Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians.

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.

Effect of cumulative dose of brentuximab vedotin maintenance in relapsed/refractory classical Hodgkin lymphoma after autologous stem cell transplant: an analysis of real-world outcomes.

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse <12 months (RL<12) from the end of frontline therapy. Cohort 1 had patients with >75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity.

COVID-19 related immune hemolysis and thrombocytopenia.

The current pandemic due to coronavirus disease 2019 (COVID-19) has posed an unprecedented challenge for the medical communities, various countries worldwide, and their citizens. Severe acute respiratory syndrome coronavirus 2 has been studied for its various pathophysiological pathways and mechanisms through which it causes COVID-19. In this study, we discussed the immunological impact of COVID-19 on the hematological system, platelets, and red blood cells.

Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children.

We describe how infants and children with hereditary and acquired autoimmune thrombotic thrombocytopenic purpura (TTP) initially present and how they can be promptly diagnosed and effectively managed. These are uncommon disorders that are commonly misdiagnosed and can be rapidly fatal. TTP is caused by a severe deficiency of the plasma protease, A disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13 (ADAMTS13). Measurement of ADAMTS13 activity is becoming easily accessible. A common presentation of hereditary TTP is neonatal severe hemolysis and hyperbilirubinemia. However, the median age of diagnosis is not until 5.5 years. Plasma is effective treatment for exacerbations and for prophylaxis. Plasma may be replaced by recombinant ADAMTS13 when it becomes available. Acquired TTP is more frequent in older children, in whom it is more common in girls and is commonly associated with systemic lupus erythematosus. For acquired TTP, plasma exchange and immunosuppression are the current treatment for acute episodes; caplacizumab is now commonly used in adults and may replace plasma exchange.

COVID19 infection in a patient undergoing treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) with Ravulizumab.

BACKGROUND: In the recent COVID19 pandemic, patients with hematological disorders were considered at high risk for severe disease. Limited data is available regarding the course of COVID19 infection in this subgroup. CASE PRESENTATION: We describe a case of a 32-year-old man with paroxysmal nocturnal hemoglobinuria (PNH) undergoing treatment with ravulizumab (Ultomiris) who presented with COVID19 infection. He experienced only mild symptoms and had a rapid recovery from COVID19 infection. CONCLUSION: This case may demonstrate the beneficial effects of ravulizumab on complement mediated inflammatory damage linked with COVID19 infection especially in PNH patients.

Transforming CLL management with immunotherapy: Investigating the potential of CAR T-cells and bispecific antibodies.

Immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies or T-cell engagers, have revolutionized the treatment landscape for various B-cell malignancies, including B-acute lymphoblastic leukemia and many non-Hodgkin lymphomas. Despite their significant impact on these malignancies, their application in chronic lymphocytic leukemia (CLL) management is still largely under investigation. Although the initial success of CD19-directed CAR T-cell therapy was observed in 3 multiply relapsed CLL patients, with 2 of them surviving over 10 years without relapse, recent CAR T-cell therapy trials in CLL have shown reduced response rates compared to their efficacy in other B-cell malignancies. One of the challenges with using immunotherapy in CLL is the compromised T-cell fitness from persistent CLL-related antigenic stimulation, and an immunosuppressive tumor microenvironment (TME). These challenges underscore a critical gap in therapeutic options for CLL patients intolerant or resistant to current therapies, emphasizing the imperative role of effective immunotherapy. Encouragingly, innovative strategies are emerging to overcome these challenges. These include integrating synergistic agents like ibrutinib to enhance CAR T-cell function and persistence and engineering newer CAR T-cell constructs targeting diverse antigens or employing dual-targeting approaches. Bispecific antibodies are an exciting "off-the-shelf" prospect for these patients, with their investigation in CLL currently entering the realm of clinical trials. Additionally, the development of allogeneic CAR T-cells and natural killer (NK) cells from healthy donors presents a promising solution to address the diminished T-cell fitness observed in CLL patients. This comprehensive review delves into the latest insights regarding the role of immunotherapy in CLL, the complex landscape of resistance mechanisms, and a spectrum of innovative approaches to surmount therapeutic challenges.

Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them.

Chimeric antigen receptor (CAR) T-cell therapy has ushered in substantial advancements in the management of various B-cell malignancies. However, its integration into chronic lymphocytic leukemia (CLL) treatment has been challenging, attributed largely to the development of very effective chemo-free alternatives. Additionally, CAR T-cell responses in CLL have not been as high as in other B-cell lymphomas or leukemias. However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of "armored" CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.

Mobilizing CARs: Benefits, drawbacks, and directions for outpatient CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy has heralded a new era in the treatment of various hematological malignancies, increasingly being utilized in earlier lines of therapy. Moreover, cellular therapies are currently under investigation for their potential in treating solid malignancies and autoimmune disorders. As the scope of indications for CAR-T therapy continues to expand, along with the associated reductions in costs and hospital admissions, many medical centers are transitioning towards outpatient CAR-T models. Moreover, ongoing efforts to mitigate complications such as cytokine release syndrome (CRS) or neurotoxicity include the development of premedication strategies, prompt management of adverse events, and the advancement of newer, safer CAR-T cell therapies. However, despite these advancements, the inherent risk of these life-threatening complications remains a critical concern in CAR-T therapy. Institutions must diligently anticipate and effectively manage these complications to ensure the safety and well-being of patients undergoing CAR-T therapy. This includes establishing robust protocols for timely identification and intervention of adverse events, and seamless pathways for transitioning patients to a higher level of care if necessary. This review provides an overview of the current landscape of outpatient CAR-T therapy and offers essential insights into the key clinical and operational considerations needed to implement a successful outpatient CAR-T program.

Absolute Lymphocyte Count and Outcomes of Multiple Myeloma Patients Treated with Idecabtagene Vicleucel: The US Myeloma Immunotherapy Consortium Real- World Experience.

Idecabtagene vicleucel (ide-cel) has shown impressive efficacy in relapsed/refractory multiple myeloma (RRMM). This study aimed to investigate the impact of absolute lymphocyte count (ALC) on the survival outcomes of RRMM patients treated with standard of care (SOC) ide-cel. Data were collected retrospectively from 11 institutions in the U.S. Impact of ALC parameters including pre-apheresis (pre-A), pre-lymphodepletion (pre-LD), absolute and percent difference from pre-A to pre-LD on clinical outcomes after ide-cel were examined using survival analysis. A new ALC profile was created based on univariate analysis that comprises 3 groups: normal (≥1 × 109/L) pre-LD ALC (LDN), low (<1 × 109/L) pre-LD ALC (LDL) + percent reduction <37.5 (%RL), and LDL ALC + percent reduction ≥37.5 (%RH). A total of 214 SOC ide-cel recipients were included in this analysis. The median patient age was 64 years (interquartile range [IQR], 57 to 69 years), median number of prior therapies was 6 (IQR, 5 to 9), and median duration of follow-up was 5.4 months (IQR, 2.1 to 8.3 months). Most patients had both low pre-A ALC (75.3%) and pre-LD ALC (77.2%), and the reduction from pre-A to pre-LD (median, .65 to .55 × 109/L) was statistically significant. Univariate analysis showed that the LDL + %RH group had significantly worse progression-free survival (PFS) and overall survival (OS) compared to the LDL + %RL and LDN ALC groups (6-month PFS: 40% versus 67.6% and 60.9%; 6-month OS: 69.5% versus 87% and 94.3%). In multivariable analysis, after adjusting for age, performance status, cytogenetic risk, use of bridging therapy, and extramedullary disease, PFS did not maintain its statistical significance; however, OS remained significantly worse for LDL + %RH group compared to the LDN ALC group (hazard ratio [HR], 4.3; 95% confidence interval [CI], 1.1 to 17), but the difference between the LDL + %RH versus %RL groups was not statistically significant (HR, 1.7; 95% CI, .8 to 4.0). Our findings indicate that low pre-LD ALC with high %R from pre-A to pre-LD was associated with inferior survival outcomes, particularly OS, in patients who received SOC ide-cel.

Spatiotemporal patterns and transcription kinetics of induced RNA in single bacterial cells.

Bacteria have a complex internal organization with specific localization of many proteins and DNA, which dynamically move during the cell cycle and in response to changing environmental stimuli. Much less is known, however, about the localization and movements of RNA molecules. By modifying our previous RNA labeling system, we monitor the expression and localization of a model RNA transcript in live Escherichia coli cells. Our results reveal that the target RNA is not evenly distributed within the cell and localizes laterally along the long cell axis, in a pattern suggesting the existence of ordered helical RNA structures reminiscent of known bacterial cytoskeletal cellular elements.

Morbidities and mortality in patients with hereditary thrombotic thrombocytopenic purpura.

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare disorder caused by severe ADAMTS13 deficiency. Major morbidities and death at a young age are common. Although replacement of ADAMTS13 can prevent morbidities and death, current regimens of plasma prophylaxis are insufficient. We identified 226 patients with hTTP in 96 reports published from 2001 through 2020. Age at diagnosis was reported for 202 patients; 117 were female and 85 were male. The difference was caused by diagnosis of 34 women during pregnancy, suggesting that many men and nulliparous women are not diagnosed. Eighty-three patients had severe jaundice at birth; hTTP was suspected and effectively treated in only 3 infants. Of the 217 patients who survived infancy, 73 (34%) had major morbidities defined as stroke, kidney injury, or cardiac injury that occurred at a median age of 21 years. Sixty-two patients had stroke; 13 strokes occurred in children age 10 years or younger. Of the 54 patients who survived their initial major morbidity and were subsequently observed, 37 (69%) had sustained or subsequent major morbidities. Of the 39 patients who were observed after age 40 years, 20 (51%) had experienced a major morbidity. Compared with an age- and sex-matched US population, probability of survival was lower at all ages beginning at birth. Prophylaxis was initiated in 45 patients with a major morbidity; in 11 (28%), a major morbidity recurred after prophylaxis had begun. Increased recognition of hTTP and more effective prophylaxis started at a younger age are required to improve health outcomes.

Reappraising the Role of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma: Recent Advances and Outcomes.

Hodgkin's lymphoma is a rare yet highly curable disease in the majority of patients treated with modern chemotherapy regimens. For patients who fail to respond to or relapse after initial systemic therapies, treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplantation can provide a cure for many with chemotherapy-responsive lymphoma. Patients who relapse after autologous transplant or those with chemorefractory disease have poor prognosis and represent a high unmet need. Allogeneic hematopoietic stem cell transplantation provides a proven curative therapy for these patients and should be considered, especially in young and medically fit patients. The use of newer agents in this disease such as brentuximab vedotin and immune checkpoint inhibitors can help bring more patients to transplantation and should be considered as well.

A Case of Acute Myeloid Leukemia Harboring a Rare Three-Way Translocation t(5;7;7) Involving the PDGFRB Gene and Successfully Treated with Imatinib.

Platelet-derived growth factor-beta (PDGFRB) gene maps for the receptor tyrosine kinase PDGRFß. PDGFRB gene fusions have been implicated in multiple myeloid and lymphoid neoplasms and have shown exquisite sensitivity to tyrosine kinase inhibitors. We report a case of a 29-year-old male who presented with acute myeloid leukemia who was eventually found to harbor a unique three-way translocation t(5;7;7)(q33.2;q32;q11.2) involving the PDGFRB gene. The patient initially achieved a complete response after induction with daunorubicin and cytarabine, but when he returned for consolidation, his white cell count had increased, and he was found to have an underlying myeloproliferative neoplasm. He was given consolidation with high-dose cytarabine and imatinib with excellent response, and ultimately received a matched unrelated donor transplant. The patient remains in remission to this day more than eight years later.

Visualization of induced RNA in single bacterial cells.

Visualization of RNA in live cells is a challenging task due to the transient character of most RNA molecules and the lack of adequate methods to label RNA noninvasively. Here, we describe a system for regulated RNA synthesis and visualization of RNA in live Escherichia coli cells based on protein complementation. This method allows for labeling RNA with a relatively small protein complex that becomes fluorescent only when bound to an RNA. This method greatly reduces the high fluorescence background characteristic of methods employing intact fluorescent proteins. A short reporter RNA was shown to localize at the cell periphery in nonrandom patterns.