Prognostic factors and treatment outcomes of allogeneic stem cell transplantation in lymphoid malignancy

Mariotti J., Zucchinetti C., Giordano L., De Philippis C., Mannina D., Sarina B., Taurino D., Carbon R., Santoro A., Bramanti S.

New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody–drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor T-cell (CAR-T) therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving an Allo-SCT after immunotherapy in the pre-CAR-T era. We compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years: 59% vs 46%), overall survival (4 years: 77% vs 44%), non-relapse mortality (4 years:19% vs 22%), acute (6 months: 15% vs 21%) and chronic (4 years: 18% vs 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower, although significance was not reached, after immunotherapy (4 years: 4% vs 14%). The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. In conclusion, consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR-T.

Chung H., Cho H.

Schmidt W.M., Perera N.D., Buadi F.K., Hayman S.R., Kumar S.K., Dispenzieri A., Dingli D., Cook J., Lacy M.Q., Kapoor P., Leung N., Muchtar E., Warsame R.M., Kourelis T., Binder M., et. al.

AbstractAllogeneic stem cell transplant (allo SCT) for multiple myeloma (MM) is potentially curative in some, while toxic in many others. We retrospectively analyzed 85 patients diagnosed with MM who underwent allo SCT as frontline or salvage therapy between 2000 and 2022 at Mayo Clinic Rochester and examined patient outcomes and prognostic markers. Overall survival (OS), progression free survival (PFS), treatment related mortality (TRM), and relapse rates (RR) were estimated using the Kaplan Meier method and competing risk models. Median follow-up was 11.5 years. Median OS and PFS were 1.7 and 0.71 years, respectively. Five-year OS and PFS were 22.2% and 15.1%, respectively. One-year TRM was 23.5%. Twelve patients demonstrated durable overall survival, living 10+ years beyond their allo SCT. This subgroup was more likely to have no or one prior auto SCT (p = 0.03) and to have been transplanted between 2000 and 2010 (p = 0.03). Outcomes were poor in this cohort with long follow-up, with few patients surviving 5 years or more, and most relapsing or dying within 2 years. We would expect better outcomes and tolerability with an expanded array of novel therapeutics and would prefer them to allo SCT.

Baek D.W., Moon J.H., Lee J.H., Kang K., Lee H.S., Eom H., Lee E., Lee J.H., Lee J., Park S.K., Kim S.J., Yoo K.H., Yoon S., Koh Y., Kang H.J., et. al.

AbstractThis study aimed to identify the benefits of autologous-stem cell transplantation (auto-SCT) and allogeneic-SCT (allo-SCT) in patients with aggressive T-cell lymphomas to aid in the selection of transplantation type in clinical practice. This study retrospectively analyzed data from 598 patients who underwent transplantation for T-cell lymphomas from 2010 to 2020. In total, 317 patients underwent up-front SCT as consolidation therapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 68.7% and 76.1%, respectively. Patients who underwent auto-SCT had significantly better OS (p = 0.026) than those who underwent allo-SCT; however, no statistical difference in PFS was found. Transplantation was used as a salvage therapy in 188 patients who had relapsed/refractory disease. Overall, 96 (51.1%) patients underwent auto-SCT and 92 (48.9%) patients underwent allo-SCT. Auto-SCT improved long-term survival in patients with complete remission (CR). Allo-SCT demonstrated better 3-year PFS in patients with partial remission and relapsed/refractory disease status. However, >50% of patients died within 1 year of allo-SCT. As a consolidative therapy, up-front auto-SCT demonstrated a survival benefit. Auto-SCT was also effective in patients who achieved CR after salvage therapy. If the disease persists or cannot be controlled, allo-SCT may be considered with reduced intensity conditioning.

Michel C., Robin M., Morisset S., Blaise D., Maertens J., Chevalier P., Castilla-Llorente C., Forcade E., Ceballos P., Yakoug-Agha I., Poire X., Carre M., Bay J., Beguin Y., Loschi M., et. al.

AbstractAllogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2–4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32–1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28–1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.

Bruch P., Dietrich S., Finel H., Boumendil A., Greinix H., Heinicke T., Bethge W., Beelen D., Schmid C., Martin H., Castagna L., Scheid C., Schäfer-Eckart K., Bittenbring J., Finke J., et. al.

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20–73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.

Hamadani M., Ngoya M., Sureda A., Bashir Q., Litovich C.A., Finel H., Chen Y., Boumendil A., Zain J., Castagna L., Cashen A.F., Blaise D., Shadman M., Pastano R., Khimani F., et. al.

Abstract Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Wullenkord R., Berning P., Niemann A., Wethmar K., Bergmann S., Lutz M., Schliemann C., Mesters R., Keßler T., Schmitz N., Berdel W.E., Lenz G., Stelljes M.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0–163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance.

Tanaka J.

Cellular therapies for malignant lymphoma include autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and adaptive cellular therapy using EBV-specific T cells, cytokine-induced killer (CIK) cells, NKT cells, NK cells, chimeric antigen receptor T (CAR-T) cells and chimeric antigen receptor NK (CAR-NK) cells. In this review we discusses recent advances of these cellular therapies and consider ways to optimize these therapies. Not only a single strategy using one of these cellular therapies, but also multi-disciplinary treatment combines with antibodies, such as an anti-tumor antibody and an immune checkpoint antibody, may be more effective for relapsed and refractory lymphoma.

Du J., Yu D., Han X., Zhu L., Huang Z.

Importance Hematopoietic stem cell transplant (HSCT) is an advisable option for refractory or relapsed peripheral T-cell lymphoma (R/R-PTCL), but whether allogeneic HSCT or autologous HSCT is more beneficial is unknown. Objective To compare the effectiveness and safety of allogeneic HSCT vs autologous HSCT in patients with R/R-PTCL. Data Sources A systematic search of the PubMed, Embase, the Cochrane Central Register of Controlled Trials, Wanfang, and China National Knowledge Infrastructure databases with the search itemsrefractory or relapsed peripheral T-cell lymphoma,ASCT/autologous stem-cell transplantation,allo-HSCT/allogeneic stem-cell transplantation,therapeutic effect, andtreatmentwas conducted for articles published from January 12, 2001, to October 1, 2020. Study Selection After duplicate and irrelevant publications were discarded, 329 were ineligible according to the inclusion (clinical trials or retrospective studies with >10 samples) and exclusion criteria (articles without overall survival [OS], progression-free survival [PFS], and transplantation-related mortality [TRM]). Thirty trials were included in the meta-analysis. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data Extraction and Synthesis Data on study design, individual characteristics, and outcomes were extracted. All statistics were pooled by applying a random-effects model. Main Outcomes and Measures The prespecified main outcomes were OS, PFS, and TRM. Results Of 6548 articles, data extracted from the 30 studies (including 880 patients who underwent allogeneic HSCT and 885 who underwent autologous HSCT) were included in this meta-analysis. In the allogeneic HSCT group, a 3-year OS of 50% (95% CI, 41%-60%) and PFS of 42% (95% CI, 35%-51%), a 5-year OS of 54% (95% CI, 47%-62%) and PFS of 48% (95% CI, 40%-56%), and a 3-year TRM of 32% (95% CI, 27%-37%) were observed. In the autologous HSCT group, a 3-year OS of 55% (95% CI, 48%-64%) and PFS of 41% (95% CI, 33%-51%), a 5-year OS of 53% (95% CI, 44%-64%) and PFS of 40% (95% CI, 24%-58%), and a 3-year TRM of 7% (95% CI, 2%-23%) were observed. Conclusions and Relevance In this systematic review and meta-analysis, OS and PFS were similar in the allogeneic HSCT and autologous HSCT groups; however, allogeneic HSCT was associated with specific survival benefits among patients with R/R-PTCL.

Jason P. Cooper, Barry E. Storer, Noa Granot, Boglark Gyurkocza, Mohamed L. Sorror, Thomas R. Chauncey, Judith Shizuru, Georg-Nikolaus Franke, Michael B. Maris, Michael Boyer, Benedetto Bruno, Firoozeh Sahebi, Amelia A. Langston, Parameswaran Hari, Edward D. Agura, et. al.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010–2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010–2017. When outcomes from 2004 +/- 2009 and 2010–2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004–2009 and P <.0001 for 2010–2017), profression-free survival (P=.002 for 2004–2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

García-Cadenas I., Yáñez L., Jarque I., Martino R., Pérez-Simón J.A., Valcárcel D., Sanz J., Bermúdez A., Muñoz C., Calderón-Cabrera C., García E., Alonso L., Suárez-Lledó M., González Vicent M., Heras I., et. al.

Post-transplant lymphoproliferative disorder (PTLD) is an infrequent complication of allogeneic stem cell transplant (allo-SCT).To estimate the frequency and management of PTLD in Spain and to identify prognostic factors influencing outcomes.Multicenter, retrospective analysis of allo-SCT performed in 14 transplant units over a 15-year period.102 PTLD were diagnosed among 12 641 allo-SCT, leading to an estimated frequency of 0.8%. PTLD was diagnosed at a median of 106 days after SCT. Eighty-seven cases (85%) were diagnosed between 2007 and 2013. At diagnosis, 22% and 17% of the patients had gastrointestinal tract and CNS involvement. Eighty-seven (85%) received rituximab treatment, alone or in combination with immunosuppression reduction, with an ORR of 50.6%. With a median follow-up for survivors of 58 months, the 2-year overall survival (OS) was 33% and the PTLD-related mortality 45%. Age ≥ 40 years, malignant underlying disease, non-response to rituximab, and severe thrombocytopenia or lymphocytopenia at PTLD diagnosis were associated with worse overall survival.Only a small proportion of allografted patients were diagnosed a PTLD. Its clinical course was highly aggressive, and prognosis poor, especially in those failing rituximab. The prognostic impact found of the platelet, and lymphocyte count at diagnosis requires further confirmation.

Zahid U., Akbar F., Amaraneni A., Husnain M., Chan O., Riaz I.B., McBride A., Iftikhar A., Anwer F.

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

Genadieva-Stavrik S., Boumendil A., Dreger P., Peggs K., Briones J., Corradini P., Bacigalupo A., Socié G., Bonifazi F., Finel H., Velardi A., Potter M., Bruno B., Castagna L., Malladi R., et. al.

To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years.A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study.With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT.With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.

Kim H.T., Zhang M.-., Woolfrey A.E., St. Martin A., Chen J., Saber W., Perales M.-., Armand P., Eapen M.