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.

Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow. DIAGNOSIS: aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML. MUTATIONS AND KARYOTYPE: Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively. RISK STRATIFICATION: The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R. TREATMENT: Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Ringing in a new future.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematologic malignancy belonging to the category of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes. While certain clinical features, including anemia and thrombocytosis, are common to both the MDS and MPN disease components, the biologic consequences of the spliceosome mutation SF3B1 results in notable clinical exceptions. Importantly, both overall and leukemia free survival are shorter for MDS/MPN-RS-T when compared to essential thrombocythemia (ET). In the case of MDS/MPN-RS-T, thrombotic risk is not associated with the presence of JAK2V617F, nor history of prior thrombosis, but is associated with the presence of the mutated spliceosome gene SF3B1. In this review, we highlight the biology, pathology, risk stratification, and treatment approach to MDS/MPN-RS-T. In particular, we focus on clinical management concepts, which are largely borrowed from MDS and MPN, including the use of cytoreduction, bone marrow stimulating agents, and the role of allogeneic stem cell transplantation. We end by highlighting unmet needs and future research priorities in MDS/MPN-RS-T.

Cellular Therapy During COVID-19: Lessons Learned and Preparing for Subsequent Waves.

An evidence-based triage plan for cellular therapy distribution is critical in the face of emerging constraints on healthcare resources. We evaluated the impact of treatment delays related to COVID-19 on patients scheduled to undergo hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy at our center. Data were collected in real time between March 19 and May 11, 2020, for patients who were delayed to cellular therapy. We evaluated the proportion of delayed patients who ultimately received cellular therapy, reasons for not proceeding to cellular therapy, and changes in disease and health status during delay. A total of 85 patients were delayed, including 42 patients planned for autologous HCT, 36 patients planned for allogeneic HCT, and 7 patients planned for CAR-T therapy. Fifty-six of these patients (66%) since received planned therapy. Five patients died during the delay. The most common reason for not proceeding to autologous HCT was good disease control in patients with plasma cell dyscrasias (75%). The most common reason for not proceeding to allogeneic HCT was progression of disease (42%). All patients with acute leukemia who progressed had measurable residual disease (MRD) at the time of delay, whereas no patient without MRD at the time of delay progressed. Six patients (86%) ultimately received CAR-T therapy, including 3 patients who progressed during the delay. For patients with high-risk disease such as acute leukemia, and particularly those with MRD at the time of planned HCT, treatment delay can result in devastating outcomes and should be avoided if at all possible.

Traipsing Through Muddy Waters: A Critical Review of the Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) Overlap Syndromes.

Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs) are molecularly complex, clinically heterogeneous diseases that exhibit proliferative and dysplastic features. Diagnostic criteria use clinical, pathologic, and genomic features to distinguish between disease entities, though considerable clinical and genetic overlap persists. MDS/MPNs are associated with a poor prognosis, save for MDS/MPN with ring sideroblasts and thrombocytosis, which can behave more indolently. The current treatment approach is risk-adapted and symptom-directed and largely extrapolated from experience in MDS or MPN. Gene sequencing has demonstrated frequent mutations involving signaling, epigenetic, and splicing pathways, which present numerous therapeutic opportunities for clinical investigation.

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T) - "2021 update on diagnosis, risk-stratification, and management".

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 109 /L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.

Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category consists of 5 neoplastic subtypes: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL1-negative atypical chronic myeloid leukemia (aCML), MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (U). Cytogenetic abnormalities and somatic copy number variations are uncommon; however, >90% patients harbor gene mutations. Although no single gene mutation is specific to a disease subtype, certain mutational signatures in the context of appropriate clinical and morphological features can be used to establish a diagnosis. In CMML, mutated coexpression of TET2 and SRSF2 results in clonal hematopoiesis skewed toward monocytosis, and the ensuing acquisition of driver mutations including ASXL1, NRAS, and CBL results in overt disease. MDS/MPN-RS-T demonstrates features of SF3B1-mutant MDS with ring sideroblasts (MDS-RS), with the development of thrombocytosis secondary to the acquisition of signaling mutations, most commonly JAK2V617F. JMML, the only pediatric entity, is a bona fide RASopathy, with germline and somatic mutations occurring in the oncogenic RAS pathway giving rise to disease. BCR-ABL1-negative aCML is characterized by dysplastic neutrophilia and is enriched in SETBP1 and ETNK1 mutations, whereas MDS/MPN-U is the least defined and lacks a characteristic mutational signature. Molecular profiling also provides prognostic information, with truncating ASXL1 mutations being universally detrimental and germline CBL mutations in JMML showing spontaneous regression. Sequencing information in certain cases can help identify potential targeted therapies (IDH1, IDH2, and splicing mutations) and should be a mainstay in the diagnosis and management of these neoplasms.

Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U): More than just a "catch-all" term?

The clinicopathology of MDS and MPN are not mutually exclusive and for this reason the category of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) exists. Several sub-entities have been included under the MDS/MPN umbrella, including MDS/MPN-unclassifiable (MDS/MPN-U) for those cases whose morphologic and clinical phenotype do not meet criteria to be classified as any other MDS/MPN sub-entity. Though potentially regarded as a wastebasket diagnosis, since its integration into myeloid disease classification, MDS/MPN-U has been refined with increasing understanding of the mutational and genomic events that drive particular clinicopathologic phenotypes, even within MDS/MPN-U. The prototypical example is the identification of SF3B1 mutations and its durable association with MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), an entity previously buried within, but now a separate category outside of MDS/MPN-U. Continued and enhanced study of those entities under MDS/MPN-U, a perhaps provisional category itself, is likely to progressively identify commonality between many "unclassifiables" to establish a new classifiable diagnosis.

Tratamiento actual de las neoplasias mieloproliferativas: frente a tres escenarios / Current treatment of myeloproliferative neoplasias: three scenarios

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Treatment of MDS/MPN and the MDS/MPN IWG International Trial: ABNL MARRO.

PURPOSE OF REVIEW: MDS/MPNs comprise a group of rare hematologic malignancies that balance features of myeloproliferation and bone marrow failure. Given overlapping clinical features and rarity of incidence, MDS/MPNs have long posed a diagnostic and therapeutic challenge. Herein, we sought to review recent advances in diagnosis and emerging therapeutic strategies and highlight the upcoming ABNL MARRO study which aims to individualize therapy for patients with MDS/MPN. RECENT FINDINGS: Focused study of molecular mutations in MDS/MPNs has provided improved diagnostic clarity. Specific gene mutation or patterns of mutation have been increasingly described and have helped to distinguish between clinically similar diseases. While the current treatment landscape consists largely of therapies that have been co-opted from related disease, the emergence of prospective clinical trials specifically focused on MDS/MPN and the increased use of targeted agents represent progress for patients with MDS/MPN. An improved understanding of the molecular drivers of myeloid diseases has provided diagnostic clarity and renewed hope of targeted therapies for MDS/MPN patients. The upcoming ABNL MARRO study hopes to leverage this knowledge to match patients with targeted therapeutic options specific to molecular drivers of their disease.

Soluble Interleukin-7 receptor levels and risk of acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Interleukin-7 is a cytokine essential for T cell homeostasis. IL-7 binds to cellular IL-7 receptors in competition with a soluble form of the receptor (sIL-7Rα). We hypothesized that altered sIL-7Rα levels may cause adverse outcomes in patients undergoing HSCT. In parallel, we investigated the impact of the IL-7Rα SNP rs6897932, which has been associated with release of IL-7R. The sIL-7Rα levels decreased during HSCT (from 114ng/ml before to 48ng/ml at day +14 (P<0.0001)). This pattern was inversely mirrored by IL-7. The IL-7/sIL-7Rα ratio at day +14 was significantly higher in patients developing grades II-IV aGVHD (OR=4.3, P=0.026). Furthermore, donor carriage of the rs6897932 T allele was associated with reduced sIL-7Rα levels, increased risk of grades II-IV aGVHD (OR=2.4, P=0.055) and increased transplant-related mortality (CC=4.5%, CT=21.4% and TT=27.3%, P=0.0037). In conclusion, this study suggests an impact of sIL-7Rα levels and rs6897932 donor genotype on alloreactivity and outcome after HSCT.

Turning the tide in myelodysplastic/myeloproliferative neoplasms.

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress.

Clinical course and end-of-life care in patients who have died after allogeneic stem cell transplantation.

PURPOSE: Allogeneic stem cell transplantation may cure approximately 50% of patients, however, a significant part of the other half might benefit from a high-quality palliative care medicine at the end of life. Somatic, psychic and spiritual needs of these patients may differ from those of patients suffering from incurable solid tumours and are not comprehensively evaluated so far. METHODS: To address this question, data from charts of 123 patients who have died after allogeneic stem cell transplantation were extracted. In detail, the time line of the clinical course, the symptoms, the administered drugs and other applied procedures were analysed. RESULTS: Approximately one half of the patients, who have died after stem cell transplantation, did not live more than 5 months. Two-thirds of patients died within 14 months after SCT. 28.5% of the patients could not be discharged after transplantation. However, a significant proportion had a low ECOG-score (0-1) prior to death, indicating a high degree of mobility. Major symptoms were weakness, fatigue and need for aid at daily activities. Severe pain, dyspnoea and obstipation, as known from patients suffering from advanced solid tumours, were rare. In consequence, use of opioids seemed to be less frequent than in patients with solid tumours. Measures of intensive care and i.v.-drug administration were applied to a significant proportion of patients. CONCLUSION: The present investigation indicates that the somatic, psychic and spiritual end-of-life-care after allogeneic stem cell transplantation could be optimised. A significant problem for the transplantation team seems to be the realisation of necessity to switch the curative concept into a palliative ambition. Requirements are a subsequent prospectively conducted investigation and an intensification of cooperation between transplant and palliative care teams.

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T.

Spliceosomal mutations, especially mutations in SF3B1, are frequently (>80%) identified in patients with refractory anemia with ringed sideroblasts (RARS) and myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T; previously known as RARS-T), and SF3B1 mutations have a high positive predictive value for disease phenotype with ringed sideroblasts. These observations suggest that SF3B1 mutations play important roles in the pathogenesis of these disorders and formation of ringed sideroblasts. Here we will review recent insights into the molecular mechanisms of mis-splicing caused by mutant SF3B1 and the pathogenesis of RSs in the context of congenital sideroblastic anemia as well as RARS with SF3B1 mutations. We will also discuss therapy of SF3B1 mutant MDS, including novel approaches.

[Improving diagnosis coding in the ProMise database: Guidelines of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Difficultés de codage des diagnostics dans la base de données ProMISe : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

In the attempt to harmonize clinical practices between different centers belonging to the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), our society set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. Here, we report our recommendations regarding diagnosis and disease status coding in the ProMISe database used by the SFGM-TC.

Epidemiología de la leucemia mieloide crónica en España y sus posibles implicaciones terapéuticas / Epidemiology of chronic myeloid leukemia in Spain and its possible therapeutic implications

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Surveying the landscape of MDS/MPN research: overlap among the overlap syndromes?

The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) lie at the interphase of phenotypically opposing bone marrow malignancies. They are characterized by concomitant features of bone marrow failure and myeloproliferation and are generally associated with a poor prognosis. Although much is unknown with respect to the clinical course and molecular biology of MDS/MPNs, emerging research is beginning to uncover the key defining characteristics of this designation. In this review, we will discuss the features of MDS/MPN diseases that unify there clinical and molecular course and those that define distinct disease entities. We will discuss advances in genetics and MDS/MPN modeling, as well as translational discoveries that are anticipated to inform the diagnosis, prognostication, and treatment of MDS/MPNs in the near future.