Outcome of Patients with Relapsed/Refractory AIDS-Related Lymphoma In the AIDS Malignancy Consortium (AMC) 1997–2008

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3569-3569
Author(s):  
Ariela Noy ◽  
Ulas Darda Bayraktar ◽  
Neel Gupta ◽  
Adam M. Petrich ◽  
Page Moore ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Infectious Complications ◽  
High Dose ◽  
Hiv Diagnosis ◽  
Curative Intent ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Aids Related Lymphoma

Abstract Abstract 3569 Introduction: High dose therapy (tx) with autologous hematopoietic stem cell transplantation (AHSCT) in (rel/rfr) lymphoma is the standard of care in the general population with chemosensitive disease. The feasibility of second line therapies (Tx) and AHSCT in (rel/rfr) AIDS related lymphoma (ARL) has been shown in a number of trials. However, the true impact of 2nd line tx and AHSCT is unknown, as nearly all studies focus on those already with disease sensitive to 2nd therapy going onto transplantation. The only recent study capturing patients (n=50) before 2nd line tx showed 49% progression-free survival (Re et al. Blood 2009). Here, we retrospectively analyzed the outcome of patients (pts) presenting at 13 US AIDS Malignancy Consortium sites with (rel/rfr) ARL in the HAART era. Patients and Methods: HIV-positive pts initiating tx for (rel/rfr) ARL between 1997–2008 were included. Overall survival (OS) was calculated from the initiation of 2nd line tx. Results: A total of 126 pts received 2nd line tx. Only those 88 pts who received 2nd line with curative intent to treat (ITT) were included in the analysis. Baseline and selected clinical characteristics are summarized in the table. Median CD4 at HIV diagnosis was 110 (n=37) with a range of 12 to 1000. At ARL dx, median CD4 was 152 (5-803). 47% had an opportunistic infection (OI) prior to ARL. 2nd line tx were: ICE (n=34), EPOCH (n=16), ESHAP (n=11), High-dose MTX variants (n=10), Hodgkin's specific tx (n=5), DHAP (n=4) and others (n=8). Thirty-two (36%) had a response to 2nd line tx (CR, n=21; PR, n=11). Of 50 pts with grade ≥3 toxicities, the most common were thrombocytopenia (46%) and neutropenic fever (44%). Six pts died during 2nd line tx due to infectious complications, with 1 aspergillosis. Best response to 2nd line tx: Thus, CR/PR was 32/88 (36%) in ITT analysis. Only 10/32 CR/PR pts went onto AHSCT due to availability and changing treatment paradigms. Conditioning was BEAM (n=9) and Bu/Cy (n=7). No pt went onto allotransplant. At AHSCT day +90, 10 pts were in CR. For all pts, median follow-up was 122 weeks (range, 8–597), median OS was 38 weeks (95% CI, 27–63). Reflecting the 65% prevalence of pts refractory to 2nd line tx in the non-AHSCT group, OS was longer in pts who underwent AHSCT compared to those who did not (2-year OS: 55.3% vs. 31.0%). Surprisingly, 1-year OS in the CR/PR pts was 87.5±12.5% for AHSCT and 81.8±8.2% for non-AHSCT. One Burkitt pt survived a year without AHSCT. Discussion: Rel/rfr ARL was treated aggressively in this largest ever reported cohort, but CR/PR was only 32/88 (36%) in ITT analysis. Not all CR/PR pts went onto AHSCT due to changing treatment paradigms and regional availability. Aggressive 2nd line tx and ASHCT was feasible despite prior low CD4 and OI, but DFS may be possible without transplant. We cannot draw conclusions about the impact of AHSCT from this retrospective cohort. Similarly, it is not known whether survival in (rel/rfr) ARLs is equivalent to the HIV negative population. The current paradigm is to offer pts with rel/rfr ARLs AHSCT if disease is chemosensitive and no contraindication exist. New strategies are needed for 2nd line therapy, particularly in rel/rfr BL. Disclosures: No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 877-877
Author(s):  
Mauricette Michallet ◽  
Peter Dreger ◽  
Laurent Sutton ◽  
Ronald Brand ◽  
Sue Richards ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Disease Status ◽  
Primary Objective ◽  
Phase Iii ◽  
Induction Treatment ◽  
Hematopoietic Stem ◽  
Binet Stage ◽  
The Impact

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Endobronchial brachytherapy with curative intent: the impact of reference points setting according to the bronchial diameter

2017 ◽  
Vol 58 (6) ◽  
pp. 849-853 ◽  
Author(s):  
Yoshihito Nomoto ◽  
Noriko Ii ◽  
Shuichi Murashima ◽  
Yasufumi Yamashita ◽  
Satoru Ochiai ◽  
...  
Keyword(s):  
External Beam Radiotherapy ◽  
Progression Free Survival ◽  
High Dose Rate ◽  
Reference Points ◽  
High Dose ◽  
Curative Intent ◽  
Bronchial Wall ◽  
Reference Dose ◽  
Bronchial Lumen ◽  
The Impact

Abstract Endobronchial brachytherapy (EBB) is an effective treatment for endobronchial tumors. However, bronchial toxicity caused by over-irradiation remains problematic. To decrease bronchial toxicity, we developed a source-centralizing applicator for EBB. The purpose of the present study was to assess the efficacy and safety of EBB with varying reference dose points according to the bronchial diameter, using a source-centralizing applicator. We reviewed 15 patients with endobronchial carcinoma who were treated with curative intent using a combination of external beam radiotherapy (EBRT) and high-dose-rate EBB between 2005 and 2014. During each EBB session, we used a source-centralizing applicator that maintained the source-delivering catheter in the center of the bronchial lumen. Reference dose points were 5–7 mm from the source axis, depending on the bronchial diameter. The median radiation doses of EBRT and EBB were 40 Gy in 20 fractions and 18 Gy in 3 fractions, respectively. The median observation period was 36 months. The 3-year overall survival, progression-free survival and local control rates were 79%, 77% and 100%, respectively. Grade 2 radiation pneumonitis was observed in two cases. Bronchial toxicities, such as hemoptysis or the symptoms of chronic bronchitis, were not observed. EBB with varying reference dose points according to bronchial diameter, using a source-centralizing applicator, is a promising procedure that may be effective for tumor elimination and reducing toxicity to the bronchial wall.

First and Second High Dose Treatment Supported by Autologous Hematopoetic Cell Transplantation Rescue in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4528-4528
Author(s):  
Sinem Civriz Bozdag ◽  
Pervin Topcuoglu ◽  
Meral Beksac ◽  
Osman Ilhan ◽  
Muhit Ozcan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Transplantation ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Early Period ◽  
Progression Free Survival ◽  
Response Rates ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival

Abstract Abstract 4528 Purpose: We aimed to evaluate the outcome of multiple myeloma patients underwent double autologus hematopoietic cell transplantation in our center. Patient&Method: We retrospectively analyzed 31 multiple myeloma patients (22F;9M) receiving two times high dose therapy supported by auto-HCT in Adult BMT Unit of Ankara University between 2005–2010. Median age was 52 years (34–66ys) prior to first auto-HCT. We evaluated the response rates of progression free survival (PFS) of both transplantation, respectively and also overall survival (OS) from the diagnosis. Results: The median time from diagnosis to the first transplantation was 11 months (5–68ms). The response rates were 87% before the first auto-HSCT [2 Complete response (CR),4 near-CR, 7 very good partial remission (VGPR), 14 PR) but four patients (11%) had refractory disease. The response of first auto-HCT was complete remission or partial response in 50% of the pts and 36% for stable disease. Only 4 pts was progressed at early period of 1st auto-HCT. The median time from the 1st to 2nd auto-HSCT was 16 months (3–64 ms). Seventy-seven percent patients sue to progressive disease responded completely or partially to one or two step treatment regimens before the second auto-HSCT. When evaluated the responses after the second auto-HCT, 14 (46%) patients were in CR or near-CR, 12 (38%) for stabile disease and 5 for refractory. PFS was estimated similar after both first and second auto-HCT (median 9 months vs 10 months, p=0.3) (Graphic 1). Five- year OS from the diagnosis was 75±10%. Conclusion: PFS of the myeloma pts was estimated similar median time after 1st&2nd auto-HSCT. Collection of adequate hematopoietic stem cells enough for more than one auto-HCT in myeloma patients can be appropriate. Although the majority of responses after the first AHSCT were partial responses, complete or near complete responses were dominant after the second AHSCT.Improvement in responses and the similarity of progression free survival can be explained by the contribution of the new antimyelom treatment options Disclosures: No relevant conflicts of interest to declare.

scholarly journals Autologous Stem Cell Transfusions on Multiple Days in Patients with Multiple Myeloma - Does It Matter?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3252-3252
Author(s):  
Thomas Pabst ◽  
Sebastian Moser ◽  
Ulrike Bacher ◽  
Barbara Jeker ◽  
Behrouz Mansouri Taleghani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Cd34 Cells ◽  
The Impact

Introduction: Autologous stem cell transplantation (ASCT) following high-dose chemotherapy (HDCT) is a cornerstone in the standard first-line treatment in myeloma (MM) patients. Freezing of the hematopoietic stem cells (HSC) to bypass the time between stem cell collection and completion of HDCT is crucial for this process. Due to the vulnerability of HSC, adding of anti-freezing agents such 5-10 vol% dimethyl-sulfoxide (DMSO) to hematopoietic stem cells is mandatory. DMSO exerts toxic effects after administration, and toxicity of DMSO is dose-related. However, guidelines for this procedure are missing, and transplant centers have implemented varying limitations of maximum total DMSO administration, ranging from 20-70 g per day. At our center, the maximum transplant volume is 300 mL per day with DMSO at 5 vol%. For patients with transfusion volumes above these limits, the transplant procedure is split over several days. Methods: In this single center study, we retrospectively analyzed the impact of multiple day transplantation procedures on survival rates and hematological recovery in 271 patients with MM patients undergoing first melphalan-based ASCT. Results: 244 (90%) received ASCT within a single day, and this group was termed Tx1. The Tx2-3 group comprised 23 patients receiving stem cells on 2 days, and four patients on 3 days. Both groups (Tx1 and Tx2-3) did not differ in clinical characteristics or number/types of induction therapy lines. The remission status pre-transplant was comparable. Plerixafor was given more frequently in Tx2-3 than Tx1 (p=0.0715). At the day of SC collection, peripheral CD34+ counts were lower in Tx2-3. The final administered autograft volume was higher in Tx2-3 patients. The amount of transplanted CD34+ cells/kg b.w. was lower in the Tx2-3 group, mirroring poorer mobilization of CD34+ cells (p<0.0001). The median recovery for neutrophils was 13 days for Tx2-3 and 12 days for Tx1 (p=0.0048), and for platelets 18 versus 14 days (p=0.0004). Tx2-3 patients had longer median hospitalization duration (23 versus 19 days; p=0.0006). The median follow-up was 56 months. Relapse-free survival (RFS) was 39 months, and 169 relapses (62%) occurred so far. Median OS was 91 months, and 82 patients (30%) have died during follow-up. Tx2-3 patients had shorter median RFS (21 versus 40 months for Tx1; p=0.0245), and shorter median OS with 55 versus 93 months (p=0.0134) (Figure 1). Conclusions: Our data suggest that multiple day transplantation is associated with poor CD34+ mobilization and is observed in roughly 10% of myeloma patients. Patients with multiple day transplant procedures had later neutrophil and platelet engraftment, longer hospitalization duration, more febrile episodes, and inferior OS and RFS. This suggests to consider myeloma patients with the need for multiple day transplantation as a patient group at increased risk that needs enhanced surveillance strategies. Disclosures No relevant conflicts of interest to declare.

High Dose Therapy and Autologous Stem Cell Transplantation Still Improves Progression Free Survival in First Relapse for DLBCL in the Rituximab Era: A Study Using Patients as Their Own Controls.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2191-2191
Author(s):  
Anna Sureda ◽  
Carme Canals ◽  
Nicolas Mounier ◽  
Roberto Foa ◽  
Eulogio Conde ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Impact

Abstract Autologous stem cell transplantation (ASCT) remains the treatment of choice for patients (pts) with diffuse large B-cell lymphoma (DLBCL) that relapse after first line chemotherapy (CT). Nevertheless, the impact of the use of the anti-CD20 monoclonal antibody (Rituximab®) (RTX) with combination CT on the ulterior results of the transplantation procedure has to be determined. One of the main factors affecting survival after ASCT is a short first remission duration. This study was designed to evaluate the benefit of this strategy, in pts with DLBCL achieving after salvage CT a 2nd complete remission (CR2), by retrospectively comparing for each pt the progression free survival (PFS) after ASCT with the duration of the previous CR. Adult DLBCL pts with MEDB information available autografted in CR2 between 1990 and 2005 in EBMT centres were included in the analysis. A total of 386 pts (224 males, median age 47 (18–71) years] were evaluated. 294 pts (74%) did not receive RTX prior to ASCT, 67 pts (17%) did receive it at all and in 34 pts (9%) this information is missing. Duration of CR1 was 12 (3 – 142) months [median (range)]; it lasted less than 6 months in 25% of the cases and was longer than 24 months in 25% of the pts. Median time from diagnosis to ASCT was 25 (6–181) months. Peripheral blood was used as the source of hematopoietic stem cells in 311 pts (81%). The BEAM protocol was the conditioning regimen most frequently used (n = 244, 63%) and only 5.5% pts were conditioned with TBI-containing regimens. After a median follow up after ASCT for surviving pts of 42 months, overall survival (OS) was 63% and PFS 48%. 158 pts did relapse after ASCT [median (range), 10 (3–200) months] and 32 pts died from non-relapse mortality. When each patient was taken as her/his own control, PFS after ASCT was longer than CR1 (p &lt; 0.001). During the initial phase of the disease, 74% pts experienced 1st relapse in less than 2 years, compared with only 32% of the patients who experienced 2nd relapse 2 years after ASCT. The use of RTX prior to ASCT did not impair the beneficial effects of the autologous procedure in the whole population of pts (RTX no: 66% vs 33%, p &lt; 0.001; RTX yes: 73% vs 26%, p = 0.001). 2-years PFS after ASCT was significantly lower in patients with a CR1 &lt; 12 months (p &lt; 0.001). However, in this subgroup of patients PFS after ASCT was significantly longer than CR1 duration when studying each pt as his/her own control (p = 0.001). ASCT can significantly increase PFS in comparison with the duration of CR2 in DLBCL and can change disease course. The use of RTX prior to ASCT does not decrease the beneficial effect of pts autografted in CR2 when compared to their prior CR1 duration. The duration of CR1 remains one of the most important prognostic factors for ASCT outcome.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Human Genetic Diversity Alters Therapeutic Gene Editing Off-Target Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3993-3993
Author(s):  
Linda Yingqi Lin ◽  
Samuele Cancellieri ◽  
Jing Zeng ◽  
Francesco Masillo ◽  
My Anh Nguyen ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Clinical Trials ◽  
Genome Editing ◽  
Gene Editing ◽  
Conflicts Of Interest ◽  
African Ancestry ◽  
Great Promise ◽  
Personal Genome ◽  
Hematopoietic Stem ◽  
The Impact

Abstract CRISPR gene editing holds great promise to modify somatic genomes to ameliorate disease. In silico prediction of homologous sites coupled with biochemical evaluation of possible genomic off-targets may predict genotoxicity risk of individual gene editing reagents. However, standard computational and biochemical methods focus on reference genomes and do not consider the impact of genetic diversity on off-target potential. Here we developed a web application called CRISPRme that explicitly and efficiently integrates human genetic variant datasets with orthogonal genomic annotations to predict and prioritize off-target sites at scale. The method considers both single-nucleotide variants (SNVs) and indels, accounts for bona fide haplotypes, accepts spacer:protospacer mismatches and bulges, and is suitable for personal genome analyses. We tested the tool with a guide RNA (gRNA) targeting the BCL11A erythroid enhancer that has shown therapeutic promise in clinical trials for sickle cell disease (SCD) and β-thalassemia (Frangoul et al. NEJM 2021). We find that the top predicted off-target site is produced by a non-reference allele common in African-ancestry populations (rs114518452, minor allele frequency (MAF) = 4.5%) that introduces a protospacer adjacent motif (PAM) for SpCas9. We validate that SpCas9 generates indels (~9.6% frequency) and chr2 pericentric inversions in a strictly allele-specific manner in edited CD34+ hematopoietic stem/progenitor cells (HSPCs), although a high-fidelity Cas9 variant mitigates this off-target. This report illustrates how population and private genetic variants should be considered as modifiers of genome editing outcomes. We expect that variant-aware off-target assessment will be required for therapeutic genome editing efforts going forward, including both ongoing and future clinical trials, and we provide a powerful approach for comprehensive off-target prediction. CRISPRme is available at crisprme.di.univr.it. Disclosures No relevant conflicts of interest to declare.

scholarly journals Stereotactic Ablative Radiotherapy for the Treatment of Oligometastatic Cancer: A Clinical Review as Part of a Health Technology Assessment

2021 ◽  
Vol 1 (3) ◽  
Author(s):  
Chantelle C. Lachance ◽  
Khai Tran ◽  
Elizabeth Carson ◽  
Joanne Kim ◽  
David Palma ◽  
...  
Keyword(s):  
Clinical Review ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Clinical Effectiveness ◽  
Standard Of Care ◽  
The Body ◽  
Stereotactic Ablative Radiotherapy ◽  
High Dose ◽  
Normal Tissues ◽  
Oligometastatic Cancer

Oligometastatic cancer (cancer with a limited number of metastases) represents an intermediate state between cancer confined to a single location in the body and cancer that has metastasized — or spread — widely. One treatment option, for which there is growing interest, is stereotactic ablative radiotherapy, also known as SABR. SABR precisely delivers a high dose of radiation to ablate tumours at specific sites while minimizing the radiation dose to surrounding normal tissues. SABR may be used independently or alongside other treatment options in the management of oligometastatic cancer. This CADTH clinical review evaluated the evidence regarding the clinical effectiveness and safety of SABR with or without standard of care (SOC) for people with oligometastatic cancer and found the following: SABR in addition to SOC may offer a benefit in terms of overall survival (OS) and progression-free survival (PFS). The findings for the effectiveness of SABR alone compared with SOC were mixed and deemed inconclusive. There are insufficient data related to adverse events (AEs) at the present time to draw conclusions regarding the safety of SABR relative to SOC alternatives. Note that the CADTH Clinical Review Report will be updated every 3 months to ensure the findings remain up-to-date as new evidence emerges.

scholarly journals Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5631-5631 ◽  
Author(s):  
Cassidy Brothers
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Severe Neutropenia ◽  
High Dose ◽  
Cell Transplant ◽  
Curative Intent ◽  
Hematopoietic Stem

Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.

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