Multiple Myeloma (MM) is still considered an incurable disease. However, the availability of novel and effective therapies is making the prospect of eradicating the malignant clone and converting MM into a curable disease realistic. In this context, the detection of minimal residual disease (MRD) has become of utmost importance. The high spatial genomic heterogeneity that characterizes MM patients explains the potential persistence of residual disease even in bone marrow (BM) MRD negative patients, highlighting the need of different techniques able to detect the disease within and outside of the BM.1 The prognostic usefulness of both MRD assessment and functional imaging response after treatment have been established.2 The combination of BM and imaging techniques has a direct impact on prognosis, with patients reaching double MRD negativity having the best outcome.3 Recently, sustained BM MRD-negativity and its association with an excellent outcome is emerging in clinical trials.4 Diffusion-weighted whole body MRI (DW-MRI) is increasingly used in the management of MM. It produces images in which the contrast between tissues is based on differences in the motion of water at a cellular level and permits to estimate cell density with the so-called apparent diffusion coefficient (ADC). The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) with a 5-point scale defining the range of imaging response after treatment from complete (RAC 1) to progressive disease (RAC 5).5 We have previously shown that RAC criteria were able to independently stratify patients with different outcomes after autologous stem cell transplantation (ASCT).6 Data regarding the predictive role of sustained imaging MRD-neg assessed by DW-MRI are lacking. With this aim, we implemented DW-MRI and RAC criteria in MM patients both after ASCT and at 1 year during maintenance therapy in order to evaluate the predictive information of sustained imaging MRD negativity on outcome. All transplant-eligible MM patients newly diagnosed at our institution between January 2016 and December 2019 who received maintenance therapy after ASCT were retrospectively analyzed. Treatment response according to IMWG criteria was assessed before maintenance. DW-MRI was performed at day +100 after ASCT, and thereafter at 1 year to monitor imaging-residual-disease. In patients receiving double ASCT, DW-MRI performed at day +100 after the second one was considered. Protocol details and application of RAC criteria in our external validation of MY-RADS guidelines in clinical practice have been previously published. BM samples were also collected for MRD assessment by 8-color multiparametric flow-cytometry (MFC, sensitivity 10−5) at day +100 after ASCT, and thereafter at 1-year in MRD-neg patients in order to assess sustained MRD negativity. We focused on the predictive role of sustained 1-year DW-MRI-neg on progression free survival (PFS) and overall survival (OS). PFS after second-line treatment was also evaluated. Kaplan–Meyer method was used to estimate survival curves and multivariate analysis (Cox proportional hazard models) was performed to evaluate the influence of prognostic factors on outcome. In patients with available 1-year BM MRD evaluation, the concordance between BM and DW-MRI results was calculated (Cohen's kappa statistics). This study has been approved at our institution by the local Ethics Committee and has been done in accordance with the Declaration of Helsinki. We identified 70 newly-diagnosed MM patients who underwent ASCT followed by maintenance therapy and had a DW-MRI scan at day +100 after ASCT and at 1-year. Induction regimens used were: VTD in 55 (79%), VRD in five (7%), Dara-VRD in six (9%), KRD in three (4%), KCD in one (1%). Forty patients (57%) received a single ASCT (MEL200), whereas double ASCT was performed in 30 patients (43%). All patients received lenalidomide maintenance, in combination with daratumumab in six (9%) and with carfilzomib in one (1%). Median follow-up duration was 46 months. Median age was 61 years (40–73), 28 (40%) patients were ISS stage III and 21 (30%) of them had high-risk cytogenetics (t[4;14] and/or t[14;16] and/or del17p and/or 1q gain/amp1q abnormalities). IMWG responses at day +100 after ASCT were: PR 6 (8%), VGPR 15 (21%), CR 38 (54%), and sCR 11 (16%). Complete imaging response according to MY-RADS was achieved after ASCT in 41 patients (RAC 1: 59%), whereas residual disease was observed in 29 patients (RAC >2:41%). BM MFC for MRD detection was available before maintenance in 61 patients and was negative in 39 (64%) patients. At 1-year DW-MRI complete imaging response (RAC 1) was observed in 53 (76%) patients, whereas residual disease was documented in 17 patients (24%). BM MRD evaluation at 1-year was available in 35 patients and was negative in 29 (83%). The concordance between 1-year DW-MRI and BM MFC MRD results was high (85%, kappa 0.46: 8% both positive, 77% both negative). Median PFS was significantly longer for patients with imaging MRD-neg at 1-year (RAC 1) compared to patients with residual disease on DW-MRI (RAC ≥2) (median PFS: 55.4 vs. 28.4 months; 3-years PFS: 91% vs. 30%, respectively [HR 0.12; 95% CI: 0.04–0.35; p < 0.0001]) (Figure 1A). Survival of imaging MRD-neg patients at 1-year was significantly longer for patients with RAC1 versus RAC ≥2 (median OS: NR vs. 63 months; 3-years OS: 100% vs. 82%, respectively [HR 0.13; 95% CI: 0.03–0.66; p 0.0007]) (Figure 1B). Upgrade of imaging response from RAC ≥2 at maintenance start to RAC1 at 1-year was observed in 13 patients (19%) Their outcome was superimposable to that of other MRD-neg patients at 1-years. Fifteen out of 17 RAC ≥2 patients at 1-year after ASCT (88%) were treated with the following second-line therapies at biochemical or clinical relapse: DVD: 6 (40%), KD reinduction and ASCT: 6 (40%), KPD:1 (7%), and PVD in 2 (13%) patients. Their median PFS was 13 months. Notably, of 29 patients in sustained MFC MRD-neg at 1-year, two had imaging-residual-disease on DW-MRI. Both developed aggressive extramedullary relapse, one with CNS involvement. Among the prognostic parameters available at 1-year after transplant in all 70 patients (IMWG response, cytogenetic risk profile, ISS stage and RAC score at 1-year), multivariable analysis showed that both PFS and OS were independently affected only by DW-MRI persistent disease (RAC ≥2): p < 0.001, HR 0.12 (95% CI: 0.05–0.30) for PFS, p = 0.032, HR 0.20 (95% CI: 0.05–0.87) for OS. MRD evaluation, an essential step toward achievement of operational cure in MM, has evolved from a single timepoint assessment to repeated monitoring of MRD over time, since sustained BM MRD-neg appears a better predictor of longer PFS and OS. Few data have been reported to date regarding sustained imaging MRD-negativity during maintenance therapy using PET and ancillary studies are under investigations in clinical trials. To our knowledge, this is the first report describing the prognostic value of sustained imaging MRD-negativity assessed by DW-MRI in MM. Our results highlight the ability of DW-MRI to identify a significant proportion of patients who fail to achieve sustained imaging MRD-negativity at 1-year during maintenance therapy (RAC ≥2: 24%), whose outcome is dismal despite being responsive according to IMWG criteria. Compared to RAC1 patients their PFS was halved and OS was significantly shorter. Moreover, their PFS after salvage with the most effective standard second-line combination therapies available was very short. The retrospective nature of our observations, the relatively low number of patients and the lack of BM MFC evaluation at 1-year in the entire cohort of patients represent major limitations of our study, which requires further confirmation. Nevertheless, they lend support to the use of functional imaging techniques to allow a better dynamic risk assessment in order to identify patients at increased risk of relapse and particularly poor prognosis. For patients failing to achieve sustained DW-MRI MRD-negativity, an earlier use of novel emerging salvage treatments, such as CAR-T cells or bispecific antibodies may be considered. Angelo Belotti designed the research and analyzed data and wrote the paper, Rossella Ribolla collected data and performed research, Claudia Crippa collected data, Marco Chiarini performed the research, Viviana Giustini performed the research, Samantha Ferrari collected data, Annalisa Peli collected data, Chiara Cattaneo collected data, Aldo Roccaro supervised research, Barbara Frittoli performed research, Luigi Grazioli performed research, Giuseppe Rossi analyzed data and wrote the paper, Alessandra Tucci analyzed data and wrote the paper. We thank the patients and staff of the Department of Hematology, Spedali Civili, Brescia. We also thank the Department of Radiology, Spedali Civili, Brescia. AMR: Fondazione AIRC; Fondazione Regionale per la Ricerca Biomedica, ERA-NET TRANSCAN-2. The authors declare no conflict of interest to disclose. The data that support the findings of this study are available from the corresponding author upon reasonable request; the data are not publicly available due to privacy and ethical restrictions.
Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively ( p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m 2 compared with those receiving 800–999 mg/m 2 ( p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m 2 had poorer PFS outcomes compared with those who received ≥600 mg/m 2 ( p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.
To the Editor: Despite recent therapeutic advances, outcomes remain poor for older patients with acute myeloid leukemia (AML). For patients in the USA diagnosed with AML between 2010–2017, the 5-year overall survival (OS) rate was 22% for patients aged 60–69 years, and only 5% for those aged ≥70 years. Survival outcomes are influenced by patientand disease-related factors, including age, comorbidities, cytogenetic abnormalities, gene mutations, and persistence of leukemic cells after intensive chemotherapy (IC) (i.e., measurable residual disease [MRD]). For patients with AML in remission, hematopoietic stem cell transplantation (HSCT) is often the only potentially curative option, but many patients are not candidates for HSCT due to advanced age, poor performance status, comorbidities, patient preference, or favorable AML European Leukemia Net risk, particularly in younger patients. Thus, there is a need for effective maintenance therapies to prolong survival among HSCT-ineligible patients in complete remission. In the randomized, double-blind, phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA) significantly prolonged OS and relapse-free survival (RFS) versus placebo in patients ≥55 years with AML in first remission after IC who were not HSCT candidates. At the July 2019 primary data cutoff, with a median follow-up time of 41.2 months, approximately one-quarter of all patients were alive and in survival follow-up. Here, we present updated OS outcomes (data cutoff March 2022) with the median follow-up time now 55.5 months and investigate clinical and biological variables predictive of long-term survival, defined here as survival ≥3 years from randomization, in patients treated with Oral-AZA or placebo. The study design was described in detail in Wei et al. Briefly, patients aged ≥55 years with intermediate-or poor-risk cytogenetics at diagnosis who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) with IC, were randomized 1:1 to receive Oral-AZA 300-mg or placebo once-daily for 14 days in repeated 28-day cycles. Patients in the Oral-AZA arm could continue treatment in an optional open-label extension phase after trial unblinding (Figure S1). The primary endpoint was OS, defined as the time from randomization until death. Patients who withdrew consent or were lost to follow-up were then censored for OS. OS was estimated by Kaplan–Meier methods and compared between treatment groups by stratified log-rank test. NPM1 and FLT3 gene mutations were assessed locally at diagnosis for most patients; post-IC MRD status was assessed centrally at study screening by multiparameter flow cytometry. During study therapy, surveillance bone marrow monitoring for hematologic remission and MRD status was performed every 3 cycles from cycles 3–24, then every 6 cycles or as clinically indicated. For patients MRD+ at baseline (≥0.1%), MRD response was defined as achieving MRD negativity (<0.1%) at ≥2 consecutive assessments during study. In all, 472 patients were randomized to Oral-AZA (n = 238) or placebo (n = 234). At diagnosis, 86% of patients had intermediate-risk cytogenetics, 29% had NPM1, and 14% had FLT3 (Table S1). Median age was 68 (range 55–86) years and 47% of patients were MRD+ at screening. Median OS at the primary data cutoff (median follow-up 41.2 months) was 24.7 versus 14.8 months with Oral-AZA versus placebo, respectively (p < .001); estimated 2-year survival rates were 50.6% versus 37.1% (difference [Δ] +13.5%; 95% confidence interval [CI], +4.5% to +22.5%). Over one-fourth of randomized patients (26.5%) were being followed for survival and censored for OS, including 71 patients still receiving Oral-AZA (n = 45) or placebo (n = 26) (Figure S2). After unblinding, 39 (16%) patients continued receiving Oral-AZA in an optional extension phase and 6 patients discontinued (3 withdrew consent, 2 relapsed, and 1 died). Patients still receiving placebo at unblinding had treatment discontinued and were followed for OS. After the primary data cutoff, patients not receiving active therapy (including patients who discontinued Oral-AZA during the extension phase) were followed for OS for up to 12 months. At the updated March 2022 cutoff, median study follow-up was 55.5 months and 25 (11%) patients were receiving Oral-AZA maintenance in the extension phase (Figure S2). Overall, 54 (23%) patients in Received: 31 October 2022 Revised: 10 January 2023 Accepted: 12 January 2023
Chronic anemia is the most frequent presentation of myelodysplastic syndromes (MDS), but precise diagnosis, still based mainly on marrow precursors' morphology, is frequently challenging. Indeed, MDS-like dysplasia may be observed in non-clonal cytopenias and hematologic disorders, including nutritional/copper deficiencies, toxin exposures, and inherited disorders like red blood cell (RBC) membrane defects. We herein investigated the genetic landscape of MDS patients defined “young” due to the atypical early onset of the disease (≤60 years) and anemia as the main cytopenia. Genetic analysis by whole exome sequencing (WES) is recommended for young de novo MDS patients with no syndromic signs, to detect germline variants predisposing to myeloid malignancies, but could also help to make a differential diagnosis with RBC defects.
Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60–75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40–0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53–0.94). A sub-group of patients with equipoise, likelihood at least 30%–70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75–1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.
Patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing non-hematologic malignancies. 1 Definitive or adjuvant radiation therapy is often a critical component of management for localized solid organ cancers. With the advent of novel agents for CLL, such as bruton tyrosine kinase inhibitors (BTKi) and the BCL-2 inhibitor venetoclax, patients with CLL often receive continuous daily therapy. Prior studies have reported disease flare 2 and inferior outcomes among patients where BTKi therapy was interrupted, regardless of the reason for the hold. 3 On the other hand, worse outcomes are reported in patients with melanoma receiving concurrent radiotherapy and BRAF inhibitors. 4 Platelet dysfunction associated with BTKi also raises concerns for increased bleeding and/or synergy with radiation-induced thrombocytopenia. Safety data to guide the concurrent administration of radiation therapy for a second cancer in patients receiving ongoing CLL novel agent treatment are lacking. Increased toxicity from either component could potentially result in suboptimal delivery of curative intent radiotherapy and substantially impact patient outcomes. The aim of this study was to assess the adverse event profile of concurrent radiation treatment of second primary malignancies in patients receiving novel agent treatment for CLL.
Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 1209 The primary objective was to assess the risk of DP expressed as time adjusted rate (TAR) and its relationship to TD in CML pts who underwent TD. Pts eligible to TD who did not discontinue constituted the reference cohort. A flexible statistical approach allowed to attribute pts to the two groups according to their situation about TD (TD yes or no). Events developing in pts after the end of TD were considered associated to TD if they developed within 36 months since the end of TD. One secondary endpoint was the TAR of molecular relapse (MR, i.e. loss of MMR). Results: From July 24th, 2020 to November 10th, 2022, 907 pts were registered, of whom 870 were evaluable for the analysis (5152 person years). Median follow up was 5.5 years (IQR 2.6-8.6), median age at diagnosis was 50 years (IQR 40-61). Sokal score was low in 46.3%, intermediate in 34.8% and high in 18.9%. 505 pts (58%) attempted TD, 365 (42%) did not. MR occurred in 172/505 (34.1%) pts after TD, for a TAR of 11.8/100 person years (95% confidence interval (CI) [10.1-13.7]), but also in 64/365 (17.5%) pts of the reference cohort, for a TAR of 2.3/100 person years (95%CI [1.8-3.0]), p<0.0001. A representation of the estimated proportion of pts with MR is provided in the figure. Only one pt experienced DP to lymphoid BP, 55 after the end of TFR; he received BMT and is presently in remission. This event developed more than 36 months after MR, which was the protocol limit for considering an event linked to TD. Therefore, at the time of DP this pt was contributing to the reference cohort. Thus, the risk of DP was 1/870 or 0.1% (95% CI [0.0-0.6]) in the overall cohort, ranging from 0/505 or 0%, (95% CI 0.0-0.6%]) in the discontinuation cohort to 1/365 or 0.3% (95% CI [0.0-1.5%]) in the reference cohort. The TAR of DP was 0.019/100 person years (95%CI [0.003-0.138]) in the overall cohort, ranging from 0.0 (95%CI [0-0.002]) in the discontinuation cohort to 0.030 (95%CI [0.004-0.215]) in the reference cohort. The difference of this risk between the two cohorts is not statistically significant.
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with acute leukemia. Despite this, studies have shown that only a minority of patients ultimately proceed to allo-HCT. The primary objective of this prospective, observational study was to identify the rate of allo-HCT in patients for whom it was recommended, and reasons why patients deemed appropriate and eligible for HCT did not subsequently undergo transplant. Between April 2016 and April 2021, adult patients with newly diagnosed or relapsed/refractory acute leukemia were enrolled at the time of induction/reinduction therapy. Initial transplantation workup and allo-HCT recommendations were made during the early phase of induction/reinduction. Of the 307 enrolled patients, allo-HCT was recommended to 85% ( n = 259), of whom 66% ( n = 170) underwent transplant. Donor sources comprised 54% human leukocyte antigen (HLA)-matched unrelated donors, 20% HLA-matched sibling donors and HLA-mismatched graft sources with 15% umbilical cord blood units, 8% HLA-mismatched unrelated donors, and 4% HLA-haploidentical donors. The most common reason for transplant disqualification in the 89 patients in whom it was initially recommended was persistent/relapsed disease (70%), followed by early patient death (10%). In this prospective study, we report a high allo-HCT rate, which may be due to early transplant referral and workup. The main allo-HCT barrier was disease control, followed by early patient death. With the increasing availability of HLA-mismatched graft sources, the lack of donor availability was not a transplant barrier. Further development of novel transplant strategies for patients not achieving remission and improvements in induction regimens could result in increased allo-HCT utilization.
A 64-year-old New Zealand European male was transferred to Waikato Hospital (tertiary-level facility) with recent non-ST elevation myocardial infarction and severe mitral valve regurgitation secondary to severe triple-vessel coronary artery atherosclerosis. Comorbidities included diabetes mellitus, atrial fibrillation, hypertension, and gout. Coronary artery bypass grafting and bioprosthetic mitral valve replacement were performed; two platelet transfusions were given intraoperatively. Postoperative complications included profound vasoplegia requiring intra-aortic balloon pump (IABP), multiple vasopressors, and acute renal failure. Patients who undergo complex cardiac surgery with combined coronary revascularization and valve replacement are at increased risk for postoperative cardiac failure requiring life support measures such as IABP and vasopressor therapy.1, 2 From the hematologist's perspective, such patients are at increased risk for thrombocytopenia, coagulation abnormalities, bleeding/anemia, and need for blood product replacement.3 During the first 120 h (5 days) postsurgery, the platelet count fell from 251 (preoperative value) to 87 × 109/L on postoperative day (POD) 4, with the downward slope accelerating during the first 36 h following IABP placement (Figure 1; until end of POD4). Associated laboratory abnormalities included: elevated lactic acid (peak, 4.7 mmol/L [reference range, 0.6–2.4]), progressive rise in alanine transaminase (ALT) to peak value of 792 U/L (reference range, 0–55) on POD3, rise in the international normalized ratio (INR) to 2.1 (reference range, 0.8–1.2), elevated activated partial thromboplastin time (APTT) values (e.g., 43 s [reference range, 25–38] at time of peak INR), and first detection of nucleated red blood cells (nRBCs) on POD2. Fibrinogen rose to elevated levels beginning on POD2 (peak on POD4, 6.5 g/L [reference range, 1.5–4.0]). The patient's overall clinical picture improved: by POD4, the IABP was removed, and by POD5, vasopressin and dobutamine were stopped (low-dose norepinephrine was continued). The initial platelet count fall to approximately 100 × 109/L by POD3 reflects the postcardiac surgery state, where ~50% declines by POD2–POD3 are expected.4 In this patient, intraoperative platelet transfusions were given, so clearance of transfused platelets exacerbated the early platelet count fall. The use of IABP is associated with further platelet count decrease.5 Overall, the patient's platelet count changes are expected for this clinical situation. The elevated INR indicates either transient liver dysfunction (“shock liver”), disseminated intravascular coagulation (DIC), or both. However, this patient exhibited elevated fibrinogen levels that remained steady from PODs 2 to 5 (peak INR on POD4), arguing somewhat against a major effect of DIC (however, there is an entity known as “high-fibrinogen DIC” in some patients who develop ischemic limb losses, where a more severe degree of thrombocytopenia would be expected6). By the end of POD4, the IABP had been removed, lactic acidemia had resolved, ALT levels had peaked and were beginning to decline, and the INR had nearly normalized; in combination, these clinical and laboratory events suggest that the patient's presumptive thrombocytopenia of critical illness should also stabilize and improve. However, over the subsequent 120-h period (Figure 1; POD5 to end of POD9), the platelet count decline accelerated, reaching a nadir value of 9 × 109/L (POD9); on POD6, a cold purple left foot, with pulses, was noted (not the limb that had had the IABP). Limb ischemia in critical illness can indicate localized problems (e.g., deep vein thrombosis, limb artery thrombosis) or systemic events such as DIC associated with circulatory shock (cardiogenic, septic).7 Whereas absent pulses suggest large artery occlusion, limb ischemia with detectable pulses can indicate microvascular thrombosis. Indeed, bilateral microvascular thrombosis involving lower (and sometimes upper) limbs—manifesting as “symmetrical peripheral gangrene”—is associated with the triad of acute DIC, shock, and proximate acute ischemic hepatitis (shock liver); here, procoagulant/anticoagulant imbalance results from DIC with shock liver predisposing to severe depletion of hepatically synthesized natural anticoagulants, protein C, and antithrombin.6, 7 Although the discussant (Theodore E. Warkentin) routinely measures protein C and antithrombin activity levels in this clinical setting, this is infrequently performed in most medical communities. On POD6, when limb ischemia was first noted, the platelet count measured 31 × 109/L, the INR was 1.5, and the fibrinogen was only 0.8 g/L. No test for fibrin-specific marker, such as d-dimer, was performed. The peripheral blood film showed red cell fragments; moreover, prominent normoblastemia (circulating nRBCs) was evident from POD2 to POD11. Pan-culture yielded no evidence of microbial infection. This patient's laboratory picture is consistent with DIC. Postcardiac surgery patients develop prominent elevated fibrinogen (acute phase reactant) levels by POD3 (~5–6 g/L)8; thus, a fibrinogen <1.0 g/L is striking. Also consistent with DIC is the presence of red cell fragments (schistocytes). Normoblastemia is typically seen in critically ill patients with progressive limb microthrombosis,6, 7 likely reflecting tissue hypoxia (circulatory shock) and DIC with red cell fragmentation and an associated bone marrow response.9 Table 1 lists potential explanations for DIC in critical illness. No evidence of sepsis was found in the patient. Further, his shock state had resolved (normal lactate levels) when thrombocytopenia became severe. An uncommon explanation for DIC to consider is severe heparin-induced thrombocytopenia (HIT), particularly the variant, “autoimmune heparin-induced thrombocytopenia (aHIT),” caused by highly pathological aHIT antibodies that activate platelets even in the absence of heparin10, 11; overt DIC with hypofibrinogenemia has been reported in such patients.12, 13 Although other (non-heparin) drugs, such as antibiotics, can cause severe thrombocytopenia,14 this entity mimics acute immune thrombocytopenia (isolated severe thrombocytopenia without coagulopathy). Careful review of medications, particularly heparin exposure, is indicated. Medications included preoperative dabigatran, simvastatin, allopurinol, felodipine, glycerol trinitrate, aspirin, clopidogrel, and metformin; postoperatively, the patient received multiple inotropes, perindopril, and, from POD4, empiric meropenem treatment. Table 2 summarizes heparin exposure, which included three injections of enoxaparin (100 mg per dose) given 7–9 days preoperatively, and a single 5000-unit unfractionated heparin (UFH) injection given at coronary angiography 8 days pre-surgery. Intraoperative UFH totaled 85 000 units. Only a single 40 mg dose of enoxaparin was given in the early postoperative period (POD2); importantly, no heparin product was given beyond POD2. The intra-/perioperative exposure to heparin products warrants careful consideration for a diagnosis of HIT. A recent study of 129 subjects with serologically confirmed HIT postcardiac surgery15 showed that 75% of patients develop HIT between POD5 and POD10, inclusive; in the minority (10%) that developed “early” HIT (prior to POD5), all had received heparin during the 10 days prior to cardiac surgery, with the timing of preoperative heparin explaining occurrence of early postoperative HIT. However, in this case, the immediate preoperative platelet count (251 × 109/L) was higher than values obtained earlier in the hospitalization, arguing somewhat against preoperative heparin exposure being responsible for early postoperative HIT. Further, as discussed, the early postoperative platelet count declines appeared consistent with the patient's critical illness. A useful way to approach a patient with possible postcardiac surgery HIT is to plot the serial platelet counts and to look closely for a platelet count fall occurring during the POD5–POD10 window characteristic of HIT.15 In this patient, the dramatic platelet count decline observed, from 87 (shortly before POD5) to 11 × 109/L (POD7), with repeat platelet count of 10 × 109/L later that same day, a nearly 90% platelet count fall, occurring rapidly and without ongoing heparin exposure, is consistent with severe aHIT superimposed in a patient with early postoperative critical illness.16 Applying the 4Ts score17 likely underestimates the likelihood of HIT in this patient. The timing of onset of the postoperative platelet count fall is at best unclear, if not too early (0–1 point); the platelet count nadir is unusually low (0 points); there is no clear thrombosis (limb ischemia points to “possible” thrombosis, 1 point); and the patient is critically ill, although improving (0–1 point). Overall, the 4Ts score (maximum, 3 points) could be construed as “low probability.”17 Yet, a “gestalt” assessment, by an experienced clinician, would point out that the accelerating platelet count decline in the POD5–POD10 window, occurring several days after the last exposure to heparin, together with overt DIC, in a patient who otherwise seems to be improving, points strongly to a potential diagnosis of severe aHIT. A HIT screen, performed late on POD5 using the particle gel immunoassay (PaGIA; Bio-Rad Laboratories, Auckland, NZ), was positive. However, confirmatory HIT testing with a platelet activation assay was not performed (the serotonin release assay [SRA] is not available in New Zealand). The PaGIA is a rapid HIT test with high diagnostic sensitivity that is not available in the United States, but which has been used in New Zealand and elsewhere.18 (Recently, the PaGIA was discontinued worldwide.) Like other PF4-dependent immunoassays, a positive result is not specific for HIT, especially postcardiac surgery, where nonclinically significant anti-platelet factor 4 (PF4)/heparin antibodies are often formed.19 PaGIA diagnostic specificity is high (>99%) if patient serum diluted 1/32 yields a positive result18 (retesting with diluted serum was not performed in this case). A similar situation holds for other PF4-dependent immunoassays—for example, strong positive results by enzyme immunoassay or chemiluminescence assay indicate a high likelihood of HIT.20 Treatment for HIT is warranted in this clinical situation. Treatment for HIT was initiated with the direct thrombin inhibitor (DTI), bivalirudin, at a renally adjusted dose of 80 μg/kg/h (for estimated glomerular filtration rate (eGFR) 53 mL/min) and monitored by APTT (target therapeutic range, 80–100 s). However, platelet recovery was slow (Figure 2); a normal platelet count was not reached until POD32. The overall clinical picture of severe thrombocytopenia occurring during the POD5–POD10 day period, accompanied by DIC, microvascular limb ischemia, and delayed platelet count recovery, is strongly suggestive of aHIT.10 This severe manifestation of HIT is gaining increasing attention, for several reasons. First, such patients have highly pathological aHIT antibodies that cause strong platelet activation in vitro, using the SRA, even in the absence of heparin, that is, heparin-independent platelet-activating antibodies.10, 21 Second, these highly pathogenic antibodies recognize antigen sites on PF4 similar to those caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) antibodies,22 a severe prothrombotic anti-PF4 disorder.21 Third, management differs from classic HIT, as high-dose IVIG is recommended to interrupt aHIT antibody-induced platelet activation.23 Fourth, these patients are at greater risk for anticoagulant treatment failure—including progression of limb ischemia to necrosis, including with DTI treatment, perhaps due to “APTT confounding” (inadequate DTI dosing due to difficulties in determining “therapeutic” APTT values) as well as DTI inhibition of protein C activation by thrombin.24 Accordingly, the discussant favors anticoagulation with factor Xa inhibitors (e.g., fondaparinux, danaparoid [not available in the United States], rivaroxaban, or apixaban), agents that do not require APTT monitoring.24 The patient's limb ischemia resolved within 48 h, he exhibited good clinical recovery and was discharged on POD27, on warfarin (target INR, 2.0–3.0) and aspirin 100 mg po daily; the maximum INR measured during warfarin thromboprophylaxis was 2.0. At 3-month postdischarge, warfarin was changed to dabigatran 150 mg per os twice daily. HIT treatment guidelines suggest postponing initiation of warfarin anticoagulation until platelet count recovery; this is because warfarin, administered during acute HIT, is a risk factor for microthrombosis, particularly with supratherapeutic INR levels (>4.0).24 However, in this patient, no adverse effect of warfarin was seen. Two years later, the patient represented to hospital with prosthetic valve endocarditis associated with Enterococcus faecalis. Medical management failed and a plan was made to proceed with redo sternotomy and mitral valve replacement. Preoperatively, the platelet count was normal, and a screening test for HIT antibodies was negative (lateral flow immunoassay [STAGO ANZ STic Expert, Forest Hill, Australia]). Because of concerns regarding the potential for HIT recurrence, bivalirudin rather than heparin was used for intraoperative anticoagulation. There are differing opinions on how to handle this situation of repeat heart surgery in a patient with a remote history (>3 months prior) of HIT, with negative testing for HIT antibodies. The American Society of Hematology (ASH) guidelines suggest using heparin for intraoperative anticoagulation, since HIT recurrence (if it occurs) will take at least 5 days, at which point non-heparin anticoagulation can be given. However, there is a small chance—estimated at less than 3%—of HIT recurrence, as a manifestation of aHIT, the entity I believe the patient had 2 years earlier. Indeed, a well-documented example of recurrent aHIT with repeat heparin exposure was reported in a patient whose two postcardiac surgery episodes of HIT—separated by 20 years—represented two distinct episodes of aHIT.25 Intraoperative bivalirudin was initiated at 1 mg/kg at knife-to-skin and then infused at 2.5 mg/kg/h until just before cardiac bypass was discontinued. Citrated-dextrose was used to prime the cell saver. Bivalirudin was monitored with activated clotting time (ACT), aiming for a target range of 2.5 times baseline. Redo cardiac surgery was technically challenging due to extensive adhesions. Initial low-level bleeding during careful exposure of the surgical field was exacerbated by the anticoagulant effects of bivalirudin; approximately 2500 mL of blood was returned from the cell saver. The infected mitral valve was successfully explanted and replaced. Due to a patent left internal mammary artery graft, surgery proceeded with moderate hypothermia (30°C) for myocardial protection. Bivalirudin was stopped just before the cardiac bypass was disconnected. Ongoing bleeding and persistently raised ACT delayed chest closure for 4½ h, with numerous intra-/early postoperative blood products given (4 units red cell concentrates [RCCs], 4 units fresh frozen plasma [FFP], 50 units [~500 mL] cryoprecipitate, 1 platelet transfusion), and postoperative acute kidney injury documented. Approximately 10 h post-chest closure, cardiac tamponade prompted return to the operating room, with the evacuation of large retrosternal hematoma and additional transfusions (10 units RCCs, 4 units FFP, 20 units [~200 mL] cryoprecipitate). Seven RCC units were also given over the subsequent 5 days. Ultimately, the patient made a good recovery. Use of hypothermia may have resulted in delayed bivalirudin clearance and prolonged anticoagulant effect. The challenges of major intra-/early postoperative bleeding associated with bivalirudin anticoagulation highlight why many practitioners choose intraoperative anticoagulation with heparin—despite a history of previous aHIT—in this situation. Fortunately, the patient's bleeding was manageable. This patient illustrates several challenging aspects regarding the diagnosis and management of HIT. First, the patient's clinical course is consistent with a highly atypical clinical presentation consistent with the severe subtype, aHIT. Such patients can develop severe thrombocytopenia, overt DIC, and microvascular thrombosis, with delayed platelet count recovery despite the absence of ongoing heparin administration. Second, the case illustrates how test availability for HIT antibodies varies in different jurisdictions; for example, in New Zealand, it is challenging to obtain a platelet activation test such as the SRA. Even in the United States—where the SRA can be performed—it is uncommon for the test to be performed both in the absence and presence of heparin; yet, definitive laboratory diagnosis of aHIT requires a functional (platelet activation) test performed both with and without heparin, as strong serum-induced serotonin release in the absence of heparin is the pathological hallmark of aHIT.10 Third, this case illustrates the treatment dilemma that arises when a patient who is believed to have a diagnosis of severe aHIT requires repeat cardiac surgery. In theory, such a patient can receive heparin safely for the cardiac surgery itself (given the absence of HIT antibodies at the time of surgery) with vigilance in the postoperative period to evaluate for potential aHIT occurrence during the characteristic POD5 to POD10 period; at this time, if aHIT occurs, a non-heparin anticoagulant plus high-dose IVIG would be appropriate. Alternatively, one can perform the surgery with a non-heparin anticoagulation strategy, such as with bivalirudin. In this case, the second approach was adopted. Although major postoperative bleeding occurred, the ultimate outcome was favorable. We thank Ms. Jo-Ann I. Sheppard for preparing the two figures. Theodore E. Warkentin has received lecture honoraria from Instrumentation Laboratory (Werfen); has provided consulting services to Ergomed, Instrumentation Laboratory (Werfen), Octapharma, Paradigm Pharmaceuticals, and Veralox; has received research funding from Instrumentation Laboratory (Werfen), and has provided expert witness testimony relating to HIT and non-HIT thrombocytopenia. Khalid Al-Azri, Kate Goldstone, Julia Phillips, Jack Bhana, and Nishith Patel declare no relevant conflicts of interest. The patient provided written permission for this report (institutional approval is not required for case reports in our medical community). All data generated or analyzed during this study are included in this published article.
Introduction/Background/Significance: Acute undifferentiated leukemia (AUL) is a rare, aggressive leukemia lacking expression of lineage-specific markers.Diagnostic and therapeutic challenges include differentiating AUL from acute leukemias of ambiguous lineage (ALALs).The diagnosis of AUL is made once comprehensive immunophenotyping, cytogenetics, and molecular genomics exclude any lineage-specific leukemia.Materials and Methods/Case Presentation/Objective: A 56-year-old woman presented with easy bruising, petechial rash, and fevers for 2 weeks.Laboratory tests revealed a hemoglobin of 8.5 g/dL, WBC 8.1 K WBC/μL, and platelets of 5,000 platelets/μL.Serum LDH was mildly elevated at 288 U/L.Peripheral blood smear showed increased blasts.Bone marrow aspirate and biopsy showed 75% blasts that expressed no specific lineage markers.Cytogenetics were normal, and molecular findings revealed the presence of an IDH1 mutation.A diagnosis of AUL was confirmed.The patient was treated with FLAG-IDA (fludarabine 30 mg/m 2 x 5 days, cytarabine 1.5 g/m 2 x 5 days, idarubicin 8 mg/m 2 x 3 days, and G-CSF with tbo-filgastrim 480 μg from day 1 x 7 days).Her induction course was complicated by neutropenic fever and sepsis requiring intravenous antibiotics.A bone marrow from day 23 of treatment revealed a complete response with incomplete hematologic recovery.The patient was referred for allogenic hematopoietic stem cell transplantation (HSCT).Results/Description/Main Outcome Measure: ALALs are extremely rare hematologic malignancies, accounting for < 4% of all leukemias.AUL is a subset of ALAL defined by the absence of any immunophenotypic lineagespecific markers and of acute myeloid leukemia (AML)-or acute lymphoblastic leukemia (ALL)-defining cytogenetics.AUL has a higher incidence in older patients, with a median age of onset of 74 years.Based on a retrospective analysis of 1888 patients with AUL, median overall survival if chemotherapy was administered was 13 months (95% CI, 11-15 months) versus 1 month if no treatment was delivered.There is no standard of care treatment for AUL, although most reported cases received AML induction regimens rather than ALL regimens.In a retrospective study of 54 cases of ALALs (of which 24 assigned to AUL based on WHO 2016 classification), all but 2 patients received AML treatment regimens, including 54% of patients who received standard 7+3 (7 days of cytarabine and 3 days of anthracycline-based therapy), 11% of patients who received hypomethylating agents, and supportive care for the remaining 35% of patients.In a review of outcomes of 8 patients with AUL after allogenic HSCT, median overall survival at 1 year was 37.5% (95% CI, 9.9%-65.9%). Conclusion:AUL is a rare hematological malignancy with a decreasing incidence over time due to improved diagnostics and classification.Optimal treatment is unclear given the lack of lineage markers, with most reported cases utilizing AML-based treatments.Outcomes remain poor in AUL.Our case highlights an example of AUL for which the FLAG-IDA regimen was utilized with achievement of a complete response with incomplete hematologic recovery after cycle 1 of induction.The patient was subsequently referred for allogenic HSCT and achieved a prolonged remission of >1 year duration.
For our initial systematic review of drug-induced thrombotic microangiopathy (DITMA) in 2015,1 we adapted our previous literature search strategy for identification of articles reporting drug-induced thrombocytopenia (DITP) to identify articles reporting patients with DITMA (Table S1). Our criteria for evaluating reports of DITMA to determine levels of evidence for a causal association of the drugs with TMA were developed in 2015 (Table S2).1 We used these criteria in our subsequent systematic review2 and again in this current systematic review of articles published during 2018–2023. In this current review we identified one new drug with definite evidence supporting a causal association with the occurrence of TMA (Table 1). In this current review we also identified two drugs that had evidence suggesting a probable causal association with the occurrence of thrombotic thrombocytopenic purpura (TTP), and 10 reports describing five immune checkpoint inhibitors (ICIs) with probable or possible causal associations with TTP (Table 1). We had not previously identified reports with evidence for a causal association with TTP. We have previously described TTP and DITMA as distinct primary TMA syndromes.3 Using our criteria to evaluate reports of DITMA,1 which they adapted for evaluating reports of drug-induced TTP (DI-TTP), Scholfield et al. recently reviewed 90 reports (describing 97 drugs) that described DI-TTP.4 They concluded that none of the 97 drugs (including the two drugs and two ICIs that we identified as having probable evidence for causing DI-TTP) had definite or probable evidence for causing TTP. We address this discrepency in this report. Onasemnogene abeparvovec was described in five patients (three reports) as a probable cause of TMA (Table S3). Together, these three reports provided definite evidence (Table S2). Onasemnogene abeparvovec is an adeno-associated virus gene therapy approved in 2019 for treatment of children with spinal muscular atrophy. Without treatment, life expectancy of these children is <2 years. An estimated 1400 children have been treated with onasemnogene abeparvovec. These five infants developed TMA 5–8 days after administration of onasemnogene abeparvovec. They presented with oliguria and developed severe microangiopathic hemolysis, thrombocytopenia, and acute kidney failure, the diagnostic clinical features of TMA. ADAMTS13 activity was normal. Escherichia coli was not identified in stool cultures. Treatments included plasma exchange, corticosteroids, and eculizumab. Four children survived, two with persistent hypertension, one with nephrotic syndrome. One infant died on day 40 with staphylococcal sepsis. There was no documentation of an immune-mediated reaction with onasemnogene abeparvovec causing TMA, and the infrequency of TMA indicates that onasemnogene abeparvovec is not inherently toxic. Although there were no apparent risk factors that occurred in all five children (such as preceding infection, vaccine exposure, previous treatment with nusinersen), it can be assumed that these children had a congenital or acquired vulnerability for toxicity-induced DITMA. Using criteria that we developed to evaluate reports of DI-TTP (Table S4), we identified two articles describing a probable association of drugs with episodes of TTP (Table 1). Because TTP is an autoimmune disorder the pathogenesis of DI-TTP5 may be different from DITMA. Therefore, we deleted the DITMA exclusion criterion that the suspected drug had been taken daily for more than 1 year. We also identified 10 articles describing TTP associated with ICIs that had probable or possible causal association with TTP (Table 1, Table S5). A 57-year-old woman with chronic uveitis had been treated with infliximab infusions every 4 weeks for more than 1 year when TTP was initially diagnosed (Table S3). Grave's disease, also an autoimmune disorder, had been diagnosed and treated for 30 years previously. She had fatigue and ecchymoses, thrombocytopenia (platelet count, 9000/μL), and microangiopathic hemolytic anemia. ADAMTS13 activity was <5%. She had no evidence of systemic lupus erythematosus. Infliximab was stopped. She was successfully treated with plasma exchange, prednisone, and rituximab. When uveitis recurred 8 months later, she received two infusions of infliximab at a 4-week interval with careful platelet monitoring. Six days after her second infusion she had asymptomatic thrombocytopenia (platelet count, 9000/μL) and microangiopathic hemolytic anemia; ADAMTS13 activity was 26%. Infliximab was discontinued and she was again treated with plasma exchange, prednisone, and rituximab. Her platelet count normalized in 12 days; her ADAMTS13 activity returned to 100% in 6 weeks. Although infliximab infusions every 4 weeks for more than 1 year did not violate the DITMA exclusion criterion that “the suspected drug had been taken daily for more than one year,” it violated the principle of prolonged prior treatment. The occurrence of relapse 5 weeks after initial re-exposure to infliximab is also longer than the typical time for a recurrent episode of DITP or DITMA with re-exposure to the drug. These differences of the infliximab report from the clinical courses of DITP and DITMA may be related to the different pathogenesis of autoimmune disorders.5 The recurrence of severe thrombocytopenia and microangiopathic hemolytic anemia following restarting infliximab is strong clinical evidence for recurrent TTP. Although the ADAMTS13 activity of 26% is uncommon in patients with TTP, activities ≥10% may occur at the time of the initial diagnosis of TTP. ADAMTS13 activities ≥10% may be more common at the time of relapse episodes of TTP because they are typically diagnosed earlier than initial episodes (Table S6). The subsequent recovery of ADAMTS13 activity to 100% is also consistent with a relapse of TTP. A 37-year-old man with chronic myeloid leukemia had been treated with daily dasatinib for 15 months when TTP was diagnosed. He had characteristic clinical and laboratory features of TTP: hematocrit 34%; platelet count 14 300/μL, creatinine 2.1 mg/dL, unconjugated bilirubin 2.2 mg/dL, lactic dehydrogenase (LDH) 1052 U/L, haptoglobin <8 mg/dL. ADAMTS13 activity was 6%. Dasatinib was stopped. He was treated with plasma exchange and prednisone, recovering in 2 weeks. Prednisone was continued for 3 months. Two weeks after recovery from TTP, dasatinib was restarted. One month after prednisone was stopped his platelet count decreased from 220 000/μL to 100 000/μL, he was asymptomatic, other laboratory values were normal. ADAMTS13 activity was 15%. Dasatinib was stopped; no treatment for TTP was given. One month later ADAMTS13 activity was normal. Fifteen months of daily dasatinib is inconsistent with the DITMA exclusion criterion that the suspected drug had been taken daily for more than 1 year. Also, treatment with dasatinib for 4 months before a relapse occurred is an unusually long interval for a recurrence of DITMA. However, these increased durations may be consistent with the pathogenesis of autoimmune disorders.5 Although this patient did not have a clinical relapse, he did have asymptomatic thrombocytopenia and moderately severe ADAMTS13 deficiency, consistent with the clinical course of acquired, autoimmune TTP. During the clinical remission of acquired autoimmune TTP, asymptomatic recurrences of severe ADAMTS13 deficiency and subsequent spontaneous recovery commonly occur (Table S6). ICIs can cause many different autoimmune disorders. Our literature search identified 10 reports of TTP attributed to five ICIs (Table S5); the data are similar to our previous documentation of ICI-induced immune thrombocytopenia (ITP). Similar to ICI-induced ITP, the episodes of TTP occurred from 9 days to 24 weeks after beginning ICI treatment. All 10 patients had severe ADAMTS13 deficiency (<3%–9%). ADAMTS13 inhibitor activity was measured in five patients; all were increased (0.6–3.7 Bethesda units). ICIs were discontinued and were not resumed following recovery from TTP. Because of the documented ability of ICIs to cause the occurrence of multiple autoimmune disorders, we believe that these 10 reports with probable or possible association with the occurrence of TTP support the concept of DI-TTP. The presumed pathogenesis of DITP and DITMA is that drugs bind to the complementarity-determining regions of latent autoantibodies, increasing their binding affinity to their target antigen (a platelet antigen in DITP, multiple antigens in DITMA).6 The pathogenesis of DI-TTP may be different from the pathogenesis of DITP and DITMA. Acquired, autoimmune TTP is caused by autoantibodies that block ADAMTS13 activity. Some patients with acquired, autoimmune TTP may have preceding asymptomatic mild or moderate ADAMTS13 deficiency, similar to the common asymptomatic ADAMTS13 deficiency in patients following recovery from an episode of TTP (Table S6). Binding of drugs to latent, asymptomatic anti-ADAMTS13 autoantibodies may be the etiology of DI-TTP. The occurrence of drug-induced autoimmune disorders may require a long duration of drug exposure. An example is drug-induced systemic lupus erythematosus (SLE). The occurrence of drug-induced SLE, a common disorder, requires prolonged exposure to the causative drug, often several months.5 This experience with drug-induced SLE supports the concept that DITMA may occur following prolonged exposure to the causative drug. The Scholfield report's4 designation of “Unlikely” for both infliximab and dasatinib was probably because of the prolonged preceding exposure to these drugs. We accept that the occurrence of DI-TTP remains uncertain, that there is no definite evidence supporting the occurrence of DI-TTP. Certainly, we will require additional reports with definite or probable evidence. This project had no outside support. The authors have no conflict with this topic or these data. The data that supports the findings of this study are available in the supplementary material of this article. Table S1. Literature search to identify articles reporting patients with drug-induced thrombotic microangiopathy or thrombotic thrombocytopenic purpura. Table S2. Criteria for assessing reports of individual patients with suspected drug-induced thrombotic microangiopathy (TMA) and levels of evidence for determining an association of the suspected drug and TMA. Table S3. Articles reporting drug-induced thrombotic microangiopathy and drug-induced thrombotic thrombocytopenic purpura. Table S4. Criteria for assessing reports of individual patients with suspected drug-induced thrombotic thrombocytopenic purpura (DI-TTP) and levels of evidence for documenting a causal association of the suspected drug with TTP. Table S5. Thrombotic thrombocytopenic purpura (TTP) attributed to treatment of cancer with an immune checkpoint inhibitor: 10 reports with evidence for probable (three reports) or possible (seven reports) evidence for a causal association with TTP. Table S6. Experience of the Oklahoma TTP Registry with diagnosis and follow-up during remission from acquired, autoimmune thrombotic thrombocytopenic purpura. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
It has become increasingly clear that social determinants impact the health outcomes of patients with multiple myeloma (MM). Within private-payer healthcare models, low-income, unmarried status, uninsured status, and living in low socioeconomic status (SES) index areas are all associated with poorer health outcomes.1 Though the mechanism by which SES impacts outcomes is unknown, previous studies have highlighted disparities in accessing treatment within private-payer models. However, there is limited data examining the association of SES with MM-related health outcomes within a public-payer universal healthcare system. Ontario, Canada, has a universal healthcare system that covers chemotherapy drug and administration costs for provincial funding regimens. Therefore, we performed a retrospective cohort study using the Institute for Clinical Evaluative Sciences (ICES) population-based administrative database to evaluate the association between socioeconomic marginalization and the likelihood of receiving treatment, and overall survival (OS) among treated patients in Ontario. Given the theoretical equal access to care, and data that MM outcomes are improved with universal versus private-payer healthcare in the United States, we hypothesized that socioeconomic marginalization would not affect the health outcomes of Ontarian patients with MM. Patients diagnosed with MM between 2007 and 2018 were identified using the International Classification of Diseases (ICD) histology codes for MM, as described previously.2 Patients untreated by 1-year post-diagnosis and lacking ICD codes for symptomatic end-organ dysfunction were presumed to have smoldering MM (SMM) and were excluded.3 The Ontario Marginalization (ONMARG) index at diagnosis was used as an area-level surrogate measure of SES. It is a validated composite score incorporating census data on material deprivation (income, education, employment, reliance on government assistance), residential instability (people per dwelling, marital status), ethnic concentration (recent immigrants, self-identified minorities), and dependency (age <15 or >65 years).4 The ONMARG index is reported in quintiles, with higher quintiles representing more marginalized areas. To simplify reporting, we grouped patients in ONMARG quintiles 2 to 4. Baseline demographic information (age at MM diagnosis, sex), diagnosis date, community size (urban if population ≥10 000, otherwise rural), and the modified Charlson-Deyo Comorbidity Index (CCI) was collected. Logistic regression was used to assess the association between ONMARG and receipt of treatment 1 year post MM diagnosis. A liberal time period for treatment initiation was used to ensure that patients experiencing treatment delays were not incorrectly classified as untreated or having SMM. Treatment was defined as the receipt of a proteosome inhibitor (PI; bortezomib), immunomodulatory drug (IMID; lenalidomide), alkylator (melphalan, cyclophosphamide), or an autologous stem cell transplant (ASCT) as these encompassed all provincially funded first-line treatments during the study period. An interaction term between age (<70 vs. ≥70) and ONMARG was used in the multivariable model to assess whether age was an effect modifier. Cox proportional hazards regression was used to assess the association between ONMARG and OS. As poverty is more prevalent in rural settings and rurality is associated with barriers to accessing healthcare,5 we used an interaction term between ONMARG and community size to assess for effect modification. Similarly, ASCT is independently associated with improved survival in MM, but ASCT rates may differ in more marginalized populations, so an interaction term between ASCT and ON-MARG index was used in the multivariable Cox model. Statistical significance was defined as p < .05. The date of the last follow up was November 2, 2022. The study was approved by the ethics board of McMaster University and followed the data confidentiality and privacy guidelines of ICES. After excluding 3359 patients with presumed SMM, our newly diagnosed MM cohort consisted of 9777 patients. At 1 year post diagnosis, 2242 (23%) of MM patients remained untreated. Among treated patients, the median time to treatment was 35 (IQR 16–85) days, with no significant difference in time to treatment between ONMARG groups (p = .630). Compared to treated patients, untreated patients tended to be older (median age 69 vs. 77 years), have more comorbidities (CCI ≥ 2 in 11% vs. 18%), and live in more marginalized areas (ONMARG Q5: 18% vs. 23%). Patients from more marginalized areas were less likely to receive treatment within 1 year of diagnosis even after adjusting for community size, time period of diagnosis, baseline CCI, sex, and age at diagnosis (ONMARG Q5 vs. Q1: OR 0.71, 95% CI 0.60–0.84; ONMARG 2–4 vs. Q1: OR 0.88, 95% CI 0.77–1.01; p < .001). Similarly, marginalization was associated with reduced odds of receiving an upfront ASCT (ONMARG Q5 vs. Q1: OR 0.82, 95% CI 0.67–1.01; ONMARG 2–4 vs. Q1: OR 0.74, 95% CI 0.64–0.85; p < .001). We further studied the likelihood of receiving treatment within 3 months of diagnosis and the results remained consistent even after adjusting for confounding. Neither age nor community size was the effect modifier on the association between ONMARG and the likelihood of receiving treatment (pinteraction = 0.086 and pinteraction = 0.357, respectively). The median OS of MM patients treated versus untreated by 1 year post diagnosis was 4.3 (95% CI 2.1–4.5) versus 0.9 (95% CI 0.7–1) years, respectively. As treatment rates differed between ONMARG quintiles, we restricted our OS analyses to patients treated within 1 year of diagnosis (baseline characteristics are summarized in Table 1). Patients living in more marginalized areas tended to be older, female, and urban dwellers and had lower upfront ASCT rates (though this may relate to perceived age-related ASCT eligibility). The median OS of patients transplanted versus non-transplanted patients was 8.3 (95% CI 7.8–8.9) versus 2.9 (95% CI 2.8–3.0) years, respectively. Given that the association between ONMARG and survival differed among transplanted versus non-transplanted patients (pinteraction = 0.003), the multivariable analyses were stratified by transplant status. Among patients treated without an upfront ASCT, living in a marginalized area was not associated with survival after adjusting for age at diagnosis, sex, baseline CCI, time-period of diagnosis, and treatment with a PI/IMID (ONMARG Q5 vs. Q1: HR 1.03, 95% CI 0.91–1.15, p = .678; ONMARG 2–4 vs. Q1: HR 0.97, 95% CI 0.88–1.07, p = .553). Among transplanted patients, living in marginalized areas was associated with prolonged survival even adjusting for the same confounders (ONMARG Q5 vs. Q1: HR 0.82, 95% CI 0.67–1.01, p = .057; ONMARG 2–4 vs. Q1: HR 0.74, 95% CI 0.64–0.85, p < .001). Our study suggests that socioeconomic marginalization is associated with a reduced likelihood of receiving early treatment for MM, refuting the common assumption that universal healthcare results in equitable health outcomes. However, even when the barrier to accessing treatment is overcome, marginalization was not associated with inferior survival. Interestingly, we found that transplanted patients living in more marginalized areas had a significantly longer OS compared to those living in less marginalized areas; we hypothesize that this may reflect a transplant referral bias, where perhaps only the minority of fit patients from marginalized patients were assessed for ASCT. Though the mechanism by which SES impacts outcomes is not entirely clear, even in a universal healthcare system, a MM diagnosis has significant financial implications that may result in barriers to treatment, such as lost work productivity for patients and caregivers to facilitate treatment or toxicity management, or uncovered costs of supportive medication. Disparities in accessing MM treatment within a universal healthcare paradigm have also been demonstrated in a New Zealand population study which showed that ASCT rates were lower among Māori/Pasifika (Indigenous peoples) compared to Europeans/others.6 Though this study found that socioeconomic deprivation was associated with poorer survival, survival was assessed among all patients with MM, irrespective of treatment status; thus it's unclear if the inferior OS was predominantly due to low SES or lack of treatment. Our study's strengths include our use of a large, comprehensive population database with minimal loss to follow-up. Additionally, standardized provincial treatment algorithms minimize treatment-related differences that could influence survival outcomes. Furthermore, SES is a complex and multidimensional construct, and the ONMARG index encompasses multiple social domains to provide a comprehensive measure of area-level SES. Study limitations include the lack of patient-specific demographic and disease data (such as cytogenetics or baseline staging) which can impact treatment decisions, prognosis, and health outcomes. While disease-specific data is included in MM registries, patients treated in community centers or untreated patients are systematically underrepresented in these registries, therefore leading to significant bias. Given the degree of missing data, we could not evaluate the role that race, or treatment at a community versus academic center, had on health outcomes. Lastly, though we used a validated algorithm, it is possible that some untreated MM patients may have had SMM due to the overlap in ICD codes. However, given the dismal survival among untreated MM patients in this study, we believe this cohort is truly comprised primarily of newly diagnosed MM patients and not SMM patients. In conclusion, our study demonstrates that even in a universal healthcare system, disparities in accessing treatment for MM exist, especially among patients that are socioeconomically marginalized. However, once treated, marginalization was not associated with poorer survival in our cohort. Additional studies including qualitative studies with patients, caregivers, and healthcare professionals are needed to understand the patient-level and structural barriers that lead to inequitable healthcare access. Funding support was provided by Myeloma Canada and the International Myeloma Society. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). The authors acknowledge Ontario Health for access to the Ontario Cancer Registry (OCR). The authors thank the Toronto Community Health Profiles Partnership for providing access to the Ontario Marginalization Index. The opinions, results, and conclusions reported in this article are those of the authors and are independent of the funding sources or data holders. The authors have no relevant conflicts of interests to disclose. Data sharing is not applicable to this article as no new data were created or analyzed in this study.
A 13-year-old Indian boy presented with dysuria and intermittent fever for 6 weeks. Physical examination showed no specific abnormality. His blood count showed a white cell count of 26.8 × 109/L, hemoglobin concentration 109 g/L, mean cell volume 82.9 fL, and platelet count 24 × 109/L. His blood film showed marked neutrophilia and 26% blast cells; the neutrophils and eosinophils were packed with aberrantly staining, mainly purple granules, some of which were giant (all images ×100 objective). No granules or Auer rods were detected in blast cells. Immunophenotyping showed the blast cells to express CD13, CD33, CD117, CD34, CD38, and CD7. There was no expression of myeloperoxidase, CD64, cytoplasmic CD3, or B-lineage markers. Cytogenetic analysis showed a normal male karyotype. There were no clinical features of Chédiak–Higashi syndrome. A diagnosis of acute myeloid leukemia (AML) complicated by the pseudo-Chédiak–Higashi anomaly was made. The patient responded to induction chemotherapy with abnormal granulocytes disappearing from the blood; the few neutrophils then present did not have abnormal granules. The patient was well enough to be discharged and was to seek further treatment elsewhere. The pseudo-Chédiak–Higashi anomaly is well recognized but rare in AML. Usually the abnormal granules are found in blast cells, but occasionally they have been identified in promyelocytes and myelocytes.1-3 They stain variously, pink or purple. They are usually peroxidase-positive but not invariably.4 Auer rods are also not infrequently present. An association with t(8;21) has been reported in at least three patients,3, 5, 6 but no other consistent cytogenetic abnormality has been recognized. This patient is exceptional in that the granules were confined to mature granulocytes. The authors declare no conflicts of interest.
Jorge Monge receives consulting fees from Bristol Myers Squibb. Meri Razavi, Liming Bao, and Sanjay S. Patel have no conflicts of interest to disclose.
Dr. Lichtman and Dr. Prchal have no competing interests. The authors did not use artificial intelligence (AI) in the preparation of this manuscript. None.
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly identified disease caused by somatic alterations in UBA1 which produce a recalcitrant inflammatory state along with hematologic disturbances. Patients with VEXAS can have a wide spectrum of clinical symptoms and providers should be familiar with the heterogeneity of associated clinical features. While hematologic parameters may be generally non-specific, peripheral blood features of macrocytosis, monocytopenia, and/or thrombocytopenia coupled with bone marrow vacuolization of erythroid or myeloid precursors should raise suspicion for this condition. Due to an increased mortality, prompt recognition and accurate diagnosis is paramount. Access to testing for confirmation of UBA1 variants is not yet universally available but clinicians should understand the current available options for genetic confirmation of this disease. Treatment options are limited due to lack of prospective clinical trials but cytokine directed therapies such as interleukin-6 inhibitors and JAK-STAT inhibitors as well as hypomethylating agents such as azacitidine have shown evidence of partial effect. Though cases are limited, allogeneic stem cell transplantation holds promise for durable response and potential cure. The intent of this review is to outline the pathophysiology of VEXAS syndrome and to provide a practical approach to diagnosis and treatment.
Silicone lymphadenopathy occurs following migration of silicone particles through the lymphatic system to regional nodes and more distal extranodal sites as a consequence of implant rupture or “gel bleed”. This silicone migration and tissue deposition with granulomatous reaction may cause systemic symptoms which can mimic lymphoma – fatigue, fever, and sweats. It is an important condition to be aware of and to consider in the context of bone marrow granulomatosis. The authors declare no conflicts of interest.
Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m2 ) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hbmass ), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kgBM ) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kgLBM ). Hbmass /BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kgBM ) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kgLBM )/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R2 = .72, p < .001) and Hbmass (R2 = .81, p < .001). These data may only be valid for BV/Hbmass when assessed by CO re-breathing. Hbmass /LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis.
