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Blood Podcast
Itacitinib in haploidentical hematopoietic cell transplantation, diagnosis and management of purpura fulminans, and lack of evidence for sickle cell crisis-associated mortality in individuals with sickle cell trait
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Welcome to the March 27, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. Today we'll learn more about using idacitinib for the prevention of graft versus host disease in haploidentical transplants, diagnosis and management of purpurafulminans, and results of a systemic review seeking evidence for sickle cell crisis associated mortality in individuals with sickle cell trait. We first examined data in the Blood article entitled Idicitinib for prevention of graft versus host disease and cytokine release syndrome in haploidentical Transplantation by Ramsey Abboud of the Washington University School of Medicine in St. Louis, Missouri and colleagues. Haploidentical hematopoietic cell transplantation, or HaploHCT, is a potentially curative treatment for patients with hematological malignancies who lack an HLA matched donor. Many patients have a family member who could provide a half matched transplant, with the potential for greatly expanding the pool of available donors. However, this imperfect match comes at a cost of increased immune reactivity, leading to a high prevalence of graft versus host disease, or gvhd, as well as cytokine release syndrome, or crs, in patients who receive these transplants. Preclinical research has implicated the JAK STAT signaling pathway in the pathophysiology of both GVHD and crs, leading to interest in the use of JAK inhibitors to potentially reduce the rates and severity of these complications. Both the JAK1.2 inhibitor ruxolitinib and the JAK1 specific inhibitor idacitinib have been shown in early trials to reduce GVHD in patients receiving matched allogeneic transplants. The authors of the first paper we'll be discussing investigated whether addition of idacitinib to standard GVHD prophylaxis for haplohct might help reduce complications in haploidentical transplants as well. The authors enrolled 42 patients in a single ARM open label phase 2 trial. Idacitinib was added to standard post transplant prophylaxis that also included cyclophosphamide tacrolimus and mycophenolate mofetil. All patients started receiving idacitinib three days before transplant at a dose of 200 milligrams per day. Twenty patients in the pilot phase received the same dose of idicitinib for 100 days post transplant, while another 22 patients in the expansion phase received idacitinib for 180 days post transplant. Idicitinib dosing was then tapered off over another two months in both groups. Patients in the study had a range of hematological malignancies with acute myeloid leukemia as the Most frequent at 60%, 21% had acute lymphoblastic leukemia and another 10% had myelodysplastic syndromes. About half of the patients with these three conditions had measurable disease at transplantation. The patients were followed for a median of 453 days. None of the patients experienced primary graft failure, suggesting that idicitinib treatment does not interfere with the engraftment process. All patients had full donor chimerism by 30, 100, and 180 days. Although this was not a randomized controlled trial, the addition of idacitinib appeared to reduce rates of severe GVHD compared with historical controls. None of the patients in this trial developed grade 3 or 4 acute GVHD at 100 or 180 days. By comparison, past studies of haplohct have found grade 3 to 4 acute GVHD in about 15% of patients. The incidence of chronic GVHD was also low, occurring in only 5% of patients at one year post transplant. This result suggests that idacitinib did not interfere with the activity of post trans transplant. Cyclophosphamide idicitinib also appeared to prevent severe cases of cytokine release syndrome. This complication was generally mild or absent, with no cases above grade 1. In previous trials of Haplohct, about 30% of patients had grade 2 CRS and about 20% had grades 3 to 5 CRS. Relapse rates were low in the current trial, occurring in 10% of patients at 1 year and 14% at 2 years. One year overall survival was 80%. Non relapse mortality was also low at 8% after 180 days. Three patients died of viral pneumonia, including two who had COVID 19 infections. The authors used flow cytometry and single cell RNA sequencing of peripheral blood to investigate immune reconstitution in these patients, comparing these findings to those of control patients who had received haplohct with standard prophylaxis that did not include itacitinib. Immune reconstitution was similar between the two groups, suggesting that idacitinib treatment did not result in major suppression of any specific immune cell subset. Surprisingly, idicitinib treatment was associated with an increase in monocytes and with higher expression of monocyte activation markers Idicitinib was also associated with fewer naive T cells which have been implicated in promoting severe gvhd. Overall, the authors concluded that idicitinib use was safe in haplohct and likely contributed to reduced toxicities without impairing engraftment. They suggested that a larger placebo controlled trial of idacitinib is warranted in this setting. In an accompanying commentary, Nicholas von Bubnov of the University Cancer Center Schleswig Holstein in Lubeck, Germany noted that this study represents the first prospective trial of a JAK inhibitor as GVHD prophylaxis in haplohct. He congratulated the authors on a well performed clinical trial. He cautioned that larger trials will be needed both to confirm idacitinib's activity in reducing rates of severe GVHD and to show that it does not have negative consequences for graft viability, non relapse mortality and graft allo reactivity against the malignancy being treated. Next up we'll discuss recommendations in the blood article entitled How I Diagnose and Treat Acute Infection Associated Purpura Fulminans by Pavan K. Beneputi of Massachusetts General Hospital and Julie Aror Lassman of the Dana Farber Cancer Institute, both located in Boston, Massachusetts. This article included a patient case. The authors described a previously healthy 39 year old man who presented to the emergency department with a sore throat malaise, a rapidly expanding purpuric rash on his face and knees and dusky discoloration of his hands and feet. Initial lab studies were consistent with severe consumptive coagulopathy and end organ ischemia. He reported being bitten by a dog three days earlier and a peripheral blood smear showed signs of a gram negative bacterial infection. He soon developed shock and his condition deteriorated rapidly. The clinical team diagnosed purpurafulaminans or PF and treated him accordingly the next day. Results from further tests done at admission showed abnormally low protein C protein s and antithrombin antigen levels helping to confirm their diagnosis. The authors of this article reviewed the diagnosis, management and underlying pathophysiology of this challenging condition. PF is a life threatening hematologic emergency that requires a high index of suspicion and rapid treatment. Because it progresses so quickly, PF is almost always treated empirically, ideally within the first few hours of presentation. PF cases such as this that are associated with an infection have a mortality rate of around 60%. Complications can include extensive scarring, tissue loss and sometimes amputation. The patient presented with a clinical tetrad that is characteristic of pf. This includes rapid onset of thrombotic disseminated intravascular coagulation, profound depletion of endogenous anticoagulants, particularly protein C, A triggering infection and characteristic skin findings. Skin findings associated with PF include reddish blue, irregular reticular mottling which progresses to branching purpuric lesions and full thickness skin necrosis. The nose, knees and feet are typically affected first. Patients with PF may also have lactic acidosis that is out of proportion to the severity of their hemodynamic shock. While PF is challenging to treat, its clinical course is relatively predictable. The treatment recommendations in this review are are based on what is known of PF's pathophysiology, a limited amount of clinical data and the author's expert opinions. Multiple lines of evidence suggest that PF is caused by the loss of protein C, which plays an important role in the regulation of coagulation and in endothelial cytoprotection. Initial management of PF thus includes repletion of protein C protection, preferably using protein C concentrate. Plasma exchange may also be performed using fresh frozen plasma to increase protein C levels if the concentrate is not immediately available. PF is also characterized by low antithrombin and protein S levels. The authors recommended antithrombin repletion while protein S levels generally recover on their own once thrombosis is controlled. Intravenous vitamin K is also recommended to support endogenous production of protein C and protein S. The authors also recommended use of unfractionated heparin for therapeutic anticoagulation in patients with pf, suggesting that the risk of bleeding posed by this therapy is outweighed by the clinical harm of rapid uncontrolled coagulation. Nevertheless, they noted that caution should be exercised in older frail patients or others with a high risk of bleeding. The authors recommended against use of low molecular weight heparin in patients with PF because these patients usually experience transient renal failure. They also recommended against use of direct thrombin inhibitors such as argatroban, which theoretically might interfere with protein C activation and are also associated with an increased risk of myocardial infarction. Long term anticoagulation is not needed in patients who have recovered from PF because they have no known long term prothrombotic risk. Patients with PF should also receive additional transfusion support which may include use of cryoprecipitate. Platelet concentrate packed red blood cells and or fresh frozen plasma packed red blood cells may be needed for days or weeks after after the resolution of critical illness because of red blood cell damage and inflammation associated suppression of erythropoiesis. The authors recommended against the use of single component colloid preparations such as intravenous immunoglobulin or albumin that do not contain the coagulation factors needed in patients with pf. With regard to surgical treatment, the authors recommended against early amputation because viable tissue may still be present in areas that appear to be necrotic. Overall, they suggested a conservative approach to debridement and amputation. Our 39 year old patient received protein C and antithrombin concentrates, intravenous unfractionated heparin, cryoprecipitate and fresh frozen plasma within six hours of initial presentation. Renal replacement therapy was also started early but was later discontinued. After five days, his coagulation parameters had normalized and his shock had resolved. His limb ischemia also improved, although areas of necrosis remained. With meticulous wound care and minimal bedside debridement, he lost the fourth and fifth distal phalanges of his left hand and nine of 10 phalanges on his feet. After 58 days in an inpatient rehabilitation center, he was able to return to his work as a graphic designer designer. In the final part of today's podcast, we'll discuss findings in the Blood article entitled Sickle cell trait does not cause sickle cell crisis, leading to exertion related death, a systemic review by Lachelle Weeks of the Dana Farber Cancer Institute and colleagues. Globally, nearly 8 million people are estimated to be living with sickle cell disease. A much larger population, estimated at 300 million, have sickle cell trait, the carrier state for this disease. People with sickle cell disease experience considerable morbidity, leading to a median survival of only 48 years. People with sickle cell trait, on the other hand, have a similar lifespan to the general population. Over the years, the presence of sickle cell trait has been invoked as a cause of sudden death stemming from an acute vaso occlusive pain crisis, sometimes related to overexertion. Such crises have been used to explain sudden deaths among military recruits, athletes, and individuals being held in police custody. The authors of this paper decided to investigate the clinical and epidemiological evidence underlying these assumptions about individuals with sickle cell trait. They performed a systemic review of the clinical literature intended to answer two questions. First, do individuals with sickle cell trait actually experience acute pain crises similar to those found in individuals with sickle cell disease? And second, are individuals with sickle cell trait more likely than those without this trait to experience sudden death as a result of intense physical exertion. The authors identified 1,474 potential papers using keyword citations that might answer these questions. Articles were excluded from further analysis if they did not report original data, if they did not report on individuals with a confirmed laboratory diagnosis of sickle cell trait, or if they did not include the outcomes of interest. In order to look only at uncomplicated acute pain crises similar to those experienced by individuals with sickle cell disease, the authors also excluded articles on more complicated pain episodes such as those caused by organ infarction, splenic sequestration, cancer, or rhabdomyolysis. Eighteen of the 1,474 papers met their requirements and were analyzed in more detail. Four of the 18 papers purported to show that individuals with sickle cell trait can experience acute pain crises. However, closer examination revealed that none of the four combined a clear diagnosis of sickle cell trait with a clear description of acute pain crises. In answer to question one, the authors concluded that there is no published evidence for the occurrence of acute pain crises in individuals with sickle cell trait. The other 14 papers reported on mortality in individuals with sickle cell trait. Only one of these papers reported on exertion related deaths and included individuals both with and without sickle cell trait. This one article was a retrospective cohort analysis of medical records from about 48,000 black soldiers stored in the Stanford Military Data Repository. Laboratory data confirmed the presence or absence of sickle cell trait in these soldiers. Carrying the sickle cell trait was not associated with an increased risk of death in this cohort. Rates of battle related and non battle related deaths were also similar in individuals with or without the trait. However, carrying this trait was associated with a 54% higher risk of of heat related exertional rhabdomyolysis. In answer to question 2, the authors of the systemic review concluded that there is insufficient evidence to support the idea that deaths related to overexertion are more common in individuals with sickle cell trait than in those without. The review authors also noted that they found multiple reports that used the presence of sickled red blood cells at autopsy as evidence that a sickle cell crisis had occurred. Rather than indicating a crisis. They said that this finding is a normal response to reduced oxygen saturation in deceased individuals who carry the sickle cell trait. Overall, they concluded that there is no evidence to support use of the terms vaso occlusive pain episode, sickle cell crisis, exertional sickling with SCT or similar terms on death certificates for individuals with sickle cell trait. For a list of additional authors, as well as more detailed articles and commentaries on which this podcast is based, please go to bloodjournal. Org. Be sure to join us next week for another episode of Blood Podcast. Thank you for listening.