American Journal of Hematology

doi: 10.1002/ajh.27237pmid: 38314662

This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo‐SCT) for Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo‐SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo‐SCT: 101; non‐SCT: 46) were eligible for this analysis. In the multivariate analyses, allo‐SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30–0.97; p = .04) and relapse‐free survival (RFS) (aHR: 0.21; 95% CI: 0.12–0.38; p < .001). The 5‐year adjusted OS and RFS were 73% and 70% in the allo‐SCT cohort, whereas they were 50% and 20% in the non‐SCT cohort. Despite the higher non‐relapse mortality (aHR: 3.49; 95% CI: 1.17–10.4; p = .03), allo‐SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05–0.20; p < .001). In addition, allo‐SCT was also associated with superior graft‐versus‐host disease‐free, relapse‐free survival (aHR: 0.43; 95% CI: 0.25–0.74; p = .002). Propensity score‐matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo‐SCT in CR1 had superior survival and lower relapse compared with the non‐SCT cohort.

doi: 10.1002/ajh.27242pmid: 38348608

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real‐world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019–2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 109/L and 115.8 g/L and 107 × 109/L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre‐ and post‐pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.

Two recent guidelines, the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO‐HAEM5) and the International Consensus Classification (ICC), were published to refine the diagnostic criteria of acute myeloid leukemia (AML). They both consider genomic features more extensively and expand molecularly defined AML subtypes. In this study, we compared the classifications of 1135 AML cases under both criteria. According to WHO‐HAEM5 and ICC, the integration of whole transcriptome sequencing, targeted gene mutation screening, and conventional cytogenetic analysis identified defining genetic abnormalities in 89% and 90% of AML patients, respectively. The classifications displayed discrepancies in 16% of AML cases after being classified using the two guidelines, respectively. Both new criteria significantly reduce the number of cases defined by morphology and differentiation. However, their clinical implementation heavily relies on comprehensive and sophisticated genomic analysis, including genome and transcriptome levels, alongside the assessment of pathogenetic somatic and germline variations. Discrepancies between WHO‐HAEM5 and ICC, such as the assignment of RUNX1 mutations, the rationality of designating AML with mutated TP53 as a unique entity, and the scope of rare genetic fusions, along with the priority of concurrent AML‐defining genetic abnormalities, are still pending questions requiring further research for more elucidated insights.

doi: 10.1002/ajh.27254pmid: 38400519

Here we report on the first prospective study evaluating the safety and long‐term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator‐containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty‐six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose‐limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft‐vs‐host disease (GVHD). Treatment‐related mortality (TRM) at 5 years was 12%. With a median follow‐up of 48.7 months, the 5‐year overall survival (OS) and progression‐free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5‐year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator‐containing regimen of HSCT.

doi: 10.1002/ajh.27252pmid: 38357714

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9–12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14–35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1–6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3‐year overall survival was 62% (95% CI, 48%–76%) and 1‐year non‐relapse mortality was 26% (95% CI, 14%–38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant‐specific risk score, higher‐intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3‐year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

Current guidelines suggest a 3‐month anticoagulant treatment course for isolated distal deep vein thrombosis (IDDVT), but shorter durations of treatment are frequently prescribed in clinical practice. We investigated whether a 6‐week treatment with low‐molecular‐weight heparin (LMWH) at intermediate dosage can be an effective and safe alternative to vitamin K antagonists (VKA) in patients with IDDVT (non‐inferiority trial). In a multicenter, open‐label, randomized trial, 260 outpatients with symptomatic IDDVT were randomly assigned to receive either LMWH followed by VKA for 12 weeks or LMWH 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. The follow‐up was 6 months and the primary endpoint was the composite measure of recurrent venous thromboembolism (VTE) defined as: recurrence or extension of IDDVT, proximal DVT, and pulmonary embolism (PE). The study was stopped prematurely due to slow recruiting rates. The primary efficacy outcome occurred in 14 patients receiving LMWH (10.8%) and in five patients receiving VKA (3.8%); risk difference was 0.069 (95% CI: 0.006–0.132), hazard ratio 2.8 (95% CI: 1.04–7.55). There was one PE in the VKA group and one proximal DVT in the LMWH group. IDDVT recurrence was 10.0% in the LMWH group versus 3.1% in the VKA group (p = .024). Two patients had clinically relevant bleedings (1.6%) in the LMWH group versus one (0.8%) in VKA group (p = .56). In conclusion, VKA for 12 weeks seems superior to LMWH for 6 weeks in reducing the risk of VTE recurrences in our cohort of outpatients with IDDVT.

Multiparameter flow cytometry (MFC) measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) independently predicts poor outcomes in acute myeloid leukemia (AML). Conversely, its prognostic value in the newly defined disease entity, myelodysplastic neoplasm (MDS)/AML is unknown. To assess the relationship between disease type, pre‐HCT MRD, and post‐HCT outcomes, we retrospectively analyzed 1265 adults with MDS/AML (n = 151) or AML (n = 1114) who received a first allograft in first or second morphologic remission at a single institution between April 2006 and March 2023. At 3 years, relapse rates (29% for MDS/AML vs. 29% for AML, p = .98), relapse‐free survival (RFS; 50% vs. 55%, p = .22), overall survival (OS; 52% vs. 60%, p = .073), and non‐relapse mortality (22% vs. 16%, p = .14) were not statistically significantly different. However, a significant interaction was found between pre‐HCT MFC MRD and disease type (MDS/AML vs. AML) for relapse (p = .009), RFS (p = .011), and OS (p = .039). The interaction models indicated that the hazard ratios (HRs) for the association between pre‐HCT MRD and post‐HCT outcomes were lower in patients with MDS/AML (for relapse: HR = 1.75 [0.97–3.15] in MDS/AML vs. 4.13 [3.31–5.16] in AML; for RFS: HR = 1.58 [1.02–2.45] vs. 2.98 [2.48–3.58]; for OS: HR = 1.50 [0.96–2.35] vs. 2.52 [2.09–3.06]). On the other hand, residual cytogenetic abnormalities at the time of HCT were equally informative in MDS/AML as in AML patients. Our data indicate that MFC‐based pre‐HCT MRD testing, but not testing for residual cytogenetic abnormalities, is less informative for MDS/AML than AML patients when used for prognostication of post‐HCT outcomes.

doi: 10.1002/ajh.27263pmid: 38409747

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage–dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH‐H), 9 interdigitating dendritic cell sarcoma (MH‐IDC), and 8 Langerhans cell sarcoma (MH‐LC). The median age at diagnosis was 61 years (range, 3–83). Thirty‐three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8–50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first‐line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.