Aggressive Lymphoma after CD19 CAR T-Cell Therapy [Case report]

Highlight(s): This case shows a connection between clonal hematopoiesis and the development of secondary T-cell neoplasia in the context of chimeric antigen receptor (CAR) T-cell therapy.

The development of a fatal, clonal, autonomously proliferating CD4−CD8− CAR+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autologous transplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis. The results rule out the hypothesis that insertional mutagenesis contributed to the appearance of these mutations. However, it is plausible that CD19-induced CAR T-cell proliferation may have facilitated or accelerated the outgrowth of this preexisting malignant T-cell clone.

Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma [Retrospective study]

Highlight(s): In multiple myeloma (MM), measurable residual disease (MRD) is assessed in bone marrow (BM). However, less invasive evaluation of peripheral residual disease (PRD) in blood could be advantageous and less cumbersome. This study supports the use of less  invasive PRD monitoring during maintenance or observation in transplant-eligible patients with MM.

This study analyzed the prognostic value of PRD monitoring after 24 cycles of maintenance in 138 transplant-eligible patients with MM enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials (PETHEMA/GEM Cooperative Group). PRD was assessed using next generation flow (NGF) and mass spectrometry (MS). Positive PRD by NGF in 16/138 (11.6%) patients was associated with a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and overall survival (OS) were 2.5 and 47 months, respectively. Considering patients’ MRD status in BM as the reference, PRD detection using NGF showed a positive predictive value of 100% and predictive negative value of 73%. Patients with undetectable PRD according to both NGF and MS showed 2-year PFS and OS rates of 97% and 100%, respectively. In multivariate analyses including the Revised International Staging System and the complete remission status, only MRD in BM and PRD by NGF showed independent prognostic value for PFS. Presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, LA, December 10-13, 2022.

Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange [Retrospective study]

Highlight(s): Caplacizumab, an anti–von Willebrand factor nanobody, is approved for immune thrombotic thrombocytopenic purpura  (iTTP) treatment,  improving platelet count recovery and survival. This study showed that therapeutic plasma exchange (TPE)-free iTTP management (caplacizumab with immunosuppression alone) in experienced centers is an effective and safe treatment strategy.

This is a retrospective study of 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. The median time to platelet count normalization was similar between the 2 cohorts (3 and 4 days; p = 0.31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling, reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose, and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B virus coinfection, an ovarian teratoma with associated antiplatelet antibodies, and multiple platelet transfusions before the  correct diagnosis may have impeded the immediate treatment response in these patients. The accompanying editorial commentary mentions that this study demonstrates a viable option in clinical scenarios where TPE is not available, there are delays in the initiation of TPE, or there is an inability to administer blood products to the patient.

Febrile Neutropenia in Patients with Duffy-null Associated Neutrophil Counts and Multiple Myeloma or AL amyloidosis [Retrospective study]

Highlight(s): The impact of Duffy-null associated neutrophil counts (DANC) on adverse events such as febrile neutropenia in patients with hematological malignancies is largely unknown. In this study, patients with DANC did not have a higher incidence of febrile neutropenia or treatment reductions/interruptions. Duffy status was also not associated with differences in immunomodulatory drug upfront-dose reductions, stem cell mobilization or collection, or supportive treatments. Inclusion of Duffy status in clinical trials should be considered to allow different metrics by Duffy status including enrollment criteria and unbiased subgroup analyses of outcomes.

Individuals with DANC have lower peripheral absolute neutrophil count (ANC) and do not express the Duffy antigen (Fy) on red blood cells. This biological variation is related to a homozygous single nucleotide polymorphism in the promoter region of a gene (atypical chemokine receptor 1, ACKR1) detected in individuals with ancestry from sub-Saharan Africa and the Arabian Peninsula.

This was a retrospective study of 136 patients treated for multiple myeloma (MM) or AL amyloidosis. The most common self-identified race/ethnicity was non-Hispanic Black (74/136, 54%). DANC was present in 52/136 (38%) patients, of whom 48/52 (92%) self-identified as Black. Diagnoses included MM (94/136, 69%). Among MM patients, the distribution of stage did not differ by Duffy status. Baseline ANCs were lower in individuals with DANC: ANC <1,800/μL (lower limit of normal) was more frequent in patients with DANC (17/50, 34%) compared to those without DANC (8/79, 10%). ANC <1000/μL was observed in 3 patients with DANC. Using the current universal grading of neutropenia by the Common Terminology Criteria for Adverse Events, 78/136 (57%) of this cohort experienced grade 2 neutropenia during treatment; yet 21/126 (17%) had a baseline ANC within the range for grade 2 neutropenia. Despite higher frequencies of baseline (including ANC <1,000 k/uL in 3 patients) and treatment-related neutropenia, patients with DANC did not have a higher incidence of febrile neutropenia or treatment reductions/interruptions. Duffy status was also not associated with differences in immunomodulatory drug upfront-dose reductions, stem cell mobilization or collection, or supportive treatments (antibiotics or immunoglobulin supplementation).

How I diagnose and treat cardiorespiratory complications of transfusion [Review]

Transfusion-related acute lung injury (TRALI [which is part of the acute respiratory 25 distress syndrome spectrum]) and transfusion associated circulatory overload (TACO) form the top two most frequently reported cardiorespiratory complications, which both occur during or soon after transfusion with objectivated dyspnea. A third category, transfusion associated dyspnea (TAD) has also been defined internationally (see Tables: 1a, 1b, 1c and 2 of original article). Here are a few key points:

TRALI. There is no biomarker to diagnose TRALI and TRALI remains a clinical diagnosis with onset during or within 6 hours of transfusion. TRALI has been classically associated with plasma-rich blood components owing to the potential presence of donor leukocyte antibodies. TRALI can also be triggered by non-immunological mechanisms. Anti-HLA antibody incompatibility testing has a high specificity if confirmed. On the other hand, not finding or not investigating the latter does not rule out TRALI as a diagnosis.

TACO. Conversely, an unchanged chest X-ray does not exclude TACO because typical clinical signs can occur before radiographically visible changes. Supportive result of a relevant biomarker: an increase of B-type natriuretic peptide concentration above the age group-specific reference range and greater than 1.5 times the pretransfusion value. The mainstay of TACO treatment is diuretics in appropriate doses, with typically fast recovery as a result. Prevention of TACO however is even more important: this is achieved by first following current evidence-based restrictive transfusion guidelines - i.e. transfusing one unit at a time- and adhering to cardiopulmonary function dependent Hb thresholds. Second, applying additional measures in patients with the mentioned higher risk of developing TACO, e.g., treatment of pre-existent fluid overload, slower infusion rates and more intensive monitoring should be strongly considered.

TRALI/TACO overlap. Especially a late onset of the dyspnea between 6-24 hours might lead us to consider a case mix with both TRALI and TACO characteristics.

TAD. Respiratory distress occurring within 24 hours of transfusion hat does not meet the criteria of TRALI, TACO, or allergic reaction and cannot be explained by the patient’s underlying condition or any other known cause.