Hemophagocytic Lymphohistiocytosis Secondary to Hodgkin's Lymphoma with Isolated Bone Marrow Involvement in a Newly Diagnosed HIV Patient.

Human immunodeficiency virus (HIV) infection is known to be associated with the development of Hodgkin's lymphoma (HL). Exclusive extranodal bone marrow involvement is less common. Co-infection by other viruses, such as the Epstein-Barr virus (EBV), increases the incidence of a frequent complication denominated by hemophagocytic lymphohistocytosis (HLH). We present the case of a 50-year-old patient with the above clinical spectrum who develops several serious complications during treatment.

Primary Effusion Lymphoma, Multicentric Castleman's Disease, and Kaposi's Sarcoma in an HHV-8 and HIV-Positive Patient: A Case Report.

Primary effusion lymphoma (PEL), Kaposi's sarcoma (KS), and multicentric Castleman's disease (MCD) is an uncommon group of diseases included in the same spectrum with related characteristics. The coexistence of all of them in the same individual is a rare occurrence. We present the case of a 25-year-old patient diagnosed with human immunodeficiency virus (HIV) and the development of all these related pathologies. Despite the use of intensive treatment according to the latest recommendations, the evolution was unfavorable. This case reflects the need for new therapies and research in this field.

Risk prediction of CMV reactivation after allogeneic stem cell transplantation using five non-HLA immunogenetic polymorphisms.

Despite advances in the understanding of the pathophysiology of cytomegalovirus (CMV) infection, it remains as one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of this study was to determine the genotype of cytokines and chemokines in donor and recipient and their association with CMV reactivation. Eighty-five patients receiving an allo-HSCT from an HLA-identical sibling donor were included in the study. Fifty genes were selected for their potential role in the pathogenesis of CMV infection. CMV DNAemia was evaluated until day 180 after allo-HSCT. CMV reactivation was observed in 51/85 (60%) patients. Of the 213 genetic variants selected, 11 polymorphisms in 7 different genes (CXCL12, IL12A, KIR3DL1, TGFB2, TNF, IL1RN, and CD48) were associated with development or protection from CMV reactivation. A predictive model using five of such polymorphisms (CXCL12 rs2839695, IL12A rs7615589, KIR3DL1 rs4554639, TGFB2 rs5781034 for the recipient and CD48 rs2295615 for the donor) together with the development of acute GVHD grade III/IV improved risk stratification of CMV reactivation. In conclusion, the data presented suggest that the screening of five polymorphisms in recipient and donor pre-transplantation could help to predict the individual risk of CMV infection development after HLA-identical allo-HSCT.

Cytokine release syndrome after allogeneic stem cell transplantation with posttransplant cyclophosphamide.

Cytokine release syndrome (CRS) is a systemic inflammatory response with aberrant immune activation and immune hyperstimulation, that leads to increased cytokine levels and inflammation. CRS has been described after antibody and cellular-based therapies. The use of posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has led to the extension of allogeneic HSCT to patients without HLA-identical donors. Furthermore, PTCy has also been introduced in matched and unrelated donor HSCT. However, description of incidence and clinical impact of CRS on outcomes in these patients is scarce. We retrospectively analyzed 107 consecutive haplo-HSCT and 39 HLA-identical HSCT with PTCy from 2010 to 2017 in our institution. We used published CRS criteria to identify 76% and 14% of patients who developed CRS after haplo-HSCT and HLA-identical HSCT, respectively. Most patients presented CRS grades 1 and 2. Only one patient from the whole series presented grade 3 CRS and required tocilizumab therapy. The use of peripheral blood stem cells (PBSC), as well as total nucleated cells infused were associated with an increased risk of CRS. Patients who presented CRS developed grade II-IV acute GVHD more frequently than those who did not (60% vs 28.6% respectively, P = .012). The development of CRS was not significantly associated with nonrelapse mortality or overall survival. CRS is a frequent complication after PBSC haploidentical T-repleted HSCT, but significantly less frequent after HLA-identical HSCT. Most cases are mild. Prompt identification allows adequate management of severe forms.

Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 10(9) /l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 10(9) /l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6-25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed.

Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives.

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman's disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman's disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Daratumumab and Nelarabine Treatment as Salvage Therapy for T-Lymphoblastic Lymphoma: A Case Report.

T-cell lymphoblastic lymphoma is an uncommon lymphoid neoplasm in adults, although more frequent in children and teenagers, that often affects the mediastinum and bone marrow, requiring intensive chemotherapy protocols. Its prognosis is poor if a cure is not achieved with first-line treatments. We present a case report of a 19-year-old man diagnosed with this type of lymphoma due to significant respiratory distress and a mediastinal mass. He received treatment according to the hyper-CVAD regimen, with a complete metabolic response. However, seven months later a new mediastinal growth was observed, leading to salvage treatment with a combination of nelarabine and daratumumab. We observed not only refractoriness, but also leukemization, which prompted consideration of hematopoietic stem cell transplantation. Based on this case, we conducted a review of pharmacological treatment options for refractory or relapsed lymphoblastic lymphoma, as well as the role of radiotherapy in managing mediastinal disease. This case report highlights the limited evidence available regarding later-line treatments, with unusual reports regarding employing our combination of daratumumab and nelarabine, and emphasizes the importance of achieving cures in the first line of treatment.

Invasive Cutaneous Candidiasis, Autoimmune Hemolytic Anemia and Pancytopenia: A Challenging Scenario for Waldenström Macroglobulinemia in an Elderly Patient.

Waldenström macroglobulinemia (WM) is a slowly progressive hematologic malignancy that usually responds rapidly to treatment. Being a lymphoplasmacytoid neoplasm, it is associated with a monoclonal IgM component, which may be associated with multiple manifestations and symptoms. We report the case of a 77-year-old woman diagnosed with WM following the development of severe and sudden pancytopenia associated with a cold agglutinin syndrome. In order to treat the WM and the underlying hemolysis, treatment with rituximab, corticosteroids and cyclophosphamide was started. Despite the improvement in hemolysis parameters, pancytopenia persisted, and we started a second line with ibrutinib. During treatment the patient developed an uncommon invasive fungal infection (IFI) with bone marrow granulomatosis and myelofibrosis. This case shows an unusual clinical course with a poor hematopoietic response to treatment and a large number of intercurrent complications.

Results of haploidentical transplant in patients with donor-specific antibodies: a survey on behalf of the Spanish Group of Hematopoietic Transplant and Cell Therapy.

Background: Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT. Methods: We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes. Results: Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI >10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI >20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF. Conclusions: Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF.

Elafin as a Predictive Biomarker of Acute Skin Graft-Versus-Host Disease After Haploidentical Stem Cell Transplantation Using Post-Transplant High-Dose Cyclophosphamide.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell-replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed ("discovery cohort"). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs.14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the "validation cohort." These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis.

Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience From the Madrid Group of Hematopoietic Transplant.

Background: Donor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT. Methods: Patients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies. Results: We identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with > 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with > 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with > 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%. Conclusions: Despite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.

ST2 and REG3α as Predictive Biomarkers After Haploidentical Stem Cell Transplantation Using Post-transplantation High-Dose Cyclophosphamide.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell-replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

Posttransplant cyclophosphamide vs cyclosporin A and methotrexate as GVHD prophylaxis in matched sibling transplantation.

Posttransplant cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PTCy in HLA-identical HSCT is less explored. We conducted a retrospective study of 107 consecutive patients undergoing an HLA-identical sibling (10/10) HSCT in 2 centers in Spain, 50 with GVHD prophylaxis with methotrexate-cyclosporin A (MTX-CsA) and 57 using a PTCy-based regimen with additional immunosuppression. Graft source was unmanipulated mobilized peripheral blood stem cells (PBSC) in most patients (97 patients, 91%). Cumulative incidences of grade II to IV and III to IV acute GVHD at 100 days were lower in the PTCy group (22.6% vs 52.2%, P = .0015; 8.8% vs 24.4%, P = .016), without statistically significant differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (16.7% vs 26%, P = .306). At 2 years, no statistically significant differences were observed in OS (78% vs 56%, P = .088), EFS (62.5% vs 48%, P = .054), relapse (28% vs 27%, P = .47), and NRM (8.8% vs 24%, P = .054). The composite endpoint of GVHD and relapse-free survival (GRFS) was favorable for the PTCy group (24% vs 48%, P = .011), PTCy being the sole independent factor identified in the multivariate analysis for this endpoint. In this study, PTCy combination with additional immunosuppression using mostly PBSCs grafts showed a reduction of acute GVHD rate and an impact on GRFS, with safety results comparable with those obtained with MTX-CsA. Further prospective studies are needed to confirm these observations..

Allogeneic stem-cell transplantation in HIV-1-infected patients with high-risk hematological disorders.

INTRODUCTION: Although a number of patients with HIV infection and hematological disease have successfully undergone allogeneic hematopoietic stem-cell transplantation (HSCT), short and long-term outcomes remain not well known. We report the largest Spanish experience treating HIV-infected adult patients with high-risk hematological malignancies with allogeneic HSCT. METHODS: We retrospectively reviewed 22 HIV-positive patients who received allogeneic HSCT in five centers in Spain. RESULTS: A total of 22 patients with high-risk hematological malignancies were transplanted between 1999 and 2018. Median age was 44 years. With a median follow-up of 65 months (8-112), overall survival and event-free survival were 46%. Nonrelapse mortality was 14% at 12 months and relapse was 24% at 24 months. Grade II-IV acute graft-versus-host disease (GVHD) rate was 44%, and moderate/severe chronic GVHD rate was 41% at 24 months. All patients received combination antiretroviral therapy. Two patients showed severe toxicity related to drug interaction with antiretroviral therapy. 68% of patients showed infectious complications with viral infections as the most frequent cause. Two patients had invasive aspergillosis and one patient presented disseminated tuberculosis. All survivors except one maintained undetectable HIV load at last follow-up after HSCT. CONCLUSION: Allogeneic HSCT is an effective therapy for high-risk hematological malignancies in patients with HIV infection, and long-term HIV suppression with combination antiretroviral therapy is feasible. However, drug interactions with antiretroviral agents, occurrence of GVHD, and frequent infectious complications account for a complex procedure in this population. Selected HIV-infected patients with hematologic malignancies should be considered for allo-HSCT when indicated, in experienced centers.