Rituximab Given after High Dose Therapy and Autologous Stem Cell Transplantation Induces Durable Clearance of Minimal Residual Disease in about Half of the Patients with Follicular Non Hodgkin’s Lymphoma : 36 Months Results of a Multicenter Open Label Phase II Trial (M39012 Trial).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 747-747 ◽  
Author(s):  
Franck Morschhauser ◽  
Christian Recher ◽  
Noel Milpied ◽  
Remi Gressin ◽  
Gilles Salles ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Post Treatment ◽  
High Dose ◽  
Molecular Response ◽  
High Dose Therapy ◽  
Free Survival ◽  
Group A ◽  
Group B ◽  
Minimal Residual

Abstract In patients with follicular non hodgkin’s lymphoma (FL), high dose therapy and autologous stem cell transplantation (ASCT) can improve disease free survival. However, patients with minimal residual disease (MRD) after ASCT relapse in most cases. The use of immunotherapy in patient with a MRD state after ASCT is an attractive strategy. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy alone or in combination with chemotherapy in FLNH. The purpose of the present study is to evaluate the efficacy of rituximab on MRD after ASCT. Methods : Three months after ASCT, 39 patients (median age: 48 years) including 14 patients with clinical MRD (group A: nodal or extra-nodal mass > 1 cm but < to 3 cm; bone marrow infiltration less than 30% allowed) and 25 patients with molecular MRD (group B: complete clinical response but bcl-2 gene rearrangement detectable by clonospecific PCR in blood and/or marrow) were eligible to receive Rituximab (375 mg/m2 IV, once a week for 4 weeks). Clinical examination, imaging and blood and bone marrow sampling for centralized molecular MRD studies by clonospecific PCR (sensitivity of the PCR assay : 10-6) were performed at day 50 and every 6 months post treatment. Results: In group A, overall clinical response rate was 36 % (5/14) at day 50 and 71 % (10/14) at 12, 24 and 36 months post treatment, respectively. Median time to response was 183 days. Median Progression free survival (PFS) was not reached and PFS was 62 % at M36. In responders, no relapse was observed. In group B, molecular response (conversion from PCR positive to PCR negative status) was achieved in 12/23 (52 %), 11/22 (50 %), 10/22 (45 %) and 11/24 (46 %) assessable patients at day 50, 12, 24 and 36 months post treatment, respectively. Median time to response was 185 days. Four molecular responders became persistently PCR positive and had a clinical relapse. Median clinical PFS was not reached. Treatment was well tolerated. Only one serious adverse event (AE) was reported as related during the study (grade 3 NCI granulocytopenia). No patient was withdrawn for AE. Conclusion: Rituximab is effective in 71 % of the patients with clinical MRD after ASCT with a response maintained at 3 years. The molecular response induced by rituximab persisted after 3 years of follow-up in 46 % of the patients. These results demonstrate that in FL patients with MRD after ASCT, Rituximab is well tolerated and effective completing the effect of intensive chemotherapy and inducing durable response. Further studies are required to identify the most effective program in combination with rituximab which may result in a chance of cure.

Molecular Level of Minimal Residual Disease in Bone Marrow Before High-Dose Therapy and Autologous Stem Cell Transplantation Is a Prognostic Parameter in Patients with Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1496-1496 ◽  
Author(s):  
Roland Fenk ◽  
Mark Korthals ◽  
Nina Sehnke ◽  
Ingmar Bruns ◽  
Akos Czibere ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Induction Therapy ◽  
Residual Disease ◽  
High Dose ◽  
High Dose Therapy ◽  
Prognostic Group ◽  
Minimal Residual

Abstract Background: Using real-time quantitative (RQ) PCR we recently (Haematologica89,2004) identified a prognostic cut-off level of residual clonotypic cells in the bone marrow of patients with multiple myeloma before high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (PBSCT). In this study we validate this report with a larger number of patients. Patients and Methods: Bone marrow samples of 68 patients with stage II/III multiple myeloma and heavy chain disease were obtained at the time of diagnosis and after induction therapy and stem cell collection but before single HDT and autologous PBSCT. Sequencing of the patient specific immunoglobulin heavy chain (IgH) locus was successful in 51 patients (75%). For 49 patients (72%) RQ-PCR using allele-specific oligonucleotide (ASO) Taqman probes together with LightCycler technology could be established with a sensitivity of 10−4 to 10−6 and linear amplification conditions. The proportion of clonotypic cells was assessed as IgH / 2 beta-actin ratio in percent. Patients were divided in two prognostic groups by a threshold level of 0.03% clonotypic cells. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.05% (range: 0–21%). Time to progression (TTP) from the time of diagnosis of patients in the ¨good¨ prognostic group (n = 21) was 51 months and significantly (p = 0.002) longer in comparison to 20 months of patients with a pre-transplantation minimal residual disease level of more than 0.03% in BM (n = 28). Overall survival (OS) of patients within the ¨good¨ prognostic group was also significantly prolonged (median OS: not reached versus 46 months, p = 0.03). Univariate analysis also revealed kind of maintenance / consolidation therapy (thalidomide, interferon, reduced intensity conditioning (RIC) allogeneic transplant) and cytogenetic banding analysis as prognostic markers for TTP. For OS kind of maintenance therapy, cytogenetic abnormalities, ISS stage, CRP and LDH levels were of prognostic relevance. In multivariat analysis grouping by pre-transplantation MRD level was an independent prognostic factor for either TTP and OS. Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for TTP and OS of patients with multiple myeloma. This finding has two controversial implications. One conclusion could be, that induction therapy should be continued and intensified e.g. with novel agents until a low MRD level is achieved. An alternative conclusion is, that a low tumor burden after induction therapy may be a surrogate parameter for chemosensitive disease, which makes patients more susceptible for high-dose chemotherapy. Therefore, further MRD studies are needed to answer this important question.

12-Year Experience with High-Dose Rituximab-Containing Autologous Stem Cell Transplantation for SOX11-Positive Mantle Cell Lymphoma Patients in First Remission: Emerging Lymphoma-Free Survival Plateau After 3 Years,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4138-4138
Author(s):  
Zaher I Chakhachiro ◽  
Rima M Saliba ◽  
Grace-Julia Okoroji ◽  
Martin Korbling ◽  
Amin M Alousi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Lymph Node ◽  
Cell Lymphoma ◽  
High Dose ◽  
Ki 67 ◽  
Free Survival ◽  
Mantle Cell ◽  
Group A ◽  
Group B

Abstract Abstract 4138 Background: The addition of high-dose rituximab to conditioning regimens has been shown to improve outcomes of autologous stem cell transplantation (ASCT) for mantle cell lymphoma (MCL) patients (pts) in first partial (PR) or complete remission (CR)(Tam C et al. Blood 2009,113:4144). It has been suggested that absence of SOX11 expression can identify a subtype of indolent MCL with excellent outcomes that might be managed more conservatively than conventional MCL. We now report updated results of ASCT for 40 MCL pts treated at our center between 05/99 and 10/10. We also report on SOX-11 expression in a subset of these pts. Methods and Patients: Pts had a median age of 54 years (range, 38–72), and 30% were older than 60 years. At diagnosis, 60% had IPI>1, 30% had intermediate/high MIPI, 88% had stage IV disease, and 78% had bone marrow involvement. 28% had blastic features and Ki-67 was ≥30% in 11/23 (52%) pts who were tested. Pts were treated with R-CHOP or R-hyper-CVAD × 4 cycles induction in 30% and 45% respectively (Group A). Since 2001, pts were referred to ASCT only if they failed to achieve CR with >4 cycles of R-hyper-CVAD induction (n= 10, 25%) (Group B). Prior to transplant, CR (or CR unconfirmed-CRu) was present in 62% pts; 38% were in PR, and 18% were PET+. Conditioning was R-BEAM and R-Cy-TBI conditioning in 77% and 23% respectively. Pts received R during stem cell collection with R administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. Pts then received additional R at 1000 mg/m2 on days +1 and +8 after ASCT, as previously described. Pts were staged with CT, PET (whenever indicated) scans, bone marrow biopsy, and colonoscopy (if history of GI involvement) every 3 months for the first year, every 6 months for 5 years, then yearly thereafter. Results: a. SOX11: Formalin-fixed, paraffin-embedded tissue biopsy sections were assessed by immunohistochemistry (IHC) using anti-Sox-11 rabbit polyclonal antibody (Abcam, Cambridge, MA; 1:1500). For IHC controls we used a tissue microarray including 13 cases of MCL in addition to one complete section of MCL serving as positive controls, and sections from two cases of small lymphocytic lymphoma involving lymph node serving as negative controls. The 11 cases consisted of five GI biopsies, three lymph node biopsies, two bone marrows and one testis. 10/11 showed positive staining for SOX11. The case with negative staining, a GI biopsy, had scattered positive cells. b. Clinical outcome : Following transplantation, CR/CRu was achieved in 100% pts. With a median follow-up of 37 months (range, 6–145), 10 pts experienced recurrent disease. All progressions occurred within 3 years, with a clear plateau emerging subsequently (Figure). The projected lymphoma-free-survival at 10-year, was 65% (95%CI, 44–80). A tendency for a higher risk of relapse was observed in R-hyper-CVAD resistant pts (Group B) pts [4/10 pts (40%) vs 6/30 (20%) in Group A; HR 2.5 (95%CI, 0.7–9.2), p=0.2)], and in pts with ki-67 ≥30% [HR 2.2 (95%CI, 0.4–11), p=0.3). MIPI, blastic histology, age (> 60 years), disease status at transplant (CR/PR) and conditioning were not found to be of prognostic value in our study. 2 pts (5%) developed myelodysplasia, one of which was concurrent with progression. Conclusions: ASCT with high-dose rituximab has the potential to cure a proportion of pts with MCL after response to induction chemotherapy. Our results are favorable despite the inclusion of pts who were resistant to R-hyper-CVAD. Randomized studies comparing this strategy to conventional chemo-immunotherapy are warranted. The prognostic significance of Ki-67 level needs to be assessed in a larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.

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.

Does High Dose Cytosine Arabinoside Improves Disease Free Survival for Down Syndrome Acute Myelocytic Leukemia Patients?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4612-4612
Author(s):  
Mahasen Saleh ◽  
Ashraf Khairy ◽  
Mohammed Al-Mahr ◽  
Hassan El-Solh ◽  
AbdulRahman Al-Musa ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Disease Free Survival ◽  
High Dose ◽  
Acute Myelocytic Leukemia ◽  
Free Survival ◽  
Post Induction ◽  
Myelocytic Leukemia ◽  
Group A ◽  
Group B ◽  
Disease Free

Abstract Acute myelocytic leukemia (AML) in Down Syndrome (DS) children is characterized by a young age of onset (< 2 years), a low white blood cell count and high frequency of Megakaryocytic leukemia. DS children with AML have higher disease free survival (DFS) rates as compared to non DS AML patients. Previous studies have suggested that intensification chemotherapy may not be necessary for the treatment of DS children with AML. The objective of this study was to clarify the effectiveness and toxicities of using high dose Cytosine Arabinoside (HD AraC) intensification in the treatment of DS AML. Clinical data for children (<14 years) with DS AML, diagnosed between September 2000 to May 2005, were retrieved from the hospital data base. Patients were divided into two groups; Group A patients received chemotherapy containing HD AraC, while Group B patients did not. A total of 15 patients were included, eight in Group A and seven in group B. The median age at diagnosis was 22 months (A=23 months, B=22 months). The two groups were matched regarding their clinical and laboratory parameters. There was no significant difference in DFS between groups A and B, 75% and 85% respectively (P = 0.82) at a mean observation period of 42.9 months for group A and 23.12 months for group B. The median time to relapse was 6 months for group A and 8 months for group B. The overall treatment related toxicity was higher in Group A patients but achieved only borderline significance (P = 0.06). However, when toxicity was assessed separately for induction and post induction phases of chemotherapy there were significantly more infectious events (17 v. 2; p=0.0006) in the post induction phase which includes HD AraC intensification in Group A. Even when only serious infections (bacteremia, fungal infection, sepsis) were included in the evaluation this difference persisted (7 v. 1; p=0.0339), with less toxicity for Group B patients. No such difference was noted between the two groups during induction chemotherapy. In conclusion the use of HD AraC in post-induction intensification phases for DS AML children does not improve DFS and is associated with more treatment related toxicity.

Taperring Treatment According Minimal Residual Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4960-4960 ◽  
Author(s):  
Ihab A. Eldessouki ◽  
Eman Z Kandeel ◽  
Shady Adnan ◽  
Mohammed Ghareeb ◽  
Ola Gaber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Disease Free ◽  
Minimal Residual

Abstract In spite its established prognostic role in ALL and being a powerful method for patient stratification, Minimal residual disease in AML is still an area of research need to be investigated to decide its value in AML treatment. In this is a retrospective study, 388 adult AML patients from period 2009-2014 in NCI Cairo University were included, comparing minimal residual disease to other prognostic factors to determine its value as an independent prognostic factor to stratify AML patients and to assess possibility of treatment tapering according MRD. We divided patients in to 3 groups according cytogenetics: favorable, intermediate, poor risk. (We considered patients having negative MRD: those having day 28 and day 42 BMA free for MRD less than 0.01) All patients with FLT3 were excluded prior start this study because we proved by other study its grave prognosis and it outweigh MRD as independent prognostic factor, and eventually those patients will relapse within a short period of time. 5 years disease free survival First group patient with favorable cytogenetics: included 156 patients. We found that 76 patients who become MRD negative post first cycle induction had significantly better disease free survival 64% and overall survival 61.7% compared to those having persistence MRD ( 80 patient) post first cycle of induction 24%, 14% respectively with p value 0.02. Out of 76 patients had negative MRD, 29 patients just took 2 cycles of chemotherapy one induction chemotherapy and one consolidation. Those patients continued to maintain CR in spite receiving 2 cycles of chemotherapy which confirm powerful prognostic impact of MRD with DFS : 61, OS 59.3% which showed no significant difference from those who completed their chemotherapy (p value : 0.07) Those patients didn't continue treatment due to medical problems or non compliance or insurance coverage problems. Those who had persistence MRD post first cycle of induction had prognosis resembling those of poor cytogenetics. Out of 80 patients having persistent MRD, 9 died prior relapse due to medical problems. 64 relapsed and took salvage chemotherapy then kept under follow up. 23 patient did allogenic bone marrow transplantation, 9 were in CR and were done due to persistence MRD and 14 patient did due to relapse and transplantation were done in second CR. patients who had did allogenic transplantation had better disease free survival and overall survival. Second group intermediate risk: 103 patients. We had 40 patients with negative MRD, whose DFS and OS were 59% and 55% respectively. Of those patients, 14 received only 2 cycles of chemotherapy and also showed favorable prognosis in spite being intermediate risk and retained CR. DFS : 57%, OS 55% with no statistical difference between those continued chemotherapy or not. 63 Patients had positive MRD, out of them 5 patients had lost follow up. DFS was13% and OS was 11%. 47 patients relapsed took salvage chemotherapy and kept under follow up out of which 16 patients did bone marrow transplantation. 11 patients did bone marrow transplantation due to persistence MRD and they had longer disease free survival compared to those had salvage chemotherapy and kept under follow up. Same disease free survival overall survival to those did BMT post second CR. Third group with poor risk cytogenetic included 127 patients. 32 patients got MRD negative (DFS: 38% OS: 8%). Out of which 9 didn't receive further chemotherapy post 2 cycles. Again with no significant p value between both groups (P: 0.08) We had 95 patients with persistent MRD post induction. 11 patients lost follow up. 65 relapsed and received salvage chemotherapy DFS 29% and OS: 5%. 19 patients did allogenic bone marrow transplantation. 8 patients did allogenic bone marrow transplantation due to persistence MRD. We found that poor risk cytogenetic outweighs MRD and only patients did BMT had favorable outcome regarding disease free survival 42% and overall survival 11%. Finally we conclude that minimal residual disease can be used as independent prognostic factor. Also MRD can be used as in stratifying patients and tailoring the treatment plan allowing the possibility to stop treatment at a less number of cycles and preventing further chemotherapy complications. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Proteomic Profile of Peripheral Blood and Bone Marrow Sera on Molecular Response in Patients with Chronic Myeloid Leukemia: Preliminary Data

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5515-5515
Author(s):  
Nicola Sgherza ◽  
Vito Garrisi ◽  
Giacoma De Tullio ◽  
Simona Serratì ◽  
Angela Iacobazzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Preliminary Data ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Differentially Expressed ◽  
Molecular Response ◽  
Proteomic Profile ◽  
Group A ◽  
Group B

Abstract BACKGROUND. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by an aberrant protein (BCR–ABL) which is a constitutively active tyrosine kinase. According to the latest ELN recommendations for the management of CML, molecular response (MR) is best assessed according to the International Scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts. It is expressed and reported as BCR-ABL1% on a log scale where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of respectively 1 (MR1), 2 (MR2), 3 (MR3), 4 (MR4), 4.5 (MR4.5) logs below the standard baseline that was used in the IRIS study. Recent advances in the proteomic field have allowed us to better understand the biology of several cancer types and/or discover new candidate biomarkers, but very few data are available in CML. AIMS. The purpose of this study was to evaluate a possible correlation between depth of MR and proteomic profile in sera samples obtained from the peripheral blood and bone marrow of CML patients. PATIENTS AND METHODS Samples were consecutively and prospectively obtained from 20 CML patients observed between January and June 2014 at the Hematology Unit of the National Cancer Research Centre “Istituto Tumori Giovanni Paolo II” in Bari, Italy. Each individual involved in the study signed an informed consent form authorizing the Institute to utilize their biological tissues for research purposes. All patients at diagnosis displayed the classic t(9;22) Ph chromosome according to standard cytogenetics. The BCR/ABL transcript at RT-PCR was b3a2 in 13 patients and b2a2 in 7 patients. Peripheral blood and bone marrow samples were centrifuged within 30 minutes of sample taking. Serum specimens were immediately collected and frozen at −80°C. Twenty sera from peripheral blood were sampled from 5 patients in MR1 response, four in MR2, eight in MR3, two in MR4 and 1 patient at diagnosis; for eleven patients serum from bone marrow was also available; in particular 2 were sampled from patients in MR1, 3 in MR2, 4 in MR3, 1 in MR4 and 1 at diagnosis. Patients were grouped in two cohorts: the first comprised those with lower molecular response to MR3 (group A: 10 patients) and the second greater than or equal to MR3 (group B: 10 patients). The association of proteomic profile with molecular response was performed using the SELDI ToF Mass Spectrometry platform. Each specimen was spotted on an IMAC30 metal affinity protein-chip, prepared according to the manufacturer's instructions, and analyzed in duplicate. RESULTS Fourteen differentially expressed peaks were highlighted when comparing peripheral sera from group A and group B, but none was statistically significant. When comparing 11 available serum samples from the bone marrow of groups A (6) and B (5), four peaks (m/z 10629, m/z 3889, m/z 7772, m/z 7987) were reported as differentially expressed in a statistically significant way (p<0.05). Focusing the differential expression analysis in peripheral sera only on MR1 patients (including one patient at diagnosis) versus MR4 patients, one peak at m/z 11092 was identified as significantly and differentially expressed (p < 0.05) (Figure 1). Similarly, comparing bone marrow sera only from MR1 and MR4 patients respectively, 32 peaks were differentially expressed. Once again the peak at m/z 11092 resulted under expressed in MR1 patients, and interestingly the single patient at diagnosis had the lowest value. No statistical differences were evidenced when comparing peripheral blood and bone marrow sera obtained from b3a2 and b2a2 patients. CONCLUSIONS These preliminary data suggest that an over-expression of m/z 11092 in serum obtained from peripheral blood and bone marrow could be associated with a deeper molecular response; further investigations are needed on a larger number of patients in order to confirm or refute our results and, to definitively characterize the peak at m/z 11092. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Extension of bone marrow involvement and cytopenias in patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 222-222
Author(s):  
Daniel D Almeida Preto ◽  
Marcella de Oliveira Gonçalves Prince Soares ◽  
Wilson Eduardo Furlan Matos Alves ◽  
Marcos Alves de Lima ◽  
Joao Antonio Junior Neif ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factor ◽  
Bone Marrow Involvement ◽  
Bone Lesions ◽  
Castration Resistant Prostate Cancer ◽  
Event Free Survival ◽  
Free Survival ◽  
Castration Resistant ◽  
Group A ◽  
Group B

222 Background: Most of bone metastatic castration-resistant prostate cancer (mCRPC) patients present variable extension of bone marrow involvement which in some cases may influence hematopoiesis. Cytopenias may hinder clinical practice, especially in decision making, regarding the use of myelotoxic drugs. The aim of this study was to assess whether the extension of bone marrow involvement in mCRPC patients is a prognostic factor for developing cytopenias. Methods: We retrospectively reviewed 1649 hemograms from 103 bone mCRPC cases. Patients were pooled in two groups, according to the extension of bone metastasis assessed by skeletal scintigraphy: ≤10 lesions (group A) and >10 lesions or superscan (group B). Time for cytopenia event (event-free survival) and overall survival (time from first cytopenia event until death) were calculated using the Kaplan-Meier method and differences between survivals were tested using the log-rank test. Univariable analysis were performed to determine any significant prognostic factor. Results: The median event-free survival (EFS) was longer in patients with ≤10 bone lesions (group A) on the margin of significance (41.9 vs 23.6 months; p=0.051). The exploratory analyses for severe cytopenia events (grade 3-4) also showed a longer EFS for group A (51.8 vs 31.7 months; p=0.050). When group B was stratified into two subgroups (11-20 bone lesions vs >20 or superscan), there was no significant difference in EFS (19.1 vs 24.2 months; p=0.14). The median overall survival (OS) was 3.3 (1.9-4.6) months, regardless the extension of bone involvement. Patients in the group with more bone lesions showed higher mean PSA levels (55.5 vs 40.3 ng/mL; p=0.01). ECOG, stage disease, Gleason score, visceral metastases, types of cytopenia event (anemia, neutropenia or thrombocytopenia), number of chemotherapy lines, and antialgic radiotherapy did not show difference between groups. Conclusions: The extension of bone metastasis in mCRPC seems to be a prognostic factor for developing cytopenias, but is not related to OS. Additional analyzes with a larger sample are needed to assess whether any clinical variables may be associated with cytopenia event.

Assessment of Minimal Residual Disease (MRD) In Relapsed CLL Patients Treated with Fludarabine and Cyclophosphamide with or without Rituximab (REACH)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1390-1390
Author(s):  
Annika Dufour ◽  
S. K Bohlander ◽  
Karsten Spiekermann ◽  
Stephanie Schneider ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Small Sample ◽  
Patient Specific ◽  
Molecular Response ◽  
Igh Rearrangement ◽  
Minimal Residual

Abstract Abstract 1390 Introduction: Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher et al. Leukemia, 2009). Patients who remain MRD positive after treatment have a higher risk of relapse. Eradication of MRD is therefore a desirable clinical endpoint of treatment. We were interested to assess this correlation in REACH, a randomized international clinical study in previously treated CLL patients, randomized 1:1 for treatment with rituximab, fludarabine and cyclophosphamide© R-FC (276 patients) or FC alone (276 patients); (Robak et al. JCO 2010). Methods: While MRD quantification by flow cytometry requires an identifiable stable phenotype and fresh blood samples, PCR based methods can be performed centrally on frozen samples. We have therefore developed a Realtime Quantitative (RQ) PCR method, using patient-specific IgVH (immunoglobulin variable heavy chain) gene rearrangements as targets. Briefly, genomic DNA was isolated from CD19 sorted B-cells. ASO (allele-specific oligonucleotide) primers were designed matching the hypervariable N-D-N region of the patient-specific leukemic clone and used with reverse consensus primers and hydrolysis probes annealing to the family-specific joining region of the IGH rearrangement (Brüggemann et al., Leukemia, 2004). Maximum sensitivity and quantitative range were defined for every RQ-PCR. Patients were categorized as molecular responders (MRD negative) if there was no detectable clonal IgH rearrangement, using a sensitivity cut-off of 1×10-4. Molecular response was assessed at the time of CR confirmation and 6 months later (if CR was maintained). Results: Among the 103 patients who achieved CR during the study, 86 patients had at least one MRD assessment in peripheral blood, 92 patients in bone marrow. Since many patients had a CR confirmation at different time points during the follow-up period, we initially analyzed the MRD levels only in patients who had achieved confirmed complete response at end of treatment +/−3 month (“EOT - period”). The rate of MRD negativity in blood (22 pts: 5(15) FC, 6(7)R-FC) at EOT was 33% for patients treated with FC, and 86% for patients treated with R-FC (p=0.06); In bone marrow at the EOT (61 patients: 5(27) FC, 20(34) R-FC) the rates were 19% and 59%, respectively (p= 0,02), indicating higher efficacy of the Rituximab containing regimen in eradication of residual disease; This is in line with the previously reported results using FACS analysis of MRD in the CLL8 trial; the differences in the detection rate in blood versus bone-marrow, suggest a higher sensitivity for detection of MRD in bone marrow. We therefore compared the levels of MRD negativity in samples from blood and bone marrow in patients where both samples were taken at the same time point. Results were concordant in 8/9 patients, one patient had a positive result in bone marrow with no detectable signal in blood. This supports the notion that assessment of MRD in bone marrow of CLL patients may be more sensitive than assessment in blood only. However, for a definitive statement larger sample size would be needed. We then correlated MRD status at EOT, regardless of treatment arm, with PFS: In line with previous reports, there was a clear trend to longer PFS in patients who had reached MRD negativity (median PFS not reached), while patients with residual disease had shorter PFS; however, due to small sample numbers, statistical significance could not be reached. We also analyzed the correlation of MRD negativity reached at any time during and after treatment with PFS, bearing in mind that this sample set is inherently biased, since patients with early progression will be lost from the analysis; the results are consistent with the EOT findings. Summary: ASO IgVH RQ-PCR is a powerful method to detect residual levels of disease in CLL patients with clinical complete response and undetectable MRD correlates with longer PFS. Among patients in REACH achieving clinical CR on either study arm, a higher percentage achieved MRD negativity on the R-FC arm, consistent with the increased efficacy shown for the Rituximab treatment arm by the REACH clinical data. Disclosures: Mundt: Roche: Employment. Smith:Roche: Employment. Lin:Genentech: Employment. Barrett:Roche: Employment. Hurst:Genentech: Employment. Geisler:Roche: Research Funding, Speakers Bureau. Hiddemann:Roche: Research Funding.

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