.7301). SF3B1 and NOTCH1 mutated patients had a shortened PFS (median PFS 38.4 vs 71.1 months, p=0.038 and median PFS 62.4 vs 82.2 months p=0.0302, respectively). In conclusion abbreviated FCR therapy is effective for patients achieving MRD-veremission after 4 cycles. SF3B1 and NOTCH1 mutated patients had a short PFS and may benefit from alternative first-line treatment. This finding emphasizes the role mutational profiling will play in optimising and personalising therapy in CLL in the future. Reference: Tam C, O'Brien S, WierdaW, et al. “Long-term results of the fludarabine, cyclophosphamide and rituximab regimen as initial therapy of chronic lymphocytic leukemia” Blood 2008 Aug 15;112(4):975-80 Böttcher S, Ritgen M, Fischer K, et al. "Minimal Residual Disease Quantification is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial" J Clin Onc 2012 Mar 20; 30(9):980-8. StilgenbauerS,SchnaiterA,PaschkaP, et al. "Gene mutations and treatment outcome in chronic lymphocyticleukemia: results from the CLL8 trial" Blood 2014 May 22;123(21):3247-54 Chiaretti S, Marinelli M, Del Giudice I, et al."NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukaemia undergoing first-line treatment: correlation with biological parameters and response to treatment"LeukLymphoma 2014 Dec; 55(12):2785-92 Figure 1 Patient outcomes by MRD status in ICORG 07-01 Trial Figure 1. Patient outcomes by MRD status in ICORG 07-01 Trial Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Crotty: BMS, Takeda, Novartis, Janssen, Roche: Honoraria. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

A Significant Early Detection Of Poor Outcome In Acute Myeloid Leukemia Patients Having a Minimal Residual Disease Using Multiparameter Flow Cytomerty Combined To Mixed Chimerism At Three Months After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4639-4639
Author(s):  
Florence Beckerich ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Adriana Plesa ◽  
Valerie Dubois ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Minimal Residual ◽  
Acute Myeloid

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative strategy for acute myeloid leukemia (AML) patients in complete remission (CR) presenting poor prognostic factors or with relapsed/refractory disease. However, the risk for disease recurrence following allo-HSCT remains significant and associated with poor outcomes. After transplantation, the early detection of minimal residual disease (MRD) using immunophenotyping combined to chimerism documentation before morphological relapse may allow for immediate interventions and can lead to better results. Immunophenotyping using Multiparameter Flow Cytometry (MFC) and chimerism documentation by PCR have been widely used to track disease recurrence, although a validated consensus on the use of these techniques in the post-allo-HSCT follow-up has not been established yet. The aim of our study was to evaluate the impact of positive MRD by MFC associated to chimerism documentation at 3 months after allo-HSCT on patients overall and progression-free survival (OS, PFS). Patients and Methods We evaluated 137 AML patients who received allo-HSCT in a single center between January 2005 and October 2012 at our department and for whom a 3 months MRD evaluation and chimerism documentation has been performed using MFC, and PCR analysis. There were 71 (52%) males and 66 females with a median age of 47 years (range: 19-66), 77% had de novo AML, 20% had secondary AML and 3% had biphenotypic AML. According to cytogenetics, 40% were normal, 51% were unfavorable (9% classified as failure). According to molecular markers, 9% were favorable, 31% intermediate, 44% unfavourable and 16% had no molecular markers. At allo-HSCT, 46% of patients were in first complete remission (CR1), 25% were in CR 2 and 29% had active disease; 40% received a full intensity conditioning and 60% got reduced intensity one. As cell source, 35% were bone marrow, 53% peripheral blood and 12% cord blood cells. Donors were related in 53% of the cases (45% were 10/10 HLA matched) and unrelated in 47% of cases (20% were 10/10 HLA matched). MFC was performed using BM samples with a sensitivity of 0.01%. Chimerism analysis was performed on marrow and/or blood samples using polymerase chain reaction (PCR) based on informative polymorphic short tandem repeat with an accuracy of ± 5%, a mixed chimerismwas defined by having 5% or more of recipient cells. Results After transplantation, all patients engrafted, the cumulative incidence of acute GVHD at 3 months was 19.9% (95% CI: 16.2-20.6) while the cumulative incidence of chronic GVHD reached 26.7% (95% CI: 22.9-30.5) at 1 year. After a median follow-up of 16 months (range: 3-77), the median OS was 66 months (65-NR) with a 3 years probability of 64% (95% CI: 56-73), the median PFS was 32 months (13-NR) with a 3 years probability of 50% (95% CI: 37-58) while the transplant related mortality rate reached 13.6% (95% CI: 10-16) at 2 years. The 3 months chimerism evaluation (n=137) showed a mixed chimerism in 12 (9%) patients, while the MFC (n= 62) detected 15 patients with leukemic cells. Sixty eight patients showed morphological relapse after a median time of 4.8 months (1-34.7); the correlation study between MRD positivity, mixed chimerism detection and morphological relapse showed a higher correlation for both chimerism and MFC (correlation=0.69, p<0.001) than if we consider chimerism or MFC alone. Multivariate analysis showed a significant worse OS for patients with 3 months positive MFC [1 year OS of 20% vs. 80%, HR= 4 (95% CI: 1.4-11.7), p=0.01] and patients with mixed chimerism [1 year OS of 21% vs. 70%, HR= 4 (95%CI: 1.3-12.1), p=0.01]; these results were still valid even after stratification on disease status at transplantation. These results applied also in terms of PFS for positive MFC [1 year PFS of 13% vs. 76%, HR= 3.6, p=0.02], and mixed chimerism[1 year PFS of 0% vs. 70%, HR= 7, p=0.001], Figure 1. Conclusion The 3 months MRD evaluation using MFC combined to chimerism documentation seems to be an independent prognostic factor on overall and progression-free survival for AML patients undergoing allo-HSCT. The standardisationof this evaluation may lead to the identification of patients with high relapse risk suggesting the need of early therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib

Blood ◽  
2021 ◽  
Author(s):  
Victoria Wang ◽  
Curtis A. Hanson ◽  
Renee Tschumper ◽  
Connie Lesnick ◽  
Esteban Braggio ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Phase 3 ◽  
Free Survival ◽  
Hazard Ratios ◽  
Additional Support ◽  
Over Time ◽  
Measurable Residual Disease

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (&lt; 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

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