Acute graft-versus-host disease (GVHD) is a common immune complication that can occur after allogeneic haematopoietic cell transplantation (alloHCT). Acute GVHD is a major health problem in these patients, and is associated with high morbidity and mortality. Acute GVHD is caused by the recognition and the destruction of the recipient tissues and organs by the donor immune effector cells. This condition usually occurs within the first 3 months after alloHCT, but later onset is possible. Targeted organs include the skin, the lower and upper gastrointestinal tract and the liver. Diagnosis is mainly based on clinical examination, and complementary examinations are performed to exclude differential diagnoses. Preventive treatment for acute GVHD is administered to all patients who receive alloHCT, although it is not always effective. Steroids are used for first-line treatment, and the Janus kinase 2 ( JAK2) inhibitor ruxolitinib is second-line treatment. No validated treatments are available for acute GVHD that is refractory to steroids and ruxolitinib, and therefore Nature Reviews Disease Primers | (2023) 9:27 2 0123456789();:Primer late onset acute GVHD (first episode more than 100 days after transplantation), recurrent acute GVHD (new episode of acute GVHD more than 100 days after transplantation in a patient with a history of classic acute GVHD), or persistent acute GVHD (classic acute GVHD symptoms that persist for more than 100 days after transplantation).Acute GVHD can also be graded based on severity as I (mild), II (moderate), III (severe) and IV (very severe), based on quantification of skin rash for skin acute GVHD, serum bilirubin level for liver acute GVHD, volume of diarrhoea for lower GI acute GVHD and persistent nausea for upper GI acute GVHD 9 . Grade I acute GVHD is usually not considered as clinically important given its lack of effect on patient outcome 10 ; therefore, most studies focus on grade II-IV and severe grade III-IV acute GVHD. Several systems can be used for grading acute GVHD. The MAGIC grading system is not yet used in routine clinical practice; however, it is used in this Primer as it facilitates and helps standardize acute GVHD clinical data collection, as shown by the development and validation of the electronic eGVHD application to assist health-care professionals in the assessment of acute GVHD in clinical practice 11,12 .This Primer discusses the epidemiology and pathophysiological mechanisms of acute GVHD. This Primer also discusses management, patient quality of life (QOL) and outstanding research questions including the need for more efficient prophylaxis. Epidemiology IncidenceIn the absence of effective prophylaxis, most patients develop acute GVHD; for example, in one historical series, only 19 of 93 patients did not develop acute GVHD when no prophylaxis was administered 13 . Nevertheless, acute GVHD can still occur, despite the routine use of prophylaxis after alloHCT. Acute GVHD incidence varies considerably depending, predominantly, on the degree of mismatch between HLA ...

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3033 Poster Board II-1009 Donor lymphocyte infusion (DLI) approach alone for treatment of relapse has led to significant response in CML. For non CML diseases however, DLI remains relatively disappointing. Lymphodepletion may enhance anti-tumor effects of transferred T cells in vivo through several mechanisms including the elimination of suppressive CD4+CD25+ T-regulatory cells, NKT cells, with creation of an immunologic “space” with recruitment of homeostatic proliferative cytokines such as IL-7 and IL-15. DLI efficacy might be improved through manipulation of the recipient immune environment to allow for in vivo expansion of donor T cells. We postulated that induction of a relative lymphopenia in a graduated fashion may reduce toxicities and be sufficient to upregulate in vivo homeostatic cytokines to the benefit of transferred T cells. Therefore, we designed a dose-escalation study of DLI preceded by lymphodepletion with fludarabine (Flu) and cyclophosphamide (Cy). Lymphodepletion was proposed to avoid an overwhelming toxicity due to severe GVHD. We treated 17 patients (median age at transplant : 46 y (18 - 67) for relapse of various hematologic malignancies (6 AML/MDS, 4 ALL, 3 Hodgkin's disease, 2 T-NHL, 2 multiple myeloma) following allogeneic transplantation (5 myeloablative conditioning, 12 RIC; donors: 10 siblings, 7 MUD). To avoid overwhelming toxicity due to severe GVHD, we proceeded by sequentially escalating both LD and T cell doses infused with the DLI. Lymphodepletion consisted in Flu 25 mg/m2/d for 3 days followed by infusion of 1×107 CD3+ cells/Kg. If no GVHD developed and disease persisted or progressed, the same LD was followed by a second DLI at 5×107 CD3+ cells/Kg. At the next step, LD combined both Cy 600 mg/m2 for one day and Flu 25 mg/m2/d for 3 days followed by DLI at 5×107 CD3+ cells/Kg. Twenty-five LD-DLI were performed. Prior LD-DLI, eight patients received DLI not preceded by LD. Ten, six and one patient(s) received respectively one, two or three LD-DLIs. The first LD-DLI was given at a median of 234 days (range 62 days – 14 y 11 m) following allogeneic transplantation. Median follow-up after the first LD-DLI was 153 days (54-538). The cumulative incidence of grade II-IV acute GVHD was 36 %. The median onset of acute grade II-IV GVHD following the last LD-DLI was 31 days (range 15-59) not significantly different from a control group of 64 patients receiving DLI without lymphodepletion (34 days, range 12-120). Tumor response to LD-DLI was observed in 7 patients, 3 achieved CR, 4 achieved PR. At last follow-up, 7 pts died: 6 due to relapse (3 AML/MDS, 2 ALL, 1 T-NHL) and 1 from lung carcinoma. No patient died due to GVHD. Overall survival from LD-DLI was 55 % at one year. Although, there is some risk associated with lymphopenia in patients receiving multiple cycles of fludarabine therapy in this post-transplantation context, we did not observed significant infection. Study of the immunomodulatory effects of LD in these patients (pre- and post-LD-DLI T cells including Treg and cytokine secretion) are currently being further characterized. We conclude that LD-DLI has an acceptable toxicity if used in a stepwise manner or adapted to the severity of the disease. Disclosures No relevant conflicts of interest to declare.

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With the continuous improvement in survival of cancer patients, including those with multiple myeloma, related to the novel treatment agents and therapeutic approaches, the probability for patients to develop cardiovascular disease has significantly increased, especially in elderly patients and those with additional risk factors. Multiple myeloma is indeed a disease of the elderly population and so these patients are, solely by age, at an increased risk of cardiovascular disease. Risk factors for these events can be patient-, disease- and/or therapy-related, and they have been shown to adversely impact survival. Cardiovascular events affect around 7.5% of patients with multiple myeloma and the risk for different toxicities has considerably varied across trials depending on patients’ characteristics and treatment utilized. High grade cardiac toxicity has been reported with immunomodulatory drugs (odds ratio [OR] around 2), proteasome inhibitors (OR 1.67–2.68 depending on the specific agent, and generally higher with carfilzomib), as well as other agents. Cardiac arrhythmias have also been reported with various therapies and drug interaction plays a significant role in that setting. Comprehensive cardiac evaluation before, during and after various anti-myeloma therapy is recommended and the incorporation of surveillance strategies allows early detection and management resulting in improved outcomes of these patients. Multidisciplinary interaction including hematologists and cardio-oncologists is critical for optimal patient care.