Advancing the understanding of venetoclax in t(11;14)-positive multiple myeloma: a comprehensive review of clinical evidence and future prospects.

Venetoclax is a selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL2), as a targeted therapy for multiple myeloma (MM) patients. It was initially approved by the United States Food and Drug Administration for the treatment of chronic lymphocytic leukemia in April 2016 and later for acute myeloid leukemia in October 2020. However, venetoclax is used as an off-label in a subset group of relapsed and refractory multiple myeloma (RRMM) patients with the presence of translocation t(11;14). Preclinical and clinical studies have highlighted the potential of venetoclax in the management of MM patients, with a specific focus on t(11;14) as a predictive biomarker for initiating venetoclax-based treatment. Later, several studies in RRMM patients that used venetoclax in combination with dexamethasone or/and proteasome inhibitors have shown promising results, in which management guidelines have included venetoclax as one of the options to treat MM patients. Hence, this review focuses on the use of venetoclax in RRMM, clinical efficacy, safety, dosing strategies, and predictive biomarkers for initiating venetoclax. Additionally, we discuss ongoing studies that are investigating different combination of venetoclax regimens in MM patients.

De novo lymphoid blastic phase chronic myeloid leukemia: report and contemporary discussion.

OBJECTIVE: We herein describe two cases of de novo lymphoid blastic transformation in patients with no history of chronic-phase chronic myeloid leukemia (CP-CML), both of whom were labeled initially as Philadelphia positive B-Acute Lymphoblastic Leukemia (B-ALL). METHODS: The first patient was an 18-year-old male who presented with subjective fever, intentional weight loss, generalized fatigue, and headache. Investigations showed leukocytosis (312 × 10^3/ul), thrombocytopenia and anemia. Flowcytometry was consistent with B-ALL, with aberrant expression of CD13 and CD33. He was found to be positive for BCR::ABL by FISH, and karyotype confirmed the presence of the Philadelphia chromosome. He received a pediatric-inspired regimen and achieved remission with negative measurable residual disease (MRD) by flowcytometry, however with persistent cytogenetic abnormality using FISH for BCR::ABL. FISH abnormality was confirmed to be in the myeloid compartment using myeloid segregated FISH, reclassifying the disease to de novo lymphoid blastic phase CML. The second patient was a 52-year-old male who presented with fever and shortness of breath. Bilateral cervical lymphadenopathy and hepatosplenomegaly were identified on examination, and investigations showed leukocytosis (371 × 10^3/ul), anemia, and thrombocytopenia. BCR::ABL rearrangement was identified by FISH, molecular testing, and confirmed with karyotype. He was treated with Mini-CVD and Ponatinib, achieved complete remission with negative MRD by flow cytometry, however molecular studies showed BCR-ABL1 level at 58% IS indicating a persistent cytogenetic abnormality. RESULTS: De novo lymphoid blastic-phase CML can therefore be difficult to differentiate from Philadelphia positive B-ALL due to their overlapping clinical and laboratory picture, implying the need to do myeloid compartment evaluation at the time of diagnosis. CONCLUSION: With recent progress in the treatment of Philadelphia positive B-ALL, including the role of transplant with the use of novel agents, a better characterization of this disease entity in retrospective and prospective trials is warranted.

Use of Thrombopoietin Receptor Agonists in Pregnancy: A Review of the Literature.

The management of immune thrombocytopenic purpura (ITP) involves several lines of therapy such as corticosteroids and intravenous immunoglobulin. With the emergence of novel therapies such as thrombopoietin receptor agonists (TPO-RAs), there has been a shift in treatment modalities. Eltrombopag and romiplostim have proven to be effective in the management of ITP through clinical studies, but their safety in pregnancy remains uncertain. The purpose of the study is to review the literature to evaluate the safety of TPO-RAs in pregnant women. Ten case reports and a cohort study pertaining to the use of TPO-RAs in pregnancy were obtained. According to the reported cases and prospective study, the use of eltrombopag and romiplostim appears to be relatively safe in the first, second, and third trimesters, as there were no reported congenital malformations. Low fetal birth weight has been observed following the administration of eltrombopag during the second trimester, whereas preterm birth has occurred following the administration of eltrombopag in the third trimester. Eltrombopag and romiplostim seem relatively safe. Further studies are necessary to clarify their safety during pregnancy.

Role of 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Imaging in the Prediction of Prognosis in Patients With Indolent Lymphoma: Prospective Study.

BACKGROUND: The role of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in indolent lymphoma has been minimally studied. OBJECTIVE: This study aims to assess the value of FDG-PET/CT in predicting the prognosis of indolent lymphoma. METHODS: We prospectively recruited 42 patients with indolent lymphoma. A total of 2 patients were excluded, and 40 underwent baseline PET/CT and follow-up at various time points. A total of 9 patients were observed only, 7 received 4 doses of rituximab alone, and 24 received chemoimmunotherapy. Metabolic response on follow-up PET/CT was assessed using the maximum standardized uptake value (SUVmax) and Deauville criteria (DC). We aimed to obtain the best SUVmax and DC to predict optimal survival rates, risk stratification, and optimize therapeutic strategies. The mean follow-up from the initial diagnosis was 33.83 months. RESULTS: SUVmax <4.35 at interim PET/CT provided the best discrimination, with a progression-free survival (PFS) of 100% and a median survival time of 106.67 months compared with SUVmax ≥4.35 (P=.04), which had a PFS of 43.8% and a median survival time of 50.17 months. This cutoff was also valuable in predicting overall survival at baseline, that is, 100% overall survival with baseline SUVmax <4.35, versus 58.4% for SUVmax ≥4.35 (P=.13). The overall survival of patients with a baseline DC score <3.0 was 100%, with a median overall survival of 106.67 months. CONCLUSIONS: We demonstrated the utility of PET/CT in indolent lymphomas. SUVmax (<4.35 vs ≥4.35) on interim PET/CT performed best in predicting PFS.

Clinical course and outcomes of COVID-19 in hematopoietic cell transplant patients, a regional report from the Middle East.

The coronavirus disease-2019 (COVID-19) caused by SARS Coronavirus 2 (SARS-CoV-2) is a potentially lethal infection. Cancer patients, and specifically hematopoietic cell transplant (HCT) recipients are severely immunocompromised and may be at a higher risk of a complicated course with this infection. We aimed to study the COVID-19 outcomes and severity in post HCT patients. We retrospectively reviewed post-HCT patients diagnosed with COVID-19 between March 15, 2020, and December 1, 2020 at 10 transplant centers across the Middle East. We identified 91 patients with confirmed SARS-CoV-2 infection across 10 transplant centers. The median age upon presentation with COVID-19 was 35. Fifty two patients were post allo-HCT while the remaining 39 patients were post auto-HCT. The median time from transplant was 14.9 months. Mortality rate was 4.4%. Hospital admission rate was 53%. ICU admission rate was 14%. Mechanical ventilation rate was 10%. Oxygen supplementation rate was 18%. Time from HCT to COVID-19 >6 months was associated with lower admission rates and lower rates of the "severity" composite endpoint. Antibody responses was seen 67% of evaluable patients. In this series of HCT recipients, we report overall favorable clinical outcomes for patients with COVID-19 and provide preliminary insights into the clinical course of this disease in this specific population.

Prolonged Survival of a Patient with Chronic Myeloid Leukemia in Accelerated Phase with Recurrent Isolated Central Nervous System Blast Crisis.

BACKGROUND Chronic myeloid leukemia (CML) is usually a tri-phasic myeloproliferative neoplasm, characterized by the presence of the BCR-ABL1 fusion gene, derived from a balanced translocation, t(9;22)(q34;q11). BCR-ABL tyrosine kinase inhibitors (TKI) are used to treat patients with CML. The addition of pegylated interferon-alpha2b to imatinib or dasatinib results in promising deep molecular responses. Because imatinib shows poor penetration into the central nervous system (CNS), the CNS may become a sanctuary site in patients on prolonged imatinib therapy for CML. It is extremely rare for the blast phase in patients with chronic phase CML to affect the CNS without concomitant bone marrow involvement. CASE REPORT This report describes a 57-year-old woman who was diagnosed with accelerated phase (AP) CML and failed high dose imatinib therapy. Despite achieving an excellent molecular response to dasatinib in 6 months, she developed recurrent isolated CNS blast crisis. Survival was prolonged after treatment with intrathecal chemotherapy and whole-brain radiation therapy combined with dasatinib. After achieving long and deep molecular remission with dasatinib and a few months of pegylated interferon-alpha2a, she lived for 18 months in treatment-free-remission (TFR). At age 65 years, she died of progressive rectal carcinoma with septic shock, cancer-related venous thromboembolism, and a possible autoimmune disorder. CONCLUSIONS This patient with accelerated phase CML and 2 isolated CNS blast crises died in TFR 8.5 years after her initial diagnosis and 7.5 years after her first isolated CNS blast crisis. Survival resulted from tailoring of therapies around her comorbidities.

The use of 5-azacytidine in pregnant patient with Acute Myeloid Leukemia (AML): a case report.

BACKGROUND: The management of Acute Myeloid Leukemia (AML) during pregnancy remains challenging as both the maternal and fetal outcomes should be considered. Several reports suggested that chemotherapy can be administered safely during the second and third trimester of pregnancy. However, the use of 5-azacytidine presents limitation due to lack of data. CASE PRESENTATION: A 28-years-old woman in the 26th week of gestation diagnosed with FLT3/ITD-mutated AML, complete remission was induced by Daunorubicin and Cytarabine, and subsequently with 5-azacytidine (75 mg/m2 daily for 7 days) with no fetal hematological or toxicity issues. Fetal ultrasound showed no aberrant morphology. Fetal size below the 5th percentile with normal umbilical artery dopplers, normal middle cerebral artery dopplers and ductus venosus doppler. Three weeks post 5-azacytidine, the team determined the most appropriate time for delivery after balancing the risks of prematurity and prevention of disease relapse since patient in hematological remission. The patient underwent elective lower segment caesarian section and had a baby girl delivered at 35 weeks of gestation weighing 1670 g without apparent anomalies. CONCLUSION: Treatment using 5-azacytadine during last trimester of pregnancy resulted in no major fetal and maternal complications. These findings concluded that 5-azacytadine during the third trimester of pregnancy seems to be safe however, potential risks of this agent should be considered.

An Intriguing Case of Eosinophilia with FIP1L1/PDGFRA Rearrangement Who Presented as Thrombotic Thrombocytopenic Purpura.

Myeloid neoplasm with eosinophilia and FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) rearrangement is a multi-organ disease with diverse clinical presentation. Thrombotic thrombocytopenic purpura (TTP) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic organ damage. To our knowledge, only one case of eosinophilia with FIP1L1-PDGFRA rearrangement presented as a case of thrombotic thrombocytopenic purpura reported in the literature. We herein report a case of a young male patient with hypereosinophilic syndrome and FIP1L1-PDGFRA rearrangement who presented with asthma, transient ischemic attacks (TIA), and confusion. He had an acquired TTP that was successfully treated with plasma exchanges (PLEX), corticosteroids, rituximab, and later with the addition of imatinib mesylate (Gleevec, Novartis). He remains in complete remission on imatinib 100 mg daily for more than 28 months of follow-up.

Systemic Lupus Erythematosus Presenting as Hematoma of the Hand Due to Acquired Inhibitors to Factor VIII: Early and Prolonged Remission Achieved with Upfront Rituximab.

Acquired hemophilia is a rare autoimmune disorder that is a result of antibodies against clotting factor VIII and it presents with excessive or prolonged bleeding, often into the muscles. Thrombotic phenomena with lupus anticoagulant are common in patients with systemic lupus erythematosus (SLE). We report a rare case of a young female with no significant past medical history presenting with hematoma of the hand who was later on found to have acquired hemophilia, SLE with antiphospholipid antibodies (APLA). She was successfully treated with upfront rituximab and prednisolone leading to early and prolonged remission. No increased incidence of infections was noted. Upfront rituximab appears to be a safe and effective option in the management of such patients when compared to use of cytotoxic agents such as cyclophosphamide; however, further data from randomized studies is needed. Neutropenia and acquired hemophilia should also be considered to be listed under hematological manifestations of SLE diagnostic criteria, as they are not uncommon in such patients.

Thrombotic thrombocytopenic purpura - analysis of clinical features, laboratory characteristics and therapeutic outcome of 24 patients treated at a Tertiary Care Center in Saudi Arabia.

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. The primary aim was overall response rate (ORR) assessment in the treated patients. METHODS: This retrospective study included 24 patients treated during 2006-2015. TTP patients with microangiopathic hemolysis (MAHA) and thrombocytopenia were included. We analyzed clinical features, laboratory characteristics and treatment outcomes of 24 TTP patients treated at our tertiary care center (KFMC). RESULTS: Twenty-four TTP patients (18 females; 6 males) had a mean age of 33.5±13.9 years; 22(91%) had neurologic features, 7(29%) fever, 10(42%) renal impairment; 4(20.83%) cardiac manifestations; 22(91.7%) had triad with additional neurologic abnormalities; only 2(8.2%) had pentad of TTP. Majority (54.16%) had idiopathic TTP. All patients received therapeutic plasma exchange (TPE); 23(95.8%) received adjunctive corticosteroids and 13(54.2%) received rituximab either due to refractoriness to TPE on ~day7, or earlier. Twenty-one out of 24 (87.5%) achieved complete remission (CR) without any subsequent relapse. At 22 months (median, range 1-113), 20 patients (83.3%) are alive at the time of report. Three patients died during acute episode because of sever disease or delayed treatment and one died in CR. CONCLUSION: TPE, steroids and or rituximab was very effective in preventing high risk of mortality and achieving durable CR in 87.5% of patients. More awareness is needed for early diagnosis and early referral to centers with appropriate tertiary care facilities..

The benefit of consolidation radiotherapy to initial disease bulk in patients with advanced Hodgkin's disease who achieved complete remission after standard chemotherapy.

BACKGROUND/PURPOSE: The aim of this study was to evaluate the role of consolidation radiotherapy (RT) in advanced-stage Hodgkin's disease (HD) with initial bulky sites after radiological complete remission (CR) or partial response (PR) with positron emission tomography-negative (metabolic CR) following standard chemotherapy (ABVD [Adriamycin, bleomycin, vinblastine, and dacarbazine]) six to eight cycles. PATIENTS AND METHODS: Adult patients with advanced-stage HD treated at our institute during the period 2006 to 2012 were retrospectively evaluated. One hundred and ninety-two patients with initial bulky disease size (>7 cm) who attained radiological CR/PR and metabolic CR were included in the analysis. One hundred and thirteen patients who received radiotherapy (RT) as consolidation postchemotherapy (RT group) were compared to 79 patients who did not receive RT (non-RT group). Disease-free (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method and were compared according to treatment group by the log-rank tests at P ≤0.05 significance level. RESULTS: The mean age of the cohort was 33 (range: 14 to 81) years. Eighty-four patients received involved-field radiation and 29 patients received involved-site RT. The RT group had worse prognostic factors compared to the non-RT group. Thirteen (12%) relapses occurred in the RT group, and 19 (24%) relapses occurred in the non-RT group. Nine patients (8%) in the RT group died, compared to eleven patients (14%) in the non-RT group. Second malignancies were seen in only five patients: three patients in the RT group compared to two patients in the non-RT group. At 5 years, overall DFS was 79%±9% and OS was 85%±9%. There was significant statistical difference between the RT group and the non-RT group regarding 5-year DFS: 86%±7% and 74%±9%, respectively (P ≤0.02). However, the 5-year OS was 90%±5% for the RT group and 83%±8% for the non-RT group, with no statistical difference (P ≤0.3). CONCLUSION: The results of our study suggest that consolidation RT in patients with advanced-stage HD with initial bulky disease who had postchemotherapy radiologic CR or PR with metabolic CR improved the DFS.

Primary burkitt lymphoma of the fourth ventricle in an immunocompetent young patient.

Primary Burkitt lymphoma of the central nervous system (CNS) is rare, with only few cases reported in the literature. An 18 year-old immunocompetent male presented with multiple cranial nerves palsies and was found to have a mass predominantly in the 4th ventricle of the brain. Tumor was surgically removed and showed morphological and immunohistochemical features consistent with Burkitt lymphoma. The patient responded very well to anthracycline based chemotherapy with high dose methotrexate (HD MTX) and intrathecal (IT) chemotherapy delivered by Ommaya reservoir. Primary Burkitt lymphoma of the CNS is a rare entity that poses differential diagnostic challenge with other small round blue cell tumors.

Surgeon and haematologist: a review of comprehensive care for patients with inherited bleeding disorders in Northern Ireland.

BACKGROUND: Management of patients with inherited bleeding disorders has improved since the introduction of Comprehensive Care Centres (CCC) in the United Kingdom (UK). In the event such patients need surgery, the aim of the multidisciplinary team is to facilitate outcomes as good as what would be expected in a non-bleeding disorder patient. A review of such comprehensive care was carried out in patients with inherited bleeding disorders when they needed surgery at Northern Ireland CCC. Aims of the study were to evaluate surgical morbidity and mortality in these patients. METHODS: All patients with inherited bleeding disorders who underwent non-orthopaedic surgery between 2008 and 2012 were identified from the CCC records within the Belfast Health and Social Care Trust (BHSCT) in Northern Ireland (NI) and their case records reviewed. RESULTS: 28 patients received elective and emergency surgery during this period. There was minimum morbidity and no mortality in this cohort. CONCLUSIONS: Surgery in patients with inherited bleeding disorders has become safe with the advent of multidisciplinary CCCs. Close communication between surgeon and haematologist is key in the successful management of these complex patients.