Clinical factors associated with autologous stem cell transplantation outcomes in multiple myeloma: upfront transplant with MEL200 remains the standard of care.

Autologous stem cell transplantation (ASCT) remains the mainstay of the treatment in newly diagnosed transplant-eligible multiple myeloma (MM) patients. This retrospective study was performed to investigate the potential prognostic markers which may modify transplant course in a total of 256 ASCT recipients [median age: 58 (30-74) years; male/female: 138/118], including pretransplant (PET0) and day + 60 (PET2) PET/CT assessments and comparative analysis of melphalan (Mel) dose. Better responses with significantly higher complete response/very good partial response rates were achieved in patients who proceeded to transplant within 301 days from diagnosis (p < 0.001). Patients who had received < 1.5 lines of treatment prior to transplant had significantly higher probability of overall survival (OS) (p = 0.004) and progression-free survival (PFS) (p < 0.001). The probability of OS was significantly higher in patients with low Eastern Cooperative Oncology Group (ECOG) performance score (PS = 0-1) (p = 0.003) and HCT-Comorbidity Index (HCT-CI = 0) (p = 0.011). The number of involved areas (p = 0.028) and maximum standardized uptake value (SUVmax) (p = 0.021) in PET0 represented significant impact on OS. The probabilities of OS (p < 0.001) and PFS (p = 0.01) were significantly better with Mel200 mg/m2 conditioning compared to Mel140 mg/m2. Conditioning with Mel200 mg/m2, early and upfront ASCT and low pretransplant treatment burden were found to be significantly associated with ASCT outcome in MM patients. Despite its predictor impact on survival and prognosis, further studies are warranted to standardize PET/CT-based response assessments before being used as a guide for treatment decisions in clinical practice.

Pomalidomide, Bortezomib, and Dexamethasone in Lenalidomide-Pretreated Multiple Myeloma: A Subanalysis of OPTIMISMM by Frailty and Bortezomib Dose Adjustment.

INTRODUCTION: A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment. METHODS: Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed. RESULTS: Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without. CONCLUSION: Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.

Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. METHODS: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). FINDINGS: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections). INTERPRETATION: After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. FUNDING: Janssen Research & Development and Pharmacyclics.

Long-term Results of Imatinib Discontinuation in Patients with Chronic-phase Chronic Myeloid Leukemia: A National Multicenter Prospective Study

Objective: The discovery of imatinib was a milestone for chronic myeloid leukemia (CML). As the life expectancy of CML patients has approached that of the general population, research has shifted towards improving quality of life and economic considerations. After 2010, it was shown that some patients could maintain molecular response even after discontinuing imatinib. This national multicenter prospective cohort study aimed to observe the long-term consequences of discontinuing imatinib therapy in adult chronic-phase CML patients. Materials and Methods: We enrolled 41 CML patients from 4 different centers in this non-randomized single-arm trial. Molecular responses of all patients were re-evaluated using real-time polymerase chain reaction at a single center. The median follow-up time after imatinib discontinuation was 48 months (minimum-maximum: 6-81 months). Results: The rate of molecular relapse-free survival at 48 months was 33.2% (confidence interval: 48.2-18.2). Twenty-seven of 41 patients lost their major molecular response, treatment was started again, and deep molecular response was re-achieved with imatinib in all cases. There was no significant relationship between molecular relapse and clinical factors such as duration of treatment or molecular response status. Discontinuing imatinib resulted in savings of approximately 4,392,000 Turkish lira or 245,150 US dollars. Conclusion: Tyrosine kinase inhibitor discontinuation with close molecular monitoring is a safe option and provides important national economic benefits for chronic phase CML patients. This approach should be considered for all eligible patients. This is the first tyrosine kinase inhibitor discontinuation study from Türkiye.

Preconditioning Modified-Easix as a Predictor of Prognosis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is associated with severe complications, most of which share a common physiopathological background characterized by endothelial dysfunction. A novel risk assessment model, endothelial activation and stress index (EASIX), has been introduced as a predictor of endothelial activation. This retrospective study was performed to evaluate the predictive impact of EASIX/modified-EASIX (mEASIX) on transplant outcome. Medical records of 398 alloHCT recipients [median age: 43(17-71) years; M/F: 243/155] were examined. EASIX/mEASIX were calculated at specific time points before and after transplantation. EASIX/mEASIX were significantly associated with transplant complications including engraftment syndrome, sinusoidal obstruction syndrome, febrile neutropenia and transplant associated thrombotic microangiopathy. The probability of overall survival was significantly higher in low-preconditioning mEASIX (day -7) group (37% vs 25.2%; p = 0.008; HR: 2.057; 95% CI: 1.208-3.504). The probabilities of day30 mortality (2.9% vs 19.4%; p = 0.017; HR: 7.028; 95% CI: 1.418-34.836), day100 mortality (9% vs 33%; p = 0.004; HR: 4.469; 95% CI: 1.619-12.336) and non relapse mortality (44.8% vs 61.4%; p = 0.005; HR: 2.551; 95% CI: 1.318-4.941) were lower in low-preconditioning mEASIX (day -7) group. This retrospective cohort analysis demonstrates the significant impact of EASIX/mEASIX on transplant complications and survival. Prospective analyses are mandatory to assess the predictive role of EASIX/mEASIX in clinical practice.

Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study.

PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.

Is flow cytometry useful in determining central nervous system involvement in patients with hematological malignancy? Analysis with a prospective cohort.

Central nervous system (CNS) involvement occurs in approximately 5-15% of patients in hematological malignancies. Early diagnosis and treatment is essential for a successful approach to CNS involvement. The gold standard method for diagnosis is cytological evaluation, but its sensitivity is low. Flow cytometry (FCM) from cerebrospinal fluid(CSF) is another method used to identify small groups of cells with abnormal phenotype. In our study, we compared FCM and cytological findings in the evaluation of CNS involvement in our patients with hematological malignancies. 90 patients [58 males, 32 females] were included in the study. CNS involvement was positive in 35(%38.9) patients, negative in 48(%53.3) patients, and suspicious (atypical) in 7(%7.8) patients by flow cytometry and it was positive in 24(%26.7) patients, negative in 63(%70) patients, and atypical in 3(%3.3) patients by cytology. While the sensitivity and specificity were found to be respectively 68.5% and 100% by cytology, it was found to be 94.2% and 85.4% by flow cytometry. Flow cytometry, cytology and MR findings were significantly correlated with each other in both prophylaxis (p < 0.001) and patients with prediagnosis of CNS involvement. Although the gold standard diagnostic method in the diagnosis of CNS involvement is cytological, its sensitivity is low and it can give false negative results at a rate of 20-60%. Flow cytometry is an ideal objective and quantitative method for identifying small groups of cells with abnormal phenotype. Flow cytometry can be used routinely in the diagnosis of CNS involvement in patients with hematological malignancies with cytology, since it can detect fewer malignant cells, has a higher sensitivity, and provides easy and faster results.

[Comparison of the Results of Galactomannan and Beta Glucan Antigen Tests in the Suspicion of Invasive Pulmonary Aspergillosis]. / Invaziv Pulmoner Aspergilloz Süpheli Hastalarda Galaktomannan ve Beta Glukan Antijen Testlerinin Karsilastirilmasi.

Opportunistic fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Invasive aspergillosis (IA) has an important place among these infections with ~ 250.000 cases annually. Reducing the mortality rate due to invasive aspergillosis is possible with early diagnosis and treatment of the disease. Because of the low sensitivity in microscopic examination, the time consuming of culture growth, and the difficulties in distinguishing colonization/infection, serological methods are frequently used in the diagnosis of invasive aspergillosis. The aim of this study was to determine the diagnostic performance of galactomannan and beta glucan tests for the diagnosis of invasive pulmonary aspergillosis (IPA). Sixty patients, followed up with the suspicion of invasive pulmonary aspergillosis in Gazi University Hospital were included in the study. The clinical classification of the patients was made according to the revised European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria. A total of 10 patients were classified as probable invasive aspergillosis and 20 patients were classified as possible invasive fungal disease. Demographic data of the patients and various risk factors were recorded. One hundred and thirty serum and nine bronchoalveolar lavage (BAL) fluid samples were studied with Plateliaᵀᴹ Aspergillus Ag (Bio-Rad, France), Dynamiker Aspergillus Galactomannan and Dynamiker Fungus (1-3)-beta-D-Glucan (Dynamiker, China) kits. Sensitivity and specificity values were calculated according to U.S. Food and Drug Administration (FDA) approved Plateliaᵀᴹ Aspergillus Ag test. According to this study, the most important risk factors in the development of IPA were the use of steroids and immunomodulatory drugs. The sensitivity of the galactomannan test in the probable group was 77.8%, the specificity was 96.7%, the sensitivity of the beta glucan test was 61.1%, and the specificity was 92.6%. When these two tests were evaluated together, it was observed that the sensitivity in the probable group increased to 83.3% and the specificity decreased to 89.3%. The combined use of galactomannan and beta glucan tests increases the diagnostic sensitivity. Although the presence of prolonged neutropenia is an important risk factor for IA, the use of steroids and immunomodulatory drugs should be kept in mind in non-neutropenic patients.

Occurrence of familial Mediterranean fever in haemophilia patients.

INTRODUCTION: This is the first study of simultaneous occurrences of Familial Mediterranean Fever (FMF) in patients with haemophilia. AIM: The aim was to investigate the frequency and clinical characteristics of FMF in patients with severe haemophilia. METHODS: Our study included 30 patients with severe haemophilia (26 haemophilia A and four haemophilia B). All 30 patients are screened for MEFV genotypes in FMF according to the new Eurofever/PRINTO diagnostic criteria. All cohorts were genetically tested for FMF and thrombophilia. RESULTS: Eight (26%) of 30 haemophilic patients were diagnosed with FMF. Six different heterozygous FMF mutations including M694V (n = 2), E148Q (n = 2), V726A(n = 1), P369S (n = 1), E148Q/K695R (n = 1) and E148Q/M694I (n = 1) were identified. Seven had haemophilia A and only one had haemophilia B. Four (50%) patients had a positive family history and three of them had extraarticular findings specific to FMF. Only one haemophilia B patient received colchicine. Target joints in the knee, ankle, and elbow were identified in three FMF patients. The number of target joints in eight patients with FMF was significantly lower than in twenty-two patients without FMF (p < .05). The annual number of suspected joint bleedings in FMF patients admitted to the hospital was 40; however, 15 (37.5%) were documented bleedings in ultrasounds. Hereditary thrombophilia was detected in seven of eight patients. CONCLUSION: Our data indicate that screening for FMF may be useful in patients with haemophilia who develop arthritis without prominent bleeding and have a positive family history in many Mediterranean countries, including Turkey.

Is comprehensive geriatric testing guiding in the identification of multiple myeloma patients who are candidates for autologous stem cell transplantation? A prospective analysis.

Multiple myeloma (MM) is a hematological malignancy of older adults. This study aimed to investigate the differences in performance, comorbidity scores, and comprehensive geriatric assessment (CGA) before and after induction therapy in newly diagnosed MM patients, as well as the factors that may be associated with improved performance status after induction therapy. Thirty-seven consecutive patients aged 50 years and older, who were newly diagnosed with MM, were included in the study. The patients underwent performance status evaluation and CGA when first diagnosed and after 4 cycles of induction chemotherapy. The performance status of 11 patients (40.7%) changed after induction therapy. Improvement in performance status was significantly lower in patients who were frail according to the Fried frailty criteria and IMWG scores (60% vs. 25%, p = 0.04), (30.0% vs. 6.2%, p = 0.02), taking more than 2 medications due to comorbidities (p = 0.01, confidence interval 0.06-0.09) and those with renal involvement (80.0% vs. 18.7%, p = 0.002). Those with bone involvement were more prevalent among the patients whose performance status improved (87.5% and 50.0%, p = 0.03). This study demonstrated that performance status might improve after induction therapy. Results suggest that CGA before induction therapy can predict performance status change. These results might have implications for predicting at the time of diagnosis, whether an MM patient can be a transplant candidate after induction therapy.

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

INTRODUCTION: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. METHODS: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. RESULTS: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. CONCLUSIONS: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics.

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis.

In this subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285), we evaluated efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with carfilzomib-dexamethasone (Isa-Kd) versus Kd in older (≥70 years of age, n = 86) and younger (<70 years, n = 216) patients with relapsed multiple myeloma (MM). Patients received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks in the Isa-Kd arm, and approved schedule of carfilzomib (twice weekly) and dexamethasone in both study arms. Primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included rates of overall response (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR). Addition of Isa to Kd resulted in improved PFS in elderly patients (hazard ratio, 0.36 [95% CI, 0.18-0.75]) consistent with the significant PFS improvement observed in the overall IKEMA population. Treatment with Isa-Kd improved depth of response versus Kd, with higher rates of ≥VGPR (73.1% vs. 55.9%), MRD- (23.1% vs. 11.8%), and CR (38.5% vs. 23.5%). Although the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in Isa-Kd, the incidence of serious TEAEs was similar between arms. Fewer elderly patients definitively discontinued treatment due to TEAEs in Isa-Kd than Kd: 11.8% versus 23.5%. In conclusion, Isa-Kd provides a consistent benefit versus Kd in elderly patients, with a manageable safety profile, and represents a new treatment option for patients with relapsed MM, independent of age.

Comparison of daily oral iron replacement therapy with every other day treatment in female reproductive age patients with iron-deficiency anemia.

Iron-deficiency anemia (IDA) is accepted as the most common cause of anemia in the world. The main goals of iron replacement therapy are to normalize the hemoglobin level and to replace iron stores. Current guidelines for treating iron deficiency recommend daily divided doses of iron to increase absorption. Hepcidin is a key regulator of systemic iron balance and acts in harmony with intracellular iron metabolism. Daily dosing and divided doses may increase serum hepcidin and decrease iron absorption. In this study, it was aimed to compare the effectiveness of daily and every other day oral iron replacement therapy in women of reproductive age with iron-deficiency anemia. We included premenopausal female patients aged between 18 and 50 years with iron-deficiency anemia. Forty patients were given oral iron therapy at a daily dose of 2*80 mg (iron sulfate). Forty-three patients were given iron treatment at a dose of 2*80 mg (iron sulfate) every other day. After 2 months of oral iron therapy, there was a significant improvement in hemoglobin, mean corpuscular volume, serum iron, total iron-binding capacity, and transferrin saturation in both groups. The values of hemoglobin, serum iron, transferrin saturation, and ferritin significantly increased at the end of the treatment for both groups. Although the median hepcidin level on the 15th-day measurement in the every other day treatment group was higher than that in the daily treatment group, there was no significant difference. As a result, the patients' compliance with the treatment can be increased by offering treatment every other day instead of daily, since it provides similar treatment effectiveness.

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics.

OBJECTIVE: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse. METHODS: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS). RESULTS: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. CONCLUSIONS: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

Immunomolecular evaluation of dihydroartemisinin effects on apoptosis in chronic lymphocytic leukemia cell lines.

INTRODUCTION: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown to induce apoptosis in many types of cancer cells. In this study, we aimed to determine the effects of DHA on apoptosis in human chronic lymphocytic leukemia (CLL) cell lines. METHODS: The cells were treated separately and combined by DHA and Fludurabine (FLU) during 24, 48 and 72 hours. The cell viabilities determined by XTT method. Following separate and combined treatment of IC50 concentrations of DHA and FLU to the cells during 24 hours, the cells were analyzed by flow cytometry to determine the effects on apopotis staining with AnnexinV FITC and PI. mRNA and protein expression levels of TCTP, Mcl-1, Bcl-2, Bax and Caspase-3 were analyzed to find out the molecular mechanisms of apoptosis by using quantitative real-time PCR and flow cytometric methods. RESULTS: Treatment with DHA alone or in combination with FLU induced apoptosis in a dose dependent manner in CLL cells. DHA alone was more effective than FLU alone or combined treatment with DHA and FLU. Our results suggest that Bcl-2 protein family member Bax was active in the apoptotic response of CLL cells after DHA treatment. Moreover, the apoptotic response induced by DHA was independent from the p53 mutation status of the CLL cells. CONCLUSION: DHA might be a potential anti-cancer therapeutic for CLL.

Hematopoietic Cell Transplant-Composite Risk (HCT-CR): A Novel Predictor of Prognosis in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curable treatment modality for hematologic disorders. Transplant-related mortality remains high despite prominent scientific and technologic improvements. In consideration with the potential impact of patient- and disease-related factors on transplant outcome, this retrospective study was performed to investigate the predictive role of pretransplant HCT-composite risk (HCT-CR) score in allo-HCT recipients. METHODS: A total of 313 patients with acute leukemia (male/female: 192/121; median age, 36 [18-71] years) were included in this study. The study cohort was divided into 2 subgroups based on pretransplant HCT-CR categories. The HCT-CRlo group included low-risk patients, and the HCT-CRint-hi group consisted of intermediate-, high-, and very high-risk patients. RESULTS: In the whole cohort, overall survival (OS) and 5-year OS were found to be 32.2% and 45.1%, respectively. Probability of OS was significantly better in the HCT-CRlo group compared with the HCT-CRint-hi group (P < .001). Leukemia-free survival (LFS) and 3-year LFS were 59.5% and 65.1%, respectively. Probability of LFS was better in the HCT-CRlo group compared with the HCT-CRint-hi group (P = .001). Nonrelapse mortality (NRM) and 3-year NRM were estimated to be 38.1% and 27.5%, respectively. Probability of NRM was significantly higher in the HCT-CRint-hi group compared with the HCT-CRlo group (P = .012). In multivariate analysis, HCT-CR was shown to have significant prognostic impact in acute lymphoblastic leukemia patients (P = .023; hazard ratio, 2.613; 95% CI, 1.142-5.982). CONCLUSION: Pretransplant evaluation of patient- and disease-related factors is essential for the accurate prediction of posttransplant survival. Further efforts to evolve current criteria for pretransplant risk assessment would eventuate in better transplant outcomes.

Evaluation of clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab in Turkey: a multicenter retrospective analysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare X-linked genetic disorder. On the contrary to its name, it is a multisystemic disease and various symptoms other than hemoglobinuria could be occurred. It could be life threatening especially because of thromboembolic events. In the last decade, a terminal complement inhibition with eculizumab approved with promising results for PNH patients. We conducted this study to evaluate the long term experience of eculizumab therapy from Turkey for the first time. Our cohort included 138 patients with PNH treated with eculizumab between January 2008 and December 2018 at 28 centers in Turkey. Laboratory and clinical findings at the time of diagnosis and after eculizumab therapy were recorded retrospectively. The median age was 39 (range 18-84) years and median granulocyte PNH clone size was 74% (range 3.06-99.84%) at the time of diagnosis. PNH with bone marrow failure syndrome was detected in 49 patients and the rest of 89 patients had classical PNH. Overall 45 patients (32.6%) had a history of any prior thrombotic event before eculizumab therapy and only 2 thrombotic events were reported during the study period. Most common symptoms are fatigue (75.3%), hemoglobinuria (18.1%), abdominal pain (15.2%) and dysphagia (7.9%). Although PNH is commonly related with coombs negativity, we detected coombs positivity in 2.17% of patients. Seven months after the therapy, increased hemoglobin level was seen and remarkably improvement of lactate dehydrogenase level during the treatment was occurred. In addition to previous studies, our real life data support that eculizumab is well tolerated with no serious adverse events and improves the PNH related findings.