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1.
Anti-CD25 Radioimmunotherapy with BEAM Autologous Hematopoietic Cell Transplantation Conditioning in Hodgkin Lymphoma
Herrera, A. F., Palmer Ph, D. Jm, Adhikarla, V., Yamauchi, D. M., Poku, E. K., Bading, J., Yazaki, P., Dandapani, S., Mei, M. G., Chen, R. W., et al
Blood advances. 2021
Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL and we hypothesized that the addition of 90Y-antiCD25 (aTac) to BEAM AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled onto this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution and a third developed an unrelated catheter-associated bacteremia; therefore 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed and 0.6mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive > 2500cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with 3 or more risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL and we are further evaluating the efficacy of this approach in a phase 2 trial. The clinical trial was registered at clinicaltrials.gov (NCT01476839).
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2.
Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.
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3.
Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation
Malki, M. M. A., Song, J. Y., Yang, D., Cao, T., Aldoss, I., Mokhtari, S., Dadwal, S., Marcucci, G., Karanes, C., Snyder, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The negative impact of Iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well-recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin level (SF) of 2000 ng/ml. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/ml was 26.1% (95%CI: 10.6%-44.7%) and 52.1% (95%CI: 40.1%-62.8%), respectively; HR=2.26 (95%CI: 1.28-4.00, P=0.005). Two-year non-relapse mortality rate was higher among patients with SF >2000 ng/ml (56.5%, 95%CI: 33.3%-74.4%) compared to SF ≤2000 ng/ml (30.1%, 95%CI: 20.0%-40.9%); HR=2.18, (95%CI: 1.10-4.31, P=0.025). Neutrophil engraftment at 42 days was 78.3% (95%CI: 53.5%-90.8%) in patients with SF >2000 ng/ml, versus 91.8% (95%CI: 82.1%-96.4%) in patients with SF ≤2000 ng/ml; HR=0.58 (95%CI: 0.35-0.96, P=0.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95%CI: 29.4%-70.8%) for SF>2000 ng/ml versus 80.8% (95%CI: 69.5%-88.3%) for SF ≤2000 ng/ml; HR=0.48 (95%CI: 0.23-0.98, P=0.044). In conclusion, IO defined by SF of 2000 ng/ml is a strong adverse prognostic factor for UCB-HCT and should be a considered when UCB is chosen as the graft source for patients without a fully matched donor.
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4.
Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial
Aldoss, I., La Rosa, C., Baden, L. R., Longmate, J., Ariza-Heredia, E. J., Rida, W. N., Lingaraju, C. R., Zhou, Q., Martinez, J., Kaltcheva, T., et al
Annals of internal medicine. 2020
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Editor's Choice
Abstract
Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT). Objective: To determine the safety and efficacy of Triplex. Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933). Setting: 3 U.S. HCT centers. Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation. Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens. Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection. Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients. Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia. Primary Funding Source: National Cancer Institute and Helocyte.
PICO Summary
Population
CMV-seropositive HCT recipients at high risk for CMV reactivation (n=102)
Intervention
Intramuscular injections of Triplex CMV vaccine (n=51)
Comparison
Placebo (n=51)
Outcome
Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.
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Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch
Al Malki, M. M., Gendzekhadze, K., Yang, D., Mokhtari, S., Parker, P., Karanes, C., Palmer, J., Snyder, D., Forman, S. J., Nademanee, A., et al
Transplantation. 2019
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Abstract
BACKGROUND While Tacrolimus/Sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor (URD) HCT (2005 - 2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range=2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95%CI: 43.0-52.0) and 43.6% (95%CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of non relapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% vs. 50.7% at 5 years, p=0.034), primarily due to greater risk of NRM (33.5% vs. 21.7%, p=0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% vs. 12.8%, p=0.022) and infection (33.0% vs. 18.1%, p<0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (HR= 2.21, 95%CI: 1.16-4.23; p<0.01) and mMUD (HR=1.55, 95%CI:.1.15-2.08; p=0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.
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Protective effect of HLA-DPB1 mismatch remains valid in reduced-intensity conditioning unrelated donor hematopoietic cell transplantation
Malki, M. M. A., Gendzekhadze, K., Stiller, T., Mokhtari, S., Karanes, C., Parker, P., Snyder, D., Forman, S. J., Nakamura, R., Nademanee, A.
Bone marrow transplantation. 2019
Abstract
A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.
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7.
Provisional Title: Safety Analysis of Brentuximab Vedotin From the Phase 3 AETHERA Trial in Hodgkin Lymphoma in the Posttransplant Consolidation Setting
Nademanee, A., Sureda, A., Stiff, P., Holowiecki, J., Abidi, M., Hunder, N. N., Pecsok, M., Uttarwar, M., Purevjal, I., Sweetenham, J.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
The phase 3 AETHERA trial demonstrated brentuximab vedotin's (BV) efficacy as consolidation therapy in patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression following autologous hematopoietic stem cell transplant (auto-HSCT; hazard ratio [HR]=0.57; P<0.001). The objective of this analysis is to provide further detail on the most common and clinically important treatment-emergent adverse events (TEAEs) in the AETHERA BV arm including their occurrence and management. AEs of clinical importance occurring in patients who participated in AETHERA (BV + best supportive care [BSC], n=165; placebo + BSC, n=164) were evaluated for time to onset, manageability through dose modification, and resolution. As previously reported, peripheral neuropathy (PN; 67%), infections (60%), and neutropenia (35%) were the most common BV-associated TEAEs. Neutropenia was managed with dose delays and granulocyte colony-stimulating factor; no dose reductions or discontinuations were required. The majority (57%) of PN cases were managed with dose delays and reductions. The median time to PN onset was 13.7 (range, 0.1-47.4) weeks. After end of treatment, PN continued to resolve; symptom resolution was similar to that in the placebo arm at 3 years, demonstrating reversibility. BV had no significant impact on preexisting PN. Patients with PN-related dose modifications had progression-free survival (PFS) comparable to patients without. Other less common but serious AEs, including pulmonary toxicities, hepatotoxicity, and cardiotoxicity, were rare in both arms and managed with BV dose modifications or discontinuations. Secondary malignancies were rare and reported in patients with comorbidities or other risk factors. Consolidation therapy with BV for patients with HL at high risk of relapse after auto-HSCT is associated with sustained PFS. The most common AEs in the BV arm were manageable and reversible. Awareness of these AEs and management approaches will enable healthcare providers and patients to plan the safest and most effective treatment plan.
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8.
Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma
Herrera, A. F., Palmer, J., Martin, P., Armenian, S., Tsai, N. C., Kennedy, N., Sahebi, F., Cao, T., Budde, L. E., Mei, M., et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;29(3):724-730
Abstract
BACKGROUND We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. PATIENTS AND METHODS Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. RESULTS Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. CONCLUSIONS Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).
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Melphalan-Based Reduced Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Al Malki, M. M., Nathwani, N., Yang, D., Armenian, S., Dadwal, S., Salman, J., Mokhtari, S., Cao, T., Sandhu, K., Rouse, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Allogeneic hematopoietic stem cell transplantation (AlloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study, we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent AlloHCT with melphalan (Mel)-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with "semi-ablative" nature of this regimen. With a median follow up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative Incidence (CI) of relapse at 1- and 2-years were 17.0% and 19.3%, respectively. 100-day CI of grade II-IV acute GVHD was 37.7% (grade III-IV: 18.9%), and 2-year CI of chronic GVHD was 61.9% (45.9% extensive). The only significant predictor for poor OS was high/very high disease risk index (DRI). Transplant-related complication/morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion; AlloHCT with Mel-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse and favorable OS and PFS in patients with 70 years of age or older.
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Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Chemotherapy in Mantle Cell Lymphoma Patients Is Associated with Higher Rates of Hematopoietic Progenitor Cell Mobilization Failure despite Plerixafor Rescue
Salhotra, A., Shan, Y., Tsai, N. C., Sanchez, J. F., Aldoss, I., Ali, H., Paris, T., Spielberger, R., Cao, T. M., Nademanee, A., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1264-1268
Abstract
Induction regimens for mantle cell lymphoma (MCL) can be categorized into highly intensive regimens containing cytarabine and less intense regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) or rituximab with bendamustine (R-bendamustine). Prior publications have shown rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) can be associated with stem cell mobilization failures. However, those studies did not include the use of plerixafor as rescue for stem cell mobilization failure. We examined our database of 181 consecutive MCL patients who received upfront therapy from 2005 to 2015 with either R-hyperCVAD or less intense chemotherapy (R-bendamustine and R-CHOP only) regimens to assess impact of frontline chemotherapy on collection of hematopoietic cell progenitors before autologous stem cell transplantation (ASCT). In the preplerixafor era (before August 16, 2009), a significant difference in peripheral blood stem cell (PBSC) collection failure between the R-hyperCVAD (12%) and other chemotherapy (11%) groups was not established. However, in the postplerixafor era, use of R-hyperCVAD chemotherapy was associated with significantly higher rates of hematopoietic progenitor cell collection failures (17%) compared with that observed in the other chemotherapy group (4%; P=.04). The rates of mobilization failure declined to 4% in the postplerixafor era from 11% in the preplerixafor era for patients receiving less intensive chemotherapy. Conversely, the rate of mobilization failure increased in the R-hyperCVAD group from 12% in the preplerixafor era to 17% in the postplerixafor era. Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT.