Risk Assessment for Newly Diagnosed Fit Young Patients with Multiple Myeloma in the Era of Novel Treatment Modalities: Should There Be Additional Factors Taken into Consideration??

Introduction: The optimal treatment for young patients with high-risk newly diagnosed multiple myeloma (NDMM) remains a challenge. Methods: We retrospectively evaluated 58 NDMM patients younger than 55 years treated in our center from 2010 to 2021 with the current recommended protocols. Results: After a median follow-up of 48 months, median overall survival (OS) was not reached; however, approximately 25% of them died within 4 years after diagnosis. Advanced disease stage, presence of extramedullary disease, elevated LDH, and less than very good remission before autologous hematopoietic stem-cell transplantation adversely affected patient survival. Based on these factors, we created a risk-assessment scoring system that sufficiently discriminated young NDMM patients at risk of poor outcome. The 4-year OS was superior for patients with zero to two factors to those with three to five factors (86% vs 44%, p<0.001). Conclusion: The proposed scoring system could be reliably used at diagnosis and at interim disease evaluation in aiming for personalized treatment for young NDMM patients.

Establishment of the First Comprehensive Adult and Pediatric Hematopoietic Stem Cell Transplant Unit in the United Arab Emirates: Rising to the Challenge.

Hematopoietic stem cell transplantation (HSCT) is increasingly indicated for various malignant and non-malignant diseases. In the United Arab Emirates (UAE), patients that could benefit from the procedure commonly need to seek medical care abroad in view of the lack of a comprehensive HSCT facility that could offer the full spectrum of interventions and monitoring protocols. This comes with considerable challenges related to coverage and logistics of travel. It also limits the continuity of clinical care, and presents inconvenience to patients who come from a different cultural background. In this article, we share our experiences and lessons learned during the establishment of the first comprehensive adult and pediatric HSCT unit in the UAE that is designed to cater for local citizens and residents, as well as neighboring countries facing similar availability challenges.

Allogeneic Stem Cell Transplantation in Patients with High-Risk Multiple Myeloma: Utopia or Continuous Challenge in Aiming for Cure?

OPINION STATEMENT: Nowadays, several novel agents have been introduced in the treatment of multiple myeloma, not only resulting in high response rates and prolonged survival but also offering good quality of life. However, the potential of cure, especially for patients with advanced or unfavorable disease features, remains elusive. Allogeneic hematopoietic stem cell transplantation, based mainly on the graft vs. myeloma effect, can offer prolonged disease control and probability of cure but unfortunately at the cost of considerable transplant-related toxicity rates. Therefore, the role of allogeneic hematopoietic stem cell transplantation in the treatment of multiple myeloma has been called into question. Recently, several studies, particularly those with long-term follow-up, demonstrated a trend of survival superiority for allografted patients with high-risk disease. These data fuel again the interest in allogeneic stem cell transplantation for selected patients with high-risk multiple myeloma, especially if the high remission rates which can be achieved with the currently used treatment protocols could be long-life sustained through the additional exploitation of the long-lasting anti-multiple myeloma effect, originating from the allograft.

Non-transplantable cord blood units as a source for adoptive immunotherapy of leukaemia and a paradigm of circular economy in medicine.

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.

Clinical course and outcomes of COVID-19 in hematopoietic cell transplant patients, a regional report from the Middle East.

The coronavirus disease-2019 (COVID-19) caused by SARS Coronavirus 2 (SARS-CoV-2) is a potentially lethal infection. Cancer patients, and specifically hematopoietic cell transplant (HCT) recipients are severely immunocompromised and may be at a higher risk of a complicated course with this infection. We aimed to study the COVID-19 outcomes and severity in post HCT patients. We retrospectively reviewed post-HCT patients diagnosed with COVID-19 between March 15, 2020, and December 1, 2020 at 10 transplant centers across the Middle East. We identified 91 patients with confirmed SARS-CoV-2 infection across 10 transplant centers. The median age upon presentation with COVID-19 was 35. Fifty two patients were post allo-HCT while the remaining 39 patients were post auto-HCT. The median time from transplant was 14.9 months. Mortality rate was 4.4%. Hospital admission rate was 53%. ICU admission rate was 14%. Mechanical ventilation rate was 10%. Oxygen supplementation rate was 18%. Time from HCT to COVID-19 >6 months was associated with lower admission rates and lower rates of the "severity" composite endpoint. Antibody responses was seen 67% of evaluable patients. In this series of HCT recipients, we report overall favorable clinical outcomes for patients with COVID-19 and provide preliminary insights into the clinical course of this disease in this specific population.

Repeated courses of escalating doses of Nivolumab in refractory Hodgkin lymphoma with recurrent relapses post allografting: A safe and effective treatment approach.

For patients with Hodgkin Lymphoma (HL) who experience relapse post allogeneic stem cell transplantation, limited treatment options exist, and the ultimate outcome is poor. Recently, the programmed cell death protein-1 (PD-1) inhibitors have shown remarkable efficacy in patients with refractory/relapsed HL, also demonstrating an acceptable safety profile. However, due to effects on T-cell activity, the use of PD-1 inhibitors post allografting may potentially increase the risk of treatment-emergent graft versus host disease. We herein report the clinical course of a patient who experienced multiple relapses of HL post allogeneic stem cell transplantation. He failed several treatment modalities but he responded to escalating doses of the PD-1 inhibitor nivolumab, given at two different treatment time points, also demonstrating minimal and easily manageable toxicity.

Favorable Outcome After Adjuvant Involved-Field Radiotherapy After Autologous Hematopoietic Stem-Cell Transplantation in Patients With High-Risk Relapsed/Refractory Lymphoma: A Single-Center Experience.

BACKGROUND: Patients with refractory or relapsed lymphoma diagnosed with bulky disease at relapse or with residual disease after salvage treatment are considered to have a dismal outcome, even after autologous hematopoietic stem-cell transplantation, as a result of disease recurrence. To minimize the risk of relapse after receipt of a transplant, involved-field radiotherapy (IFRT) to sites of either bulky or localized residual disease has been utilized; however, the ideal timing for irradiation remains controversial. The aim of this study was to assess the safety and efficacy of IFRT in the early period after transplantation. PATIENTS AND METHODS: We retrospectively evaluated the outcome of 24 autografted patients with relapsed/refractory lymphoma who presented with bulky disease at relapse or who had a persistent localized residual mass after salvage treatment and consolidated with IFRT within 4 months after autografting. RESULTS: No significant toxicity was noticed during the early postradiotherapy period, while graft function was not impaired. After a median follow-up of 3 years for survivors, 21 patients were alive, 19 of whom were event free, while 2 patients died of disease recurrence and 1 died of treatment-related myelodysplastic syndrome. The 3-year overall, lymphoma relapse-free, and event-free survival rates were 86%, 86%, and 82%, respectively. CONCLUSION: Taking into consideration the poor-risk features of the study cohort, IFRT provided early after autologous hematopoietic stem-cell transplantation showed a safe and well-tolerated toxicity profile and demonstrated long-term effective tumor control, as reflected in the promising survival rates.

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma.

Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation.

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5-99·3%] and 32·2% (95% CI: 19·1-54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2-42·0%) and 3·2% (95% CI: 1·1-8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.

Correction to: Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host.

Invasive aspergillosis (IA) represents a leading cause of mortality in immunocompromised patients. Although adoptive immunotherapy with Aspergillus-specific T cells (Asp-STs) represents a promising therapeutic approach against IA, the complex and costly production limits its broader application. We generated Asp-STs from a single blood draw of healthy individuals or IA patients in only 10 days, by either Aspergillus fumigatus (AF) lysate or peptide stimulation of mononuclear cells. The cells were phenotypically and functionally characterized, and safety was assessed in xenografts. Healthy donor-derived and lysate- or peptide-pulsed Asp-STs presented comparable fold expansion, immunophenotype, and Th1 responses. Upon cross-stimulation, only the lysate-pulsed Asp-STs were empowered to respond to peptide stimulation, although both cell products induced hyphal damage. Importantly, Asp-STs cross-reacted with other fungal species and did not induce alloreactivity in vivo. IA patient-derived T cells displayed an anergic phenotype that prohibited sufficient expansion and yield of meaningful doses of Asp-STs for autologous immunotherapy. Using a rapid and simple process, we generated, from healthy donors but not IA patients, functionally active Asp-STs of broad specificity and at clinically relevant numbers. Such an approach may form the basis for the effective management of IA in the context of allogeneic hematopoietic cell transplantation.

Favorable impact of extracorporeal photopheresis in acute and chronic graft versus host disease: Prospective single-center study.

BACKGROUND: Graft vs host disease (GVHD) is the most severe complication of allogeneic hematopoietic cell transplantation. Conventional immunosuppressive therapy increases morbidity and mortality without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in steroid-dependent and steroid-refractory disease. STUDY DESIGN AND METHODS: We studied the safety and efficacy of ECP as a second- or third-line treatment in GVHD. RESULTS: ECP was administered in 21 patients with grade III-IV acute GVHD and 88 patients with extensive chronic GVHD, without ECP-related adverse events. Eight patients receiving four or less ECP sessions were not further analyzed. The majority of acute GVHD patients (84%) presented partial (15) or complete (1) response to ECP. Immunosuppression was reduced in 10 of 19 patients and ceased in 1 of 19 patients. One-year cumulative incidence (CI) of transplant-related mortality (TRM) (17.6%) was associated with the lack of response to ECP and steroid refractoriness. With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) (52.5%) was independently associated with a higher number of ECP sessions. Regarding chronic GVHD, complete response was achieved in 35 patients, whereas partial response in 25 patients, leading to an overall response rate of 73%. Cutaneous sclerosis manifestations were associated with higher response rates. With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of TRM (24.1%) was associated only with a number of ECP sessions. The 5-year OS (64.5%) was independently associated with number of ECP sessions and cutaneous manifestations. CONCLUSION: Our findings suggest that ECP is safe and effective for GVHD and should be considered early in the course of GVHD, before irreversible end-organ damage has been established.

De Novo Psoriasis Vulgaris Diagnosed after Nivolumab Treatment for Refractory Hodgkin's Lymphoma, Completely Resolved after Autologous Hematopoietic Stem Cell Transplantation.

The programmed cell death protein-1 (PD-1) inhibitor nivolumab has been recently approved as an effective and safe treatment for patients with refractory/relapsed Hodgkin's lymphomas. Dermatological adverse events, mainly skin rash, have been reported in 1-5% of patients. We describe a case of de novo psoriasis vulgaris (PsV), diagnosed after nivolumab treatment for refractory Hodgkin's lymphoma. After administration of 6 cycles, skin lesions appeared in the right tibia, forearms, and dorsum of hands, and biopsy confirmed the diagnosis of PsV. The lesions completely resolved after autologous stem cell transplantation (ASCT) which was performed in the context of the treatment for the primary disease. PsV is an inflammatory skin disease, and it is considered to be mediated through cytotoxic T-cells. PD-1 blockage may lead to expansion of such T-cells, resulting thus in PsV appearance. The early published studies showed that nivolumab represents a safe treatment approach. PsV occurrence has not been reported so far in patients treated with nivolumab for hematological diseases, and it seems that long-term follow-up is necessary to fully clarify the entirety of PD-1 inhibitors' skin adverse events. Additionally, this clinical observation provides an evidence for a potential exploitation of ASCT in refractory and severe forms of PsV.

Transplant-associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation.

Renewed interest has emerged in transplant-associated thrombotic microangiopathy (TA-TMA) with novel prognostic, diagnostic, and treatment algorithms. We aimed to investigate the incidence, prognostic factors, morbidity, and mortality of TA-TMA in allogeneic hematopoietic cell transplantation (HCT) recipients. We enrolled consecutive HCT recipients (1990-2017). Among 758 patients, 116 (15.5%) were diagnosed with TA-TMA. In the multivariate analysis, TBI-based conditioning, viral infections, acute and chronic GVHD remained independent predictors of TA-TMA. With a median follow-up of 23 (range 0.1-329) months, TA-TMA resulted in significantly lower overall survival (OS). In the multivariate analysis, TA-TMA remained an independent predictor of OS, along with relapse, acute, and chronic GVHD. Among 116 TA-TMA patients, 70 developed renal (56) and/or neurologic (26) dysfunction that would be necessary for TA-TMA diagnosis according to the Bone Marrow Transplant Clinical Trials Network criteria. TA-TMA patients with renal dysfunction showed increased rates of acute GVHD, but no difference in OS compared to patients without renal dysfunction. However, neurologic dysfunction resulted in significantly lower OS. In conclusion, TA-TMA is associated with increased morbidity and mortality in allogeneic transplant recipients. Successful prevention and treatment strategies of infections and GVHD need to be timely employed to improve survival in this complex setting.

Positive impact of brentuximab vedotin on overall survival of patients with classical Hodgkin lymphoma who relapse or progress after autologous stem cell transplantation: A nationwide analysis.

The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after autologous stem cell transplantation (auto-SCT) is poor. Recently, the anti-CD30 monoclonal antibody-drug conjugate, brentuximab vedotin (BV), has shown remarkable activity in the setting of R/R cHL. In the pivotal phase II study, BV produced an overall response rate of 75% and a median progression-free survival of 6.7 months. Although these results have been reproduced by large registry studies, the impact of BV on the overall survival (OS) of patients with R/R cHL has not been addressed so far. The aim of this study was to examine the impact of BV on OS in the setting of post auto-SCT R/R cHL. Analysis was performed in a group of patients with R/R cHL after a previous auto-SCT reported in the Greek registry during the last 2 decades. By using a multivariate model and censoring patients at the time of subsequent allo-SCT or treatment with immune checkpoint inhibitors, we showed that treatment with BV in the posttransplant relapse setting has a positive impact on the outcome and results in significant improvement of OS. To our knowledge, this the first published study, addressing the impact of BV on the OS in the setting of posttransplant relapse.

The Role of Low-dose Anti-thymocyte Globulin as Standard Prophylaxis in Mismatched and Matched Unrelated Hematopoietic Peripheral Stem Cell Transplantation for Hematologic Malignancies.

INTRODUCTION: Anti-thymocyte globulin (ATG)-based immunosuppressive therapy is often used in allogeneic hematopoietic cell transplantation to reduce incidence and severity of graft-versus-host disease (GVHD). PATIENTS AND METHODS: In our observational study, ATG (rabbit, Thymoglobulin; Sanofi, 5 mg/kg) was administered as a standardized part of the conditioning in 97 patients with a median age of 34 years (range, 14-58 years), allotransplanted for hematologic malignancies from matched (8/8; n = 52) and allele or antigen mismatched (7/8; n = 43 and 6/8; n = 2) unrelated donors. RESULTS: Five-year overall survival (OS) was 46.9%, disease-free survival was 46.5%, and treatment-related mortality was 20.6%, with a median follow-up of 29 months (range, 1-145 months). Acute GVHD (grade ≥ II) cumulative incidence was 26.9% in matched versus 50.5% in mismatched patients (P = .060), whereas extensive chronic GVHD was 45.6% versus 50%, respectively (P = .310). Five-year OS was 62.2% for the matched patients and 27.9% for the mismatched patients (P = .003) owing to a higher treatment-related mortality rate in mismatched patients (P = .032). In multivariate analysis including age, gender, time until transplantation, disease phase, mismatched donor, ABO mismatch, number of CD34+ infused, acute and chronic GVHD, the significant unfavorable factors for OS were HLA mismatch and advanced disease phase. CONCLUSION: A relatively low-dose ATG is effective in acute GVHD prophylaxis, leading to promising survival rates in matched transplants. Further comparative studies with adjusted ATG dose depending on Human leukocyte antigen disparity or alternative donors are warranted.