Secondary primary malignancies after CD-19 directed CAR-T-cell therapy in lymphomas: A report from the Italian CART-SIE study.

Secondary primary malignancies (SPM) have been reported after anti-BCMA or anti-CD19 chimeric antigen receptor (CAR)-T-cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR-T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART-SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR-T was relatively low and consistent with previous studies.

ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party.

Introduction: Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. Methods: We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. Results: 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. Discussion: The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.

The black swan: a case of central nervous system graft-versus-host disease.

OBJECTIVES: Graft-versus-host disease (GVHD) of central nervous system is an atypical and rare manifestation of chronic GVHD, presenting with a heterogeneous spectrum of signs and symptoms. Diagnosis of neurological manifestations of GVHD can be highly challenging and remain associated with dismal prognosis, significant morbidity, and reduced quality of life. CASE PRESENTATION: In this report, we describe a 39-year-old woman developing neurological signs and symptoms 8 months after allogeneic HSCT magnetic resonance imaging showed multifocal hyperintense lesions involving the periventricular region and frontal subcortical white matter. There was no laboratory evidence of infective or malignant etiology, and the case was diagnosed as CNS-GVHD. The patient was treated with intravenous methylprednisolone pulse therapy and the clinical conditions gradually improved. After few months, patient symptoms progressed despite the addition of high-dose intravenous immunoglobulin, tacrolimus, and a new course of high dose steroids. To engage targeted therapy, the patient underwent brain biopsy that revealed a loss of myelin fibers, perivascular and diffuse infiltration of T cells, and macrophages associated with reactive gliosis, representing a demyelinating disease. We intensified treatment with cyclophosphamide and subsequently introduced ibrutinib as salvage strategy. Despite a magnetic resonance imaging showing great regression of the demyelinating lesions, patient's conditions deteriorated and she died 16 months after HSCT. CONCLUSIONS: CNS-GVHD is a rare complication of HSCT that is difficult to diagnose. Based on our experience, brain biopsy may represent a useful diagnostic tool when the clinical features of neurological symptoms are ambiguous or in patients without evidence of preceding chronic GVHD.

Impact of second-degree related donor on the outcomes of T cell-replete haploidentical transplantation with post-transplant cyclophosphamide.

Donor selection may contribute to improve clinical outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy). Impact of second-degree related donor (SRD) was not fully elucidated in this platform. We retrospectively compared the outcome of patients receiving Haplo-SCT either from a SRD (n = 31) or a first-degree related donor (FRD, n = 957). Median time to neutrophil and platelet recovery did not differ between a SRD and a FRD transplant (p = 0.599 and 0.587). Cumulative incidence of grade II-IV acute graft-versus host disease (GVHD) and moderate-severe chronic GVHD was 13% and 19% after SRD vs 24% (p = 0.126) and 13% (p = 0.395) after FRD transplant. One-year cumulative incidence of non-relapse mortality (NRM) was 19% for SRD and 20% for FRD (p = 0.435) cohort. The 3-year probability of overall survival (OS) and progression-free survival (PFS) was 42% vs 55% (p = 0.273) and 49% vs 35% (p = 0.280) after SRD and FRD transplant, respectively. After propensity score adjustment or matched pair analysis, the outcome of patients receiving Haplo-SCT from a SRD or a FRD did not differ in terms of NRM, OS, PFS, acute and chronic GVHD. Our results suggest that a SRD is a viable option for Haplo-SCT with PT-Cy when a FRD is not available.

Sorafenib maintenance after hematopoietic stem cell transplantation improves outcome of FLT3-ITD-mutated acute myeloid leukemia.

In a retrospective analysis, 21 acute myeloid leukemia patients receiving single-agent sorafenib maintenance therapy in complete remission (CR) after hematopoietic stem cell transplantation (HSCT) were compared with a control group of 22 patients without maintenance. Sorafenib was initiated a median of 3 months (IQR: 2.3-3.5) after allogeneic HSCT with a median daily dosage of 400 mg (range: 200-800) orally, and lasted a median of 11.3 months (IQR: 3.3-24.4). No significant increase in graft versus host disease or toxicity was observed. Adverse events were reversible with dose adjustment or temporary discontinuation in 19/19 cases. With a median follow-up of 34.7 months (IQR: 16.9-79.5), sorafenib maintenance significantly improved cumulative incidence of relapse (p = 0.028) as well as overall survival (OS) (p = 0.016), especially in patients undergoing allogeneic HSCT in CR1 (p < 0.001). In conclusion, sorafenib maintenance after allogeneic HSCT is safe and may improve cumulative incidence of relapse and OS in FLT3-ITD-mutated AML.

Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia: final results of the GITMO prospective trial GANDALF-01.

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population.

Impact of anti-thymocyte globulin dose for graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation from matched unrelated donors: a multicenter experience.

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.

Extracellular Vesicles as Biomarkers of Acute Graft-vs.-Host Disease After Haploidentical Stem Cell Transplantation and Post-Transplant Cyclophosphamide.

Even with high-dose post-transplant cyclophosphamide (PT-Cy) which was initially introduced for graft-versus-host disease (GvHD) prevention in the setting of HLA-haploidentical transplantation, both acute and chronic GvHDs remain a major clinical challenge. Despite improvements in the understanding of the pathogenesis of both acute and chronic GvHDs, reliable biomarkers that predict their onset have yet to be identified. We recently studied the potential correlation between extracellular vesicles (EVs) and the onset of acute (a)GvHD in transplant recipients from related and unrelated donors. In the present study, we further investigated the role of the expression profile of membrane proteins and their microRNA (miRNA) cargo (miRNA100, miRNA155, and miRNA194) in predicting the onset of aGvHD in haploidentical transplant recipients with PT-Cy. Thirty-two consecutive patients were included. We evaluated the expression profile of EVs, by flow cytometry, and their miRNA cargo, by real-time PCR, at baseline, prior, and at different time points following transplant. Using logistic regression and Cox proportional hazard models, a significant association between expression profiles of antigens such as CD146, CD31, CD140a, CD120a, CD26, CD144, and CD30 on EVs, and their miRNA cargo with the onset of aGvHD was observed. Moreover, we also investigated a potential correlation between EV expression profile and cargo with plasma biomarkers (e.g., ST2, sTNFR1, and REG3a) that had been associated with aGVHD previously. This analysis showed that the combination of CD146, sTNFR1, and miR100 or miR194 strongly correlated with the onset of aGvHD (AUROC >0.975). A large prospective multicenter study is currently in progress to validate our findings.

CMV retinitis in a stem cell transplant recipient treated with foscarnet intravitreal injection and CMV specific immunoglobulins.

Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.

Impact of donor age and kinship on clinical outcomes after T-cell-replete haploidentical transplantation with PT-Cy.

Donor selection contributes to improve clinical outcomes of T-cell-replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

Optimal Delivery of Follow-Up Care After Allogeneic Hematopoietic Stem-Cell Transplant: Improving Patient Outcomes with a Multidisciplinary Approach.

The increasing indications for allogeneic stem-cell transplant in patients with hematologic malignancies and non-malignant diseases combined with improved clinical outcomes have contributed to increase the number of long-term survivors. However, survivors are at increased risk of developing a unique set of complications and late effects, besides graft-versus-host disease and disease relapse. In this setting, the management capacity of a single health-care provider can easily be overwhelmed. Thus, to provide appropriate survivorship care, a multidisciplinary approach for the long-term follow-up is essential. This review aims at summarizing the most relevant information that a health-care provider should know to establish a follow-up care plan, in the light of individual exposures and risk factors, that includes all organ systems and considers the psychological burden of these patients.

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications.

Extracellular vesicles (EVs) play an important role in the cellular crosstalk by transferring bioactive molecules through biological barriers from a cell to another, thus influencing recipient cell functions and phenotype. Therefore, EVs are increasingly being explored as biomarkers of disease progression or response to therapy and as potential therapeutic agents in different contexts including in hematological malignancies. Recently, an EV role has emerged in allogeneic hematopoietic cell transplantation (allo-HCT) as well. Allogeneic hematopoietic cell transplantation often represents the only curative option in several hematological disorders, but it is associated with potentially life-threatening complications that can have a significant impact on clinical outcomes. The most common complications have been well-established and include graft-versus-host disease and infections. Furthermore, relapse remains an important cause of treatment failure. The aim of this review is to summarize the current knowledge, the potential applications, and clinical relevance of EVs in allo-HCT. Herein, we will mainly focus on the immune-modulating properties of EVs, in particular those derived from mesenchymal stromal cells, as potential therapeutic strategy to improve allo-HCT outcome. Moreover, we will briefly describe the main findings on EVs as biomarkers to monitor graft-versus-host disease onset and tumor relapse.

Haplo-identical allografting with post-transplant cyclophosphamide in high-risk patients.

Haplo-identical transplants (Haplo-Tx) are an important alternative for patients with hematological malignancies who lack a HLA-identical donor. Seventy-one T-replete Haplo-Tx were performed in 70 high-risk patients at our center; 22/70 (31%) patients with refractory/relapsed leukemia received sequential salvage therapy (SeqTh) with high-dose chemotherapy followed by Haplo-Tx during the chemotherapy-induced neutropenia. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (days + 3 and + 4) with tacrolimus and mycophenolic acid. After a median follow-up of 29.2 months, 3-year overall survival (OS) and event-free survival (EFS) were 43.8 and 40.2%, while 3-year cumulative incidences (CIs) of non-relapse mortality (NRM) and relapse (RI) were 27 and 33%. Day 100 and day 400 CI of grade III-IV acute and moderate-severe chronic GVHD were 11 and 15%. Three-year RI was significantly lower in patients in complete remission (CR) versus those not in CR at the time of transplant (21.5 vs. 48%, p = 0.009) and in patients who received PBSC as compared to BM (22 vs. 45%, p = 0.009). In patients treated with SeqTh, 3-year OS was 19%, while 3-year RI and NRM were 52 and 28% at a median follow-up of 50 months. Overall, Haplo-Tx was feasible in heavily pretreated high-risk patients without a suitable HLA-identical donor.

Eltrombopag for the Treatment of Refractory Pure RBC Aplasia after Major ABO Incompatible Hematopoietic Stem Cell Transplantation.

Pure RBC aplasia (PRCS) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many therapeutic options are available to treat this condition, including erythropoietin, rituximab, bortezomib, plasma exchange, immunoadsorption, donor lymphocyte infusion, mesenchymal stem cells, antithymocyte globulin, and high-dose steroids; however, treatment outcomes are often variable and can sometimes lead to disappointing results. In this brief article we report our experience with 2 patients with PRCA after major ABO-incompatible HSCT who were resistant to multiple therapeutic interventions and who eventually benefited from treatment with eltrombopag, a thrombopoietin mimetic approved by the US Food and Drug Administration for the treatment of patients with immune thrombocytopenic purpura or severe aplastic anemia refractory to immunosuppressive agents or not eligible for HSCT. Data from these 2 patients show that eltrombopag was effective in treating erythroid aplasia and transfusion dependence after HSCT in patients who did not benefit from multiple previous treatments. Moreover, eltrombopag was well tolerated, with only a transient thrombocytosis requiring dose adjustment and no evidence of clonal evolution. Based on the positive results obtained in these 2 patients, we suggest that eltrombopag may have a favorable effect on unilineage cytopenias such as PRCA. Further studies in a large proportion of patients are mandatory to confirm these preliminary results.

Hematopoietic cell transplantation comorbidity index and risk of developing invasive fungal infections after allografting.

We evaluated the potential correlation of the hematopoietic cell transplantation comorbidity index (HCT-CI) with the risk of developing post-transplant invasive fungal infections (IFIs). Between January 2009 and March 2015, 312 consecutive patients who received a first allograft entered the study. Low/intermediate HCT-CI risk score (0-2) was observed in 172/312 (55%), whereas high HCT-CI score (≥3) was seen in 140/312 (45%). Overall, 51/312 (16%) patients experienced IFI, defined as possible in 19 (6%), probable in 27 (9%), and proven in 5 (2%). Cumulative incidence of probable-proven IFI at 1 year was 8.5% with a significant higher incidence in patients with high HCT-CI (12%) vs. those with low-intermediate HCT-CI (5%; p = 0.006). There was a strong trend for a higher incidence of baseline severe pulmonary comorbidity in patients who developed probable-proven IFI (p = 0.051). One-year cumulative incidence of non-relapse mortality was higher in patients with IFI vs. those without, 49 and 16% (p < 0.001). By multivariate analysis, disease status at transplant and high HCT-CI, when combined with acute GVHD, were independently associated with the risk of post-transplant IFI. This study shows that a high HCT-CI predicts the risk of developing IFI and may indicate the need of mold-active antifungal prophylaxis in high-risk patients.

Late-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide.

Hepatic Veno-Occlusive Disease (VOD) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). Here we report two patients receiving an allogeneic HSCT who developed late onset VOD with atypical clinical features. The two patients presented with only few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing regimen and received grafts from an unrelated donor. The first patient did not experience painful hepatomegaly and weight gain and both patients showed only a mild elevation in total serum bilirubin level. Most importantly, the two patients developed clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy confirmed the diagnosis of VOD. Intravenous defibrotide was promptly started leading to a marked clinical improvement. Based on our experience, liver biopsy may represent a useful diagnostic tool when the clinical features of VOD are ambiguous. Early therapeutic intervention with defibrotide represents a crucial issue for the successful outcome of patients with VOD.