Real-World Clinical Outcomes and Adverse Events in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Single-Center Retrospective Study.

Background and Objectives: The treatment of chronic lymphocytic leukemia (CLL) has acquired new targeted therapies. In clinical trials, ibrutinib improved outcomes safely. Real-world data called for a reappraisal of ibrutinib strategies. We report on a single center's experience with ibrutinib monotherapy, aiming to explore the outcomes, tolerability, and prognosis of CLL patients in routine clinical practice. Materials and Methods: Data were collected from all CLL patients treated with ibrutinib at Fundeni Clinical Institute, Bucharest, Romania, between January 2016 and June 2021. Results: A total of one hundred twenty-three CLL adult patients were treated with ibrutinib. Of the patients, 87% had relapsed/refractory CLL. The median age at ibrutinib initiation was 65 years; 44.7% of patients were staged Rai III/IV. At 32-month median follow-up, the median progression-free survival (PFS) was 50 months, the overall survival (OS) was not reached, and the overall response rate (ORR) was 86.2%. The age or number of previous therapies did not impact outcomes or tolerability. An Eastern Cooperative Oncology Group performance status (ECOG PS) score ≥ 2 and shorter time from initiation of last therapy (TILT) before ibrutinib predicted inferior PFS. Baseline characteristics had no impact on the OS except for TILT in R/R CLL patients. Drug-related adverse events (AEs) of any grade and grade ≥ 3 AEs were reported in 82.1% and 30.9% of the patients, respectively. Infections were the most common AEs (29.3%). Drug discontinuation was permanent in 43.9% of patients, mainly due to disease progression (17.1%) and toxicity (8.9%). Patients with a Cumulative Illness Rating Scale (CIRS) score ≥ 6 had a higher risk for toxicity-related discontinuation. An ECOG PS ≥ 2 predicted an increased rate of permanent discontinuation and grade ≥ 3 AEs. Conclusions: The outcomes of this study align with the results from ibrutinib clinical trials. Our study demonstrated that poor patient fitness, early relapse before ibrutinib, and permanent ibrutinib discontinuation are essential outcome determinants. Patient comorbidity burden and fitness were significant predictors for ibrutinib intolerance.

Determining diagnostic delays in Romanian multiple myeloma patients using the Aarhus statement.

Introduction: Multiple Myeloma (MM) is classified as one of the most challenging cancers to diagnose, and the hematological malignancy is associated with prolonged diagnostic delays. Although major steps have been made in the improvement of MM patient diagnosis and care, Romanian patients still face long diagnostic delays. Thus far, there have been no studies evaluating the factors associated with diagnostic errors in Romanian MM patients. Methods: Using the Aarhus statement, we prospectively determined the diagnostic intervals for 103 patients diagnosed with MM at Fundeni Clinical Institute, between January 2022 and March 2023. Results: Our data revealed that the main diagnostic delays are experienced during the "patient interval." Patients spend a median of 162 days from the first symptom onset until the first doctor appointment. Bone pain is the most frequently reported symptom by patients (78.64%), but it leads to a medical-seeking behavior in only half of the reporting patients and results in a median delay of 191 days. The changes in routine lab tests are considered most worrisome for patients, leading to a medical appointment after a median of only 25 days. The median primary care interval was 70 days, with patients having an average of 3.7 medical visits until MM suspicion was first raised. The secondary care interval did not contribute to the diagnostic delays. Discussion: Overall, the median diagnostic path for MM patients in Romania was more than 6 months, leading to a higher number of emergency presentations and myeloma-related end-organ damage.

The Efficacy of Carfilzomib Treatment in Bortezomib-Refractory Patients-Real Life Experience in a Tertiary Romanian Hospital.

Background: Proteasome inhibitors (PIs) represent one of the most effective classes of therapy for patients with multiple myeloma (MM) and are incorporated in many of the current treatment regimens. The first-generation PI, bortezomib, has shown impressive results in patients with either newly diagnosed or relapsed/refractory MM, but once patients become resistant, treatment is increasingly challenging. Although the existing data show that the second-generation PI, carfilzomib, is highly efficient, there is still limited knowledge regarding the response to carfilzomib-based therapy in bortezomib-resistant patients. The aim of this study was to evaluate carfilzomib treatment performance in bortezomib-sensitive versus -refractory patients, in a real-life eastern European country setting. Methods: We retrospectively evaluated 127 adult patients exposed to bortezomib with relapsed or refractory MM, that subsequently received a carfilzomib-based therapy. We investigated the differences in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) after carfilzomib-based therapy between the two patient groups. Results: The ORR in the bortezomib-sensitive group was significantly higher than that in the refractory group, leading to a superior PFS in this category of patients. For patients presenting with a high cytogenetic risk, we observed a significant difference in PFS between the bortezomib-sensitive and -refractory group, while standard cytogenetic risk patients presented a similar PFS regardless of the bortezomib sensitivity status. In addition, in patients with ISS (International Staging System) stage I or II, the previous sensitivity to bortezomib correlated with an improved PFS, while for patients with ISS stage III, both groups had a comparable PFS. No significant differences in OS were observed between the two groups. Conclusions: In countries where novel or experimental therapies are not readily available, carfilzomib-based therapy can still be a viable therapy option for patients presenting with bortezomib-refractory status, an ISS stage III, and standard cytogenetic risk.

Translation, Cultural Adaptation, and Validation into Romanian of the Myeloproliferative Neoplasm Symptom Assessment Form-Total Symptom Score (MPN-SAF TSS or MPN-10) Questionnaire.

Background: Patients with myeloproliferative neoplasms (MPNs) experience a high disease-related symptom burden. A specific instrument to evaluate quality of life (QoL), i.e., the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10), was developed. We conducted the translation, cultural adaptation, and validation into Romanian of the MPN-10. Methods: We translated the MPN-10 and tested its psychometric properties. Results: We recruited 180 MPN patients: 66 polycythemia vera (36.67%), 61 essential thrombocythemia (33.89%), 51 primary and secondary myelofibrosis (SMF) (28.33%), and 2 MPN-unclassifiable (1.11%). The mean TSS was 19.51 ± 16.51 points. Fatigue, inactivity, and concentration problems were the most cumbersome symptoms. We detected scoring differences between MPN subtypes regarding weight loss (p < 0.001), fatigue (p = 0.006), early satiety (p = 0.007), night sweats (p = 0.047), pruritus (p = 0.05), and TSS (p = 0.021). There were strong positive associations between TSS and inactivity, fatigue, and concentration problems, and moderate negative correlations between QoL scores and all MPN-10 items. Cronbach's α internal consistency coefficient was 0.855. The Kaiser-Meyer-Olkin construct validity test result was 0.870 and the Bartlett Sphericity Test was significant (p < 0.001). Symptom scores were loaded into one single factor according to the exploratory factor analysis. Conclusions: The Romanian MPN-10 version displayed excellent psychometric properties and is a reliable instrument for assessing symptom burden and QoL in Romanian MPN patients.

Evans Syndrome as a Possible Complication of Brentuximab Vedotin Therapy for Peripheral T Cell Lymphoma.

Recently, Brentuximab Vedotin (BV) has emerged as an important therapy not only for Hodgkin's Lymphoma, but also for CD30-positive T cell lymphomas. Although anemia and thrombocytopenia are common myelosuppressive side effects, to our knowledge, this is the first described case of Evans Syndrome associated with BV therapy. We present the case of a 64-year-old female, diagnosed with relapsed Peripheral T Cell Lymphoma Not Otherwise Specified (PTCL-NOS), who, after receiving six cycles of BV, developed authentic severe autoimmune hemolytic anemia with strong positive direct anti-globulin (Coombs) test, simultaneously associated with severe immune thrombocytopenia. The patient was unresponsive to systemic corticotherapy, but fully recovered after a course of IV immunoglobulin.

Quantitative SPECT/CT Parameters in the Assessment of Transthyretin Cardiac Amyloidosis-A New Dimension of Molecular Imaging.

AIMS: Cardiac transthyretin amyloidosis (ATTR) represents the accumulation of misfolded transthyretin in the heart interstitium. Planar scintigraphy with bone-seeking tracers has long been established as one of the three main steps in the non-invasive diagnosis of ATTR, but lately, single-photon emission computed tomography (SPECT) has gained wide recognition for its abilities to exclude false positive results and offer a possibility for amyloid burden quantitation. We performed a systematic review of the existing literature to provide an overview of the available SPECT-based parameters and their diagnostic performances in the assessment of cardiac ATTR. Methods and Methods: Among the 43 papers initially identified, 27 articles were screened for eligibility and 10 met the inclusion criteria. We summarised the available literature based on radiotracer, SPECT acquisition protocol, analysed parameters and their correlation to planar semi-quantitative indices. RESULTS: Ten articles provided accurate details about SPECT-derived parameters in cardiac ATTR and their diagnostic potential. Five studies performed phantom studies for accurate calibration of the gamma cameras. All papers described good correlation of quantitative parameters to the Perugini grading system. CONCLUSIONS: Despite little published literature on quantitative SPECT in the assessment of cardiac ATTR, this method offers good prospects in the appraisal of cardiac amyloid burden and treatment monitoring.

Real-world use of carfilzomib combined with lenalidomide and dexamethasone in patients with multiple myeloma in Europe and Israel.

Clinical trials have demonstrated the efficacy and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM); however, prospective real-world data are limited. This real-world, prospective, observational study evaluated carfilzomib use, effectiveness and safety in adults with RRMM. Data are presented for a subset of patients (n = 383) who received carfilzomib in combination with lenalidomide and dexamethasone (KRd). The overall response rate (ORR) was 83.6% among 360 evaluable patients. Treatment responses were better when KRd was administered at earlier therapy lines than at later lines of therapy (ORR: second line, 85.3%; third line or later, 81.0%). In patients with the anti-CD38 antibody-refractory disease, ORR was higher when KRd was administered earlier than at later therapy lines (second line/third line, 75.0%; fourth line or later, 60.0%). An ORR of 68.1% and 82.0% was achieved in the lenalidomide-refractory and not lenalidomide-refractory subgroups, respectively. KRd was consistently administered per the European label (twice weekly dose of 27 mg/m2) and the median time to discontinuation was 14.6 months. The safety profile of KRd was consistent with previous studies. These real-world data highlight the effectiveness of KRd as a treatment for patients with RRMM, including those with disease refractory to lenalidomide or anti-CD38 antibodies.

Proteasome inhibition in combination with immunotherapies: State-of-the-Art in multiple myeloma.

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for around 1.8% of all neoplastic diseases. Nowadays, clinicians have a broad arsenal of drugs at their disposal for the treatment of MM, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, CAR T-cell therapies and antibody-drug conjugates. In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. Studies suggest that the early use of immunotherapy may improve outcomes significantly. Therefore, in our review we specifically focus on the combination therapy of proteasome inhibitors with novel immunotherapies and/or transplant. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their combinations with immunotherapies.

Real-World Use and Effectiveness of Carfilzomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma in Europe.

This prospective, observational study examined the real-world use of carfilzomib across 11 European countries in adults with relapsed/refractory multiple myeloma (RRMM) who received at least one prior line of therapy. Carfilzomib and dexamethasone (Kd) use, effectiveness and safety were analyzed. In total, 271 patients received Kd among 701 adults enrolled. The median relative dose intensity of carfilzomib was 82.7% (20/56 mg/m2, twice weekly). The overall response rate (ORR) to Kd was 68.8% (95% confidence interval [CI], 62.7-74.5): 79.2% in second line (2L), 71.6% in third line (3L) and 63.1% in fourth line or later (4L+). The ORR was 59.9% (95% CI, 51.1-68.1) in the lenalidomide-refractory subgroup and 67.7% (95% CI, 48.6-83.3) in the not lenalidomide-refractory subgroup. In the anti-CD38 refractory subgroup, the ORR was 51.6% (95% CI, 38.6-64.5); ORRs were higher when Kd was received at 2L/3L (66.7%) than at 4L+ (49.1%). Overall, patients were treated for a median time of 7.7 months. One-fifth of patients reported treatment-related treatment-emergent adverse events (≥grade 3), with a safety profile consistent with previous clinical trials. This study demonstrated the real-world use, effectiveness and safety of Kd in patients with RRMM. Despite the increasing number of new therapeutic strategies to treat RRMM, Kd remains a safe and effective option, even for older, frail and lenalidomide- or anti-CD38 mAb-refractory patients.

Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature.

Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. This has however dramatically improved in the last few years with the increased usage of the novel therapies such as proteasome inhibitors and haematopoietic cell transplantation, in the case of timely diagnosis and initiation of treatment. The treatment for AL is directed by the haematologist working closely with the cardiologist when there is a significant cardiac involvement. Transthyretin (TTR) is a protein that is produced by the liver and is involved in the transportation of thyroid hormones, especially thyroxine and retinol binding protein. ATTR results from the accumulation of transthyretin amyloid in the extracellular space of different organs and systems, especially the heart and the nervous system. Specific therapies for ATTR act at various levels of TTR, from synthesis to deposition: TTR tetramer stabilization, oligomer aggregation inhibition, genetic therapy, amyloid fibre degradation, antiserum amyloid P antibodies, and antiserum TTR antibodies. Treatment of systemic amyloidosis has dramatically evolved over the last few years in both AL and ATTR, improving disease prognosis. Moreover, recent studies revealed that timely treatment can lead to an improvement in clinical status and in a regression of amyloid myocardial infiltration showed by imaging, especially by cardiac magnetic resonance, in both AL and ATTR. However, treating cardiac amyloidosis is a complex task due to the frequent association between systemic congestion and low blood pressure, thrombo-embolic and haemorrhagic risk balance, patient frailty, and generally poor prognosis. The aim of this review is to describe the current state of knowledge regarding cardiac amyloidosis therapy in this constantly evolving field, classified as treatment of the cardiac complications of amyloidosis (heart failure, rhythm and conduction disturbances, and thrombo-embolic risk) and the disease-modifying therapy.

Muscle involvement with pseudohypertrophy in systemic light chain amyloidosis: Case report.

RATIONALE: Muscle pseudohypertrophy is a rare manifestation of light chain amyloidosis (AL) amyloidosis. PATIENT CONCERNS: A 63-year-old woman presented with a 2-year history of progressive asthenia, macroglossia, dysphonia, cachexia, hypotension, paresthesia, and lower limb muscle hypertrophy. DIAGNOSIS: Free serum lambda light chains were increased, and fat pad biopsy demonstrated Congo red-positive deposits. Additionally, electromyography showed a myopathic pattern, whereas muscle biopsy revealed amyloid deposits. A diagnosis of λAL with cardiac, renal, nervous system, and skeletal muscle involvement was established. INTERVENTIONS AND OUTCOMES: The patient received 3 subsequent lines of therapy over the following 23 months, with very slow hematological remission followed by resolution of organ dysfunction. LESSONS: Despite its rarity, muscle involvement should be considered in patients diagnosed with AL amyloidosis associated with unexplained muscle hypertrophy or weakness associated with macroglossia or elevated troponin T levels in the absence of clear cardiac involvement.

Patient Preferences for Multiple Myeloma Treatments: A Multinational Qualitative Study.

Background: Investigational and marketed drugs for the treatment of multiple myeloma (MM) are associated with a range of characteristics and uncertainties regarding long term side-effects and efficacy. This raises questions about what matters most to patients living with this disease. This study aimed to understand which characteristics MM patients find most important, and hence should be included as attributes and levels in a subsequent quantitative preference survey among MM patients. Methods: This qualitative study involved: (i) a scoping literature review, (ii) discussions with MM patients (n = 24) in Belgium, Finland, Romania, and Spain using Nominal Group Technique, (iii) a qualitative thematic analysis including multi-stakeholder discussions. Results: MM patients voiced significant expectations and hopes that treatments would extend their lives and reduce their cancer signs and symptoms. Participants however raised concerns about life-threatening side-effects that could cause permanent organ damage. Bone fractures and debilitating neuropathic effects (such as chronic tingling sensations) were highlighted as major issues reducing patients' independence and mobility. Patients discussed the negative impact of the following symptoms and side-effects on their daily activities: thinking problems, increased susceptibility to infections, reduced energy, pain, emotional problems, and vision problems. MM patients were concerned with uncertainties regarding the durability of positive treatment outcomes, and the cause, severity, and duration of their symptoms and side-effects. Patients feared short-term positive treatment responses complicated by permanent, severe side-effects and symptoms. Conclusions: This study gained an in-depth understanding of the treatment and disease-related characteristics and types of attribute levels (severity, duration) that are most important to MM patients. Results from this study argue in favor of MM drug development and individual treatment decision-making that focuses not only on extending patients' lives but also on addressing those symptoms and side-effects that significantly impact MM patients' quality of life. This study underscores a need for transparent communication toward MM patients about MM treatment outcomes and uncertainties regarding their long-term efficacy and safety. Finally, this study may help drug developers and decision-makers understand which treatment outcomes and uncertainties are most important to MM patients and therefore should be incorporated in MM drug development, evaluation, and clinical practice.

Clinical characteristics in patients with hereditary amyloidosis with Glu54Gln transthyretin identified in the Romanian population.

BACKGROUND: In Romania, 23 patients have been diagnosed with hereditary transthyretin amyloidosis (ATTRh), 18 of whom have the Glu54Gln mutation. This retrospective cohort included all patients with Glu54Gln-mutated ATTRh who were diagnosed in Romania from 2005 to 2018. RESULTS: Of 18 patients, 10 were symptomatic, five were asymptomatic carriers and three died during the study. All originated from North-East Romania. Median age at symptom onset was 45 years; median age at death was 51 years. All patients had cardiac involvement, including changes in biomarkers (mean N-terminal-pro B-type natriuretic peptide: 2815.6 pg/ml), electrocardiography (15% atrial fibrillation, 38% atrioventricular block, 31% right bundle block), and echocardiography (mean interventricular septum: 16 mm, mean left ventricular ejection fraction: 49%). Scintigraphy showed myocardial radiotracer uptake in all patients. In addition, 92% of patients had polyneuropathy at diagnosis and 53% had carpal tunnel syndrome; 69% exhibited orthostatic hypotension and 31% suffered from diarrhea. No renal or liver involvement was observed. CONCLUSIONS: This is the largest Glu54Gln-mutated ATTRh cohort diagnosed to date, and to our knowledge the first describing this variant worldwide. Clinical features of this variant are early onset, neurological and cardiac involvement, aggressive disease progression and short survival. Early diagnosis and therapeutic intervention have potential to improve prognosis in ATTRh.

IgG,kappa monoclonal gammopathy of unknown significance with AL amyloidosis simulating giant cell arteritis.

Monoclonal gammopathies complicated by AL amyloidosis can mimic giant cell arteritis (GCA). We hereby present the case of a 63 year old woman in whom symptoms consistent with GCA were the first manifestations of a monoclonal gammopathy of unknown significance (MGUS) associated with amyloidosis. A 63 year old woman was admitted for temporal headache, maseterine claudication, neck and shoulder stiffness. She was recently diagnosed with carpal tunnel syndrome. On physical examination she had prominent temporal arteries, macroglosia and orthostatic hypotension. Muscular strength was normal. She had high ESR and CRP; in this clinical context, GCA was suspected. A gamma spike on serum protein electrophoresis raised the suspicion of monoclonal gammopathy (MG). Immunoelectrophoresis revealed monoclonal bands for IgG and kappa chains. Massive deposits of amyloid and no inflammation were found on temporal artery biopsy. Multiple myeloma and lymphoma were ruled out. A diagnosis of AL amyloidosis complicating MGUS was formulated. She did well on therapy with bortezomib, cyclophosphamide and dexamethasone. Cases published in medical literature reveal amyloidosis mimicking GCA in the setting of established MGUS. As far as we know, this is the first case of MGUS with IgG and kappa chains in which a GCA-like picture induced by amyloidosis was present from the very onset.

The occurrence of chronic lymphocytic leukemia after chronic phase of chronic myeloid leukemia: case report and literature review.

The occurrence of chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) in the same patient is a rare event. In published literature, CML diagnosis follows CLL diagnosis or both leukemias are diagnosed simultaneously or rarely, CLL diagnosis follows CML diagnosis. We report the case of one patient with renal adenocarcinoma who was diagnosed with CLL 60 months after CML diagnosis. At that time, the patient was in complete cytogenetic response (CCyR) and major molecular response (MMR) of CML clone according to European LeukemiaNet (ELN) recommendations and presented clinical and hematological signs of progressive CLL clone. After 24 months of regular monitoring, the patient presented signs of CLL clone expansion. The FISH (fluorescence in situ hybridization) analysis for CLL prognostic factors, performed before treatment, was positive for tumor protein p53 (TP53) and 13q14.3 mutations. The Li-Fraumeni syndrome (LFS) was considered but TP53 mutation was considered acquired and patient's reduced overall, progression free and disease free survival might sustained that hypothesis. Imatinib (IM) was stopped and patient received chemotherapy until obtained a stable partial response. Twelve months after last cycle of chemotherapy, the patient received second line treatment due CLL clone progression signs but died due to neutropenia related complications. This article is the first Romanian report of CLL occurrence after CML diagnosis and as far as we know the fourth case report of such association in published literature.