Cumulative Incidence Of Acute Grade Research Articles

Long-Term Outcomes of Prospective Clinical Trial HDR-Brachytherapy Monotherapy in Single Day in Patients with Localized Prostate Cancer

This prospective clinical trial to evaluated long-term outcomes associated with 2 fractions in a single day, one implant, high-dose-rate (HDR) brachytherapy as monotherapy for patients with localized prostate cancer. We report Genitourinary (GU) and gastrointestinal (GI) toxicity and Disease control. Between November 2010 and Feb 2016 a total of 120 patients diagnosed with low/intermediate-risk localized prostate cancer were treated. The prescribed dose was 27 Gy in 2 fractions in a day using a single implant. 34 patients (28%) were intermediate-risk cancer. 38 patients (31,7%) received hormonal therapy. We measured the incidence of no biochemical evidence of disease (bNED) based on the Phoenix definition of failure (nadir prostate-specific antigen (PSA) + 2 ng/mL). GU and GI toxicity were evaluated by CTCAE v4.0 and sexual function were prospectively documented at each follow up visit. With a median follow-up was 123 months (range 9-148) the actuarial rates of Local Control were 96%, Biochemical Control 93.4%, Distant Failure 3.3%, Disease-Free Survival 92.3 %, Metastasis-free survival 96.67% and Overall Survival was 86.7%. The cumulative incidence of acute grade (G) 1-2 GU toxicity was 20.8%, mainly frequency/urgency (10%), dysuria (10%), dribbling/hesitancy (0.8%). 3 patients required a Foley catheter during 1 week. No acute GI toxicities were recorded. Chronic G1-2 GU toxicities were 29 %, mainly dysuria (12.6%), urinary frequency/urgency (5.8%) and urinary Incontinence G2 (1.6%). 1 patient had G2 rectal bleeding and 2 patients had G3 GU toxicity requiring transurethral resection of bladder (TURB). 23.7% of patients without Hormonal therapy reported G1-2 sexual impotence after 2 years therapy. With 10 years of follow-up, our prospective data are sufficiently mature to report on efficacy and toxicity outcomes, making a single implant, 2 fractions HDR-BT an attractive option for patients with localized low/intermediate-risk prostate cancer and be able to consider it a standard of care in this setting. To the best of our knowledge, this is the first report regarding single day HDR-BRT as monotherapy with a median follow-up of 10 years.

P1351: CHARACTERIZING ALLOGENEIC STEM CELL TRANSPLANTATION SAFETY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AFTER PEMBROLIZUMAB THERAPY

Background: Although allogeneic stem cell transplantation (allo-SCT) and programmed cell death 1 (PD-1) blockade have separately shown efficacy in some lymphoid malignancies, the safety of allo-SCT after anti–PD-1 therapy in these patients remains a high clinical interest. Aims: We present data from an analysis from 4 KEYNOTE phase 1-3 studies to describe predetermined complications in patients who received allo-SCT following pembrolizumab therapy. Methods: The analysis included patients from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials who have a known allo-SCT transplantation date received within 2 years of the last dose of study pembrolizumab. Descriptive statistics were used for predefined post–allo-SCT complications of interest. The cumulative incidence of acute grade 2-4 graft-versus-host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. The cumulative incidence of post–allo-SCT transplant-related mortality (TRM) was estimated with relapse as a competing risk. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Seventy patients were included in the analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma (cHL), and the rest had non-Hodgkin lymphoma. 69 of 70 (98.6%) patients received pembrolizumab monotherapy; 1 patient received pembrolizumab + lenalidomide. Median duration on study treatment was 5.3 months (range, 0.7-29.6) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Before transplantation, 49 patients (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 patients (44.3%) were in remission at time of transplant, and 5 patients (7.1%) had unknown disease status. Overall, 55 patients (78.6%) developed GVHD (acute, 38; chronic, 17). The estimated 6-month post–allo-SCT cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade II-IV acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade III-IV acute GVHD; 1 year post–allo-SCT was 0.21 (95% CI, 0.12-0.31) for chronic GVHD. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and veno-occlusive liver disease, occurred in 32 patients (45.7%). After a median follow-up (defined as the time from allo-SCT to data cutoff) of 40.1 months (range, 5.1-71.2), the post–allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post–allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median OS was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated post–allo-SCT cumulative incidence for TRM at 6 months was 0.09 (95% CI, 0.03-0.17) and for relapse at 26 months was 0.27 (95% CI, 0.16-0.38). PFS and OS outcomes were comparable in the subgroup of patients with cHL. Image:Summary/Conclusion: The incidence of GVHD in this population is comparable to historical data (40%-80% and 30%-70%, respectively). The incidence of severe acute GVHD may be higher than a typical modern allo-SCT series, although TRM was low. The observed PFS and OS outcomes compare favorably to historical benchmarks (2-year PFS ranging from 45%-48%; 1-year OS >80%). Altogether, this analysis lends confidence that allo-SCT is feasible for patients with lymphoid malignancies after PD-1 blockade.

Feasibility and safety of definite volumetric modulated arc therapy with simultaneous integrated boost to the dominant intraprostatic lesion in patients with unfavorable intermediate to high-risk prostate cancer.

BackgroundThe most common site of recurrence of prostate cancer after definite radiation therapy is the dominant intraprostatic lesion (DIL). This study aimed to investigate the feasibility and safety of definite volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) to the DIL in patients with unfavorable intermediate to high-risk prostate cancer.Materials and methodsIn this prospective uncontrolled clinical trial, patients were delivered VMAT at a dose of 87.75 Gy in 39 fractions or 70 Gy in 20 fractions to the DIL in combination with androgen deprivation therapy. Genitourinary (GU) and rectal toxicity, International Prostate Symptom Score (IPSS) and IPSS quality of life (IPSS-QOL) score were collected.ResultsForty-five patients with a median follow-up of 20 months were analyzed. The cumulative incidence of acute grade ≥ 2 GU and rectal toxicity was 33.1% and 9.5%, respectively. Regarding late toxicity, the cumulative incidence of grade ≥ 2 GU and rectal toxicity was 12.6% and 2.8%, respectively. During treatment, the mean increase of IPSS was +7.4 ± 4.2 and the mean increase of IPSS-QOL was +1.7 ± 1.3. However, both IPSS and IPSS-QOL scores returned to their baseline levels by 3-months post-treatment. No significant correlation between baseline characteristics and grade ≥ 2 GU or rectal toxicity was found.ConclusionFocal SIB to the DIL of ≥ 90 Gy EQD2 in unfavorable intermediate to high-risk prostate cancer patients resulted in tolerable toxicity profiles. The mean IPSS and IPSS-QOL scores both worsened during treatment; however, both scores returned to baseline level by 3 months after treatment.

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Safety of Addition of Inotuzumab Ozogamicin (CMC 544) to Bendamustine, Fludarabine, and Rituximab (BFR) Allogeneic Conditioning for Lymphoid Malignancies

Background: The cell-surface glycoprotein CD22 is expressed in more than 90% of patients with B-cell lymphoid malignancies, and has emerged as an attractive therapeutic target for B-cell cancers. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. After the conjugate binds to CD22, the CD22-conjugate complex is rapidly internalized, and calicheamicin is released. Calicheamicin binds to the minor groove of DNA and thus induces double-strand cleavage and subsequent apoptosis. Retrospective studies have suggested that inotuzumab ozogamicin is associated with a high risk of veno-occlusive disease (VOD) in patients receiving allogeneic stem cell transplantation (alloSCT). Our report is the first to prospectively study the safety of the drug when added to our standard non-myeloablative conditioning regimen, BFR (Khouri IF, et al. Blood 2014;124:2306-2312). Methods: Inotuzumab ozogamicin was infused intravenously (IV) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2, using the study design by Ji, Li, and Bekele (2007) to determine the maximum tolerated dose . Bendamustine 130 mg/m2 IV daily on days -5 to -3 together with 30 mg/m2 IV of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m2 IV on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GvHD) prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Results: This study included 21 patients (CLL=9; 3 with 17p- and 1 Richter's), mantle cell=7, follicular=3, and diffuse large cell=2; including 1 double-expresser). Median age was 59 (range, 31-70) years. Median prior treatments was 3 (range, 1-6); this includes ibrutinib+/-R (n=5), idelalisib (n=2), venetoclax (n=4), CAR-T cell with progression (n=1) and a prior autologous SCT (n=1). At study entry, 13 (62%) patients were in CR/CRu, 6 (29%) in PR, and 2 (10%) had SD. Three of the 17 scans performed (18%) were PET+. Ten (48%) received their transplants from HLA-compatible siblings and 11 (52%) from unrelated donors. The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of inotuzumab ozogamicin were 4, 2 and 15 patients, respectively. Median number of CD34+ cells infused was 6.7 x 106/kg. Twenty (95%) patients received transplants from peripheral blood and 1 (5%) from marrow. Neutrophil counts recovered to > 0.5 x 109/L a median of 6 days after transplantation (range, 0-12 days). Fifteen patients (71%) never experienced an ANC < 0.5 x 109/L nor required platelet transfusions. All patients engrafted donor cells and no secondary graft failure occurred. By day 30, median donor myeloid and T-cells were 89% and 99%, respectively. Both increased to 100% by day 90. The cumulative incidence of acute grade 2-4 GvHD and chronic extensive GvHD were 29% (5% of grade 3, and 0% of grade 4) and 35%, respectively. Two patients died due to GvHD complications. One patient with underlying cholelithiasis developed acute cholecystitis with inotuzumab ozogamicin and was able to proceed with alloSCT after recovery. No dose-limiting toxicities or VOD were observed. With a median follow-up time of 23.5 (range, 3-54) months, the OS rate was 89% (90% CLL/follicular, 86% mantle cell and 100% in diffuse large cell; also 100% for siblings, 81% for unrelated) and the PFS rate was 78%(Figure). Conclusions: Our results show that inotuzumab ozogamicin at a dose level of 1.8 mg/m2 is well-tolerated when combined with the BFR non-myeloablative allogeneic conditioning regimen for lymphoid malignancies. No added toxicity or increased myelosuppression were observed compared to our past experience with the BFR alone. The study is now expanded to further evaluate efficacy in a larger cohort of patients. [Display omitted] DisclosuresKhouri:Novartis: Research Funding. Oran:Celgene: Research Funding; Astex: Research Funding; AROG: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial

BackgroundStereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT.MethodsThree hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator’s discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used.DiscussionThe MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies.Trial registrationClinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020.https://clinicaltrials.gov/ct2/show/NCT04384770Protocol versionVersion 2.1, Aug 28, 2020.

Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: A Retrospective Cohort Study.

: Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. : We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. : We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P=.17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P=.05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD. : ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.

High dose rate brachytherapy for prostate cancer: A prospective toxicity evaluation of a one day schedule including two 13.5 Gy fractions

Background and purposeHigh dose-rate (HDR) brachytherapy (BT) provides a highly conformal method of dose delivery to the prostate. The purpose of this study is to prospectively determine the toxicity of the treatment protocol of 13.5 Gy × 2 fractions. Materials and methodsFrom 2010 through 2017, 119 patients with low (71%) or intermediate-risk prostate cancer were prospectively treated in a single institute with HDR-BT at 13.5 Gy × 2 fractions within one day. Median follow-up time was 4.4 years. ResultsActuarial rates of no biochemical evidence of disease, overall survival and metastasis-free survival for all patients were 96%,98% and 98%, respectively. The cumulative incidence of acute grade 2 and 3 genitourinary (GU) toxicity was 9% and 2%, respectively. The corresponding incidences of late GU toxicity were 18% and 1%. No grade ≥4 of either type of toxicity was detected. Multivariate analysis showed that having higher international prostate symptom score (IPSS; P = 0.041) or higher V200 (P = 0.013) was associated with a higher risk of experiencing any grade of acute GU toxicity. In addition, patients having a higher IPSS (P = 0.019) or a higher V150 (P = 0.033) were associated with a higher grade >1 acute GU toxicity. ConclusionsThe findings of this study show that HDR-BT 13.5 Gy × 2 as monotherapy was safe and effective for prostate cancer patients with low-intermediate risk.

Stratified Intense-Dose- Yttrium-90 Ibritumumab Tiuxetan (90YIT ) with Bendamustine+Fludarabine Nonmyeloablative Conditioning for Allogeneic Stem Cell Transplantation in b-Cell Malignancies

Background: Nonmyeloablative allogeneic transplantation has the potential to induce long-term remissions in patients with relapsed lymphoma. However, a non-intense conditioning regimen enhances the risk of early relapse. Anti-CD20 antibody radioimmunotherapy (90YIT) delivers radiation dose not only to the tumor cells that bind the antibody but also to inaccessible neighboring cells as a result of the cross-fire effect. Thus, we hypothesized that the addition of escalated 90YIT dose to the recently published bendamustine+fludarabine conditioning regimen (Khouri et al. Blood 2014) would facilitate early cytoreduction in such patients and promote improved long-term disease control by the allogeneic graft. Organ doses from a 90YIT weight-based activity prescription (mCi/kg) vary considerably, which justifies a dosimetry-based strategy for mCi/kg escalation.Methods and patients: On days -22 and -14, rituximab was given at 250 mg/m2 preceding 111In ibritumumab and 90YIT administration, respectively. Organ dosimetric assessment was performed based on serial 111In ibritumumab whole body scanning (0, 4, 24, 72 and 144 hours) , to select from among five 90YIT mCi/kg prescriptions (0.5, 0.75, 1, 1.25 or 1.5) that would result in an estimated 10 - 12 Gy dose to the liver, lungs or kidneys. Organ dose was corrected for patient-specific mass, based on a CT volume estimate times 1.03 g/cc for liver and kidneys, and a variable specific gravity for lungs (Simon, J Clin Monit Comput, 2000). Bendamustine 130 mg/m2 plus 30 mg/m2 of fludarabine IV were given daily on days -5 to - 3 prior to transplantation. Tacrolimus and mini-methotrexate (Mycophenolate mofetil in case of cord blood transplantation) were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant.Results: Twenty patients were studied. The median age was 58 years (range, 37-71). Lymphoma histologies included: indolent (n=8, 40%), diffuse large cell (n=6; 30%), double-hit (n=2; 10%) and mantle cell (n= 4, 20%). The median number of prior chemotherapies received was 4 (range, 2-7). At study entry, 8 patients (40%) were in complete remission following salvage therapy, 7 (35%) were in partial response, and 5 (25%) had refractory disease. Six of 16 (37.5%) patients tested were PET+. Dosimetry: The most exposed organ was either liver (16 patients) or lungs (4 patients). The distribution among the five 90YIT mCi/kg prescriptions (smallest to largest) was 2, 4, 12, 1 and 1, with a mean of 0.94 ± 0.23 mCi/kg. If all twenty patients were treated at 1 mCi/kg (the most common prescription), the 20 Gy limit employed for 90YIT clinical trials prior to approval would have been exceeded in only one patient for the liver (22.9 Gy) or lungs (20.9 Gy). The maximum liver and lung doses at 0.75 mCi/kg would have been 17.2 and 15.7 Gy, respectively. Transplant outcomes: Fifteen patients (75%) received their transplants from unrelated donors (including 1 mismatched and 2 cord blood), and only 5 (25%) from HLA-compatible siblings. The median number of CD34+ cells infused was 6.2 × 106/kg. Neutrophil counts recovered to > 0.5 × 109/L after a median of 12 days (range, 0-24 days). Platelet counts recovered to > 20 × 109/L after a median of 19 days (range, 9-30 days). By day 30, median donor myeloid and T-cells were 100% (range, 98-100). The cumulative incidence of acute grade 2-4 GVHD and chronic extensive GVHD were 25% (5% for acute grade 3-4) and 32%, respectively. Treatment-related mortality (TRM) rates at day 100 and 1 year after transplantation were 0% and 10%, respectively. The 2 cord blood transplants engrafted with 100% donor cells and none had GVHD. With a median follow-up duration of 14 months (range, 3-34 months), the overall survival and progression-free survival rates were 85% and 70%, respectively. No significant difference in survival or TRM could be detected by age, donor type, histology, disease status, PET status or number of prior therapies.Conclusions: Our results indicate that dose-intense 90YIT combined with fludarabine and bendamustine is a well-tolerated nonmyeloablative allogeneic conditioning for lymphoid malignancies, with promising results of engraftment, GVHD and survival. Our stratified 90YIT prescription results suggest that future studies with a fixed dose of 1 mCi/kg level without dosimetry would have an acceptable radiation risk to vital organs in this setting. DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Proctitis 1 Week after Stereotactic Body Radiation Therapy for Prostate Cancer: Implications for Clinical Trial Design.

Proctitis following prostate cancer radiation therapy is a primary determinant of quality of life (QOL). While previous studies have assessed acute rectal morbidity at 1 month after stereotactic body radiotherapy (SBRT), little data exist on the prevalence and severity of rectal morbidity within the first week following treatment. This study reports the acute bowel morbidity 1 week following prostate SBRT. Between May 2013 and August 2014, 103 patients with clinically localized prostate cancer were treated with 35-36.25 Gy in five fractions using robotic SBRT delivered on a prospective clinical trial. Bowel toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4). Bowel QOL was assessed using the EPIC-26 questionnaire bowel domain at baseline, 1 week, 1 month, and 3 months. Time-dependent changes in bowel symptoms were statistically compared using the Wilcoxon signed-rank test. Clinically significant change was assessed by the minimally important difference (MID) in EPIC score. This was defined as a change of 1/2 standard deviation (SD) from the baseline score. One-hundred and three patients with a minimum of 3 months of follow-up were analyzed. The cumulative incidence of acute grade 2 gastrointestinal (GI) toxicity was 23%. There were no acute ≥ grade 3 bowel toxicities. EPIC bowel summary scores maximally declined at 1 week after SBRT (-13.9, p < 0.0001) before returning to baseline at 3 months after SBRT (+0.03, p = 0.94). Prior to treatment, 4.9% of men reported that their bowel bother was a moderate to big problem. This increased to 28.4% (p < 0.0001) 1 week after SBRT and returned to baseline at 3 months after SBRT (0.0%, p = 0.66). Only the bowel summary and bowel bother score declines at 1 week met the MID threshold for clinically significant change. The rate and severity of acute proctitis following prostate SBRT peaked at 1 week after treatment and returned to baseline by 3 months. Toxicity assessment at 1 week can therefore minimize recall bias and should aid in the design of future clinical trials focused on accurately capturing and minimizing acute morbidity following SBRT.

Haploidentical, unmanipulated G-CSF-primed peripheral blood stem cell transplantation for high-risk hematologic malignancies: an update.

Emerging data demonstrate promising results of related haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) for the treatment of hematologic malignancies. Data about G-CSF primed PBSC as reliable source of graft with myeloablative conditioning are lacking. We updated the outcomes in 130 adult patients with high-risk hematologic malignancies who received haplo-PBSC transplantation consecutively under busulfan-based conditioning. PBSC were freshly isolated and infused without ex vivo T-cell depletion into the recipients. Myeloid recovery was achieved in 99.2% patients with full donor chimerism. The cumulative incidence of acute grade 3-4 GvHD, overall and extensive chronic GvHD was 14.9%, 38.6% and 16.5%, respectively. The 3-year non-relapse mortality rate was 24.1%. Non-remission prior to transplant was associated with higher incidence of relapse (P=0.006), inferior overall survival (P=0.017) and leukemia-free survival (P=0.024). These data suggest that PBSC is a reliable graft source in haploidentical, unmanipulated transplant settings under myeloablative conditioning in patients with high-risk hematologic malignancies.

Brentuximab Vedotin Followed By Allogeneic Stem-Cell Transplantation for Patients with CD30 Anaplastic or T Cell Non Hodgkin Lymphomas: A Study on Behalf of the SFGM-TC.

Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has demonstrated efficacy alone or in combination with chemotherapy in CD30 refractory Non-Hodgkin Lymphoma (NHL). It has been approved in anaplastic large cell lymphoma (ALCL) and promising results have also been published in other CD30 positive T-cell lymphomas such as cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL). In patients with relapsing or refractory NHL, BV has mainly been proposed as a bridge for autologous or allogeneic transplantation (Allo-HSCT). Very few data are available about patients with T-cell NHL receiving Allo-HSCT after BV. The aim of our study was to study safety and efficacy of this procedure in a retrospective series of patients treated on behalf of SFGM-TC.Inclusion criteria were: - CD30 positive T cell NHL including ALCL, CTCL and PTCL, - Partial or Complete response after BV treatment, - Allogeneic HSCT performed after BV as last salvage treatment. BV was administered at 1,8mg/kg dose every 3 weeks in outpatient department. Allo-HSCT was performed according to institutional guidelines.Twenty-six patients receiving Allo-HSCT in France after salvage therapy including BV were identified. Patients characteristic are summarized in Table 1. With a median follow-up of 13 months (1.5-40), 8 patients relapsed and 7 patients died. Two-year OS and PFS were respectively 76% and 47%. Among patients with ALCL (n=15) 2 patients relapsed and 2 patients died. Whereas in the CTCL group (n=5), 5 patients relapsed and 1 patient died and in the PTCL group (n=6), 1 patient relapsed and 4 patients died. Two-year OS were 93%, 80% and 21% (p<0.001) and two-year PFS were 86%, 20% and 0% (p<0.001) for ALCL, CTCL and PTCL respectively. Two-years PFS for patients in CR before Allo-HSCT (n=16) was 67% whereas patients in PR (n=6) or who progressed before transplantation (n=3) have a 25% and 0% 2-years PFS respectively (p=0,08). In multivariate analysis, only anaplastic histology had a positive impact on OS or PFS. We compared data with a control group of patients with T-cell NHL (n=52) transplanted in the same centers during the same period, not receiving BV as a salvage treatment. Day-100 cumulative incidence of acute Grade 2-4 GVHD and Grade 3-4 GVHD were 39% [20-59] and 16% [1-30] in the BV group and 46% [27-66] and 19% [8-30] in the control group (p=NS). Two-years overall chronic GVHD and extensive chronic GVHD were 33% [9-56] and 22% [0-46] in the BV group and 39% [24-53] and 15% [0-26] in the control group (p=NS). Day-100 and 1-year NRM were 12% [0-25] and 16% [1-30] in the BV group and 4% [0-9] and 8% [1-15] in the control group (p=0,07). One-year relapse incidence was 37% [14-60] and 22% [10-34] in the BV and control groups respectively (p=0,27). BV was not associated with higher GVH, NRM or relapse incidence in multivariate analysis.In conclusion, BV followed by Allo-HSCT is an option for patients with advanced CD 30 positive T cell NHL. Immunotherapy targeting CD30 before Allo-HSCT is not associated with a higher rate of GVHD, NRM or relapse incidence. Patients with ALCL have a better survival than patients with PTCL or CTCL.Table 1Patients characteristicsAll patientsALCLCTCLPTCL(n=26)(n=15)(n=5)(n=6)Sexemale15 (58%)7 (47%)4 (80%)4 (67%)Age (at Allo-HSCT)median (range)47 (21-62)40 (21-59)50 (31-62)50 (46-59)Stade (at diagnosis)I-II4 (15%)3 (20%)-1 (17%)III-IV16 (62%)11 (73%)-5 (83%)unknown1 (4%)1 (7%)--NA5 (19%)-5 (100%)-Auto-HSCT (before BV)patients8 (31%)5 (33%)-3 (50%)Lines of chemotherapy (before BV)median (ranges)2 (1-7)2 (1-4)4 (3-7)2 (1-3)Status (before BV)refractory18 (69%)9 (60%)5 (100%)4 (66%)relapsing8 (31%)6 (40%)-2 (34%)cycles of BVmedian (ranges)4 (1-8)4 (1-8)4 (4-6)4 (1-4)Treatment associated with BVno20 (77%)11 (73%)5 (100%)4 (66%)GVD2 (8%)2 (13%)--CHP2 (8%)--2 (33%)DHAP1 (4%)1 (7%)--Radiotherapy1 (4%)1 (7%)--Time between diagnosis and Allo-HSCTMonths (range)21 (6-93)13 (6-93)23 (21-43)23 (12-76)Status before Allo-HSCTCR16 (62%)13 (87%)-3 (50%)PR6 (23%)2 (13%)4 (80%)-SD/PD3 (12%)-1 (20%)2 (33%)Donor typeMRD15 (57%)5 (33%)4 (80%)6 (100%)MUD7 (27%)6 (40%)1 (20%)-CBU2 (8%)2 (13%)--Haploidentical2 (8%)2 (13%)--Conditioning3 (50%)RIC17 (65%)9 (60%)5 (100%)MAC9 (35%)6 (40%)-3 (50%)Immunosuppressive agentsCyA5 (19%)4 (27%)-1 (17%)CyA/MMF10 (38%)4 (27%)5 (100%)1 (17%)CyA/MTX11 (42%)7 (47%)-4 (66%)Anti-thymocyte globulin11 (42%)8 (53%)1 (20%)2 (33%) DisclosuresOff Label Use: Brentuximab used for CD30+ cutaneous and peripheral T cell lymphoma.

Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non–Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan

This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti–T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 109/L on day 11 and platelets > 20 × 109/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.

Comparison of Allogeneic Hematopoietic Stem Cell Transplant from HLA-Matched Related Donors and from Unrelated Donors for Intermediate- to High-Risk Adult Acute Myeloid Leukemia in Remission

Introduction: Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the most powerful method to treat intermediate- to high-risk acute myeloid leukemia (AML). Human leukocyte antigen (HLA) matched related donors (MRD) are considered the best donors in allo-HSCT, but they are only available for a small proportion of patients. With the progress of transplant skills over decades, outcome of unrelated donor (URD) HSCT has improved significantly, and the difference between MRD and URD HSCT has been steadily declining. But the role of URD HSCT has still not been well defined in AML, especially for different risk groups. We therefore compared the results of URD HSCT with MRD HSCT in adult AML patients with intermediate- to high-risk in our center.Methods: During January 2005 to December 2012, 108 adult patients with intermediate- or high-risk AML receiving allo-HSCT in complete remission (CR) in our center were admitted in this study. All patients received a standard-dose cytarabine with anthracycline or homoharringtonine as induction therapy. Consolidation courses include high-dose cytarabine or standard-dose cytarabine with anthracycline, homoharringtonine, or mitoxantrone. After consolidation, all patients received allo-HSCT in CR. High resolution DNA typing for HLA-A, -B, -C, -DRB1, and -DQB1 was performed during CR. Patients with HRD would receive HRD HSCT; while for those without HRD, URD with at least 8/10 locus match were selected as donor source. Among the 108 patients, 51 received grafts from HRD and 62 from URD. The conditioning regimen mainly involved BuCy without total body irradiation. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Rabbit antithymocyte globulin (Thymoglobulin, IMTIX-SangStat, Lyon, France) was also administered to some patients receiving URD HSCT (4.5–6 mg/kg total dose).Results: Most of the baseline characteristics were well balanced between two groups. However, The interval from diagnosis to transplantation differed significantly between two groups, with a median interval of 7 months for HRD group versus 10 months for URD group (P=0.008). Bone marrow was used as graft source in 100% and 80.7% of patients in HRD and URD groups, respectively. Another 19.3% of patients in URD group received peripheral blood stem cell as graft source. The median follow-up was 37.5 months in the whole cohort.The cumulative incidence of acute grade 2 to 4 GVHD was significantly higher in URD group compared with HRD group (40.3% vs. 13.8%, P=0.002). Chronic GVHD and extensive chronic GVHD were also significantly more frequent in URD group (chronic GVHD: 49.2% vs. 29.6%, P=0.037; extensive chronic GVHD: 22.0% vs. 3.7%, P=0.005). The treatment-related mortality (TRM) was significantly higher in the URD group (17.9% vs. 4.3%, P=0.015). While the overall survival (OS), relapse-free survival (RFS), and relapse rate were comparable between two groups (OS at 3 years: HRD 79.9% vs. URD 70.3%, P=0.146; RFS at 3 years: HRD 73.1% vs. URD 66.7%, P=0.239; relapse rate at 3 years: HRD 23.5% vs. URD 18.0%, P=0.643). Clinical characteristics were subjected into univariate and multivariate Cox analysis for OS to find prognostic factors. Cytogenetics, status at transplant (CR1 vs. CR2 to CR3), and MRD levels at transplant were identified as factors that were significantly associated with OS, whereas donor type had no significant impact.When the analysis was done in patients divided by risk stratification, we found that for intermediate-risk patients, the HRD group had a 3-year improved survival rate than URD group (RFS: 85.2% vs. 70.5%, P=0.043; OS: 85.2% vs. 72.7%, P=0.062) with a significantly reduced TRM rate (3.8% vs. 18%, P=0.025). The relapse rate were comparable between two groups (HRD 11.3% vs. URD 12.7%, P=0.649). While for high-risk patients, no differences were observed between two groups in terms of OS, RFS, TRM and relapse rate.Conclusions: For intermediate-risk AML patients, compared with URD HSCT, the results from HRD HSCT were better with improved survival rate and reduced TRM; while for high-risk AML patients, donor types had no effect on transplant outcome. Cytogenetics, status at transplant, and MRD levels at transplant were found to be independent prognostic factors for OS. DisclosuresNo relevant conflicts of interest to declare.

CD34 Selected Cells for the Treatment of Poor Graft Function after Allogeneic Stem Cell Transplantation

Poor graft function (PGF) is characterized by pancytopenia and a hypoplastic marrow, with complete donor chimerism, usually without severe graft-versus-host disease (GVHD). We report 41 patients with PGF, treated with granulocyte colony-stimulating factor–mobilized CD34 selected cells, at a median interval from transplant of 140 days, without conditioning and without GVHD prophylaxis. Donors were HLA matched siblings (n = 12), unrelated donors (n = 18), or mismatched family members (n = 11). The median number of infused CD34+ cells was 3.4 × 106/kg. The rate of trilineage recovery was 75%: 83% for HLA matched siblings and 72% for unrelated and mismatched family members (P = .3). The cumulative incidence of acute grade II GVHD was 15%, and no patient developed de novo chronic GVHD. The actuarial 3-year survival is 63%: 76% and 25% for patients with or without trilineage recovery. These data confirm the role of CD34+ selected cells from the same donor in the treatment of PGF and warrant the request for a second donation also when the donor is unrelated.

Early engraftment of G-CSF-primed allogeneic bone marrow transplantation in pediatric patients regardless of donor–recipient weight differences

Harvesting sufficient progenitor cells from bone marrow (BM) for pediatric patients is a challenging process, especially from smaller donors. Growth factor administration to donors prior to harvest results in an enrichment of the graft and leads to early engraftment. A total of 41 patients received a human leukocyte antigen-identical sibling transplantation using granulocyte colony-stimulating factor (G-CSF)-primed BM. All donors received G-CSF 10μg/kg/day for 2days prior to harvest. The median weight difference between donor and recipient was 3.9kg (range, -29.8 to 32kg), and the median number of CD34(+) cells harvested was 4.16 × 10(6)/kg (range, 1.17-31.9 × 10(6)/kg). The median time to neutrophil engraftment was 12days (range, 10-27 days), and the time for platelet engraftment was 20days (range, 12-64 days). The cumulative incidence of acute grade 2 to 3 graft-versus-host disease (GVHD) and chronic GVHD was 4.9% and 5.1%, respectively. An analysis according to the weight difference between donor and recipient showed there was no significant difference in harvested CD34(+) cell dose and in time required for engraftment between smaller and heavier donor recipients. G-CSF-primed BM allows successful engraftment and provides a valuable alternative to unstimulated BM and peripheral blood stem cells with good engraftment and tolerable GVHD even in patients with smaller donors.

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality

AbstractThis study investigated the use of a nonablative conditioning regimen to decrease toxicity and achieve engraftment of an allogeneic blood stem cell transplant, allowing a graft-versus-malignancy effect to occur. All patients had follicular or small cell lymphocytic lymphoma after relapse from a prior response to conventional chemotherapy. Patients received a preparative regimen of fludarabine (25 mg/m2 given daily for 5 days or 30 mg/m2daily for 3 days) and intravenous cyclophosphamide (1 g/m2given daily for 2 days or 750 mg/m2 daily for 3 days). Nine patients received rituximab in addition to the chemotherapy. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Twenty patients were studied; their median age was 51 years. Twelve were in complete remission (CR) at transplantation. All patients achieved engraftment of donor cells. The median number of days with severe neutropenia was 6. Only 2 patients required more than one platelet transfusion. The cumulative incidence of acute grade II to IV GVHD was 20%. Only one patient developed acute GVHD of greater than grade II. All patients achieved CR. None have had a relapse of disease, with a median follow-up period of 21 months. The actuarial probability of being alive and in remission at 2 years was 84% (95% confidence interval, 57%-94%). Nonablative chemotherapy with fludarabine/cyclophosphamide followed by allogeneic stem cell transplantation is a promising therapy for indolent lymphoma with minimal toxicity and myelosuppression. Further studies are warranted to compare nonablative allogeneic hematopoietic transplantation with alternative treatment strategies.