How I treat cytopenias after CAR T-cell therapy.

Increasing use of chimeric antigen receptor T-cell therapy (CAR-T) has unveiled diverse toxicities warranting specific recognition and management. Cytopenias occurring after CAR-T infusion invariably manifest early (<30 days), commonly are prolonged (30-90 days), and sometimes persist or occur late (>90 days). Variable etiologies of these cytopenias, some of which remain incompletely understood, create clinical conundrums and uncertainties about optimal management strategies. These cytopenias may cause additional sequelae, decreased quality of life, and increased resource use. Early cytopenias are typically attributed to lymphodepletion chemotherapy, however, infections and hyperinflammatory response such as immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome may occur. Early and prolonged cytopenias often correlate with severity of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Bone marrow biopsy in patients with prolonged or late cytopenias is important to evaluate for primary disease and secondary marrow neoplasm in both pediatric and adult patients. Commonly, cytopenias resolve over time and evidence for effective interventions is often anecdotal. Treatment strategies, which are limited and require tailoring based upon likely underlying etiology, include growth factors, thrombopoietin-receptor agonist, stem cell boost, transfusion support, and abrogation of infection risk. Here we provide our approach, including workup and management strategies, for cytopenias after CAR-T.

Alternative donor BMT with posttransplant cyclophosphamide as initial therapy for acquired severe aplastic anemia.

Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.

Outcome of adult acute myeloid leukemia patients with extramedullary disease and treatment with venetoclax/hypomethylating agents.

We evaluated response to VEN/HMA in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease (EMD). Median age was 65 (range, 19-81) years. Patients had a median of two EMD sites (range, 1-5) and 35 (76%) patients had concurrent bone marrow involvement. Twenty (43%) patients had highrisk genetic features according to the European Leukemia Net 2022 classification. Twenty-nine (63%) were relapsed or refractory after intensive chemotherapy (CTX) including 13 (28%) with prior allogeneic hematopoietic cell transplantation (allo-HCT). Patients received a median of 2 cycles of VEN/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) after VEN/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allo-HCT (CR/CRi, n=4; PR, n=2). Median follow-up was 49.1 months (95%-CI, 26.1 months - not reached) and median overall survival (OS) 6.4 months (95%-CI, 5.1-11 months). One-year and 2-years OS rates were 29.3% (95%-CI, 18.6-46.2%) and 12.3% (95%-CI, 5.5-27.6%), respectively. Age with a cut-off of 60 years had no impact on OS (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after VEN/HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and 2 (10%) died in CR. In our cohort of patients with AML with EMD with high-risk features, treatment with VEN/HMA resulted in an encouraging ORR of 54% with a CR/CRi rate of 43.5%. However, VEN/HMA alone may not be effective in maintaining disease control.

NCCN Guidelines® Insights: Systemic Mastocytosis, Version 3.2024.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Characterization of myeloproliferative neoplasms in the paediatric and young adult population.

The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%).

CCRL2 affects the sensitivity of myelodysplastic syndrome and secondary acute myeloid leukemia cells to azacitidine.

Better understanding of the biology of resistance to DNA methyltransferase (DNMT) inhibitors is required to identify therapies that can improve their efficacy for patients with high-risk myelodysplastic syndrome (MDS). CCRL2 is an atypical chemokine receptor that is upregulated in CD34+ cells from MDS patients and induces proliferation of MDS and secondary acute myeloid leukemia (sAML) cells. In this study, we evaluated any role that CCRL2 may have in the regulation of pathways associated with poor response or resistance to DNMT inhibitors. We found that CCRL2 knockdown in TF-1 cells downregulated DNA methylation and PRC2 activity pathways and increased DNMT suppression by azacitidine in MDS/sAML cell lines (MDS92, MDS-L and TF-1). Consistently, CCRL2 deletion increased the sensitivity of these cells to azacitidine in vitro and the efficacy of azacitidine in an MDS-L xenograft model. Furthermore, CCRL2 overexpression in MDS-L and TF-1 cells decreased their sensitivity to azacitidine. Finally, CCRL2 levels were higher in CD34+ cells from MDS and MDS/myeloproliferative neoplasm patients with poor response to DNMT inhibitors. In conclusion, we demonstrated that CCRL2 modulates epigenetic regulatory pathways, particularly DNMT levels, and affects the sensitivity of MDS/sAML cells to azacitidine. These results support CCRL2 targeting as having therapeutic potential in MDS/sAML.

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Hyperinflammatory syndrome resembling haemophagocytic lymphohistiocytosis following axicabtagene ciloleucel and brexucabtagene autoleucel.

Haemophagocytic lymphohistiocytosis-like toxicity following chimeric antigen receptor T cells (CAR-HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR-HLH after infusion of brexucabtagene autoleucel (n = 2) or axicabtagene ciloleucel (n = 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)-2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C-reactive protein and IL-6. Clinical improvement following treatment with anakinra (n = 2) and ruxolitinib (n = 1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life-saving treatment for CAR-HLH.

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Graft-versus-host disease risk after chimeric antigen receptor T-cell therapy: the diametric opposition of T cells.

Chimeric antigen receptor (CAR) T-cell therapy has brought a paradigm shift in the management of haematological malignancies and has opened novel avenues of investigational therapeutic strategies. Given these encouraging responses, it has become imperative to understand the full spectrum of biology and potential toxicities that can arise from these novel agents, as well as those under investigation. With the increasing use of CAR T-cell therapy for relapse following allogeneic haematopoietic cell transplantation (HCT) and the imminence of allogeneic CAR T cells, risks from T cell-based therapy, such as the previously well-recognised graft-versus-host disease (GVHD), have gained prominence and warrant explanation. In the present review, we discuss the risk of GVHD in the: (1) post-HCT setting using recipient or donor-derived CAR T cells, as well as (2) non-HCT setting using autologous, as well as allogeneic T-cell therapies. A better understanding of this risk is important to advance the field and ensure safe development and use of these agents in the clinic.

Gender-related differences in the outcomes and genomic landscape of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes show a male predominance and men with MDS/MPN have worse outcomes, but it is unknown if the mutational burden differs between genders. We reviewed 167 patients with MDS/MPN and found that men had worse overall survival [hazard ratio (HR) 2·09, 95% confidence interval (CI) 1·16-3·75; P = 0·013] independent of subtype, Revised International Prognostic Scoring System score and age at diagnosis. We analysed the genomic data of a subset of 100 patients. Men had 0·88 more somatic mutations on average (95% CI 0·20-1·56, P = 0·011) independent of subtype, sample source and blast percentage. More somatic mutations was associated with a higher incidence of transformation to acute myeloid leukaemia (subdistribution HR 1·30, 95% CI 1·01-1·70; P = 0·046). Men had 0·70 more mutations in high-risk genes [additional sex combs like-1 (ASXL1), enhancer of zeste homolog 2 (EZH2), Runt-related transcription factor 1 (RUNX1), SET binding protein 1 (SETBP1), NRAS proto-oncogene, GTPase (NRAS), stromal antigen 2 (STAG2)] on average (95% CI 0·11-1·29, P = 0·021), and 13-times higher odds of harbouring an EZH2 mutation (95% CI 1·64-102·94, P = 0·015). The presence of an EZH2 mutation was associated with worse survival among men (HR 2·98, 95% CI 1·1-8·0; P = 0·031). Our present findings suggest that the worse outcomes in men with MDS/MPN are associated with a higher number of somatic mutations, especially in high-risk genes. These results warrant validation in larger cohorts and investigation of the underlying mechanisms.

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology.

Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of transformation to acute leukemia compared to women across neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap neoplasms, and CML. More recent studies evaluating the genomic profile of patients with these neoplasms demonstrated a male predominance for mutations in high-risk genes including ASXL1, U2AF1, SRSF2 and ZRSR2. The understanding of the underlying biology is limited but a number of hypotheses have been developed and are currently being investigated. This review summarizes the current knowledge about sex-related differences in the clinical outcomes and genomic profile of patients with chronic myeloid neoplasms and discusses the hypothesized biologic mechanisms as an attempt to explain these observations.

Acute Kidney Injury after CAR-T Cell Therapy: Low Incidence and Rapid Recovery.

Chimeric antigen receptor (CAR) T cell therapy using engineered cytotoxic T cells has shown promising responses in various hematologic malignancies. Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are recognized toxicities of CAR-T, whereas kidney injury remains less well recognized. The objective of the present study was to identify the incidence of acute kidney injury (AKI) after CAR-T cell therapy, potential risk factors, and recovery of kidney function. We performed a retrospective review of 46 adult patients with non-Hodgkin lymphoma treated with CAR-T therapy between February 2018 and February 2019 at our institution. Serum creatinine values before CAR-T therapy through day 100 were used to assess AKI, as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria: grade 1, 1.5- to <2-fold of baseline; grade 2, 2- to <3-fold of baseline; grade 3, ≥3-fold of baseline. CRS and ICANS were graded using the consensus criteria of the American Society of Transplantation and Cellular Therapy. The overall incidence of CRS was 78.3% (95% confidence interval [CI], 66% to 90.5%), of whom 13% (95% CI, 3.3% to 22.8%) developed grade 3-4 CRS, whereas the overall incidence of ICANS was lower at 45.7% (95% CI, 3.1% to 60.3%). The cumulative incidence of any grade AKI by day 100 was 30% (95% CI, 16.9% to 43.9%), with a grade 1 AKI incidence of 21.7% (95% CI, 9.7% to 33.8%) and a grade 2-3 AKI incidence of 8.7% (95% CI, .4% to 17%). No patients developed severe AKI necessitating renal replacement therapy. Patients with previous autologous or allogeneic stem cell transplantation, those requiring intensive care unit level care and with grade 3-4 CRS had a higher incidence of AKI. Most patients recovered, with kidney function returning to baseline within 30 days. We conclude that with early recognition and management of CAR-T complications, the incidence of AKI is low, the severity of injury is mild, and most patients recover kidney function within 30 days.

Clinical course of COVID-19 in a liver transplant recipient on hemodialysis and response to tocilizumab therapy: A case report.

The novel coronavirus disease 2019 (COVID-19) is a highly infectious and rapidly spreading disease. There are limited published data on the epidemiology and outcomes of COVID-19 infection among organ transplant recipients. After initial flulike symptoms, progression to an inflammatory phase may occur, characterized by cytokine release rapidly leading to respiratory and multiorgan failure. We report the clinical course and management of a liver transplant recipient on hemodialysis, who presented with COVID-19 pneumonia, and despite completing a 5-day course of hydroxychloroquine, later developed marked inflammatory manifestations with rapid improvement after administration of off-label, single-dose tocilizumab. We also highlight the role of lung ultrasonography in early diagnosis of the inflammatory phase of COVID-19. Future investigation of the effects of immunomodulators among transplant recipients with COVID-19 infection will be important.

Functional connectivity in obsessive-compulsive disorder and its subtypes.

BACKGROUND: Obsessive-compulsive disorder (OCD) is an anxiety disorder with significant morbidity whose pathophysiology is not fully understood. Neuroimaging studies have characterized OCD in terms of elevated striatal and prefrontal reactivity to emotion provocation. This neural model may be informed by investigation of functional connectivity in OCD, identifying alterations in how sensory information is integrated into frontostriatal regions. METHODS: The current study employed functional magnetic resonance imaging (fMRI) to compare neural activity and connectivity in 31 OCD patients (12 washing and 19 checking subtypes) and 17 healthy volunteers in an emotion provocation paradigm using visual stimuli. RESULTS: OCD status was associated with hyper-activation of the posterior cingulate (PCg) in response to emotion provocation. Additionally, OCD patients demonstrated elevated PCg functional connectivity with the visual cortices and frontostriatal regions. Exploratory analyses suggested that stimulus-provoked activity and connectivity was elevated for checking subtypes in motor cortices, and elevated in washing subtypes in the anterior insula and orbitofrontal cortex. CONCLUSIONS: The PCg's role in moderating connectivity between the visual cortex and frontolimbic regions is muted in OCD, consistent with the PCg's suggested role in regulating attention towards emotional stimuli. Exploratory analyses suggest distinct PCg connectivity profiles in OCD subtypes, with checking linked to motor activation, but washing linked to a network supporting emotional salience. The study was not powered to fully investigate the effects of medication, patients often endorsed secondary symptom subtypes that muddied washing/checking distinctions, and the emotion provocation paradigm was of limited intensity compared to life stressors.

Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies.

This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis.

Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these 2 RIC regimens. We searched electronic databases from inception through November 1, 2017 for literature searches to identify relevant studies. A DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. Seven studies, including a total of 1955 patients, met criteria for inclusion, of which 6 were included in the overall pooled analysis because of repetition of some patients in 2 studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) and 2 in the subgroup analysis of lymphoid malignancies. Overall survival (OS) and progression-free survival were not statistically significantly different between the 2 RIC regimens in analysis of all studies. However, OS was better with FM in subgroup analysis of AML/MDS studies (HR, .83; 95% CI, .73 to .95). Nonrelapse mortality was lower with FB (HR, .64; 95% CI, .46 to .89), whereas relapse was lower with FM (HR, 1.52; 95% CI, 1.13 to 2.06) in the analysis of all studies. This meta-analysis shows that FB and FM are associated with a similar OS in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher nonrelapse mortality.