scholarly journals Treatment of Adult Patients with the Modified Protocol of the International Consortium on Acute Promyelocitic Leukemia (IC-APL)

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
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Complete Remission ◽  
Disease Progression ◽  
Minimal Residual Disease ◽  
Acute Promyelocytic Leukemia ◽  
Residual Disease ◽  
Promyelocytic Leukemia ◽  
Autologous Hct ◽  
Minimal Residual

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.

Significance of Quantification of the PML-RARa Transcript in Children with Acute Promyelocytic Leukemia: A Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1474-1474
Author(s):  
Li Zhang ◽  
Zeng Cao ◽  
Yao Zou ◽  
Min Ruan ◽  
Qinghua Li ◽  
...  
Keyword(s):  
Complete Remission ◽  
Real Time ◽  
Minimal Residual Disease ◽  
Acute Promyelocytic Leukemia ◽  
Residual Disease ◽  
Promyelocytic Leukemia ◽  
Low Risk ◽  
Minimal Residual ◽  
Risk Of Relapse

Abstract Abstract 1474 Objective: Minimal residual disease (MRD) monitoring based on the detection of PML/RARa transcripts employing PCR technology has clearly demonstrated its benefit in the diagnosis and follow-up of acute promyelocytic leukemia (APL) patients. So far, real-time quantitative PCR (RQ-PCR) has been investigated to provide prognostic indexes for APL management in many adults studies. However, there are still no data on the use of such assays for child APL therapy. The aim of this study was conducted to clarify the relationship between the level of MRD and outcome in children with newly diagnosed PML/RARa-positive APL and identify the subgroups at low-risk of relapse. Methods: Since January 2004, we have analyzed 40 child patients treated with all-trans-retinoic acid (ATRA)±arsenic trioxide (ATO) in induction, with a median follow-up of 47 months. They were monitored by RQ-PCR. Hematologic and molecular relapses were recorded. We then looked for associations between relapse risk and RQ-PCR results in children. Results: The pretreatment characteristics of the 40 patients are listed in Table 1. Thirty-nine patients (97.5%) entered complete remission (CR). The 5-year probabilities of disease-free survival (DFS) and overall survival (OS) were 73.1% and 91.4%, respectively. By employing the standardized real-time quantitative polymerase chain reaction (RQ-PCR) for minimal residual disease (MRD) monitoring, no significant difference were observed in the PML/RARa normalized copy number (NCN) between patients in continuous complete remission and those who relapsed (neither at diagnosis nor after induction). After induction therapy, eight out of 25 cases with positive RQ-PCR (more than 1 NCN) relapsed in contrast to none out of 13 patients with negative RQ-PCR(100% and 55.2% DFS at 5 years in the negative and positive RQ-PCR groups, respectively; P=0.018, Fig.1). Also of note, in the positive RQ-PCR group, the patients treated with ATRA+ATO in induction had a lower relapse rate when compared with those treated with ATRA alone (P=0.03). Conclusions: PML/RARa - based MRD monitoring by RQ-PCR might allow us to identify subgroups of patients at low risk of relapse after induction in childen. Patients with a low risk of relapse could be monitored less frequently. Combination of ATO and ATRA might decrease the relapse rate compared with ATRA alone in induction therapy for childhood APL. Disclosures: No relevant conflicts of interest to declare.

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
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Partial Remission ◽  
Progressive Disease ◽  
Residual Disease ◽  
Gm Csf ◽  
Stage 4 ◽  
Secondary Refractory ◽  
Minimal Residual

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.

High Efficacy and Good Tolerability with Rituximab In Vivo Purging Followed by High Dose Chemotheraphy and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) in Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4626-4626
Author(s):  
Yuankai Shi ◽  
Sheng Yang ◽  
Xiaohong Han ◽  
Peng Liu ◽  
Xiaohui He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Median Time ◽  
Residual Disease ◽  
High Dose ◽  
Platelet Recovery ◽  
Minimal Residual

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.

Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4439-4439
Author(s):  
Beata M. Stella-Holowiecka ◽  
Krystyna Jagoda ◽  
Aleksandra M. Holowiecka-Goral ◽  
Tomasz Czerw ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Long Term Results ◽  
Color Flow ◽  
Childhood All ◽  
Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was &lt;0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/&gt; 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2321-2321
Author(s):  
Sebastian Giebel ◽  
Beata Stella-Holowiecka ◽  
Malgorzata Krawczyk-Kulis ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 2321 Poster Board II-298 The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT. Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases. With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009). CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interferon may reduce minimal residual disease of acute promyelocytic leukemia

Leukemia ◽  
2000 ◽  
Vol 14 (6) ◽  
pp. 1153-1153
Author(s):  
M Egyed ◽  
G Rumi ◽  
B Boros ◽  
P Páldi-Haris ◽  
J Földi
Keyword(s):  
Minimal Residual Disease ◽  
Acute Promyelocytic Leukemia ◽  
Residual Disease ◽  
Promyelocytic Leukemia ◽  
Minimal Residual
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