Characteristics and Outcomes of Stem Cell Transplant Patients during the COVID-19 Era: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to identify the outcomes of stem cell transplant (SCT) patients during the COVID-19 era. Pooled event rates (PER) were calculated, and meta-regression was performed. A random effects model was utilized. In total, 36 eligible studies were included out of 290. The PER of COVID-19-related deaths and COVID-19-related hospital admissions were 21.1% and 55.2%, respectively. The PER of the use of hydroxychloroquine was 53.27%, of the receipt of immunosuppression it was 39.4%, and of the use of antivirals, antibiotics, and steroids it was 71.61%, 37.94%, and 18.46%, respectively. The PER of the time elapsed until COVID-19 infection after SCT of more than 6 months was 85.3%. The PER of fever, respiratory symptoms, and gastrointestinal symptoms were 70.9, 76.1, and 19.3%, respectively. The PER of acute and chronic GvHD were 40.2% and 60.9%, respectively. SCT patients are at a higher risk of severe COVID-19 infection and mortality. The use of dexamethasone improves the survival of hospitalized SCT patients with moderate to severe COVID-19 requiring supplemental oxygen or ventilation. The SCT patient group is a heterogeneous group with varying characteristics. The quality of reporting on these patients when infected with COVID-19 is not uniform and further prospective or registry studies are needed to better guide clinical care in this unique setting.

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Transplantation Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning.

Outcomes of myelofibrosis (MF) with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade, related in part to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplantation outcomes. However, most studies lack homogeneity in conditioning regimens used, limiting their ability to assess prognostic factors on transplantation outcomes. We aimed to identify the risk factors that predict transplantation outcomes in patients with MF who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. This single-center study included patients with MF who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. Sixty-five patients with MF met the study criteria and were included in our analysis. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (hazard ratio [HR], .33; 95% confidence interval [CI], .11 to .99; P = .048). For NRM, Hematopoietic Cell Transplantation Comorbidity Index (≥3 versus <3; HR, 10.09; 95% CI, 2.09 to 48.76; P = .004) and donor type (MUD versus MRD: HR, 5.38; 95% CI, 1.14 to 25.30; P = .033; MMUD versus MRD: HR, 10.73; 95% CI, 1.05 to 109.4; P = .045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 versus <3; HR, 3.31; 95% CI, 1.22 to 8.99; P = .019) and donor type (MMUD versus MRD: HR, 5.20; 95% CI, 1.35 to 19.98; P = .016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival, but the difference did not reach statistical significance (>12 months versus ≤12 months: NRM: HR, 7.20; 95% CI, .96 to 53.94; P = .055; OS: HR, 2.60; 95% CI, .95 to 7.14; P = .06). In a homogenous cohort of MF patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we show that donor choice and HCT-CI are the 2 strongest predictors for improved survival after allo-SCT.

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges.

The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

Autologous stem cell transplantation for large B-cell lymphoma with secondary central nervous system involvement.

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 and 88 months, respectively. The 4-year PFS and OS were 48% and 57%, respectively. In univariate analysis, complete remission (CR) at transplant, prior lines of therapy (≤2), normal lactate dehydrogenase, and parenchymal involvement were significantly associated with improved PFS. For OS, only CR at transplant and ≤2 prior lines of therapy were associated with improved survival. On multivariable analysis for PFS, CR at transplant (hazard ratio [HR], 0.278; 95% CI, 0.153-0.506; P ≤ .0001) and ≤2 prior lines of therapy (HR, 0.485; 95% CI, 0.274-0.859; P = .0131) were significantly associated with superior PFS. Similarly, CR at transplant (HR, 0.352; 95% CI, 0.186-0.663; P = .0013) and ≤2 prior lines of therapy (HR, 0.476; 95% CI, 0.257-0.882; P = .0183) were associated with improved survival. In the largest single-center study, our findings indicate that ASCT is associated with durable responses and prolonged survival in patients with SCNSL. Patients in CR at transplant and those who received ≤2 lines of therapy have particularly excellent outcomes.

Patient-Reported Outcomes for Cancer Patients with Hematological Malignancies Undergoing Chimeric Antigen Receptor T Cell Therapy: A Systematic Review.

Databases were searched to identify studies published over the past 10 years that addressed the utility of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor (CAR) T cell therapy in patients with hematological malignancies. Among 280 records, three articles covering 206 patients were eligible. The data were prospectively collected at multiple time points. The compliance rates were 70% to 94%. There was an inverse relationship between fatigue and social function among adults. The quality of life (QoL) improvement and ability to complete PROs were linked to disease status. About 40% of adults reported at least some cognitive difficulties, with a detrimental impact on mental and physical health status. In adults, the most commonly reported cognitive impairment was memory difficulties. Depression was associated with cognitive difficulties. Younger adults were at higher risk of long-term poor mental health, anxiety, and depression. For pediatric and adolescent patients, emotional dysfunction improves over time. QoL status improved over time; yet, severe cytokine release syndrome and neurotoxicity caused delayed improvement. Information regarding whether the PROs were integrated into medical records and clinical guidelines is lacking. Utilizing PROs in patients on CAR T cell therapy seems feasible and informative. Studies utilizing larger sample sizes and using validated PRO tools at different time points remain unmet needs.

Impact of Cell of Origin Classification on Survival Outcomes after Autologous Transplantation in Relapsed/Refractory Diffuse Large B Cell Lymphoma.

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P < .004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.

Outcomes of Second Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Myeloid Leukemia.

Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched-unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI <2 at HCT2.

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT. METHODS: A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed. RESULTS: Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01). CONCLUSIONS: ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

A Mildly Symptomatic Middle-Aged Woman with INT-1 Primary Myelofibrosis.

In patients with myelofibrosis (MF), allogeneic stem cell transplantation (SCT) is a curative treatment, but does entail risk of treatment-related mortality (TRM). Furthermore, a minority of patients cured of myelofibrosis are at risk of chronic graft-versus-host disease (GvHD) that may impair their quality of life. It is also pertinent to note that transplant early in the disease course results in better transplant outcome than transplant late in the disease course.1 Thus, the survival benefit of SCT needs to be weighed against early transplant related mortality (TRM) and morbidity, as well as impaired quality of life due to chronic GvHD, when deciding about timing of transplant in the natural history of disease.

Acquired Coagulopathy With Immune Checkpoint Inhibitors: An Underrecognized Association Between Inflammation and Coagulation.

INTRODUCTION: Immune-related adverse events affecting virtually every organ system have been described in individuals receiving immune checkpoint inhibitors. The spectrum of hematologic adverse effects is diverse and includes autoimmune cytopenias, hemolysis, or inhibition of coagulation factors. The interplay of inflammation and the coagulation cascade is complex, and immune checkpoint inhibitors can induce coagulopathy by disrupting the intricate link between these pathways. METHODS: We report acquired coagulopathy in two patients treated with the programmed death-ligand 1 antibodies, atezolizumab and avelumab, respectively. Clinical findings and results of extensive laboratory workup are reported. We hypothesize that cytokine release is a potential pathologic mechanism responsible for acquired coagulopathy. RESULTS: Symptoms included fever, fatigue, and disorientation in one patient and fever, myalgias, and skin rash in the other. Laboratory features included an abnormal coagulation profile; low fibrinogen levels; and elevated D-dimer, ferritin, and triglycerides. Treatment consisted of intravenous glucocorticoids in both cases and the use of fresh frozen plasma, cryoprecipitate, and clotting factor support in one patient. CONCLUSIONS: Recognition of acquired coagulopathy as a complication of immunotherapy and its aggressive management are crucial to reduce morbidity and mortality associated with this condition.

Outcome of Multiple Myeloma with Chromosome 1q Gain and 1p Deletion after Autologous Hematopoietic Stem Cell Transplantation: Propensity Score Matched Analysis.

The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of the CDKN2C gene at chromosome region 1p32 (1p-), which is also associated with inferior outcomes. In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p- after high-dose therapy and autologous hematopoietic cell transplantation (auto-HCT). From January 2006 to December 2015, 1491 newly diagnosed patients with MM underwent upfront high-dose therapy and auto-HCT at our institution. Of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p- by FISH from the cohort of 899 patients. A control group (n = 287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above 2 cohorts, using a propensity score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p-. Patients were matched for age at auto-HCT, sex, International Staging System stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen, and maintenance therapy. Sixty-seven (79%), 4 (5%), and 14 (16%) patients had 1q+, 1p-, or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p- and the control group. The median follow-up time for all patients was 29.2 months (range, 0.29 to 84.96). The cumulative incidence of 100-day nonrelapse mortality was 1.2% and 0% for the 1q+/1p- and the control group, respectively. Forty-two patients (50%) in the 1q+/1p- group achieved complete response compared with 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 41% and 79% for the 1q+/1p- group and 56% and 86% for the control group. Patients in the 1q+/1p- group were at significantly increased risk of progression or death compared to the control group (hazard ratio [HR], 2.21; confidence interval [CI], 1.18 to 4.16; P = .014). No significant association between OS in the 2 groups was observed. The outcome of the 1q+/1p- alone (with no additional high-risk cytogenetics) and the propensity score matched control groups was also compared. Median PFS for the 1q+/1p- alone subgroup was 26.6 months, compared with 38.8 months for the control group (HR, 1.9; CI, 0.9 to 4.08; P = .09). The median OS had not been reached for the 1q+/1p- alone subgroup and was 81.1 months for the control group (HR, 1.25; CI, 0.3 to 4.6; P= .73). 1q+/1p- abnormalities with amplification of CKS1B and deletion ofCDKN2Cgenes were associated with shorter PFS compared with a propensity score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+/1p- patients with MM have improved with the use of more effective induction, conditioning, and maintenance therapy compared with historical controls, but we still need more effective therapeutic approaches to fully overcome the negative impact of 1q+/1p-.

Ifosfamide-Induced Metabolic Encephalopathy in 2 Patients With Cutaneous T-Cell Lymphoma Successfully Treated With Methylene Blue.

Ifosfamide, an alkylating agent used in cancer treatments, can cause neurotoxicity. The clinical presentation can range from mild symptoms such as acute confusion to non-convulsive seizures, severe irreversible coma, and death. The benefit of methylene blue use in treating ifosfamide-induced metabolic encephalopathy is not well established. In this article, we present 2 cases of ifosfamide-induced metabolic encephalopathy responsive to methylene blue treatment.

When there is no match, the game is not over: Alternative donor options for hematopoietic stem cell transplantation in sickle cell disease.

Many patients with sickle cell disease experience severe morbidity and early mortality. The only curative option remains hematopoietic stem cell transplantation. Although HLA-matched sibling transplantation has been very successful for adults and children, the vast majority of patients with sickle cell disease do not have an HLA-matched sibling. Alternative donor options include haploidentical, unrelated umbilical cord blood, and matched unrelated donor transplantation. This report summarizes major alternative donor transplantation studies reported to date and ongoing and upcoming clinical trials. We conclude that when there is no HLA-match, all these approaches should be systematically considered before ruling out the option of hematopoietic stem cell transplantation.

Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease.

Sickle cell disease (SCD) chronically damages multiple organs over the lifetime of affected individuals. Allogeneic hematopoietic cell transplantation (allo-HCT) is the most studied curative intervention. Fully matched related marrow, peripheral blood derived, or cord blood HCT have the best transplant outcome for symptomatic patients with SCD. For patients with asymptomatic or milder disease who have this donor option available, risks and benefits of HCT should be discussed among the patient, family, treating hematologist, and transplant physician, and decision to proceed to HCT should be individualized. Myeloablative conditioning with busulfan, cyclophosphamide, and ATG has been a commonly employed regimen for children and young adults. Recently, low intensity conditioning with low dose total body irradiation and alemtuzumab is emerging as an efficacious and safe regimen for adults, young adults, and possibly children. Mixed donor chimerism (minimum ≥20% myeloid cells), from myeloablative or nonmyeloablative conditioning regimen, produces robust normal donor erythropoiesis and is sufficient to provide a clinical cure. The proportion of patients remaining on immunosuppression beyond 2 years post-HCT is likely <10% with either myeloablative or low intensity regimens. Late effects from myeloablative or reduced intensity conditioning, or from several more months of immunosuppression in low intensity conditioning may be less common than those observed in HCT for malignant indications. Nonmyeloablative approaches with low toxicities should be the focus of future research efforts. Prevention of GVHD is a shared goal in all approaches of allo-HCT in SCD.