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1.
Immune Recovery Following Autologous Hematopoietic Stem Cell Transplantation in HIV-Related Lymphoma Patients on the BMT CTN 0803/AMC 071 Trial
Shindiapina, P., Pietrzak, M., Seweryn, M., McLaughlin, E., Zhang, X., Makowski, M., Ahmed, E. H., Schlotter, S., Pearson, R., Kitzler, R., et al
Frontiers in immunology. 2021;12:700045
Abstract
We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p<0.0033). HIV(+) AHCT recipients also demonstrated lower median absolute numbers of activated B cells and lower NK cell sub-populations, compared to healthy controls (p<0.0033) and HIV(-) AHCT recipients (p<0.006). HIV(+) patient T cells showed robust IFN? production in response to HIV and EBV recall antigens. Overall, HIV(+) AHCT recipients, but not HIV(-) AHCT recipients, exhibited reconstitution of pro-inflammatory immune profiling that was consistent with that seen in patients with chronic HIV infection treated with antiretroviral regimens. Our results further support the use of AHCT in HIV(+) individuals with relapsed/refractory lymphoma.
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Autologous transplantation as consolidation for high risk aggressive T-cell non-Hodgkin lymphoma: a SWOG 9704 intergroup trial subgroup analysis
Al-Mansour, Z., Li, H., Cook, J. R., Constine, L. S., Couban, S., Stewart, D. A., Shea, T. C., Porcu, P., Winter, J. N., Kahl, B. S., et al
Leukemia & lymphoma. 2019;:1-8
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Editor's Choice
Abstract
Phase II data suggest a benefit to autotransplantation for aggressive T-cell non-Hodgkin lymphoma (T-NHL) in first remission; randomized trials have yet to validate this. We performed a retrospective analysis of aggressive T-NHL patients in the intergroup randomized consolidative autotransplant trial (SWOG 9704). Of the 370 enrolled, 40 had T-NHL: 12 were not randomized due to ineligibility (n = 1), choice (n = 2), or progression (n = 9), leaving 13 randomized to control and 15 to autologous stem cell transplantation (ASCT). Two ASCT patients refused transplant and one failed mobilization. The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38% (p = .56), and 40% vs. 45% (p = .98), respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI. Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. This and the 30% who dropped out pre-randomization mostly to progression, suggests that improved induction regimens be developed.
PICO Summary
Population
Aggressive T-cell non-Hodgkin lymphoma patients, treated with five cycles of CHOP/CHOP-R administered every three weeks; those who achieved at least a partial response were eligible for randomization (n=28).
Intervention
One further cycle of CHOP/CHOP-R followed by autologous stem cell transplantation
Comparison
Three further cycles of CHOP/CHOP-R
Outcome
Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. . The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38%, and 40% vs. 45%, respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI.
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Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation
Chen, R. W., Palmer, J. M., Tomassetti, S., Popplewell, L. L., Alluin, J., Chomchan, P., Nademanee, A. P., Siddiqi, T., Tsai, N. C., Chen, L., et al
Journal of hematology & oncology. 2018;11(1):87
Abstract
BACKGROUND Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied. METHODS We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m(2) subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m(2) intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS). RESULTS With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease. CONCLUSION Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen. TRIAL REGISTRATION ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.
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Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation
Herrera, A. F., Mei, M., Low, L., Kim, H. T., Griffin, G. K., Song, J. Y., Merryman, R. W., Bedell, V., Pak, C., Sun, H., et al
Journal of Clinical Oncology. 2017;35(1):24-31
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Abstract
Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.
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Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma
Herrera, A. F., Rodig, S. J., Song, J. Y., Kim, Y., Griffin, G. K., Yang, D., Nikolaenko, L., Mei, M., Bedell, V., Cin, P. D., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Double-hit lymphomas (DHL) and double-expressor lymphomas (DEL) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). 78 patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and FISH were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared to patients without DEL (PFS 30% v 39%, p=0.24; OS 31% v 49%, p=0.17) or between patients with DHL compared to patients without DHL (PFS 40% v 34%, p=0.62; OS 50% v 38%, p=0.46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, though limited sample size may have limited our ability to detect significant differences. In our cohort, alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
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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.
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Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology
Krishnan, A. Y., Palmer, J., Nademanee, A. P., Chen, R., Popplewell, L. L., Tsai, N. C., Sanchez, J. F., Simpson, J., Spielberger, R., Yamauchi, D., et al
Biology of Blood & Marrow Transplantation. 2017;23(6):922-929
Abstract
Standard-dose 90yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20+non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Gray Zone Lymphoma: a US Multicenter Collaborative Study
Kharfan-Dabaja, M. A., Raj, R., Nikolaenko, L., Ahmed, S., Reddy, N., Nathan, S., Cherry, M., El-Jurdi, N., Obiozor, C., Fenske, T. S., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) has been anecdotally prescribed in gray zone lymphoma (GZL), showing encouraging efficacy. We conducted a multicenter retrospective study aimed to assess outcomes after auto-HCT in 32 patients with GZL treated at 9 transplant centers in the United States. Median age of patients at transplantation was 38 (18-70) years and the majority were male (n=21, 66%). Median number of lines of therapy prior to transplantation was 2 (1-4). BEAM was the most commonly prescribed regimen (n=23, 72%). Median follow up for surviving patients was 34 (1-106) months. Median OS was not reached. The 3-year PFS and OS for all patients were 69% and 78%, respectively. Three-year PFS and OS was 100% for patients who received only 1 line of therapy prior to auto-HCT vs. 65% (PFS, p=0.25) and 75% (OS, p=0.39) for those receiving >1 line. Cumulative incidence of relapse/progression at 1-year and 3-year post-transplantation were 4% and 31%, respectively. The 3-year NRM was 0. These findings suggest that HDT and auto-HCT is an effective treatment in patients with GZL. Our findings would ideally require confirmation in a larger cohort of patients, preferably in the setting of large prospective multicenter RCTs. However, we acknowledge that such studies could be hard and improbable to conduct in GZL owing to its rarity. Alternatively, a multicenter prospective study, which includes tissue banking and a data registry, to help better understand the biology and natural history of the disease is warranted.
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RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106
Chen, R. W., Li, H., Bernstein, S. H., Kahwash, S., Rimsza, L. M., Forman, S. J., Constine, L., Shea, T. C., Cashen, A. F., Blum, K. A., et al
British Journal of Haematology. 2017;176(5):759-769
Abstract
Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression-free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL. Copyright © 2016 John Wiley & Sons Ltd.
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Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial
Alvarnas, J. C., Le Rademacher, J., Wang, Y., Little, R. F., Akpek, G., Ayala, E., Devine, S., Baiocchi, R., Lozanski, G., Kaplan, L., et al
Blood. 2016;128(8):1050-8
Abstract
Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/muL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4(+) T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.