Early Molecular Response of Marrow Disease to Biologic Therapy Is Highly Prognostic in Neuroblastoma

2003 ◽  
Vol 21 (20) ◽  
pp. 3853-3858 ◽  
Author(s):  
Irene Y. Cheung ◽  
M. Serena Lo Piccolo ◽  
Brian H. Kushner ◽  
Nai-Kong V. Cheung

Purpose: A promising treatment strategy for stage 4 neuroblastoma patients is the repeated application of anti-GD2 immunotherapy after activating myeloid effectors with granulocyte-macrophage colony-stimulating factor (GM-CSF). To use early marrow response as a prognostic marker is particularly relevant for patients not likely to benefit from this therapy. Patients and Methods: Eighty-six stage 4 neuroblastoma patients older than 1 year at diagnosis were classified in four clinical groups on protocol entry: complete remission or very good partial remission (n = 33), primary refractory (n = 33), secondary refractory (n = 10), and progressive disease (n = 10). Bone marrow samples collected before and following treatment were assayed for GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction. Response and survival analyses were performed on posttreatment samples before the third cycle at 1.8 months from protocol entry. Results: GD2 synthase mRNA was evident in pretreatment marrow samples of the four clinical groups (42%, 52%, 60%, and 80% of samples, respectively), with median transcript level of 10.0, 16.6, 26.5, and 87.2, respectively. This marker became negative following antibody plus GM-CSF in 77% of complete remission or very good partial remission, 45% of primary refractory, 25% of secondary refractory, and 0% of progressive disease group. Progression-free survival was statistically different between responder and nonresponder groups (P < .0001). Among patients with minimal residual disease, molecular responders had a significantly lower risk of disease progression at a median follow-up of 29.8 months (P = .0001). Conclusion: GD2 synthase mRNA is a sensitive response marker of neuroblastoma in the bone marrow. It is particularly useful for minimal residual disease evaluation and may potentially be useful as an early predictor of resistance to antibody plus GM-CSF immunotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4626-4626
Author(s):  
Yuankai Shi ◽  
Sheng Yang ◽  
Xiaohong Han ◽  
Peng Liu ◽  
Xiaohui He ◽  
...  

Abstract Purpose: High-dose chemotherapy (HDC) supported by APBSCT has been shown to be superior to standard therapy in NHL. However, many patients relapse due to minimal residual disease (MRD) in vivo or in the graft. Rituximab has the potential to clear both blood and bone marrow of malignant CD20+ cells, prompting this multicenter trial of in vivo purging with rituximab and HDC with APBSCT in China. Methods: Cyclophosphamide 4g/m2 was used as the mobilization regimen, CY/TBI, BEAM or CBV could be used as HDC at the discretion of the institution. Four infusions of rituximab (375 mg/m2) were given: one day before mobilization, one day before harvesting, one day before transplantation and on day 8 after transplantation. BCL-2/Ig-H translocation was measured as a marker of minimal residual disease in blood or bone marrow before mobilization and during transplantation using real-time quantitative PCR. Results: Thirty-one patients from 12 centers with histologically proven CD20+ NHL (28 aggressive, 3 indolent NHL) were enrolled. Twenty-four patients were previously untreated, and 7 patients had relapsed disease. Median yields of CD34+ cells and mononuclear cells were 5.9×106/kg and 4.4×108 /kg respectively. Median time to recovery of WBC >1.5×109/L, ANC >0.5×109/L and platelets >20×109/L after APBSCT was 10 days in each case. Median time to platelet recovery >50×109/L was 13 days. Generally, this therapeutic strategy was well tolerated with few side effects attribute to rituximab. All patients achieved a complete remission after APBSCT. At a median-follow-up of 12 months, overall survival and progression-free survival (PFS) are 87% and 73% respectively for all patients. In patients with aggressive NHL, overall survival and PFS are 85% and 73% respectively and in indolent NHL are 100% and 67% respectively. PFS and overall survival were slightly higher in previously untreated compared with relapsed patients (88% vs. 83% for PFS, 73% vs. 69% for overall survival). One of five 5 patients who were initially found to be PCR-positive and achieved PCR-negative status subsequently experienced progression accompanied by a return to PCR positivity. The remaining four patients are still in complete remission and are PCR negative. Conclusion: These results suggest that the regimen of rituximab combined with HDCT and APBSCT is effective and well tolerated for the treatment of patients with NHL.


2021 ◽  
Vol 6 (1) ◽  
pp. 56-64
Author(s):  
O. A. Vynnytska ◽  
◽  
O. I. Dorosh ◽  
L. Ya. Dubey ◽  
N. V. Dubey

Immunophenotyping of leukemia cells was studied in this work; minimal residual disease was monitored among children with acute lymphoblastic leukemia under conditions of relapse and complete remission after the application of ALLIC-BFM 2009 cytostatic therapy. The study showed that after application of ALLIC-BFM 2009 therapy, 88% of children had complete remission, and 12% had relapses. Among patients with relapses, the number of blast cells in the bone marrow was at a high level (more than 6%). Monitoring of patients during therapy established an increase in the minimal residual disease level of more than 1% after treatment in patients with recurrent disease. Immunophenotyping of blast cells among patients with relapse showed the expression of linear independent antigens HLA (93%), Auti-TdT (91%), CD10 (78%), CD38 (91%) and CD34 (57%) and B-linear antigens: CD19, CD22, CD58, CD79a, the highest expression was found for the CD19 antigen. A low level of expression of CD45 (28%) was recorded with relapses of acute lymphoblastic leukemia and high (89%) level was with complete remission of the disease. We did not detect expression of antigens characteristic of T-cell acute lymphoblastic leukemia in bone marrow of patients with acute lymphoblastic leukemia, both with relapses and with remission. At the same time, the expression of myeloid antigens (CD33 and CD13) was noted among acute lymphoblastic leukemia patients. Among patients, the incidence of acute lymphoblastic leukemia was the most pronounced in children aged from 3 to 6 years – 37 patients (35.2%) and aged from 6 to 9 years – 26 (24.8%) patients. The highest accidence was found among patients with chromosomal translocation TEL / AML – 22 (21%) patients with a median age 5 years. In second place, the frequency of mutations is the translocation of E2A / PBX1. BCR / ABL translocation was less common. It was noted in 1.9% of patients, but the expression of this gene indicated a bad course of the disease, as patients after cytostatic therapy under the ALLIC BFM 2009 program had a recurrence. Recurrence was also observed in patients with TEL/AML chromosomal translocation. Determination of minimal residual disease showed its increased level in patients with chromosomal aberrations BCR / ABL and TEL/AML throughout the treatment phase. In addition, patients in these groups were diagnosed with initial leukocytosis followed by leukopenia after a course of chemotherapy. Patients of all groups showed a decrease in hemoglobin. The biggest changes in clinical and laboratory parameters were found between patients with chromosomal translocations BCR/ABL and TEL/AML, as evidenced by the development of relapses in patients of these groups. The low level of association between karyotype disorders, with the formation of AF4/MLL and E2A/PBX1, and clinical and laboratory parameters in patients with acute lymphoblastic leukemia may indicate that the isolated clonal disorders are independent prognostic factors for the course of the disease


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1015-1015
Author(s):  
Pramod Pinnamaneni ◽  
Jeffrey L. Jorgensen ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Sherry R. Pierce ◽  
...  

Abstract Purpose – To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) after achieving initial response to therapy, in predicting outcome in patients with acute myeloid leukemia (AML) Methods – We investigated the predictive value of MRD assessment by MFC in 191 patients with newly diagnosed AML treated between February 2010 and April 2014 at our institution who had available MRD assessment. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR and at approximately 30 days and 90 days after achieving CR. Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype. Results – Of the 191 patients, 167 (87%) achieved complete remission (CR) or CR without platelet recovery (CRp). Their median age was 58 years (Range, 17-85). 84 (44%) were older than 60 years. Median WBC at presentation was 3.2 x 109/L(Range, 0.5-100.2 x 109/L) and median bone marrow blast percentage was 43% (Range, 11-96%). Cytogenetics was favorable risk in 4 (2%), intermediate risk in130 (68%) and adverse risk in 57 (30%). Treatment included cytarabine plus anthracycline in 170 (89%) and hypomethylating agents-based strategies in 21 (11%). 48 patients had available samples at 30 days post CR and 32 (67%) became MRD negative. Achieving MRD negative status was associated with a statistically significant improvement in CR duration (p=0.02) and overall survival (OS) (p=0.0005). 56 patients were evaluated for MRD status at 90 days and 45 (80%) were negative. Again, achieving MRD negative status was associated with a significant improvement in CR duration (p=0.002) and OS (p=0.0009). Conclusion – Achieving MRD negative status by MFC at 30 and 90 days post CR is associated with an improved outcome in patients with AML Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2020 ◽  
Author(s):  
Florian Chevillon ◽  
Emmanuelle Clappier ◽  
Chloe Arfeuille ◽  
Jean-Michel Cayuela ◽  
Jean-Hugues Dalle ◽  
...  

Ovarian tissue cryopreservation (OTC) is offered to women treated for acute leukemia to preserve their fertility before hematopoietic stem cell transplantation. The risk of leukemic infiltration in ovarian samples harvested before administration of chemotherapy limits ovarian tissue transplantations. We assessed the minimal residual disease (MRD) by sensitive quantitative polymerase chain reaction in cryopreserved ovarian cortex and medulla samples harvested from 30 patients in complete remission of acute leukemia, including 60 % with negative bone marrow MRD at the time of OTC. Ovarian MRD was undetectable in 21 patients (70%), detectable below 10-4 in 8 patients (27%) and between 10-3 and 10-4 in 1 patient (3%). Twenty patients (67%) had concordant MRD between bone marrow and ovarian samples. Interestingly 4 patients had positive MRD in ovarian samples while undetectable in bone marrow. Our results underline the importance of reaching the best control of the disease with undetectable or low MRD levels before OTC to minimize the risk of ovarian leukemic infiltration. The discordant results between ovarian samples and bone marrow require to test the more ovarian samples available before considering ovarian tissue transplantation.


1998 ◽  
Vol 16 (9) ◽  
pp. 3053-3060 ◽  
Author(s):  
N K Cheung ◽  
B H Kushner ◽  
I Y Cheung ◽  
K Kramer ◽  
A Canete ◽  
...  

PURPOSE To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age. PATIENTS AND METHODS Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II). RESULTS Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival. CONCLUSION Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1726-1726
Author(s):  
Habibe Kurt ◽  
Carlos E. Bueso-Ramos ◽  
Joseph D Khoury ◽  
Mark Routbort ◽  
Rashmi Kanagal-Shamanna ◽  
...  

Abstract Background Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are important prognostic biomarkers in acute myeloid leukemia (AML). Although the clinicopathologic correlates of IDH mutations have been extensively studied, the distribution of abnormal myeloid cells carrying these mutations has not been studied. Specific localization of cells carrying IDH mutations will be useful in further understanding the pathophysiology and post-treatment biology of IDH mutant cases of AML. This characterization is becoming particularly relevant for identification of minimal residual disease, especially for patients treated with novel IDHinhibitors. In this study, we characterized IDH1 p.R132H clones in bone marrow specimens involved by AML using a mutation specific antibody. Materials and Methods Bone marrow tissue sections (biopsy or clot specimens) from 32 AML cases with IDH1 p.R132H mutation were stained with IDH1 p.R132H-mutation specific antibody. These cases include 20 de novoAML and 12 cases of AML with myelodysplasia-related changes (AML-MRC). We also included 10 AML cases with wild-type IDH1 as a control. After confirmation of the positive IDH1 immunohistochemical (IHC) signal in the primary specimens, follow up bone marrow specimens (n=67) including (a) persistent disease, (b) minimal residual disease by flow cytometry, (3) complete remission by morphology and flow cytometry, but, positive for mutation by PCR, as well as (4) relapsed cases after complete remission were included in the study (in progress). We also included pre- and post-treatment (unresponsive with increasing blast counts, stable disease, persistent disease with decreasing blast counts, complete remission, and relapse) bone marrow specimens (n=72) from 16 patients treated with IDH inhibitors (in progress). Results All the IDH1 wild type AML cases were negative for IDH1 IHC stain showing 100% specificity. Positive signal was detected in all de novo AML and AML-MRC (allelic frequency ranges from 1.8% to 47% by PCR) except one AML case with 8.9% allele burden which was a limited sample; overall sensitivity was 96%. The IHC signal was detected in the cytoplasm of myelomonocytic cells, their precursors, and megakaryocytes. Erythroid precursors, lymphoid cells, endothelial cells, and osteoblasts were consistently negative. The signal intensity ranged from weak (n=10) to moderate (n=9), to strong (n=13). The positive cells predominantly showed an interstitial distribution in the bone marrow. In the de novo AML group, only the immature cells were positive in 100% of pre-treatment AML cases. However, both mature and immature cells were positive in 7/13 (54%) post-treatment AML cases (6 cases treated with hypomethylating agents). One case was transformed from MPN which also showed positivity in mature and immature cells. In two cases with complete morphologic remission and one case with minimal residual disease detected by flow cytometry, IHC signal was detected in both mature and immature cells; both patients relapsed in 8 and 11 months. In the AML-MRC group, both immature and mature cells were positive in 11/12 (92%) cases of which 2 were not previously treated indicating the possibility that IDH1 mutation is an early event. Since the remaining 9 patients were treated with hypomethylating agents, the positivity of both mature and immature cells as a result of maturation effect versus an early event cannot be assessed. Additional studies for follow-up AML cases, including cases on an IDH inhibitor clinical trial are in progress. Conclusions Our preliminary data indicate that IDH1 IHC is a highly specific and sensitive tool to detect IDH1 R132H mutated cases and can be used as a primary method to localize the population of mutation-bearing cells in the bone marrow. IHC also allows determination of whether the IDH1 mutation in the post-treatment setting is arising from immature or mature cells. IHC provides an opportunity to understand the difference between these two populations and, based on characterization of cell type and distribution, may be helpful to predict whether the risk of relapse is high. Disclosures DiNardo: Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5341-5341
Author(s):  
Alvaro Aguayo ◽  
Jorge Contreras Cisneros ◽  
Adriana Lopez Rosas ◽  
Juan Mauricio Vera Zertuche ◽  
Erick Crespo Solís

Abstract Introduction Acute promyelocytic leukemia (APL) with PML/RARA rearrangement is currently classified by the WHO as part of the group of acute myeloid leukemia with recurrent genetic abnormalities. Therapeutic improvements in chemotherapy protocols containing trans-retinoic acid (ATRA) have achieved complete response rates close to 90% and long-term relapse free survival curves of 85%. The treatment protocol of the International Consortium on Acute Promyelocytic Leukemia (IC-APL), which started in 2006, sought to improve rates of complete remission and survival in developing countries through a risk-based protocol and the implementation of daunorubicin instead of idarubicin. Recently the results of that multicenter study were published. Methods A retrospective cohort of patients with APL was studied at the Acute Leukemia Clinic of the Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico; from January 2007 to June 2013. All APL patients were recruited from 2006 to 2013. Diagnosis of APL was established based on the recommendations of the 2000 WHO and subsequently 2008. The original IC-APL chemotherapy scheme was administered. Some minor modifications to the original protocol were made: we did not search for minimal residual disease neither identify the PML / RARA isoforms at diagnosis and prophylactic intrathecal chemotherapy in high-risk patients was applied (4-6 dose cytarabine 60mg and methotrexate 12.5mg), monthly, once the consolidation therapy was finished. Patients who relapsed received rescue therapy and autologous HCT. Allogeneic HCT was performed in advaced stages. Results Of the 18 patients evaluated 11 were women (61.1%). The median age at diagnosis was 40 years, (range 21-74 years). It should be noted that 16.6% had more than 65 years. The risk classification showed 27.8% of cases as low risk, 55.6% intermediate and 16.7% of high risk. At diagnosis 22.2% of patients met the criteria for disseminated intravascular coagulation. Morphological characteristics of BMA were analyzed; in 17 patients (94.1%) BMAs were classified as classic and in one patient it was considered variant-type. Sixteen patients underwent immunophenotyping at diagnosis, 100% of which reported a classic pattern immunophenotype CD34 (-) HLA-DR (-), CD13 (+) CD33 (+), myeloperoxidase (+). The t (15, 17) (q22, q21) was demonstrated by either FISH or karyotype in 94.4% of patients and in one patient the PML/RARA rearrangement could only be demostrated by PCR. Of the 18 patients, 17 achieved complete hematologic remission (94.4%) at a median of 42 days (range 34-158 days). One patient died during induction and this patient presented multiple comorbidities. No serious complications were seen in 66.7% of patients during induction, 22.2% had grade 3-4 infection and 11.1% non-hematologic adverse events and one patient had subarachnoid hemorrhage and vasculitis. The rates of severe neutropenia and fever during induction was 61.1%. ATRA syndrome was identified in 22.2% of patients. Only 15 patients in complete hematologic remission could be analyzed by FISH or cytogenetics, of which 100% were in complete cytogenetic remission. In the 17 patients who achieved complete remission, 14 received all the programmed consolidation chemotherapy. The incidence of febrile neutropenia during consolidation was 29.4%, contrasting with 61.1% after induction. No deaths during consolidation phase were seen. Bone marrow relapse was documented in 5.9%. This patient underwent autologous HCT and subsequently died of disease progression. Of all patients, two died (11.1%), one in bone marrow aplasia after induction (5.5%) and the other in disease progression post-autologous HCT (5.5%). Median survival has not been reached. Conclusions As far as we know this is the first reported series of patients treated with the modified-IC-APL protocol after the original publication in 2013. Longer follow-up is required for survival analysis (median not reached). Implementation of quantitative RT-PCR analysis for minimal residual disease and timely detection of molecular relapse is desirable. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4923-4923
Author(s):  
Zhuanzhen Zheng ◽  
Zhenhua Qiao ◽  
Wenliang Chen ◽  
Rong Gong ◽  
Yalin Wang ◽  
...  

Abstract Abstract 4923 Objective To explore the safety and clinic therapeutic effects of using tumor activated dendritic cells (DC) accompanied cytokine induced killer (CIK) in order to feinforce opposing anti-tumor function and to eliminate minimal residual disease. Methods 59 patients entered into DCIK plus chemotherapy consolidation teams as achieved the 1st complete remission and after 1 or 2 cycle themotherapy. Collect 56 case's bone marrow monocyte cells at diagnosising to prepare tumor antigen, Collect bone marrow monocyte cells at complete remission to culture DC and CIK, using tumor antigen to activate DCs. After 7 days culturing separately then co-culture together for 1 day, collect these cells as DCs activated CIK, after scrubbing, infusing back to patients. Then these patients accept 10–15 day's immuno-regulation treatment, such as interleukine-2(IL-2) 500000u/d for one week or interferon -α(IFN-α)3,000,000u/d three times one week or thymopentin 1mg/d,2 times every week for two weeks. Those cases (one case AML-M3a,one case ALL-B,one case AML-M4a)only have routine culturing and infusion of DCs and CIK and the DCs are not activated by tumor antigen because of having no conservation leukemic cells. Results 59 cases accept DCIK immuno-therapy for 6 to 16 times respectively, in the 24 to 78 months observation stage, 42 cases OS(overall survival)and 33 cases DFS(disease free survival). No one developed therapeutic-dependent auto-allergic disease, such as fever, swollen, diarrhea, rash et al. Those three cases who accepted routine culturing and infusion of CIK and DCs that had not activated by tumor antigen didn't occure any treatment-dependency side-effects and keep hematologic complete remission, minimal residual disease test outcome persist lower under 103. Conclusion Tumor antigen activated DCs combined with CIK can reinforce anti-tumor immune function and have no obviously side-effects,accompanying with chemotherapy,those patients maybe benefit of this kind consolidation treatment and avoid routine chemo-therapeutic side reaction, temporary curative effect are satisfaction and worth popularized. Disclosures: No relevant conflicts of interest to declare.


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