Case report: Therapy-related myeloid neoplasms in three pediatric cases with medulloblastoma.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapy-related myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients.

A case of peripheral T-cell lymphoma in which therapy-related myelodysplastic syndrome developed and a second autologous transplantation was performed.

We report a case of therapy-related myelodysplastic syndrome (MDS), which developed 9 years after autologous peripheral blood stem cell transplantation (PBSCT) for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). A 65-year-old male was diagnosed with PTCL-NOS. After 6 cycles of the CHOP (cyclophosphamide [CPA], doxorubicin, vincristine, and prednisone) regimen, he achieved a first complete response (CR). He relapsed 33 months later and received salvage chemotherapy, which consisted of the CHASE regimen (CPA, high-dose cytarabine, dexamethasone, and etoposide). During the recovery phase of the first cycle of CHASE, his peripheral blood stem cells (PBSCs) were harvested and frozen in 2 bags. After 2 courses of CHASE, he underwent autologous PBSCT, which involved the use of the LEED preconditioning regimen (melphalan, CPA, etoposide, and dexamethasone) and one of the frozen bags. This resulted in a second CR. At 39 months after PBSCT, he relapsed with a tumor in his right arm. After it was resected, he received eight cycles of brentuximab vedotin and 45 Gy of involved-field irradiation concurrently and achieved a third CR. Nine years after autologous PBSCT, he was diagnosed with MDS with excess blasts 2 (MDS-EB-2). His disease progressed to acute myeloid leukemia after 2 courses of azacitidine therapy. He successfully underwent a second autologous PBSCT involving the busulfan and melphalan preconditioning regimen and the other frozen bag, which had been stored for 9 years. He has been in complete cytogenetic remission for 1 year since the second autologous PBSCT.

The clinical outcomes of haploidentical stem cell transplantation (haplo-HSCT) for patients with therapy-related myelodysplastic syndrome: comparable to de novo myelodysplastic syndrome.

Therapy-related myelodysplastic syndrome (t-MDS) is defined as a complication in patients with cancer following exposure to chemotherapy and/or radiotherapy and has an inferior outcome compared with de novo myelodysplastic syndrome (de novo MDS). This study aimed to estimate and compare the clinical outcomes of haploidentical stem cell transplantation (haplo-HSCT) for t-MDS and de novo MDS. We retrospectively analyzed 96 patients with MDS who received haplo-HSCT between January 2015 and December 2021. Eleven patients with t-MDS and 85 patients with de novo MDS were matched using the case-pair method in a 1:8 ratio with the following pairing criteria: (1) sex, (2) age (± 5 years), (3) year of haplo-HSCT (± 2 years), and (4) blast cell counts (≥ 5% or not). The 3-year overall survival and disease-free survival after haplo-HSCT for t-MDS versus de novo MDS patients were 72.7% versus 75.1% (P = 0.99) and 54.5% versus 67.0% (P = 0.50), respectively. The 3-year cumulative incidence of relapse was 36.4% versus 15.5% (P = 0.08), respectively. In multivariate analysis, there was no difference in relapse between t-MDS and de novo MDS. The 3-year cumulative non-relapse mortality rates were 9.1% versus 17.6% (P = 0.45), respectively. This study confirmed the comparable clinical outcomes of haplo-HSCT on the prognosis of t-MDS and de novo MDS.

Relapsed Waldenstrom's Macroglobulinemia and Therapy-Related Myelodysplastic Syndrome with Complex Cytogenetics: A Treatment Dilemma.

Waldenstrom's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M as defined by the World Health Organization Classification of hematological malignancies. Historically, the treatment options for WM were limited to alkylating agents and purine analogs. The introduction of immune therapy, including CD20 targeted therapy, proteasome inhibitors, and immune modulators, has provided benefit to those patients and has now become the standard of care. As WM patients become long-term survivors, treatment's late toxicities have become more apparent. Here, we report a case of a 74-year-old female who presented to the hospital with fatigue and was diagnosed with WM. She was treated with bortezomib, doxorubicin, and bendamustine, followed by rituximab. After a remission period of 15 years, the patient had a relapse of WM, and bone marrow biopsy findings were consistent with intermediate-risk t-MDS with complex cytogenetics, presenting us with a treatment dilemma. We decided to treat WM, and the patient went into VGPR with residual lymphoma cells. Despite having dysplasia and complex cytogenetics, she did not have any cytopenia. Currently, she is under observation anticipating the progression of her MDS, given her intermediate I risk status. This case features the occurrence of t-MDS after therapy with bendamustine, cladribine, and doxorubicin. This highlights the need for closer monitoring and consideration of long-term adverse effects when treating patients with indolent lymphomas, especially WM. Late complications need to be considered, and risk versus benefit analysis needs to be carefully evaluated, especially in younger patients with WM.

Splicing factor 3B subunit 1 (SF3B1) mutation in the context of therapy-related myelodysplastic syndromes.

Splicing factor 3B subunit 1 (SF3B1) somatic mutation in the context of therapy-related myelodysplastic syndromes (t-MDS) has not been well defined. In a large cohort of patients with MDS, those with known SF3B1 somatic mutation were compared as de novo MDS (n = 289) and t-MDS with mutant SF3B1 (SF3B1mut ; n = 31). Baseline characteristics, concomitant mutations, and acute myeloid leukaemia (AML) transformation were similar between the two groups. The median overall survival (OS) of de novo MDS SF3B1mut was significantly longer compared to t-MDS SF3B1mut but not significantly different when adjusted for comorbidities. Comparing t-MDS wild-type SF3B1 (SF3B1WT ; n = 241) to t-MDS SF3B1mut (n = 31), complex cytogenetics were seen in 37.4% versus 10.3% (p = 0.009), tumour protein p53 (TP53) mutation was 36.1% versus 10% (p = 0.004), and AML transformation was 34.4% compared to 12.9% (p = 0.016) respectively. OS was significantly shorter in SF3B1WT versus SF3B1mut . When applying the International Working Group for Prognosis of MDS (IWG-PM) proposed SF3B1 criteria, OS was significantly shorter in SF3B1mut t-MDS compared to de novo MDS SF3B1mut with no significance in AML transformation. Survival was compared between t-MDS SF3B1mut who met the new proposed IWG-PM criteria to t-MDS SF3B1mut who did not meet criteria to survival of SF3B1WT t-MDS. OS was 53 versus 22 and 18 months respectively (p = 0.006). AML transformation was 0%, 26.7% and 32.3% (p = 0.021). Leukaemia-free survival was not reached among the three.

Lutetium-177 Dotatate-Induced Hemolytic Anemia and Myelodysplastic Syndrome.

Lutetium-177 (177Lu) dotatate is a type of peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin for patients with progressive somatostatin receptor-positive gastrointestinal neuroendocrine tumors. While cases of therapy-related myeloid neoplasms (t-MN) have been described as a consequence of 177 Lu dotatate, there are no reports of hemolytic anemia associated with therapy. We present a case of a 68-year-old woman with metastatic low-grade neuroendocrine tumor who presented four weeks after the second dose of 177Lu dotatate with progressive fatigue and dyspnea. Laboratory workup was remarkable for hemolytic anemia. Lutetium-177 dotatate-induced hemolysis was suspected after ruling out other causes. Corticosteroid treatment was initiated with improvement in hemoglobin, and dose-reduced PRRT was planned upon discharge. Six months into the treatment course of 177Lu dotatate, macrocytic anemia was noticed on routine follow-up with normal vitamin B12 and folic acid levels. A bone marrow biopsy was done, revealing myelodysplastic syndrome (MDS) features. Given the temporal relationship between drug introduction and the objective findings, early-onset 177Lu dotatate-induced MDS was diagnosed with a plan for close hematologic follow-up. Myelodysplastic syndrome should be suspected when megaloblastic anemia develops in patients with previous 177Lu dotatate therapy. The latency period between initial treatment and MDS diagnosis reported in the literature ranges between 15 months to seven years. Apart from the unusually early onset of MDS, what is unique about our case is the development of hemolytic anemia after administration of PRRT. The clinical course and the brisk response to steroid therapy, suggest other mechanisms of PRRT toxicity besides DNA breaks, genetic mutations, and myelosuppression by an immune-mediated component that likely plays a role in 177Lu dotatate toxicity. Further investigation and monitoring are needed to identify the frequency of such adverse events and the pathophysiology of their occurrence.

Outcome of therapy-related myelodysplastic syndrome and oligoblastic acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A propensity score matched analysis.

Therapy-related myelodysplastic syndromes (t-MDS) are generally progressive and associated with poorer outcomes than de novo MDS (d-MDS). To evaluate the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for t-MDS, we conducted a propensity score matched-pair analysis of patients with t-MDS and d-MDS using a nationwide database. A total of 178 patients with t-MDS underwent allo-HSCT between 2001 and 2018, and 178 out of 3123 patients with d-MDS were selected. The probability of 3-year overall survival rate was 40.0% and 50.0% in the t-MDS and d-MDS groups, respectively (p = 0.032). The 3-year transplant-related mortality was 30.9% and 19.0% in the t-MDS and d-MDS groups, respectively (p = 0.005). The 3-year cumulative incidence of relapse was 32.8% and 33.0% in the t-MDS and d-MDS groups, respectively (p = 0.983). A multivariate analysis identified four adverse factors for overall survival in the t-MDS group: age ≥ 55 years (hazard ratio [HR], 2.09; 95% CI, 1.11-3.94; p = 0.023), the poor cytogenetic risk group (HR, 2.19; 95% CI, 1.40-4.19; p = 0.019), performance status at allo-HSCT 2-4 (HR, 2.14; 95% CI, 1.19-3.86; p = 0.011), and a shorter interval from diagnosis to transplantation (<8 months; HR, 1.61; 95% CI, 1.00-2.57; p = 0.048). The most frequent cause of transplant-related death was the infectious complications (21.6%) in t-MDS group and organ failure (12.5%) in d-MDS group. In conclusion, allo-HSCT potentially provides long-term remission in patients with t-MDS; however, further efforts to reduce transplant-related death are needed.

Secondary myeloid neoplasms after CD19 CAR T therapy in patients with refractory/relapsed B-cell lymphoma: Case series and review of literature.

Background: Several chimeric antigen receptor T cells (CAR T) targeting CD19 have induced profound and prolonged remission for refractory/relapsed (R/R) B-cell lymphoma. The risk of secondary malignancies, especially myeloid neoplasms, is of particular concern in the CAR T community, which still remains unclear. Methods: Four patients with R/R B-cell lymphoma after CD19 CAR T therapy diagnosed with secondary myeloid neoplasms (SMN) from 2 hospitals in eastern China were presented, including 3 with myelodysplastic syndrome (MDS) and 1 with acute myeloid leukemia (AML). Using single-cell RNA sequencing (scRNA-seq), we compared the cellular components of bone marrow (BM) samples obtained from one of these MDS patients and a health donor. We also provided a review of recently published literature concerning SMN risk of CAR T therapy. Results: Relevant demographic, clinical, laboratory, therapeutic and outcome data were collected and presented by chart review. In our case series, the male-female ratio was 3.0 and the median age at MDS onset was 61.25 years old (range, 50-78). Median number of previous systemic therapies was 4.5 (range, 4-5), including autologous hematopoietic stem cell transplantation (auto-HSCT) in one patient. BM assessments prior to CAR T therapy confirmed normal hematopoiesis without myeloid neoplasms. Moreover, for 3 patients with SMN in our series, cytogenetic analysis predicted a relatively adverse outcome. In our experience and in the literature, treatment choices for the patients with SMN included allogeneic hematopoietic stem cell transplantation (allo-HSCT), hypomethylating agent (HMA), period filgrastim, transfusions and other supportive care. Finally, treatment responses of lymphoma, together with SMN, directly correlated with the overall survival of this community. Of note, it appeared that pathogenesis of MDS wasn't associated with the CAR T toxicities, since all 4 patients experienced a pretty mild CRS of grade 1-2. Additionally, scRNA-seq analysis described the transcriptional alteration of CD34+ cells, identified 13 T/NK clusters, and also indicated increased cytotoxic T cells in MDS BM. Conclusion: Our study illustrated the onset and progression of SMN after CD19 CAR T therapy in patients with R/R B-cell lymphoma, which provides useful information of this uncommon later event.

A Rare Case of Leukemia Cutis as the First Presentation of a Myelodysplastic Syndrome to Acute Myeloid Leukemia Transformation.

Leukemia cutis (LC) is a rare presentation of leukemia. It is characterized by the infiltration of leukemic cells into the different layers of the skin causing varying skin manifestations. It can occur before the hematological presentation of leukemia or during the disease course and carries a poor prognosis. Here, we report a patient with therapy-related myelodysplastic syndrome (t-MDS) whose transformation to acute leukemia was heralded by the development of LC. Worrisome cutaneous lesions should not be overlooked, and a skin biopsy should be pursued to confirm the diagnosis. A high index of suspicion is the key to early recognition of sometimes nonspecific skin findings of widespread systemic disease.

Targeting TP53 Mutations in Myelodysplastic Syndromes.

Mutations in TP53 are observed in ∼20% of patients with myelodysplastic syndromes (MDS), with increased frequency seen in patients with a complex karyotype and cases of therapy-related MDS. TP53 mutations represent perhaps the single greatest negative prognostic indicator in MDS. Inferior outcomes are demonstrated with all approved treatment approaches, although hypomethylating agents remain the standard frontline treatment option. Although outcomes with allogeneic hematopoietic stem cell transplant are poor, it remains the only potentially curative therapy. Novel agents are required to improve outcomes in this molecular subgroup, with therapies that directly target the mutant protein and immunotherapies demonstrating greatest potential.

Bone Marrow Invasion of Small Cell Neuroendocrine Carcinoma of the Endometrium: A Diagnostic Pitfall Mimicking a Haematological Malignancy.

Metastasis of cancer cells to the bone marrow is relatively rare, despite being one of the most important causes of myelosuppression in patients with solid tumours. A bone marrow examination via a biopsy is the standard method of diagnosing cancer cell invasion into the bone marrow. However, it is sometimes challenging to distinguish neuroendocrine carcinoma cells from haematopoietic cells due to their small, round shape and chromosomal abnormalities resembling haematological malignancies. We herein report a case of bone marrow invasion of small cell neuroendocrine carcinoma of the endometrium mimicking therapy-related myeloid malignancy.

Therapy-related myeloid neoplasms in lymphoma survivors: Reducing risks.

Treatment for Hodgkin (HL) and non-Hodgkin's lymphoma (NHL) has changed dramatically in the last fifty years. While there are increasing numbers of long-term survivors, there has been increasing recognition of the long-term toxicities of treatments, particularly therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). The survival for t-MDS/AML is extremely poor. Multiple heterogeneous retrospective studies have reported risk factors for the development of t-MDS/AML. Chemotherapy and radiation therapy have been most closely examined as possible t-MDS/AML risk factors. In this paper, we will review the risks of t-MDS/AML for HL and NHL patients as reported in the literature and assess for any changes over time. In HL patients, the incidence of t-MDS/AML has decreased with a reduction in alkylating agents. In indolent NHL patients, we anticipate decreased incidence of t-MDS/AML as targeted therapies begin to replace cytotoxic chemotherapy.

TP53 and therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MNs) are the most serious late complications in patients treated with traditional cytotoxic chemotherapy and/or radiation. T-MNs are aggressive and chemorefractory hematologic malignancies, with a median survival of less than 6 months. TP53 mutations are highly enriched in t-MN patients, though the mechanism for this selective enrichment has only come to light over the past several years. In this review, we discuss the history and function of p53, and the role of TP53 mutations in the origin and progression of t-MNs. Emerging data has begun to elucidate who may be at highest risk of developing t-MNs, which ideally will enable us to develop preventative strategies for this devastating disease. As t-MNs may not be avoidable, novel therapies are urgently needed for this patient group and are underway as exemplified by recent investigation in restoring wild-type p53 function as well as directly targeting TP53 mutant variants. With better prevention and treatment, outcomes will hopefully begin to improve in the near future.

Secondary clonal hematologic neoplasia following successful therapy for acute promyelocytic leukemia (APL): A report of two cases and review of the literature.

Although rare, secondary clonal hematologic neoplasia may occur after successful therapy for acute promyelocytic leukemia (APL). These secondary clonal events may be considered therapy-related, but may also be due to an underlying background of clonal hematopoiesis from which both malignancies may develop. In this manuscript, we describe two patients with secondary clones after APL therapy characterized in one patient by deletion of chromosome 11q23 and, in the other, by monosomy of chromosome 7, and also provide a review of all secondary clonal disorders described after APL therapy. We suggest that since most reports identify karyotypic abnormalities not typically associated with chemotherapy, there may be another mechanism underlying secondary clonal development after complete response to initial APL therapy.

Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register.

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2·9 per 100 000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0·001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P = 0·05) and for WPSS compared to IPSS (P = 0·07). IPSS-R was superior to both IPSS and WPSS for patients aged ≤70 years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a 'real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

Therapy-related acute myeloid leukaemia and myelodysplastic syndrome in Victoria, Australia 2003-2014.

BACKGROUND: The burden of therapy-related acute myeloid leukaemia (tAML)/therapy-related myelodysplastic syndrome (tMDS) in Australia has not been characterised. AIMS: To provide insights into the incidence, associated cancers, latency and survival outcomes of patients with tAML/tMDS in Victoria, Australia, based on a state-wide cancer registry and to assess if these features are different in tAML/tMDS compared with de novo AML/MDS. METHODS: We analysed adults aged ≥20 years at diagnosis of AML/MDS reported to the Victorian Cancer Registry (VCR) between 2003 and 2014. RESULTS: In total, 73 of 3120 (2.3%) AML cases were classified tAML. tAML patients were younger than non-tAML patients at diagnosis (median age 66 vs 71 years, P = 0.000). Median overall survival was similar (6 months). Median latency to tAML was 82 months, with two incidence peaks at 1-4 and 7-8 years. In total, 59 of 73 patients had recorded cancers, the most frequent being non-Hodgkin lymphoma (NHL, 32.2%) and breast cancer (16.9%). In total, 532 of 3120 (14.1%) additional AML cases had ≥1 prior cancer (confirmation of chemoradiotherapy unavailable). tAML incidence increased (0.0/100 000 persons in 2003, 0.5/100 000 persons in 2014), as did the incidence of non-tAML with previous cancer (0.8/100 000 persons in 2003, 1.1/100 000 persons in 2014). In total, 101 of 4435 (2.3%) MDS cases were classified tMDS. Although tMDS incidence fluctuated (range 0-0.4/100 000 persons/year), the incidence of non-tMDS with prior cancer rose (1.4/100 000 persons in 2003, 1.9/100 000 persons in 2014). Compared to tAML, the tMDS cohort was older (median age 70 vs 66 years, P = 0.007). Median latency to tMDS was 42.5 months. NHL was also the most common cancer preceding tMDS, but the second most common cancer was myeloma (17.8%). In total, 1287 of 5061 (20.3%) non-tMDS patients had a prior cancer. CONCLUSIONS: The burden of tAML/tMDS in Victoria is likely to be underestimated. Linkage between VCR and clinical registries is needed to provide more accurate insights.

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma.

BACKGROUND: Temozolomide (TMZ) is now standard adjuvant therapy in combination with radiotherapy for patients with newly diagnosed malignant glioma. Treatment-related myelodysplastic syndrome and acute treatment-related leukemia (t-AML) associated with TMZ chemotherapy for patients with glioma is quite a rare complication. CASE DESCRIPTION: A 43-year-old man with an anaplastic astrocytoma received radiation therapy synchronized with ranimustine and adjuvant TMZ chemotherapy for 15 cycles. Close follow-up magnetic resonance imaging of the head during TMZ chemotherapy showed no evidence of tumor progression. One year after the completion of TMZ chemotherapy, a bone-marrow aspiration was performed because the patient's white blood cell count decreased. He was diagnosed with t-AML based on the bone marrow examination, and then he was referred to the cancer center for the treatment of t-AML. CONCLUSIONS: In this case study, we continued adjuvant TMZ therapy beyond the recommended 6 cycles. Currently, there is no consensus as to how long the adjuvant TMZ therapy should be continued for the treatment of residual tumor showing no apparent interval change. A new decision-making tool to assess the clinical benefits against the side effects for long-term adjuvant TMZ therapy is needed.

Myelodysplastic Syndromes: Updates and Nuances.

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal stem cell disorder of the blood and marrow typically diagnosed based on the presence of persistent cytopenia(s), dysplastic cells, and genetic markers. Common issues that arise in the clinical management include difficulty confirming MDS diagnosis, lack of a standard approach with novel agents in MDS, and few prospective long-term, randomized controlled MDS clinical studies to guide allogeneic blood and marrow transplant. With the recent genetic characterization of MDS, certain aspects of these issues will be better addressed by integrating genetic data into clinical study design and clinical practice.

Therapy-related myelodysplastic syndromes, or are they?

The incidence of therapy-related myelodysplastic syndromes (t-MDS) is increasing as the number of cancer survivors is increasing. While t-MDS is currently defined descriptively by prior receipt of chemotherapy and/or radiotherapy, some forms of MDS that occur post localized radiation monotherapy, biologically and clinically resemble de novo (d)-MDS more than t-MDS, and therefore may not be truly therapy-related. Although patients with t-MDS, as a group, fare worse than patients with d-MDS, a variation in individual outcomes of patients with t-MDS has increasingly been appreciated. As such, accurate risk stratification is important for counseling of patients and for clinical decision making. Most of the current clinical tools used for prognostication in t-MDS were developed for d-MDS and were not specifically validated in patients with t-MDS. The management of patients with t-MDS remains challenging, highlighting the importance of developing effective prevention strategies as well as newer, targeted, and rationally-designed therapeutic interventions.