scholarly journals KMT2A Partial Tandem Duplications (KMT2A-PTD) Is a Rare, but Recurrent Genomic Event in Childhood AML and Associated with High Rate of Co-Occurring FLT3 Mutations

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 609-609
Author(s):  
Danielle C. Kirkey ◽  
Katherine Tarlock ◽  
Rhonda E. Ries ◽  
Yi-Cheng Wang ◽  
Amanda R. Leonti ◽  
...  
Keyword(s):  
Stem Cell Transplant ◽  
High Rate ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival ◽  
High Prevalence ◽  
Flt3 Mutations ◽  
Childhood Aml ◽  
Pediatric Aml ◽  
Tandem Duplications

Abstract KMT2A partial tandem duplication (KMT2A-PTD), characterized by a large internal duplication spanning 6-8 exons, has been documented in adult AML with a prevalence of 3-10% and is associated with poor outcomes. Despite the high prevalence of KTM2A fusions and known associated outcomes, prevalence and clinical implications of KMT2A-PTD has not been well characterized in childhood AML. We interrogated the transcriptome and associated clinical and genomic data from pediatric AML patients treated on COG AAML1031 to define the prevalence of KMT2A-PTD, frequency of co-occurring genetic mutations and outcomes associated with this variant. Ribo-depleted RNA seq data from 1,294 patients with AML (age 0-29 years) enrolled on COG AAML1031 with available cytogenetic, molecular, and clinical data were utilized. Gene fusions, internal tandem duplications (ITD) and partial tandem duplications (PTD) were detected by Cicero. Conventional karyotyping and mutational analysis including NGS were used to determine additional cytogenetic and molecular abnormalities. Response was measured by 5-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS) and relapse risk (RR). Of the 1,294 patients studied, KMT2A-PTD was identified in 20 patients (1.5%). Evaluation of karyotype demonstrated striking paucity of karyotypic alterations with 75% with normal karyotype; 3 cases (15%) of trisomy 11 were identified. In contrast to KMT2A-rearranged (KMT2A-r) AML, which has the highest prevalence in young patients (median age 3.3 years), the median age with KMT2A-PTD was 13.4 years (p<0.0001). Further analysis demonstrated a high rate of co-occurrence of FLT3 mutations; 15 patients (75%) had FLT3-ITD (N=13; 65%) and/or FLT3 activating mutations (N=5; 25%). The rate of co-occurring FLT3-ITD was significantly higher in the KMT2A-PTD cohort compared to patients without KMT2A-PTD (65% vs. 19%, p<0.001). Prevalence of KMT2A-PTD in patients with FLT3-ITD was 5.7%. Additional co-occurring genetic mutations were identified in WT1 (20%) and the RAS pathway. There was a striking enrichment of mutations that are commonly associated with AML in older adults with 8/20 patients (40%) harboring mutations in IDH1/IDH2, U2AF1, and TP53, far in excess of what is seen in other pediatric AML patients (Figure 1A). We evaluated the significance of KMT2A-PTD on clinical outcome. Patients with KMT2A-PTD had a poor response to induction therapy with a morphologic CR rate of 45% and rate of residual disease (MRD) positivity by flow cytometry after initial course of therapy was 40%. Additionally, high rates of relapse were noted for patients with KMT2A-PTD with a RR of 53%. EFS for patients with and without KMT2A-PTD was 39% vs. 46%, respectively (p=0.54) with a corresponding OS of 58% and 64% (p=0.61). Outcome analysis for the KMT2A-PTD cohort demonstrated dual KMT2A-PTD/FLT3-ITD patients had an EFS of 46% compared to 29% for KMT2A-PTD/non-ITD patients (p=0.62, Figure 1B). We inquired whether hematopoietic stem cell transplant (HSCT) may modify outcomes in patients with KMT2A-PTD. Of the 20 patients with KMT2A-PTD, 7 (35%) proceeded to HSCT in CR1, with the indication in 6 of 7 patients due to FLT3-ITD high allelic ratio (HAR, ≥0.4). Stem cell transplant recipients had a DFS of 83% vs. 0% for those who continued on protocol chemotherapy (p=0.002, Figure 1C) with corresponding OS of 100% vs. 43%, respectively (p=0.05). In this large cohort of childhood AML patients treated on AAML1031, we identified a small subset of patients with KMT2A-PTD and show the high prevalence of co-occurring FLT3 mutations. Although KMT2A-PTD patients with and without FLT3-ITD had similar outcomes, the cohort who received HSCT in CR1 (most with FLT3-ITD) experienced improved outcomes compared to the rest of the cohort, suggesting that intensification of therapy may benefit this group of patients overall. Further research into KMT2A-PTD in pediatric AML will guide future risk-adapted therapy and enhance understanding of biologic implications of this lesion, including whether altered KMT2A may serve as a therapeutic target as it may for KMT2A-r AML. Figure 1 Figure 1. Disclosures Pollard: Syndax: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study

2016 ◽  
Vol 34 (6) ◽  
pp. 572-580 ◽  
Author(s):  
Stéphane Lepretre ◽  
Aurore Touzart ◽  
Thomas Vermeulin ◽  
Jean-Michel Picquenot ◽  
Aline Tanguy-Schmidt ◽  
...  
Keyword(s):  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Lymphoblastic Leukemia ◽  
Lactate Dehydrogenase Level ◽  
Lymphoblastic Lymphoma ◽  
Emission Tomography ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Positron Emission

Purpose This study evaluated the efficacy of pediatric-like acute lymphoblastic leukemia (ALL) therapy in adults with lymphoblastic lymphoma (LL). Patients and Methods This was a prospective phase II study in adults 18 to 59 years old with previously untreated LL. Patients were treated with an adapted pediatric-like ALL protocol, which included a corticosteroid prephase, a five-drug induction reinforced by sequential cyclophosphamide administration, dose-dense consolidation, late intensification, CNS prophylaxis, and a 2-year maintenance phase. Treatment response was assessed by computed tomography and optional positron emission tomography. Allogeneic hematopoietic stem cell transplant was offered to selected patients in first complete remission (CR) or unconfirmed CR. Results The study enrolled 148 patients (131 with T-lineage LL [T-LL] and 17 with B-lineage LL [B-LL]). A total of 119 patients with T-LL (90.8%) and 13 with B-LL (76.5%) reached CR/unconfirmed CR, including 26 with T-LL and two with B-LL who needed a second induction salvage course. Relapse occurred in 34 patients with T-LL and four with B-LL. In patients with T-LL, 3-year event-free survival was 63.3% (95% CI, 54.2% to 71.0%), disease-free survival was 72.4% (95% CI, 63.0% to 79.7%), and overall survival was 69.2% (95% CI, 60.0% to 76.7%). Multivariate analysis identified serum lactate dehydrogenase level and the NOTCH1/FBXW7/RAS/PTEN oncogene (a four-gene oncogenetic classifier) status but not positron emission tomography or hematopoietic stem cell transplant as independent prognostic factors for outcome in T-LL. Conclusion In adults with LL, an intensive pediatric-like ALL treatment protocol was associated with a good response rate and outcome. In patients with T-LL, the four-gene oncogenetic classifier and lactate dehydrogenase level were independent prognostic indicators.

Parainfluenza Virus Type 3 Post Stem Cell Transplant: High Prevalence but Low Mortality.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3229-3229
Author(s):  
Fiona L. Dignan ◽  
Caroline L. Alvares ◽  
Unell Riley ◽  
Mark E. Ethell ◽  
David C. Cunningham ◽  
...  
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Lower Respiratory Tract Infection ◽  
Lower Respiratory Tract ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
High Prevalence ◽  
Type 3

Abstract Parainfluenza virus type 3 (PIV 3) is a well recognised cause of respiratory illness after stem cell transplant (SCT) with an estimated incidence of 2–7%.(Wendt et al. N Engl J Med1992; 326: 921–926, Nichols et al. Blood2001; 98: 573–578). Persistently high mortality rates have been documented in this population. The largest series to date reported 75% mortality from PIV 3 lower respiratory tract infection.(Nichols et al). Treatment options are limited. There are anecdotal reports of successful use of ribavirin treatment but no randomised controlled trials have been undertaken.We undertook a retrospective review of 23 cases of PIV 3 occurring in adult SCT recipients over a 12 month period. A total of 145 patients had received a SCT in the same time period and 20 developed PIV3 infection (13.8%). The frequency of infection was 36.1% (13 of 36) in matched unrelated donor SCT recipients, 23.8% (5 of 21) in sibling allogenic SCT recipients and only 2.3% (2of 88) in autologous transplant recipients. Fourteen patients had received Campath 1-H as part of their conditioning regimen. The remaining three PIV 3 cases had a transplant date prior to the 12 month period. The median time from transplant to PIV 3 diagnosis was 54 days (range −7 to 2037 days). Only 6 cases were inpatients at diagnosis. Seventeen cases were outpatient or community acquired despite standard infection control procedures. Cases were identified by nasopharyngeal aspirate taken at the first sign of coryzal symptoms. Immunofluorescence (IF) identified PIV 3 in 13 patients and the virus was cultured in the remaining 10 cases. Eleven patients developed only upper respiratory tract symptoms and all survived. Lower respiratory tract symptoms and signs developed in 12 patients, of which 8 had a new infiltrate on chest X-ray. Four patients required invasive ventilation and one required non-invasive ventilation. Overall mortality at 30 days from PIV3 diagnosis was 4% (1 of 23). Three patients died in total but PIV 3 was not believed to be the primary cause of death in any of these patients. Autopsy confirmed post transplant lymphoproliferative disorder in one patient. The second case had septicaemia from a multiresistant coliform. Bronchoscopy in the remaining patient revealed invasive aspergillosis but IF and culture were negative for PIV 3. Early ribavirin treatment was administered in 8 patients. The primary indication for ribavirin treatment was lower respiratory tract infection. Six cases received aerosolised treatment, one intravenous and one patient received both aerosolised and IV therapy. Only one patient who received ribavirin treatment died. These results suggest a higher prevalence of PIV 3 but lower mortality than previously documented particularly in allogenic transplant recipients. We propose that the high prevalence reflects our unit policy of active surveillance for respiratory viruses and the difficulty in preventing transmission of PIV 3 especially in the outpatient setting. Ribavirin treatment may improve outcome in patients with lower respiratory tract infection but is not required in all patients with PIV 3 infection.

Second Autologous Stem Cell Transplant (ASCT) as Salvage Therapy in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1217-1217
Author(s):  
Joseph R. Mikhael ◽  
Sahar Zadeh ◽  
A. Keith Stewart ◽  
Christine Chen ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Median Overall Survival ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Free Survival ◽  
Free Interval ◽  
Ortho Biotech

Abstract Abstract 1217 Poster Board I-239 Background Single autologous stem cell transplant (ASCT) is considered the standard of care after induction therapy for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. Method Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. Results Between February 1997 and July 2009, 79 MM pts received a second ASCT for relapsed MM at our institution. Median age was 60 yrs (range 39-72) at second transplant. 48 pts (61%) were male. Immunoglobulin subtype included IgG (42), IgA (21), light chain (11), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140-200 mg/m2 in 67, busulphan and cyclophosphamide in 1, and combinations of MEL with etoposide (E) or TBI in the rest. 2nd ASCT conditioning consisted of MEL alone in 76, the remaining 3 had MEL with either TBI or E. The median time to relapse after the first transplant was 2.72 years (0.81-8.26), with a median interval between transplants of 3.61 years (1.63-9.59). Response to first transplant in 78 evaluable patients was 13 CR/nCR (17%), 56 PR/VGPR (72%), 9 MR/SD (12%). Nineteen pts received maintenance therapy between transplants. Two transplant-related deaths occurred following 2nd ASCT. In 73 evaluable patients, response to second transplant was 11 CR/nCR (15%), 57 PR (78%), 6 MR/SD (8%). After 2nd ASCT, with median follow up 5.92 years (71 months), median progression-free survival (PFS) was 18.5 months and median overall survival (OS) was 4.4 years. Long term progression-free status based on the progression-free interval after 1st ASCT is summarized Table 1. PFS based on progression free interval after 1st ASCT is outlined in Figure 1. Conclusions 2nd ASCT is a feasible and safe salvage therapy in relapsed MM patients. It is effective in providing a median progression free survival of 18.5 months and median overall survival of 4.4 years (52.8 months) after 2nd ASCT. This is comparable if not better than modern salvage chemotherapies. The longer the disease free interval after 1st ASCT the more effective 2nd ASCT is at extending both progression free survival and overall survival. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT. Disclosures Chen: Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria.

Clinically Significant Mutations, Deletions and Translocations Involving ETV6 Identified by Whole Genome and Whole Exome Sequencing; Report From NCI/COG Target AML Initiative

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 125-125
Author(s):  
Heather L. Helton ◽  
Rhonda E. Ries ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Lisa R. Trevino ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Snp Genotyping ◽  
Whole Genome ◽  
Rna Seq ◽  
Genomic Alterations ◽  
Free Survival ◽  
Whole Exome ◽  
Childhood Aml ◽  
Clinically Significant ◽  
Pediatric Aml

Abstract Abstract 125 Despite identification of genomic alterations in AML, clinically actionable variants are limited. Further, mutations identified in adult AML are less frequent or not found in childhood AML. TARGET AML initiative, a collaboration between National Cancer Institute Office of Cancer Genomics (NCI/OCG) and Children's Oncology Group (COG) provided resources to perform multi-platform analysis of a large number of pediatric AML cases in order to identify therapeutic targets in childhood AML. As part of this effort, diagnostic, remission and relapse specimens from a large cohort of children with AML were subjected to whole genome sequencing (WGS). In addition, all specimens underwent characterization by expression profiling, SNP genotyping, methylation profiling and miRNA sequencing. Specimens from a subset of patients also underwent whole exome sequencing (WES) and whole transcript sequencing (RNA Seq). Here we present data from an interim analysis of the data that identified clinically significant, novel somatic mutations, deletions and translocations involving the ETV6 gene in pediatric patients with AML. Non-silent somatic mutations of ETV6, including missense, splice site mutations and indels were identified by WGS and WES. Large deletions involving ETV6 gene were identified by WGS and SNP/CGH arrays, and novel fusion transcripts (cryptic translocations) involving ETV6 were identified by WGS and RNA Seq. We present the prevalence and clinical significance of genomic alterations of ETV6 that were identified as part of TARGET AML study. WGS and WES data were available from 54 and 22 pediatric AML patients, respectively. In these 76 selected cases, somatic mutations in ETV6 were identified and verified in 3 patients. Frequency validation was performed by sequencing of the entire coding region of the ETV6 gene in diagnostic specimens from 180 children with AML. Somatic mutations of ETV6 gene were identified in 6% of patients, of which none had cytogenetic or molecular risk features. Those with somatic ETV6 mutations had an overall survival (OS) of 20% vs. 76% for those without mutations (p=0.002) with a corresponding relapse risk (RR) of 80% vs. 29% (p=0.004), demonstrating the potential impact of ETV6 mutations in pediatric AML. Deletions involving ETV6 gene (del ETV6) were detected in 3 patients by WGS and confirmed by SNP genotyping array and by fluorescent in situ hybridization (FISH). Subsequent interrogation of the SNP genotyping data identified deletions of 12p13 involving ETV6 in 19/242 patients (8%) ranging from 0.25 Mb to >20 Mb. Those with del ETV6 lacked cytogenetic (−7, or −5/del5q) or molecular (FLT3/ITD) high-risk features, but 50% of those with del ETV6 had core binding factor (CBF) AML. All patients with del ETV6 achieved a morphologic complete remission (CR) and had no evidence of minimal residual disease at the end of induction chemotherapy. Relapse risk for patients with and without del ETV6 was 63% vs. 45% (p=0.3) with a corresponding disease-free survival (DFS) of 32% vs. 53% (p=0.2). Due to the high prevalence of CBF AML in patients with del ETV6, we inquired whether this alteration might impact outcome in patients with CBF AML. In patients with CBF AML, del ETV6 was associated with adverse outcome, where CBF patients with and without del ETV6 had an event-free survival of 0% vs. 63%, respectively (p=0.002). Of the CBF AML patients who achieved an initial CR, those with compared to those without a del ETV6 had a RR of 88% (vs. 38%, p=0.08) with a DFS of 0% (vs. 61%, p=0.009) respectively. Cryptic ETV6 translocations involving at least two distinct translocation partners represented a third class of ETV6 alterations identified by WGS and RNA Seq. FISH evaluation of select patients was available and identified 16 patients with positive FISH for ETV6 variants. Those who had ETV6 alterations by FISH had a median age at diagnosis of 3.7 years. Evaluation of remission induction rate as well as post remission outcome demonstrated that all but 3 of these 16 patients either failed to achieve a CR (N=4) or relapsed after an initial remission (82% failure rate). These data identified varying genomic alterations of ETV6 by whole genome sequencing that identify a significant proportion of pediatric AML cases with adverse outcome who may be targeted for altered therapy. Disclosures: No relevant conflicts of interest to declare.

Tandem Autologous Stem Cell Transplantation in Chemorefractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4554-4554
Author(s):  
Catherine Garnett ◽  
Chrissy Giles ◽  
Osman Ahmed ◽  
Maialen Lasa ◽  
Holger W. Auner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Free Survival

Abstract Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

Characteristics Of Multiple Myeloma Patients With 6-Year Or Longer Progression-Free Survival After a Single Autologous Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3366-3366 ◽  
Author(s):  
Kehinde U.A. Adekola ◽  
Qaiser Bashir ◽  
Nina Shah ◽  
Sai Ravi Pingali ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Progression Free Survival ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival ◽  
Autologous Transplant ◽  
Preparative Regimen

Background High dose chemotherapy followed by an autologous stem cell transplant (auto-HCT) is considered standard of care in patients with newly diagnosed multiple myeloma (MM). In a recent randomized trial, median progression free survival (PFS) after auto-HCT, with or without maintenance therapy was 46 and 27 months, respectively (McCarthy P et al. NEJM 2012). However, about 15% of patients are reported to have much longer PFS (Pineda-Roman M et al. Cancer 2008). Here we tried to identify the factors that may predict a long PFS after auto-HCT. Methods We performed a retrospective chart review of patients who received an auto-HCT for MM between January 2000 and March 2007. A total of 1135 patients underwent an auto-HCT during this period, and 194 patients (17%) had a minimum PFS of 72 months or longer after a single auto-HCT. The primary objective was to determine the variables associated with a long PFS and overall survival (OS). Results Patient characteristics and outcomes are shown in the attached Table. The median age at auto-HCT was 56 years, and the median time from diagnosis to auto-HCT was 7.5 months. Twenty-three (13%) patients had ≥ 10% plasma cells in the bone marrow at auto-HCT and only 9 patients (4.8%) had high-risk cytogenetic abnormalities. One-hundred and fifty (77%) patients received induction therapy containing either an immunomodulatory (IMiD) agent or a proteasome inhibitor (PI). At the time of the auto-HSCT, only 13 (6.7%) patients were in CR and 38 (19.6%) were CR or VGPR after induction therapy (Table). One-hundred and sixty three (84%) patients received mephalan alone as conditioning regimen. Eighty-one (42%) patients received post auto-HCT maintenance. Eighty (41%) patients achieved a CR, while 104 (54%) achieved CR + VGPR after auto-HCT. Six patients (3.1%) developed a second primary malignancy post- autologous transplant. After a median follow-up of 95.4 months, median PFS was 97.3 months and median OS has not been reached. The 10-year PFS and OS were 41% and 73% respectively. Use of melphalan alone as preparative regimen was associated with a longer PFS and OS (p=0.004 and 0.004, respectively). Achievement of CR after auto-HCT was associated with a longer PFS only (p=0.001), and the use of IMiD or a PI as induction was associated with a longer OS (p=0.01). Conclusion Approximately 17% patients achieved a median PFS of 6 years or longer after a single auto-HCT. The long PFS in this cohort may be associated with younger age, low incidence of HR cytogenetics, use of an IMiD or PI as induction therapy, relatively low disease burden at auto-HCT, transplant from the year 2000 onwards, achievement of CR in >40% and the use of melphalan alone as preparative regimen. Disclosures: Shah: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees.

A Phase III Randomized, Double Blind, Placebo Controlled Multi-Center Study Of Panobinostat For Maintenance Of Response In Patients With Hodgkin Lymphoma Who Are At Risk For Relapse After High Dose Chemotherapy and Autologous Stem Cell Transplant: Final Results After Early Trial Discontinuation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4648-4648 ◽  
Author(s):  
Bastian von Tresckow ◽  
Aleksander Skotnicki ◽  
Igur Lisukov ◽  
Shivani Srivastava ◽  
David S. Morgan ◽  
...  
Keyword(s):  
At Risk ◽  
Stem Cell Transplant ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Double Blind ◽  
Grade 3

Introduction High dose chemotherapy with autologous stem cell transplant (ASCT) is the treatment of choice for Hodgkin Lymphoma (HL) patients suffering from relapse or progression after first line therapy. However, patients with recurrence after ASCT have a very poor prognosis. Thus, the oral deacetylase inhibitor panobinostat was evaluated as maintenance therapy for patients at risk for relapse after ASCT to prevent recurrences. Methods HL patients after ASCT with at least one of the risk factors: primary refractory disease, early relapse (<12 months), multiple relapses, stage III/IV disease or hemoglobin <10,5 g/dl at relapse prior to transplant were randomized to receive oral panobinostat (45mg three times a week, every other week, QOW) or placebo (2:1 randomization) in this phase III randomized, double blind, placebo controlled multi-center trial. As per the original protocol, disease-free survival (DFS) was the primary endpoint. However, the trial was terminated prematurely due to slow recruitment and the new primary objective was the provision of drug to ongoing patients randomized to panobinostat in an open label phase and to the evaluation of safety in the whole patient population. Results The study was closed to enrollment and data were unblinded with only a total of 41 patients out of the planned 367 patients enrolled; 27 patients in the panobinostat arm and 14 patients in the placebo arm. Three patients (1 from the panobinostat arm and 2 from the placebo arm) never received treatment. Data are reported for patients treated during the randomized phase and no formal statistical analyses were conducted. The median duration of treatment was longer in the placebo arm (217 days) than in the panobinostat arm (176 days, randomized phase). The majority of patients in both treatment arms had an exposure of ≥ 24 weeks (53.8% in the panobinostat arm, 75% in the placebo arm). In the panobinostat arm, the most common reasons that patients discontinued were due to withdrawal of consent (29.8%) and adverse events (22.2%), whereas in the placebo arm, patients most commonly discontinued due to disease progression (28.6%). Most adverse events (AEs) occurred more frequently in the panobinostat arm (randomized phase). The most frequently reported AEs as compared to the placebo arm included: diarrhea (88.5%/25%), nausea (57.7%/8.3%), vomiting (46.2%/25%), fatigue (34.6%/25%), neutropenia (26.9%/33.3%), thrombocytopenia (26.9%/8.3%), oropharyngeal pain (26.9%/0%), headache (23.1%/0%), nasopharyngitis (19.2%/0%), upper respiratory infection (19.2%/8.3%), decreased appetite (15.4%/16.7%), pyrexia (15.4%/8.3%), influenza like illness (15.4%/0%) and sinusitis (15.4%/8.3%). Overall, the incidence of grade 3/4 AEs was 65.4% in the panobinostat arm during the randomized phase and 41.7% in the placebo arm. In the panobinostat arm, the most frequently reported grade 3/4 AEs were neutropenia (26.9%), thrombocytopenia (15.4%), and diarrhea, vomiting and fatigue (all 11.5%). In the placebo arm, the most frequently reported grade 3/4 AEs were neutropenia (33.3%), leukopenia (16.7%) and herpes zoster (16.7%). Although efficacy could not be formally evaluated due to the small number of patients in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study due to disease progression (28.6% vs. 14.8% panobinostat patients). Conclusion The safety observations from this study were consistent with the general safety profile known for panobinostat. The use of panobinostat in a maintenance setting in a QOW schedule appeared to have acceptable tolerability in a population of patients with HL who are at risk for relapse after high dose chemotherapy and ASCT. Disclosures: von Tresckow: Takeda: Honoraria, Reimbursement of congress, travel, and accommodation costs , Reimbursement of congress, travel, and accommodation costs Other; Novartis: Consultancy, Honoraria. Szer:Novartis: Membership on an entity’s Board of Directors or advisory committees. Sureda:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.

Efficacy and Safety Of Treatments For Relapsed Or Refractory DLBCL: Results Of a Systematic Literature Review

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5104-5104 ◽  
Author(s):  
Ann Colosia ◽  
Peter C Trask ◽  
Robert Olivares ◽  
Shahnaz Khan ◽  
Adeline Abbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Career Development Award

Abstract Background Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of non-Hodgkin’s lymphoma (NHL) cases in Western countries. Although two-thirds of patients may be cured with combination chemotherapy, in the event of treatment failure and for those who are refractory to treatment, survival is usually measured in months. Several therapeutic modalities have been utilized for patients with relapsed or refractory disease, but among patients who are not eligible for high-dose chemotherapy with stem cell transplant, a comprehensive assessment of efficacy and safety is lacking. This systematic literature review (SLR) was designed to exhaustively collect and review information on the clinical efficacy and safety of the different interventions used in the treatment of refractory or relapsed DLBCL, and if possible to perform a meta-analysis. Methods Electronic databases (PubMed, Cochrane Library, Embase) were searched for relevant studies published from 1997 to August 2, 2012. In addition, conference abstracts, bibliographic reference lists of included articles and recent reviews, and the Clinicaltrials.gov database were searched for phase 2, 3, or 4 studies displaying results, potentially unpublished in peer-reviewed journals. Main efficacy outcomes included objective response rate (ORR), complete response, partial response, duration of response, progression-free survival (PFS), and overall survival (OS). Safety endpoints focused on grade 3/4 toxicities and treatment discontinuation due to toxicity. Studies had to report on relapsed or refractory DLBCL after at least one standard treatment and patients who were not eligible to receive high-dose chemotherapy or stem cell transplant (autologous or allogeneic). Mixed type NHL studies were required to report DLBCL outcomes separately for inclusion. Results A total of 3,308 publications were identified in the first pass of a broad SLR on NHL; of these, 57 provided relevant data for DLBCL representing 54 unique studies. Of the 54 studies, there was 1 phase 3 study, 33 phase 2 studies, and 4 phase 1/2 studies (15 studies did not report the study phase and 1 was an observational study). Six studies were comparative (3 randomized trials; 3 nonrandomized trials) with two treatment arms; 48 studies were single arm. Of the 48 regimens evaluated, few regimens were represented more than once. Overall survival and PFS were often not reported or not reported separately for the patients with DLBCL in studies that enrolled patients with any of the multiple lymphoma histologies. Refractory and relapsed criteria were often not defined, and definitions were heterogeneous when available. The ORR from the few comparative studies ranged from 27% to 100%, with most estimates between 40% and 70%. PFS with low and high doses of obintuzumab was 2 months and 3 months, respectively in one study, and OS was 4 months with MEP and 7 months with C-MEP in another study. There was a common regimen in two of the randomized controlled trials, but the patient populations in these studies differed too greatly to allow a valid meta-analysis to be performed. In the single-arm studies, ORR ranged from 11% to 100%, with the estimates evenly distributed across that range. Progression-free survival was approximately 1 to 10 months. Reported median OS ranged from 1 to 13 months. Main safety concerns included thrombocytopenia, leukopenia, and neutropenia. Conclusions There is a high unmet need for effective therapies for patients with relapsed or refractory DLBCL who are ineligible for stem cell transplant. Although numerous regimens have been evaluated in single-arm trials and a handful in comparative studies, there is no clearly superior regimen for patients with relapsed or refractory DLBCL, especially in third- and later lines of therapy. FA is supported by a Clinical Career Development Award from the Lymphoma Research Foundation Disclosures: Colosia: RTI Health Solutions: Employment. Trask: Sanofi: Employment. Olivares: Sanofi: Employment. Khan: RTI Health Solutions: Employment. Abbe: Sanofi: Employment. Police: RTI Health Solutions: Employment. Njue: RTI Health Solutions: Employment. Wang: RTI Health Solutions: Employment. Sherrill: RTI Health Solutions: Employment. Ruiz-Soto: Sanofi: Employment. Kaye: RTI Health Solutions: Employment. Awan: Lymphoma Research Foundation (Career Development Award): Research Funding.

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