Novel therapeutics for myelofibrosis

Myelofibrosis (MF) includes primary MF, post-essential thrombocythemia MF, and post-polycythemia vera MF. MF is a progressive myeloid neoplasm characterized by ineffective clonal hematopoiesis, extramedullary hematopoiesis, a reactive bone marrow environment resulting in reticulin deposition and fibrosis, and a propensity for leukemia transformation. The identification of driver mutations in JAK2, CALR, and MPL has contributed to a better understanding of disease pathogenesis and has led to the development of MF-specific therapies, such as JAK2 inhibitors. Despite the fact that ruxolitinib and fedratinib have been clinically developed and approved, their use is limited due to adverse effects such as anemia and thrombocytopenia. Recently, pacritinib has been approved for a group of thrombocytopenic patients with significant unmet clinical needs. In symptomatic and anemic patients with prior JAK inhibitor exposure, momelotinib was superior to danazol in preventing exacerbation of anemia and in controlling MF-associated signs and symptoms, such as spleen size. Although the development of JAK inhibitors is remarkable, modifying the natural course of the disease remains a priority. Therefore, many novel treatments are currently under clinical development. Agents targeting bromodomain and extra-terminal protein, anti-apoptotic protein Bcl-xL, and phosphatidylinositol-3-kinase delta have been studied in combination with JAK inhibitors. These combinations have been employed in both the frontline and “add-on” approaches. In addition, several agents are being studied as monotherapies for ruxolitinib-resistant or -ineligible patients. We reviewed several new MF treatments in the advanced stages of clinical development and treatment options for cytopenic patients.

Early Safety Monitoring of COVID-19 Vaccines in Healthcare Workers

Hospital-based surveillance for adverse events was conducted on healthcare workers after they received the first dose of coronavirus disease 2019 (COVID-19) vaccine. Among the two new platform vaccines (messenger RNA- and adenoviral vector-based vaccines), the rates of systemic adverse events were significantly higher among adenovirus-vectored vaccine recipients. Fatigue (87.6% vs. 53.8%), myalgia (80.8% vs. 50.0%), headache (72.0% vs.28.8%), and fever (≥ 38.0°C, 38.7% vs. 0%) were the most common adverse events among adenovirus-vectored vaccine recipients, but most symptoms resolved within 2 days. Both types of COVID-19 vaccines were generally safe, and serious adverse events rarely occurred.

Region-Specific Differences in the Apoe4-dependent Response to Focal Brain Injury

Apolipoprotein E (apoE) plays a role in various physiological functions including lipid transport, synaptic plasticity, and immune modulation.Epidemiological studies suggest that the apoE4 allele increases the risk of post-traumatic sequelae. This study was performed to investigate regionspecific effects of the apoE4 isoform on post-traumatic neurodegeneration. Two focal brain injuries were introduced separately in the motor cortex and hippocampus of apoE4 knock-in, apoE3 knock-in, apoE knockout, and wild-type (WT) mice. Western blotting showed that the expression levels of pre-synaptic and post-synaptic markers at the recovery stage were lower in the hippocampal injury core in apoE4 mice, compared with apoE3 and WT mice. Fast glial activation (determined by immunohistochemistry with glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and cluster of differentiation 45 antibodies) was characteristic of apoE4 mice with hippocampal injury penumbra. apoE4-specific changes were not observed after cortical injury. The intensity of microglial activation in the hippocampus was inversely correlated with the volume of injury reduction on sequential magnetic resonance imaging examinations, when validated using matched samples. These findings indicate that the effects of the interaction between apoE4 and focal brain damage are specific to the hippocampus. Manipulation of inflammatory cell responses could be beneficial for reducing post-traumatic hippocampal neurodegeneration in apoE4 carriers.

Development and validation of a comorbidity index for predicting survival outcomes after allogeneic stem cell transplantation in adult patients with acute leukemia: a Korean nationwide cohort study

Background@#Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment option for acute leukemia. We aimed to identify the comorbidity factors affecting survival outcomes after alloSCT and develop a new comorbidity index tool for predicting overall survival (OS). @*Methods@#A Korean nationwide cohort of 3,809 adults with acute leukemia treated with alloSCT between January 2002 and December 2018 was analyzed as the development cohort.A retrospective cohort comprising 313 consecutive adults with acute leukemia who underwent alloSCT between January 2019 and April 2020 was analyzed as the validation cohort. @*Results@#In the development cohort, advanced age, male sex, and comorbidities such as previous non-hematologic malignancy, hypertension, and coronary or cerebral vascular disease were significantly related to poor OS. Subsequently, a new comorbidity scoring system was developed, and risk groups were created, which included the low-risk (score ≤0.17), intermediate-risk (0.17＜ score ≤0.4), high-risk (0.4＜ score ≤0.55), and very high-risk (score ＞0.55) groups. The 1-year OS rates were discriminatively estimated at 73.5%, 66.2%, 61.9%, and 50.9% in the low-risk, intermediate-risk, high-risk, and very high-risk groups in the development cohort, respectively (P ＜0.001). The developed scoring system yielded discriminatively different 1-year OS rates and 1-year incidence of non-relapse mortality according to the risk group (P =0.085 and P =0.018, respectively).Furthermore, the developed model showed an acceptable performance for predicting 1-year non-relapse mortality with an area under the curve of 0.715. @*Conclusion@#The newly developed predictive scoring system could be a simple and reliable tool helping clinicians to assess risk of alloSCT in adults with acute leukemia.

Disease modifying agents of myeloproliferative neoplasms: a review

The identification of driver mutations in Janus kinase (JAK ) 2, calreticulin (CALR), and myeloproliferative leukemia (MPL) has contributed to a better understanding of disease pathogenesis by highlighting the importance of JAK signal transducer and activator of transcription (STAT) signaling in classical myeloproliferative neoplasms (MPNs). This has led to the therapeutic use of novel targeted treatments, such as JAK2 inhibitors. More recently, with the development of next-generation sequencing, additional somatic mutations, which are not restricted to MPNs, have been elucidated. Treatment decisions for MPN patients are influenced by the MPN subtype, symptom burden, and risk classification. Although prevention of vascular events is the main objective of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients, disease-modifying drugs are needed to eradicate clonal hematopoiesis and prevent progression to more aggressive myeloid neoplasms. JAK inhibitors are a valuable therapeutic strategy for patients with myelofibrosis (MF) who have splenomegaly and/or disease-related symptoms, but intolerance, refractory, resistance, and disease progression still present challenges. Currently, allogeneic stem cell transplantation remains the only curative treatment for MF, but it is typically limited by age-related comorbidities and high treatment-related mortality. Therefore, a better understanding of the molecular pathogenesis and potential new therapies with the aim of modifying the natural history of the disease is important. In this article, I review the current understanding of the molecular basis of MPNs and clinical studies on potential disease-modifying agents.

Early Safety Monitoring of COVID-19 Vaccines in Healthcare Workers

Hospital-based surveillance for adverse events was conducted on healthcare workers after they received the first dose of coronavirus disease 2019 (COVID-19) vaccine. Among the two new platform vaccines (messenger RNA- and adenoviral vector-based vaccines), the rates of systemic adverse events were significantly higher among adenovirus-vectored vaccine recipients. Fatigue (87.6% vs. 53.8%), myalgia (80.8% vs. 50.0%), headache (72.0% vs.28.8%), and fever (≥ 38.0°C, 38.7% vs. 0%) were the most common adverse events among adenovirus-vectored vaccine recipients, but most symptoms resolved within 2 days. Both types of COVID-19 vaccines were generally safe, and serious adverse events rarely occurred.

The clinical, laboratory, and radiologic improvement due to siltuximab treatment in idiopathic multicentric Castleman’s disease

Background/Aims@#Idiopathic multicentric Castleman disease (iMCD) comprises approximately 30% of all cases of Castleman disease. It is characterized by constitutional symptoms, enlarged lymph nodes at multiple anatomical sites, and laboratory test abnormalities, which are primarily related to the overproduction of interleukin 6 (IL-6). Siltuximab is a human-mouse chimeric immunoglobulin G1κ monoclonal antibody against human IL-6. In view of the limited treatment options for iMCD, this study aimed to evaluate the efficacy and safety of siltuximab in the management of this condition. @*Methods@#In this real-world retrospective study, we administered siltuximab to 15 patients with iMCD who previously received conventional chemotherapy and/or steroid pulse therapy. The median time to a durable symptomatic response was 22 days (range, 17 to 56). The serum hemoglobin and albumin levels and erythrocyte sedimentation rates significantly normalized after the first 3 months of siltuximab treatment. Lymph node involution, assessed using imaging, was relatively gradual, demonstrating a complete or partial response at 6 months. @*Results@#On an average, the improvements in clinical, laboratory, and radiologic parameters of iMCD in responders were observed after one, three, and eight cycles of siltuximab treatment, respectively. Siltuximab demonstrated a favorable safety profile, and prolonged treatment was well-tolerated. @*Conclusions@#Despite the small sample size of the present study, the results are encouraging and demonstrate the potential of siltuximab as the first-line treatment of iMCD. Further large multicenter studies are needed to evaluate the clinical outcomes and adverse events associated with siltuximab.

Region-Specific Differences in the Apoe4-dependent Response to Focal Brain Injury

Apolipoprotein E (apoE) plays a role in various physiological functions including lipid transport, synaptic plasticity, and immune modulation.Epidemiological studies suggest that the apoE4 allele increases the risk of post-traumatic sequelae. This study was performed to investigate regionspecific effects of the apoE4 isoform on post-traumatic neurodegeneration. Two focal brain injuries were introduced separately in the motor cortex and hippocampus of apoE4 knock-in, apoE3 knock-in, apoE knockout, and wild-type (WT) mice. Western blotting showed that the expression levels of pre-synaptic and post-synaptic markers at the recovery stage were lower in the hippocampal injury core in apoE4 mice, compared with apoE3 and WT mice. Fast glial activation (determined by immunohistochemistry with glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and cluster of differentiation 45 antibodies) was characteristic of apoE4 mice with hippocampal injury penumbra. apoE4-specific changes were not observed after cortical injury. The intensity of microglial activation in the hippocampus was inversely correlated with the volume of injury reduction on sequential magnetic resonance imaging examinations, when validated using matched samples. These findings indicate that the effects of the interaction between apoE4 and focal brain damage are specific to the hippocampus. Manipulation of inflammatory cell responses could be beneficial for reducing post-traumatic hippocampal neurodegeneration in apoE4 carriers.

Development and validation of a comorbidity index for predicting survival outcomes after allogeneic stem cell transplantation in adult patients with acute leukemia: a Korean nationwide cohort study

Background@#Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment option for acute leukemia. We aimed to identify the comorbidity factors affecting survival outcomes after alloSCT and develop a new comorbidity index tool for predicting overall survival (OS). @*Methods@#A Korean nationwide cohort of 3,809 adults with acute leukemia treated with alloSCT between January 2002 and December 2018 was analyzed as the development cohort.A retrospective cohort comprising 313 consecutive adults with acute leukemia who underwent alloSCT between January 2019 and April 2020 was analyzed as the validation cohort. @*Results@#In the development cohort, advanced age, male sex, and comorbidities such as previous non-hematologic malignancy, hypertension, and coronary or cerebral vascular disease were significantly related to poor OS. Subsequently, a new comorbidity scoring system was developed, and risk groups were created, which included the low-risk (score ≤0.17), intermediate-risk (0.17＜ score ≤0.4), high-risk (0.4＜ score ≤0.55), and very high-risk (score ＞0.55) groups. The 1-year OS rates were discriminatively estimated at 73.5%, 66.2%, 61.9%, and 50.9% in the low-risk, intermediate-risk, high-risk, and very high-risk groups in the development cohort, respectively (P ＜0.001). The developed scoring system yielded discriminatively different 1-year OS rates and 1-year incidence of non-relapse mortality according to the risk group (P =0.085 and P =0.018, respectively).Furthermore, the developed model showed an acceptable performance for predicting 1-year non-relapse mortality with an area under the curve of 0.715. @*Conclusion@#The newly developed predictive scoring system could be a simple and reliable tool helping clinicians to assess risk of alloSCT in adults with acute leukemia.

Disease modifying agents of myeloproliferative neoplasms: a review

The identification of driver mutations in Janus kinase (JAK ) 2, calreticulin (CALR), and myeloproliferative leukemia (MPL) has contributed to a better understanding of disease pathogenesis by highlighting the importance of JAK signal transducer and activator of transcription (STAT) signaling in classical myeloproliferative neoplasms (MPNs). This has led to the therapeutic use of novel targeted treatments, such as JAK2 inhibitors. More recently, with the development of next-generation sequencing, additional somatic mutations, which are not restricted to MPNs, have been elucidated. Treatment decisions for MPN patients are influenced by the MPN subtype, symptom burden, and risk classification. Although prevention of vascular events is the main objective of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients, disease-modifying drugs are needed to eradicate clonal hematopoiesis and prevent progression to more aggressive myeloid neoplasms. JAK inhibitors are a valuable therapeutic strategy for patients with myelofibrosis (MF) who have splenomegaly and/or disease-related symptoms, but intolerance, refractory, resistance, and disease progression still present challenges. Currently, allogeneic stem cell transplantation remains the only curative treatment for MF, but it is typically limited by age-related comorbidities and high treatment-related mortality. Therefore, a better understanding of the molecular pathogenesis and potential new therapies with the aim of modifying the natural history of the disease is important. In this article, I review the current understanding of the molecular basis of MPNs and clinical studies on potential disease-modifying agents.

Primary neurocritical care involving therapeutic hypothermia for acute ischemic stroke patients with malignant infarct cores

BACKGROUND: Acute ischemic stroke patients with malignant infarct cores were primarily treated with neurocritical care based on reperfusion and hypothermia. We evaluated the predictors for malignant progression and functional outcomes. METHODS: From January 2010 to March 2015 ischemic stroke patients with large vessel occlusion of the anterior circulation with infarct volume >82 mL on baseline diffusion weighted image (DWI) within 6 hours from onset, with National Institutes of Health Stroke Scale ≥15 were included. All patients were managed with intent for reperfusion and neurocritical care. Malignant progression was defined as clinical signs of progressive herniation. Predictive factors for malignant progression and outcomes of decompressive hemicraniectomy (DHC) were evaluated. RESULTS: In total, 49 patients were included in the study. Among them, 33 (67.3%) could be managed with neurocritical care and malignant progression was observed in the remainder. Decompressive surgery was performed in nine patients (18.4%). Factors predictive of malignant progression were initial DWI volumes (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00 to 1.02; P=0.046) and parenchymal hematoma (OR, 6.77; 95% CI, 1.50 to 30.53; P=0.013) on computed tomography taken at Day 1. Infarct volume of >210 mL predicted malignant progression with 56.3% sensitivity and 90.9% specificity. Among the malignant progressors, 77.7% resulted in grave outcomes even with DHC, while all patients who declined surgery died. CONCLUSION: Acute ischemic stroke patients with malignant cores between 82 to 209 mL can be primarily treated with neurocritical care based on reperfusion and hypothermia with feasible results. In patients undergoing surgical decompression due to malignant progression, the functional outcomes were not satisfactory.

Brain computed tomography angiography in postcardiac arrest patients and neurologic outcome

OBJECTIVE: This study aimed to analyze intracranial vessels using brain computed tomography angiography (CTA) and scoring systems to diagnose brain death and predict poor neurologic outcomes of postcardiac arrest patients.METHODS: Initial brain CTA images of postcardiac arrest patients were analyzed using scoring systems to determine a lack of opacification and diagnose brain death. The primary outcome was poor neurologic outcome, which was defined as cerebral performance category score 3 to 5. The frequency, sensitivity, specificity, positive predictive value, negative predictive value, and area under receiver operating characteristic curve for the lack of opacification of each vessel and for each scoring system used to predict poor neurologic outcomes were determined.RESULTS: Patients with poor neurologic outcomes lacked opacification of the intracranial vessels, most commonly in the vein of Galen, both internal cerebral veins, and the mid cerebral artery (M4). The 7-score results (P=0.04) and 10-score results were significantly different (P=0.04) between outcome groups, with an area under receiver operating characteristic of 0.61 (range, 0.48 to 0.72). The lack of opacification of each intracranial vessel and all scoring systems exhibited high specificity (100%) and positive predictive values (100%) for predicting poor neurologic outcomes.CONCLUSION: Lack of opacification of vessels on brain CTA exhibited high specificity for predicting poor neurologic outcomes of patients after cardiac arrest.

Pilot study on a rewarming rate of 0.15°C/hr versus 0.25°C/hr and outcomes in post cardiac arrest patients

OBJECTIVE: Cerebral hemodynamic and metabolic changes may occur during the rewarming phase of targeted temperature management in post cardiac arrest patients. Yet, studies on different rewarming rates and patient outcomes are limited. This study aimed to investigate post cardiac arrest patients who were rewarmed with different rewarming rates after 24 hours of hypothermia and the association of these rates to the neurologic outcomes.METHODS: This study retrospectively investigated post cardiac arrest patients treated with targeted temperature management and rewarmed with rewarming rates of 0.15°C/hr and 0.25°C/hr. The association of the rewarming rate with poor neurologic outcomes (cerebral performance category score, 3 to 5) was investigated.RESULTS: A total of 71 patients were analyzed (0.15°C/hr, n=36; 0.25°C/hr, n=35). In the comparison between 0.15°C/hr and 0.25°C/hr, the poor neurologic outcome did not significantly differ (24 [66.7%] vs. 25 [71.4%], respectively; P=0.66). In the multivariate analysis, the rewarming rate of 0.15°C/hr was not associated with the 1-month neurologic outcome improvement (odds ratio, 0.54; 95% confidence interval, 0.16 to 1.69; P=0.28).CONCLUSION: The rewarming rates of 0.15°C/hr and 0.25°C/hr were not associated with the neurologic outcome difference in post cardiac arrest patients.

Predictive Role of Circulating Immune Cell Subtypes Early after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia

BACKGROUND AND OBJECTIVES: Cells of innate immunity normally recover in the first weeks to months after allogenenic hematopoietic stem cell transplantation (allo-HSCT). Their relevance in terms of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect is largely unknown. The predictive role of early recovery in the immune cells on acute GVHD and GVL effect after allo-HSCT was investigated in patients with acute leukemia who achieved the first complete remission. METHODS: Peripheral blood samples were taken at the median of 14 days (range, 12~29 days) after allo-HSCT. A cohort including 119 samples and characteristics of patients were analyzed. Immune cell populations were identified by flow cytometry. RESULTS: The median age was 49.0 years (range, 21~69) at transplantation. Univariate analysis showed that age less than 40 years old, lower frequencies of CD8+ T cells, invariant natural killer T (iNKT) cells, monocytic myeloid derived suppressor cells (M-MDSCs) and higher frequency of immature MDSCs were associated with occurrence of grade III–IV acute GVHD. Multivariate analyses showed that iNKT cells (hazard ratio (HR), 0.453, 95% CI, 0.091~0.844, p=0.024) and M-MDSCs (HR, 0.271, 95% CI, 0.078~0.937, p=0.039) were independent factors. Combination of higher frequencies of both cell subsets was associated with lower incidence of grade III–IV acute GVHD, whereas patients with lower frequency of iNKT cells and higher frequency of M-MDSCs showed significant higher probability of relapse. CONCLUSIONS: iNKT cells and M-MDSCs could be relevant cell biomarkers for predicting acute GVHD and/or relapse in acute leukemia patients treated with allo-HSCT.

Two Korean Cases of Hereditary Spherocytosis Caused by Mutations in SLC4A1

Hereditary spherocytosis (HS) is caused by mutations in the SPTA1, SPTB, ANK1, SLC4A1, and EPB42 genes, all of which encode erythrocyte membrane proteins. Mutations in SLC4A1, which encodes band 3 protein, have rarely been reported as the causative factor among Korean patients with HS. Here, we report two Korean patients with HS carrying mutations in SLC4A1. Patient 1 was a 3-year-old girl with unremarkable past and family histories and was evaluated for anemia that was detected after a complete blood count. She was suspected of having HS considering the spherocytosis of her peripheral blood smear, increased osmotic fragility, hemolytic features in blood chemistry tests, and splenomegaly. Sequence analysis revealed that the patient harbored a single heterozygous missense mutation, c.2278C>T (p.Arg760Trp) in exon 17 of SLC4A1. Patient 2 was a 23-year-old man who had a prior history of intermittent jaundice. Although the patient did not have anemia, a genetic test for HS was performed due to evidence of hemolytic features in the blood chemistry test, splenomegaly, and a family history of HS. The test confirmed a single heterozygous missense mutation, c.2423G>T (p.Arg808Leu) in exon 18 of SLC4A1.

Cytomegalovirus Colitis during Dasatinib Treatment for Patients with Hematologic Malignancy: Case Series and Literature Review

Dasatinib, a tyrosine kinase inhibitor, is widely used for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Although the drug has a potent immunosuppressive effect, infectious complications during dasatinib treatment have been reported rarely. We describe five patients who developed cytomegalovirus (CMV) colitis during dasatinib treatment, in whom the colitis was initially confused with other causes. The patients, three with chronic myeloid leukemia, and two with acute lymphoblastic leukemia, were diagnosed with CMV colitis based on endoscopic and histologic findings. The patients who examined blood CMV polymerase chain reaction were all positive. The patients received antiviral therapy in the form of either ganciclovir or valganciclovir, and the overall treatment outcome was fair. These cases suggest that physicians should consider the possibility of CMV reactivation when treating diarrhea and/or hematochezia in patients on dasatinib.

Cytomegalovirus Colitis during Dasatinib Treatment for Patients with Hematologic Malignancy: Case Series and Literature Review

Dasatinib, a tyrosine kinase inhibitor, is widely used for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Although the drug has a potent immunosuppressive effect, infectious complications during dasatinib treatment have been reported rarely. We describe five patients who developed cytomegalovirus (CMV) colitis during dasatinib treatment, in whom the colitis was initially confused with other causes. The patients, three with chronic myeloid leukemia, and two with acute lymphoblastic leukemia, were diagnosed with CMV colitis based on endoscopic and histologic findings. The patients who examined blood CMV polymerase chain reaction were all positive. The patients received antiviral therapy in the form of either ganciclovir or valganciclovir, and the overall treatment outcome was fair. These cases suggest that physicians should consider the possibility of CMV reactivation when treating diarrhea and/or hematochezia in patients on dasatinib.

Immunoglobulin G4-Related Disease Presenting with Isolated, Intractable Trigeminal Neuralgia

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated systemic condition affecting diverse organs which lately has been increasingly recognized. A 40-year-old male presents intractable trigeminal neuralgia lasting more than a year even with numerous pain medication, which lead further evaluation. The infiltrative lesion was found involving left pterygopalatine fossa where maxillary nerve locates. We report a case of IgG4-RD with a sole manifestation of intractable unilateral trigeminal neuralgia which was improved by steroid treatment.

Effectiveness of darbepoetin alfa in multiple myeloma patients receiving chemotherapy including novel agents

BACKGROUND: The aim of this study was to evaluate the effects of darbepoetin alfa (DA) on hemoglobin (Hb) concentration and the need for transfusions in multiple myeloma (MM) patients receiving chemotherapy with novel agents. METHODS: Of 251 patients with MM who received DA therapy for at least 4 weeks, 142 who did not receive RBC transfusion during 4 weeks after DA initiation and started DA therapy at baseline Hb <10.0 g/dL were analyzed. RESULTS: After 4 weeks of DA therapy, 80 (60.6%) of 132 patients with evaluable data had Hb that increased ≥1.0 g/dL from baseline, while 50 (37.9%) had Hb that increased ≥2.0 g/dL from baseline. Pretreatment Hb level did not correlate with the proportion of patients with increased Hb. The median duration of DA therapy was 9.0 weeks. At the end of DA therapy, of 135 patients with evaluable data, 86 (60.6%) had Hb that increased ≥1.0 g/dL from baseline, while 67 (47.2%) had Hb that increased ≥2.0 g/dL from baseline. Stage III disease according to the International Staging System and absence of myeloma bone disease at diagnosis were independent predictors of higher Hb response during early DA therapy. CONCLUSION: We demonstrated the efficacy of DA therapy in a homogeneous group of MM patients receiving chemotherapy. DA therapy significantly increased Hb concentration, regardless of baseline Hb level.

BCR-ABL₁ transcripts (MR(4.5)) at post-transplant 3 months as an early predictor for long-term outcomes in chronic myeloid leukemia

BACKGROUND/AIMS: The aim of this study was to identify the role of BCR-ABL1 transcript level as a predictor for post-transplant relapse and outcome in patients who underwent allogeneic stem cell transplantation (SCT) for chronic phase (CP) chronic myeloid leukemia (CML). METHODS: Of 101 patients receiving allograft in CML CP, 85 had available quantitative reverse transcriptase polymerase chain reaction data at post-transplant 3 months. These patients were divided into two groups according to molecular response (MR(4.5)), defined as a BCR-ABL₁ transcript level ≤ 0.0032% on the international scale, at 3 months based on receiver operating characteristic curve analysis of relapse. RESULTS: The 4-year overall survival and event-free survival (EFS) were 80.6% and 57.3%, respectively, and the cumulative incidence of relapse at 4 years was 29.6% after a median follow-up of 126.4 months. We performed multivariate analyses including potential variables to evaluate the early predictive role of MR(4.5) at 3 months and found that MR(4.5) at 3 months was associated with a higher EFS (p = 0.028) and showed a trend for a lower relapse rate (p = 0.089). CONCLUSIONS: our results imply that frequent molecular monitoring and immune suppressive therapy modulation are required for patients without reduction of BCR-ABL1 transcripts to this level after SCT.