Acta Haematologica最新文献

Introduction: Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare autosomal recessive disease with a homozygous or compound-heterozygous mutation in the SLC19A2 gene characterized by megaloblastic anemia, diabetes mellitus (DM), and sensorineural hearing loss with onset in childhood. Folic acid and vitamin B12 in serum are normal with dysplastic erythropoiesis in the bone marrow often mimicking myelodysplastic neoplasms (MDS) as a potential differential diagnosis. Thiamine substitution leads to normalization of anemia, without effects on hearing loss or DM.

Case presentation: We report about a 38-year-old male patient, presented with a 12-year history of anemia, insulin dependent DM, optic neuropathy, and a cataract since early childhood. The laboratory showed megaloblastic anemia. Other values were normal. The bone marrow smear showed dysplastic erythropoiesis with megaloblastic changes, and normal findings in cytogenetic and molecular genetic examinations. Next-generation sequencing-based diagnostics revealed a heterozygous missense variant in the SLC19A2 gene on the maternal allele and a 3.4 Mb inversion in the chromosomal region 1q24.2 with breaking points in FAM78B and SLC19A2 on the paternal allele. Treatment with oral thiamine 100 mg daily was initiated, and 12 weeks later hemoglobin levels and bone marrow morphology had normalized.

Conclusion: Late-onset TRMA should be considered in adult patients with indicative comorbidities and a typical phenotype, which may mimic features of MDS.

Introduction: The combination of venetoclax (VEN) and azacytidine (AZA) has demonstrated potential in achieving rapid and effective remissions in elderly patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is a promising potential cure for high-risk AML, as VEN-based therapies have a worse prognosis in elderly patients. This study aimed to assess the efficacy of sequential haploidentical HSCT following two courses of VEN and AZA therapy in patients with AML aged 55 years and older.

Methods: We conducted a retrospective study on AML patients aged 55-70 years who received intensive chemotherapy or two courses of VEN/AZA therapy, followed by haploidentical allo-HSCT (haplo-HSCT) based on disease risk degree, measurable residual disease status, and patient's preference.

Results: Between January 2019 and December 2023, 141 newly diagnosed AML patients received initial treatment with intensive chemotherapy or VEN/AZA therapy. Among them, 64 patients received haplo-HSCT, while 77 did not. The 1-year overall survival (OS) and relapse-free survival (RFS) of patients who received haplo-HSCT were significantly higher than those who did not receive haplo-HSCT (p < 0.05). Among patients who received transplantation, there was no significant difference in 1-year OS and RFS between the VEN/AZA and intensive chemotherapy groups: 76.3% versus 69.3% (p = 0.367) for OS, and 74.5% versus 69.7% (p = 0.473) for RFS. High-risk ELN stratification and the presence of ≥4 gene mutations were associated with lower OS and RFS in both univariate and multivariate analyses.

Conclusions: AML patients over 55 years of age who received haplo-HSCT after two courses of VEN/AZA therapy had outcomes similar to those who received haplo-HSCT after intensive chemotherapy, suggesting that two courses of VEN/AZA therapy as a bridge to haplo-HSCT are feasible for patients over 55 years old.

Introduction: Ruxolitinib is approved for treatment of myelofibrosis. We evaluated ruxolitinib in patients with anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count ≤100 × 109/L) at diagnosis.

Methods: This was a retrospective, secondary analysis of a Cardinal Health Oncology Provider Extended Network medical chart review of adults with myelofibrosis diagnosed between 2012 and 2016 who received first-line ruxolitinib.

Results: 176 patients received first-line ruxolitinib and were included in this analysis. At diagnosis, 120 patients had hemoglobin concentrations <10 g/dL and 59 had a platelet count ≤100 × 109/L. Most patients (95%) with thrombocytopenia also had anemia. Median time of observation after diagnosis was 21.4 months. Among patients with anemia or thrombocytopenia, ruxolitinib dose at end of study was ≥10 mg twice daily (bid) in 88.3% and 83.1%, respectively. Ruxolitinib treatment was ongoing in 76.1% of patients overall and was rarely discontinued for anemia or thrombocytopenia (n = 2 total, 1.1%). Per the treating physician, 79.7% of patients had improved symptoms and 62.7% improved spleen size.

Conclusion: Most patients with myelofibrosis and anemia or thrombocytopenia at diagnosis tolerated and maintained a ruxolitinib dose ≥10 mg bid for nearly 2 years, resulting in clinical benefit. This real-world evidence supports observations from prospective clinical trials of ruxolitinib in myelofibrosis.

Introduction: Treatment-free remission (TFR) has emerged as a new goal in the treatment of chronic myeloid leukemia (CML). TFR is considered a safe intervention because patients who experienced molecular relapse usually responded well to tyrosine kinase inhibitors resumption and regained molecular response quite efficiently. Nevertheless, there have been reports of occurrence of blast crisis during TFR.

Case presentation: We report a case of sudden lymphoid blast crisis in a CML patient who had been in TFR for 21 months without any prior molecular loss. Whole-exon sequencing identified a frameshift mutation of SETD2. In addition, we reviewed the current literature on cases of blast crisis in TFR. Only eleven cases of blast crisis have been reported among thousands of patients who discontinued tyrosine kinase inhibitor (TKI) therapy, including our patient. Of these cases, nine presented with lymphoid blast crisis. Additional gene mutations are frequently observed.

Conclusion: This case, along with others, emphasizes the necessity of implementing a long-term monitoring strategy following TKI discontinuation due to the potential for late onset of blast crisis. Systematic genetic studies in patients failing TFR should be properly carried out to further understand the mechanism and, eventually, to predict or prevent such adverse event in patients in TFR.

Introduction: Treatment for relapsed/refractory AL amyloidosis (AL) is an unmet need. The safety and efficacy of belantamab mafodotin (BLM) in multiple myeloma are known, whereas in AL data are limited.

Methods: We report a multi-center cohort of AL patients receiving BLM, and review all previous data on BLM therapy in AL.

Results: Twelve patients with a median of 3 (range 2-9) prior lines of therapy were included. The overall hematological response rate (ORR) was 75% (9/12), including 5 complete responses. Six of the 10 evaluable patients had organ responses. The median event-free survivals/overall survivals were 22.3 and 28.8 months, respectively. Grade 3 toxicities were mostly infections and keratopathy, occurring in 7/12 (58%). Hematological toxicities were rare. No grade 4/5 toxicities occurred. The review of the previous series reveals BLM provides an ORR of 60-83% with similar rates of corneal toxicity.

Conclusion: BLM, being an off-the-shelf therapy, with acceptable toxicity even in frail patients, may be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses.

Introduction: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide [Gut Liver. 2017;11(1):27-37]. The use of PPI has become a common practice and is overprescribed for all patients with cancer including patients with hematological malignancies. In the current study, we aimed to explore retrospectively the effect of PPI, on time to first treatment (TTFT) in a large cohort of patients with chronic lymphocytic leukemia (CLL) who were under watch-and-wait approach.

Methods: The cohort is based on anonymized data obtained from electronic medical records of Maccabi Healthcare Services (MHS) members, who is the second-largest healthcare organization in Israel, with 2.5 million insured patients, and received a diagnosis of CLL during this period.

Results: Our cohort included 3,474 patients with CLL who are treatment-naïve, and the median follow-up was 1,745 days (602-3,700). A total of 1,061 patients (30.5%) received a PPI agent, for a minimum of 3 months during the watch-and-wait period. The intake of PPI was found to be associated with a shorter TTFT: among PPI users, the 10-year treatment-free ratio is 79.2%, while among non-PPI users it is 90.6%.

Conclusion: Routine use of PPI in CLL patients may negatively impact their clinical course. Biology of this primary observation requires further investigation.

Introduction: High-dose therapy with melphalan followed by autologous stem cell transplant in the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, the role of upfront ASCT approach has been called into question. Several prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (triplet-alone) could result in comparable outcomes.

Methods: This was a systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT versus triplet-alone approach among myeloma patients treated with triplet therapy, which included two novel agents and a corticosteroid, as induction. Cochrane Library, PubMed and conference proceedings were searched. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), safety, and second primary malignancies (SPM). Subgroup analysis was conducted for high-risk cytogenetics.

Results: Our search yielded three trials, conducted between 2010-2018, including 1,737 patients. Two trials evaluated bortezomib plus lenalidomide (VRd) induction and the third study tested carfilzomib plus lenalidomide (KRd) induction. Maintenance was given in all trials to both arms. There was no difference in OS between the arms; the pooled OS in all patients and those with high-risk cytogenetics was hazard ratio (HR) 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials) and 0.85 (95% CI, 0.59-1.23; I2 = 0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT versus triplet-alone was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 (95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials) and HR 0.59 (95% CI: 0.44-0.7; I2 = 0%; 306 patients, 3 trials), respectively. The risk of any grade 3-4 adverse events was higher in the upfront ASCT arm versus triplet-alone approach (relative risk = 1.17 [95% CI, 1.12-1.23; 1,737 patients]). The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm versus triplet-alone approach, OR 9.7 (1.8-52.25, I2 = 0%, 1,422 patients).

Conclusion: Although upfront ASCT approach, in the era of triplet therapy, resulted in a significantly longer PFS among all patients, this did not translate into a survival benefit, regardless of cytogenetic risk. Upfront ASCT was associated with an increased rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable.