INTRODUCTION Myeloproliferative neoplasms (MPNs) are a group of rare clonal disorders of hematopoietic progenitor cells that are associated with morbidity from disease-related symptoms, thrombotic ...events, and risk of transformation to acute myeloid leukemia (AML) 1. Investigations for other malignancies including multiple myeloma were normal. 18Fluorodeoxyglucose positron emission tomography (PET) scan confirmed the right femur lesion with increased metabolic activity, but found no other abnormalities. TABLE 1 Clinical cases reports for osteolytic lesion in myeloproliferative neoplasm (MPN) Articles Patient age, gender, and diagnosis History and presentation Site of osteolytic lesion Diagnostic work-up Treatment Response Outcomes Licht et al., 1973 6 40F CML to MF In 1966, incidental finding of leukocytosis and thrombocytosis, no symptoms, no splenomegaly Bone marrow biopsy confirmed CML In April 1971 developed severe bone pain, found to have left shift and leukopenia Femur, ribs, pelvis, and skull Repeat bone marrow confirmed myelofibrosis Prednisone and 6-mecaptopurine Patient admitted as condition continue to decline N/A Death: 1 month from initial finding of lytic lesion (May 1971) Rudders & Kilcoyne 1974 7 73F MPN to MF In December 1966, found to have leukocytosis and thrombocytosis Bone marrow biopsy suggestive of MPN In July 1971, presented with chest pain, anemia, and weakness, Ribs, pelvis, femur, and skull Repeat marrow showed myelofibrosis No treatment interventions N/A Death: 17 months from initial finding of osteolytic lesion (Dec 1972) Leimert et al., 1978 8 49M Post PV MF Diagnosed in 1971 with PV, treated with phlebotomies In September 1976 developed persistent knee pain and constitutional symptoms Fibula, tibias, pelvis, and lumbar spine Bone marrow biopsy revealed fibrosis in marrow Radiation therapy to knees No improvement Death: 4 months from initial finding of osteolytic lesion (Jan 1977) Kosmidis et al., 1980 9 52 F Post PV-MF In 1959 initially diagnosed with PV based on elevated blood counts In January 1976 disease progressed to MF, with symptomatic splenomegaly, anemia In February 1978 severe acute chest pain Ribs and long bone Bone biopsy of osteolytic lesion (no further details provided) confirmed extensive fibrosis Analgesics and transfusion support N/A Death: 5 months from initial finding of osteolytic lesion (July 1978) Gruber & Osby, 1987 10 64F PMF Diagnosed with PMF in November 1974 In 1979 developed back pain that progressively worsened over the years Skull, scapulae, humeri and vertebrae Bone biopsy (site not specified) confirmed hematopoietic cells Myeloma work-up negative Analgesics, busulphan, and transfusion support Temporary relief Death: 9 years 11 months from initial finding of osteolytic lesion (October 1984) Clutterback et al., 1995 11 59M PMF 33-year history of MF, stable disease Patient presented with pneumonia, weakness, and paresthesia in his left leg with flaccid paralysis of the left foot Left femur Bone biopsy of left femur revealed hematopoietic cells, no evidence of other malignancy Intramedullary nailing of the femur Recovered from the surgery and discharged Death due to septicemia after 6 months Sadoun et al., 1997 12 30M Hyper-eosinophilic syndrome transform to MF In 1989, diagnosed with hypereosinophilic syndrome, confirmed by bone marrow aspirate In July 1992 admitted with severe hypercalcemia (3.7 mmol/l), anemia, bone pain Pelvis Repeat bone marrow biopsy confirmed transformation to MF cytogenetics remained normal Oct 1992 underwent bone marrow transplant 12-month post-transplant repeat pelvic x-ray showed resolution of osteolytic lesion Alive at last follow-up Sideris et al., 2006 13 72M Post PV MF Presented to hospital with low back pain and anemia Rib, sternum, vertebra, pelvis and calcaneus Bone biopsy (vertebrae) most aligned with MPN, N/A N/A Death: 11 months after progression to AML Jurisic et al., 2008 14 49F PMF to AML In 1991 presented with abdominal pain, splenomegaly, anemia, and general malaise Bone marrow biopsy confirmed diagnosis of PMF Condition continued to deteriorate and developed bone pain. Pelvis and long bones Multiple myeloma work-up negative Bone marrow biopsy showed 72% blast indicating transformation to AML Cytosine-arabinoside, did not achieve remission Subsequently treated with hydroxyurea did not achieve remission Did not achieve remission Alive at last follow-up Transfusion support Merry & Aronowitz. 2010 15 83M PMF 7-year history of MF diagnosis, managed with transfusion support and thalidomide Worsening fatigue and weakness, leading to fall at home Left wrist, hand, and forearm N/A Cast to left arm and wrist Transfusion support N/A Death: 1 month after admission (cause unclear) Sacre et al, 2010 16 44F PMF Longstanding history of systemic lupus erythematosus In 2002, low hemoglobin and platelets.
This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia ...(Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Inherited
mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs ...described to date harboring germline
and co-occurring somatic
variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.
Here, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterized
variants of uncertain significance.
Our results demonstrate that MDS/AML cases harboring two
variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelic
related hematologic malignancies. We further showed that the features seen in these individuals with two
variants were concordant with biallelic
disruption.
Here, we expand on previous clinicopathologic findings on
mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized
alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.
Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and the fusion proteins RUNX1-RUNX1T1 and CBFB-MYH11. International guidelines recommend monitoring for measurable ...residual disease every 3 months for 2 years after treatment. However, it is unknown if serial molecular monitoring can predict and prevent morphologic relapse. We conducted a retrospective single-center study of 114 patients in complete remission who underwent molecular monitoring with RT-qPCR of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts every 3 months. Morphologic relapse was defined as re-emergence of >5% blasts and molecular relapse as ≥1 log increase in transcript level between 2 samples. Over a median follow-up time of 3.7 years (range 0.2-14.3), remission persisted in 71 (62.3%) patients but 43 (37.7%) developed molecular or morphologic relapse. Patients who achieved <3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts at end of chemotherapy had a significantly higher risk of relapse compared to patients who achieved ≥3 log reduction (61.1% vs. 33.7%, p=0.004). The majority of relapses (74.4%, n=32) were not predicted by molecular monitoring and occurred rapidly with <100 days from molecular to morphologic relapse. Molecular monitoring enabled the detection of impending relapse and permitted pre-emptive intervention prior to morphologic relapse in only 11 (25.6%) patients. The current practice of molecular monitoring every 3 months provided insufficient lead-time to identify molecular relapses and prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia treated at our institution. Further research is necessary to determine the optimal monitoring strategies for these patients.
There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it is unknown whether mutational ...status affects survival, as seen in chronic-phase MPNs. Therefore, we performed a retrospective analysis of all patients treated at our institution with AP/BP MPNs (N = 122; AP = 14; BP = 108) to comprehensively describe the mutational profile and correlate with clinical outcomes. Targeted sequencing with a 54-gene panel was performed. Forty-four patients were treated with intensive therapy, 27 with nonintensive therapy, and 51 with best supportive care (BSC). The most common mutation was JAK2V617F, occurring in 55% of subjects; CALR was found in 13% of patients and MPL in 6%. Thirty-two (26%) patients were triple negative. Other frequently mutated genes were ASXL1 (30%), TET2 (25%), SRSF2 (22%), RUNX1 (20%), and TP53 (17%). Mutations in 1, 2, 3, and ≥4 genes were seen in 15%, 13%, 25%, and 46% of patients, respectively. There was no difference in survival between patients treated with intensive vs nonintensive therapy, and the benefit of intensive therapy was limited to patients who were able to undergo transplantation. TP53 was the only individual mutation to correlate with shorter overall survival (hazard ratio, 1.89; P = .03). In the multivariate analysis, mutated TP53, ≥4 mutations, low albumin, increased peripheral blood blasts, ≥3 cytogenetic abnormalities, and BSC were associated with shorter survival. In conclusion, mutational data enhance the understanding of patients with AP/BP MPN who are likely to benefit from current therapeutic options.
•Mutant TP53 and ≥4 mutations predict dismal outcomes with current therapeutic options in patients with accelerated/blast phase of MPNs.•The benefit of intensive therapy is only seen in patients who are able to undergo transplant.
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In myelofibrosis (MF), driver mutations in JAK2, MPL, or CALR impact survival and progression to blast phase, with the greatest risk conferred by triple-negative status. Subclonal mutations, ...including mutations in high–molecular risk (HMR) genes, such as ASXL1, EZH2, IDH1/2, and SRSF2 have also been associated with inferior prognosis. However, data evaluating the impact of next-generation sequencing in MF patients treated with JAK1/2 inhibitors are lacking. Using a 54-gene myeloid panel, we performed targeted sequencing on 100 MF patients treated with ruxolitinib (n = 77) or momelotinib (n = 23) and correlated mutational profiles with treatment outcomes. Ninety-nine patients had at least 1 mutation identified, 46 (46%) had 2 mutations, and 34 (34%) patients had ≥3 mutations. Seventy-nine patients carried a mutation in JAK2V617F, 14 patients had mutations in CALR, 6 patients had an MPL mutation, and 2 patients were triple negative. No mutation was significantly associated with spleen or anemia response. A high Dynamic International Prognostic Scoring System score and pretreatment transfusion dependence were associated with a shorter time to treatment failure (TTF), and this association retained significance on multivariable analysis. Patients with ASXL1 (hazard ratio HR, 1.86; P = .03) and EZH2 mutations (HR, 2.94; P = .009) and an HMR profile (HR, 2.06; P = .01) had shorter TTF. On multivariate analysis, ASXL1 or EZH2 mutations were independently associated with shorter TTF and overall survival. These findings help identify patients unlikely to have a durable response with current JAK1/2 inhibitors and provide a framework for future studies.
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•ASXL1/EZH2, transfusion dependence, and a high prognostic risk score predict shorter TTF in MF patients on JAK1/2 inhibitors.•These clinical and genetic factors were also associated with decreased overall survival.
PEG‐asparaginase is used as a treatment for Philadelphia‐negative acute lymphoblastic leukemia. In pediatric studies, triglycerides (TGs) were affected more by PEG‐asparaginase than by native ...L‐asparaginase (10.0% vs. 5.5%). We conducted a retrospective study to determine the safety of re‐challenging adult patients with PEG‐asparaginase after experiencing an episode of severe hypertriglyceridemia (>1000 mg/dl or 11.4 mmol/L). The incidence of hypertriglyceridemia associated with PEG‐asparaginase in adult patients was high (67.5%). Therefore, checking TGs at baseline and monitoring levels while receiving PEG‐asparaginase need to be considered and studied in prospective studies. However, in patients with hypertriglyceridemia not complicated by acute pancreatitis, re‐challenging is safe once TG levels normalize.
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