scholarly journals Rates of CR with and without Measurable Residual Disease after Induction Treatment with "7+3" or Azacitidine/Decitabine for Newly-Diagnosed AML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2792-2792
Author(s):  
Todd Yezefski ◽  
Roland B. Walter ◽  
Pamela S. Becker ◽  
Paul C. Hendrie ◽  
Vivian Oehler ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Survival Rates ◽  
Gemtuzumab Ozogamicin ◽  
Response To Treatment ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Multiparametric Flow Cytometry ◽  
Measurable Residual Disease

Abstract Introduction The importance of measurable residual disease (MRD) at time of complete remission (CR) as a predictor of relapse and/or survival either after allogeneic transplant (HCT) or chemotherapy without HCT is widely recognized (Chen et al. JCO 2015;33:1258-64). Hence, a goal of induction therapy might be not only to produce CR, but CR without MRD. Here we compare rates of CR with and without MRD after induction therapy with either (1) "7+3", (2) azacitidine (aza) or decitabine (dec) alone (aza/dec alone), or (3) regimens containing aza or dec with other low intensity treatment (aza/dec combos). Given reportedly similar survival rates with 7+3 and aza/dec alone, and the contribution of CR without MRD to survival, we hypothesized that while CR rates are higher with 7+3, there would be relatively less difference in rates of CR without MRD. Methods We analyzed 272 patients with newly diagnosed, high-risk MDS (10-20% blasts) or AML (> 20% blasts) treated with the following regimens: 7+3 (139 patients), aza/dec alone (64) or aza/dec combos (69), the latter most commonly involving gemtuzumab ozogamicin +/- vorinostat. Cytogenetic risk and response to treatment were assessed per ELN guidelines, and MRD was assessed via 10- color multiparametric flow cytometry as previously described (Chen et al. JCO 2015;33:1258-64). Results As expected, patients given 7+3 were younger, with median ages of 53 for 7+3, 63 for aza/dec alone, and 58 for aza/dec combos. In 7+3, cytogenetic risk was favorable in 29%, intermediate in 26%, and poor in 45%; for aza/dec alone 5% were favorable, 44% intermediate, and 51% poor; and for aza/dec combos, 12% were favorable, 30% intermediate, and 58% poor. As expected, CR rates were higher with 7+3: 72% vs. 14% for aza/dec alone and 17% for aza/dec combos. Rates of CR w/o MRD were also higher with 7+3: 58% vs. 9% for aza/dec alone and 13% for aza/dec combos (p<0.001), while rates of CR with MRD were more similar (14% 7+3 vs. 5% aza/dec alone and 4% for aza/dec combos. Rates of CR w/o MRD were higher with favorable risk cytogenetics (78%) than intermediate risk (24%) or poor risk (22%). The same was true considering only either the aza/dec alone group (67% vs 4% vs 9%) or the aza/dec combo group (50% vs 5% vs 10%.) Conclusion The higher CR rate seen with 7+3 than with aza/dec or its combinations is paralleled by a higher rate of CR without MRD. Multivariate analyses are currently analyzing the relation between relapse/survival and CR without MRD, cytogenetic risk, and treatment, and whether the effect of CR without MRD on these outcomes is the same with 7+3 and aza/dec or its combinations. Assuming, as expected, RFS and survival in the current population is approximately similar regardless of treatment with 7+3, aza/dec or its combinations, the failure of 7+3 to produce better survival despite higher rates of CR without MRD would suggest limitations in the use of CR without MRD as a surrogate for RFS and survival. The similar effect of cytogenetics on CR without MRD rates with 7+3, aza/dec alone or aza/dec combos suggests a qualitative similarity between these regimens that is perhaps more than often appreciated. Disclosures No relevant conflicts of interest to declare.

Correlation of Erythropoietin Stimulating Agents (ESAs) with the Post-Therapy Micro-Vessel Density (MVD) in Newly Diagnosed Myeloma Patients: a Possible Mechanism of ESAs Association with Reduced Survival Rates.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4873-4873
Author(s):  
Eirini Katodritou ◽  
Evangelos Terpos ◽  
Vassiliki Kaloutsi ◽  
Evgenia Verrou ◽  
Vassiliki Gastari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Conflicts Of Interest ◽  
Independent Predictor ◽  
Survival Rates ◽  
Response To Treatment ◽  
Newly Diagnosed ◽  
Bone Marrow Biopsies ◽  
Group Post ◽  
Post Therapy

Abstract Abstract 4873 Angiogenesis plays a significant role in the biology of multiple myeloma (MM). Erythropoiesis stimulating agents (ESAs) have been recently associated with reduced survival in a subset of cancer patients who receive ESAs, including MM but the etiology for this correlation has not been sufficiently explored. It is known that the endothelial cells produce angiogenic factors, promote the growth and survival of MM cells and carry erythropoietin receptors which in hypoxic conditions they transport the signal for their own proliferation and expansion under the influence of the endogenous erythropoietin. The aim of this study was to investigate the possible impact of ESAs administration on post-therapy angiogenesis. We studied 84 newly diagnosed MM patients (47M/37F; median age: 65 years, range: 39-82 years) who underwent conventional anti-myeloma therapy: 62 patients received VAD (53 of whom within the context of the randomized study VAD vs. TVAD, conducted by the Greek Myeloma Study Group) and 22 patients received MP. Fifty-two patients received ESAs for at least 8 weeks (ESA group), while 32 did not receive ESA (non-ESA group). MVD was assessed in bone marrow biopsies at baseline and at the time of best response by using monoclonal antibodies targeting CD34. The number of microvessels expressing the CD34 antibody was counted by two experienced pathologists through a grid at a magnification of 400x and was finally divided to the number of the high power fields used for screening the whole marrow surface. The counts were finally expressed as number of vessels per mm2 area of the involved marrow. Fifteen individuals with normal findings in the bone marrow were used as controls. Furthermore, the following cytokines that are involved in the angiogenesis process in MM were measured in the serum of both patients and controls on the day of the trephine biopsy performance: VEGF, bFGF, TGF-b, IL-6, soluble IL-6R (sIL-6R), IL-1b and TNF-α, using an ELISA methodology (R&D, Minneapolis, MN, USA). Patients characteristics between the ESA and non-ESA groups at baseline were well balanced except of Hb which was, as expected, significantly lower in the ESA-group (p<0.001). The median follow-up was 84 months (range 5-154). The median number of baseline MVD in the ESA group was 18.5/mm2 (range: 1-29.3) and in the non-ESA group 17.7/mm2 (range: 2-28.5; p=NS) and was higher compared to controls (median 1.2/mm2, range: 0-9; p<0.001 for both comparisons). The post-therapy MVD in the two groups were 16/mm2 (range: 1.8-26) for ESA and 12.8/mm2 (range: 2-29) for non-ESA group, respectively (p=0.03); the % reduction between baseline and post-therapy value was significantly greater in the non-ESA group (non-ESA group: 24.9%, range -36% to +76.6%, ESA group: 14.5%, range -410% to +85.6%, p=0.04). Myeloma patients before treatment had increased serum levels of VEGF (p=0.029), bFGF (p=0.012), IL-6 (p=0.007) and sIL-6R (p=0.047) compared to controls and showed no differences between ESA and non-ESA groups and no alterations post-therapy. Post-therapy, MVD positively correlated with the baseline MVD and baseline β2-microglobulin and negatively correlated with baseline Hb, response to treatment and PFS (p<0.05). In the ESA group but not in the non-ESA group, post-therapy MVD was negatively correlated with response to treatment (p<0.05). In the multivariate analysis, age and post-therapy MVD were the only independent predictors for OS (p=0.04 and p=0.005, respectively; Hz ratio for post-therapy MVD: 1.2, 95% CI: 1.04-1.28). In the ESA group, the multivariate analysis showed that post-therapy MVD >14/mm2 was the only independent predictor for survival (p=0.04; Hz ratio 0.136, 95% CI: 0.02-0.9) whereas in the non-ESA group, post-therapy MVD did not show any significant prognostic value, either used as a continuous or a dichotomous variable. The median PFS for patients with post-therapy MVD >14/mm2, was 13 months (95% CI: 8.5-17.5) and for patients with MVD <14/mm2 was 33 months (95% CI: 25-41; p=0.001). The median OS in patients with MVD >14/mm2 was 37 months (95% CI: 29-45) and for those with MVD <14/mm2 was 63 months (95% CI: 50-75; p=0.04). These results suggest that ESAs may negatively influence the post-therapy MVD. In the ESA group MVD negatively correlated with disease response and MVD >14/mm2 was the only independent predictor for OS. These findings could partially explain the possible association of ESAs with reduced survival rates in newly diagnosed MM patients. Prospective studies are required in order to fully investigate this current issue. Disclosures No relevant conflicts of interest to declare.

Adding The KIT Inhibitor Dasatinib (DAS) To Standard Induction and Consolidation Therapy For Newly Diagnosed Patients (pts) With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Initial Results Of The CALGB 10801 (Alliance) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 357-357 ◽  
Author(s):  
Guido Marcucci ◽  
Susan Geyer ◽  
John Zhao ◽  
Andrew J Caroll ◽  
Donna Bucci ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Rapid Screening ◽  
Induction Treatment ◽  
High Dose ◽  
Protein Chain ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Early Results

Abstract Among the prognostic cytogenetic and molecular aberrations in AML, t(8;21)(q22;q22) and inv(16)(p13q22) and their corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a protein chain of the key transctiption factor CBF), predict for a favorable outcome in pts receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, approximately 40% of these pts eventually relapse. Approximately 25% of CBF AML pts carry gain-of function mutations in the KIT gene. These mutations result in a constitutively active tyrosine kinase (TK) that contributes to aggressive leukemia growth, and is associated with unfavorable outcome. In addition, CBF AML pts with wild type KIT overexpress this protein, and this is also associated with an inferior outcome. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML. We report here on a phase II trial that combined DAS with standard chemotherapy for CBF AML. Enrollment required molecular confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays. Overall, 779 patients were screened for CBF; 69 were found to be CBF-positive and 61 were subsequently enrolled. Newly diagnosed RUNX1/RUNX1T1 or CBFB/MYH11-positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion on days 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus on days 1-3 and DAS 100 mg/d PO on days 8-21. Pts with residual disease (>5% blasts) on day 21 after first induction received a re-induction treatment with same doses of C on days 1-5, DNR on days 1-3 and DAS on days 6-19. Pts who achieved CR received consolidation therapy with HiDAC 3000 mg/m2 over 3 hours (if <60 yrs old) or 1000 m/m2 (if older) q12h on days 1,3,5 and DAS 100 mg/d PO on days 6-26 x 4 courses. Pts who remained in CR after consolidation treatments received continuation treatment with DAS 100mg/d PO x 12 months. The primary goal of this study was to insure that the CR rate and survival during induction were not inferior to historical outcomes. Between April 2011 and January 2013, we completed the planned accrual of 61 adult CBF AML pts. Median age was 51 years (yrs; range: 19.6 to 85 yrs), and 15 pts (24%) were older (>60 yrs). Half of pts were male (51%) and a majority were Caucasian (75%). Of all 61 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive. Treatment was started on average 4 days from molecular diagnosis (range: 0 to 11 days). To date, 51% of pts are still undergoing treatment; 4 pts died on treatment (2 older), 7 (4 older) had an adverse event requiring treatment interruption, and 6 refused to complete the treatment (mainly the continuation component). Observed toxicities were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity). 55 pts are currently evaluable for treatment-related toxicity. The most common grade 4 toxicities were sepsis (5), acute kidney injury (3), and respiratory failure (3). Grade 5 toxicities included respiratory failure (1) and sepsis (2). Two of these pts died during induction (respiratory failure, sepsis); both were older and CBFB/MYH11. One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yrs). The 30-day survival rate was 97% (95% CI: 89% to 99.6%) overall (98% in younger and 93% in older pts). Of 59 pts currently evaluable for response, 54 (92% of all pts; 96% younger and 80% older) achieved CR. Of the 5 patients who failed to achieve CR, 2 had RUNX1/RUNX1T1 and 3 had CBFB/MYH11. Among the 54 CR pts, no younger pt has relapsed, while 2 older pts with CBFB/MYH11 have relapsed. The median follow-up (f/u) was 11.2 months (range: 1.2 to 23.2 mos.). The 1-yr DFS and OS rates were respectively 90% and 87% for all pts; 97% and 95% for younger pts, and 63% and 62% for older pts, respectively. Early results from this study show that 1) rapid screening for CBF AML is feasible within a cooperative group, 2) DAS plus chemotherapy in CBF AML pts is tolerable including in older pts, and 3) the initial clinical outcomes are at least comparable to those historically observed in this patient population. Patients continue to be followed for survival endpoints. Molecular characterization for KIT mutations and expression levels of marrow and blood blasts is ongoing and will be correlated with toxicity and clinical outcome. Disclosures: No relevant conflicts of interest to declare.

Sequential High-Dose Dexamethasone and Response Adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) Chemotherapy Followed by High-Dose Therapy with ASCT for Newly Diagnosed Multiple Myeloma; Open-Labeled, Multicenter Phase 2 Study (KMM-94 Study)-Interim Analysis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3106-3106
Author(s):  
Jae Hoon Lee ◽  
Junshik Hong ◽  
Jin Seok Kim ◽  
June-Won Cheong ◽  
Cheolwon Suh ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Poor Response ◽  
New Drugs ◽  
Induction Treatment ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Younger Patients ◽  
High Dose Dexamethasone

Abstract Abstract 3106 Background: Induction therapy followed by ASCT is the standard therapy for the newly diagnosed younger patients with MM. Recently, new drugs such as lenalidomide or bortezomib have shown the promising results as an induction treatment. However, these drugs are not available in many countries as a front line treatment and many different type of induction treatment regimens including old regimens are used. We evaluate the efficacy and safety of the brief course of high dose dexamethasone (HD) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: One hundred fifty five newly diagnosed patients with MM from 23 institutions received 2 cycles of HD followed by PAD or VAD chemotherapy according to the response to the HD. PAD 4 cycles were given to nonresponsders and VAD 2 cycles were given to who achieved more than PR to HD. The primary endpoint was CR + nCR rate after ASCT. Among 155 patents enrolled this study from November 2009, 29 patients (19%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred fifty five patients (88 male, 69 female) were enrolled (median age; 57). 34 (22%) patients had ISS stage I, 64 (41%) stage II and 55 (35%) stage III. Thirty six (26%) patients had abnormal cytogenetics. In FISH analysis, there were 25% del13, 9% del17, 21% t (4; 14), 13% t (14; 16) and 26% t (11; 14). Among the 115 evaluable patients, CR + PR rate was 53% (61/115) after 2 cycles of HD. 61 patients (53%) received subsequent VAD chemotherapy and 54 patients (47%) received PAD chemotherapy. Among the evaluable patients, CR + PR rate after induction therapy was 83% (79%, 48/61 in VAD group vs. 89%, 48/54 in PAD group). 95 patients finished ASCT. CR + nCR rate after ASCT were 74% (74% in VAD group vs 73% in PAD group). Mortality rate of this trial was 15% (17/115). The cause of death was disease progression (n=5), bleeding (n=1) and infections (n=11). Among 115 patients in whom VAD or PAD chemotherapy was actually performed, 1 year OS was 88.1%. (VAD arm 90.7% versus PAD arm 86.1% (P=0.105): median follow-up; 16.6 months). Conclusion: Risk adapted approach using initial HD response showed good response results after ASCT compared with previous trial (CR + nCR rate of IFM 2005-01 trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who showed poor response to HD also showed similar good response rate after ASCT compared with the patients who had good response to HD in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Our data shows that almost half of the patients who responded to HD can be saved of novel agents during induction treatment, and PAD can successfully rescue the other half who are not sensitive to HD. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (9) ◽  
pp. 1926
Author(s):  
Hiroto Inaba ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Detailed Analysis ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

scholarly journals Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns

Leukemia ◽  
2021 ◽  
Author(s):  
Tanja Božić ◽  
Chao-Chung Kuo ◽  
Jan Hapala ◽  
Julia Franzen ◽  
Monika Eipel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Amplicon Sequencing ◽  
Multiparametric Flow Cytometry ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Measurable Residual Disease ◽  
Acute Myeloid

AbstractAssessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.

scholarly journals Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

1997 ◽  
Vol 2 (3) ◽  
pp. E1
Author(s):  
Roger J. Packer ◽  
Joanne Ater ◽  
Jeffrey Allen ◽  
Peter Phillips ◽  
Russell Geyer ◽  
...  
Keyword(s):  
Objective Response ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Low Grade ◽  
Significant Prognostic Factor ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

scholarly journals Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mileka Gilbert ◽  
Beatrice Goilav ◽  
Joyce J. Hsu ◽  
Paul J. Nietert ◽  
Esra Meidan ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Induction Therapy ◽  
Pediatric Nephrology ◽  
Response To Treatment ◽  
Individual Treatment ◽  
Induction Treatment ◽  
Childhood Onset ◽  
Renal Flare ◽  
Treatment Plans

Abstract Background Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. Methods Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. Results Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). Conclusions Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

scholarly journals Multiparametric Flow-Cytometry Is a Reliable Tool for Measurable Residual Disease Assessment and Risk-Stratification of FLT3-Mutated AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5083-5083
Author(s):  
Raffaele Palmieri ◽  
Luca Maurillo ◽  
Alfonso Piciocchi ◽  
Maria Ilaria Del Principe ◽  
Valentina Arena ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Board Of Directors ◽  
Residual Disease ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Npm1 Mutation ◽  
Multiparametric Flow Cytometry ◽  
Reliable Tool ◽  
Measurable Residual Disease

Background: Mutations of the gene encoding Fms Related Tyrosine Kinase 3 (FLT3), at the juxta-membrane level (ITD), represent the most common lesions found in Acute Myeloid Leukemia (AML), identifying a subgroup of patients (pts) with unfavorable prognosis. FLT3-ITD mutations are considered an unreliable tool for measurable residual disease (MRD) monitoring, due to their intraclonal heterogeneity and instability during the course of disease. Instead, multiparametric flow cytometry (MFC) may represent an alternative to monitor MRD in this molecular subset. In fact, through the recognition and monitoring of leukemia associated immunophenotypes, MFC is applicable to > 90% of AML patients with a sensitivity of 10-4. Aims: The aim of our study was to investigate the reliability of MFC in MRD assessment of 72 FLT3-ITD positive pts whose treatment allocation was prospectively decided according to the genetic/cytogenetic profile at diagnosis and post consolidation MRD. FLT3-ITD pts were to receive, after induction and consolidation, allogeneic stem cell transplant (ASCT), whatever the source of stem cells. In this subgroup analysis, we investigated if FLT3-ITD mutated pts have a different propensity to achieve high quality (e.g. MRD negative) complete remission as compared to FLT3 wildtype ones. Furthermore, we seek for a correlation between different levels of MRD and overall (OS) and disease-free survival (DFS). Methods: We included in the analysis 72 pts with de novo AML carrying FLT3-ITD mutations whose MRD assessment at the post-consolidation timepoint was available. Pts were defined as MRD-negative, when obtaining a residual leukemic cells count below the threshold of 3.5x10-4 (0.035%). MRD positive pts (with MRD ≥ 3.5x10-4 RLC) were stratified into 3 classes according to the levels of MRD (0.035%-0.1%; >0.1%-1%; >1%). We compared the MRD status and clinical outcome with a matched group of FLT3 wildtype AML (n = 203) treated in the same protocol. Results: Overall median age was 49 (range 18-60.9). The 2 cohorts were balanced in terms of age and sex distribution. In the FLT3-ITD group, 80/126 (64%) cases carried a concomitant NPM1 mutation vs 107/374 (28.6%) of FLT3 wildtype ones (p <0.001). Furthermore, FLT3 mutated pts had a median WBC count of 35x109/L vs 9.5x109/L of those FLT3 wildtype (p < 0.001). MRD determination after consolidation cycle was available in 72/126 FLT3-ITD pts (57%) and in 203/374 FLT3 wildtypeones (54.3%), respectively. After having received induction and consolidation course, 47/72 FLT3-ITD pts (65,2%) were submitted to allogenic stem cells transplantation (ASCT). At the post-consolidation time-point, MRD negativity rate was significantly lower in FTL3-ITD pts (27/72, 37.5%) as compared to those FLT3 wildtype (94/203, 46.3%). Furthermore, 38/72 (52.8%) and 10/72 (13.9%) FLT3-ITD pts had a level of MRD > 0.1% and > 1%, respectively as compared to 65/203 (33.0%) and 15/203 (7.4%) of FLT3 wildtypeones, respectively (p=0.017). When considering the different MRD stratification levels of FLT3-ITD pts, OS probability at 24 months was 57.2% (27 pts), 71.4% (7 pts), 53.6% (28 pts) and 20% (10 pts), for the MRD categories <0.035%, 0.035%-0.1%, >0.1%-1%, >1%, respectively (p=0.028). DFS probability at 24 months was 53.8% (27 pts), 71.4% (7 pts), 34.9% (27 pts) and 20% (10 pts), for the MRD categories <0.035%, 0.035%-0.1%, >0.1%-1%, >1%, respectively (p=0.038). Summary/Conclusion: We demonstrated that MRD determination by MFC is a reliable tool to assess remission quality and prognosis in FLT-ITD positive patients. This subpopulation shows a lower propensity to obtain a MRD negative CR, with the majority of pts maintaining an amount of MRD > 0.1% after standard treatment. Even though most of these pts were addressed to ASCT, post-consolidation MRD maintained its negative impact on OS and DFS, particularly for those pts with MRD >1%. In the attempt to improve the quality of response, prevent leukemia recurrence and pursue a durable remission, delivery of FLT3 inhibitors as a maintenance after transplant may represent a promising option. Disclosures Venditti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buccisano:Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7018-7018
Author(s):  
Keith Pratz ◽  
Brian Andrew Jonas ◽  
Vinod Pullarkat ◽  
Christian Recher ◽  
Andre C. Schuh ◽  
...  
Keyword(s):  
Complete Remission ◽  
Residual Disease ◽  
Disease Response ◽  
Multiparametric Flow Cytometry ◽  
Laboratory Services ◽  
Best Response ◽  
Response Table ◽  
Group Response ◽  
Grade 3 ◽  
Measurable Residual Disease

7018 Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD<10-3) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p<0.001). There is limited evidence of the clinical significance of MRD monitoring in pts receiving low-intensity chemotherapy. Herein, we explored the outcomes of pts treated with Ven+Aza who achieved both CRc and MRD<10-3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m2; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as <1 residual blast /1000 leukocytes (<10-3). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD<10-3 and 133/211 (63%) had MRD≥10-3. Median age (MRD<10-3/ MRD≥10-3) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD<10-3/ MRD≥10-3) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD<10-3/ MRD≥10-3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD<10-3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD<10-3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD<10-3response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD<10-3/ MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD<10-3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]

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