Hematologic Adverse Events Research Articles

Efficacy and Safety of Olverembatinib-Based Therapies in Patients with Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia

Background Olverembatinib is an oral, third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed in China that could effectively target wild-type and mutant BCR-ABL1 kinase. It is effective and well-tolerated for patients with chronic myeloid leukemia. However, its efficacy and safety in patients with Ph/BCR-ABL1-Positive acute lymphoblastic leukemia are not entirely clear. This study aims to analyze the efficacy and safety of Olverembatinib-based therapies in patients with Ph/BCR-ABL1-Positive acute lymphoblastic leukemia. Methods Patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia who received the Olverembatinib-based therapies in our center were included to conduct this retrospective study. Results Totally 33 patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia were included in this study with a median age of 41 years, of whom 21 (63.63%) were female. Among them, 19 subjects who had been previously treated with standard chemotherapy and three newly diagnosed patients received Olverembatinib-based therapies, while 11 patients received Olverembatinib-based therapies after hematopoietic stem cell transplantation. After the first course of the Olverembatinib-based regimen, 33 (100%) patients experienced remission (CR/CRi/ Morphologic leukemia-free state), and 22 (66.67%) achieved the negative minimal residual disease (MRD) of BCR-ABL1/ ABL. Followed by the first course of the Olverembatinib-based regimen, five patients with negative MRD were treated with HSCT successfully and 27 received the second course of Olverembatinib-based therapy, of whom 21 (77.78%) acquired negative MRD. For six patients with negative MRD of BCR-ABL1/ ABL1, Olverembatinib-based therapies could remain the negative MRD. These patients with negative MRD will receive allogeneic hematopoietic stem cell transplantation after Olverembatinib-based therapy. Olverembatinib-based therapies were generally well tolerated. Common hematologic adverse events included leukopenia, neutropenia, anemia, and thrombocytopenia. Common nonhematologic adverse events included hepatotoxicity, nephrotoxicity, myalgia, arthralgia, rash, and edema, of which most were mild. Conclusion Olverembatinib-based therapies are generally well tolerated and efficacious for patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia.

Feasibility of a Novel Academic Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory AL Amyloidosis

BACKGROUND: While anti-BCMA chimeric antigen receptor T-cell therapy (CART) have proven safe and efficient in multiple myeloma (MM), its application to AL amyloidosis (AL), has been restricted due to the frailty of this population and rarity of disease. HBI0101 therapy is a novel anti-BCMA CART-based therapy developed at Hadassah Medical Center and Bar-Ilan University for MM treatment. In a phase Ia-b/2 study (NCT04720313), HBI0101 has demonstrated manageable safety with therapeutic efficacy in over 70 MM patients. Although BCMA targeting in AL has been questioned because of relatively low expression of this antigen on AL plasma cells (PC), we have previously reported that this level of expression is sufficient to enable PC eradication by HBI0101 CART ex vivo. Based on this observation, we have treated 9 AL patients in our study, which represent the largest cohort of AL treated with anti-BCMA CART reported so far. METHODS: The patients were treated within the following cohorts: 1 received 150x10^6 CART cells, 2 received 450x10^6 CART cells and 6 received 800x10^6 CART cells. Two of the patients were treated on a compassionate basis due to concomitant myelodysplastic syndrome (MDS) / ECOG 4 performance status. Patients with creatinine clearance ≥30ml/min (n=7) received lymphodepletion with fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion, and patients with creatinine clearance <30ml/min (n=2) received lymphodepletion with bendamustine 90mg/m 2 and on days -4 and -3 before infusion. Two patients with NYHA stage 3 and MAYO stage 3b AL-related heart failure were admitted electively to the intensive care unit before infusion for close monitoring. RESULTS: Nine AL patients with relapsed/refractory disease were included, with a median of 6 prior lines of therapy (range: 3-10), all refractory to their last line of therapy. All patients were triple refractory to PI, IMiD and anti-CD38 antibody, 6 were penta-refractory and 5 were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Seven had cardiac involvement, including 4 with MAYO-stage 3a/3b at study entry. Hematologic adverse events included: grade 3-4 neutropenia in 5 patients, Grade 2-3 anemia in 3 patients, and worsening of pre-existing thrombocytopenia to grade 4 in 1 patient. Three patients developed AL-related organ deterioration (kidney- 2, heart- 1), subsequently resolved to baseline function. Cytokine-released syndrome (CRS) was observed in 7/9 (grade 1-2- 5 patients; grade 3- 2 patients). None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANs). There were no treatment-related deaths. Eight out of nine patients were evaluable for efficacy (one patient has not yet completed the first post-treatment evaluation). The overall hematological response rate was 100%, including complete responses in 5 patients, very good partial responses in 2, and partial response in 1 patient. Minimal residual disease (MRD) negativity based on flow cytometry 10^-5 was achieved in 5/8. Best hematological response was achieved after 17 to 57 days (median- 28.5 days). The hematologic responses translated into clinical improvement in all patients, whereas 6/8 met the official criteria for organ responses. With a median follow-up of 7.3 months (range: 2.5-16.5), the median duration of response thus far is 5m (range: 2.5-16.5). Updated results will be communicated at the presentation time. CONCLUSION: In the largest cohort of AL patients treated with CART reported to date, we demonstrated acceptable toxicity in this frail population, with a remarkable hematologic efficacy, leading to organ responses in most participants. Our data suggests that anti-BCMA CART modality may become a powerful clinical tool to improve organ function and survival, even in advanced AL patients.

Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis: Durable Responses and Evidence of Disease Modification

Background Most patients with primary myelofibrosis (PMF) in pre-/early fibrotic stage (pre-PMF) and at low or intermediate-1 risk by the dynamic international prognostic scoring system (DIPSS) will progress to higher risks or overt MF. There is currently no consensus on the optimal treatment for these patients. Ropeginterferon alfa 2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). Aims P1101MF is an on-going multicenter phase 2 study of ropeg in patients with pre-PMF and DIPSS low/intermediate-risk PMF. Methods Key eligibility included morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythaemia MF (PET-MF), DIPSS low/intermediate-1 risk, and the need for cytoreduction. The primary outcome were responses in haemoglobin (Hb, from 10 g/dL to upper reference range), white blood cell (WBC, < 10 x 10 9/L) and platelet (≤ 400 x 10 9/L) at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in mutant allele frequencies (MAF) of driver and non-driver genes as assessed by droplet digital polymerase chain reaction (ddPCR), quality-of-life (QOL), cytokine profiles and bone marrow morphology. Patients received ropeg at a dose of 250 mcg at week 1, followed by 350 mcg at week 2 and 500 mcg every 2 weeks from week 4 onwards. Results At the data cut-off of 30 June 2023, 37 men and 29 women with a median age of 59 (range: 30-86) years were enrolled. The diagnoses were pre-PMF (=46, 69.6%); overt PMF (N=6, 9.1%); PPV-MF (N=5, 7.5%); and PET-MF (N=9, 13.6%). Mutational profile of driver genes was JAK2V617F (N=46, 69.6%); CALR mutations (type 1/type-1 like, N=13, 19.7%; type 2/type 2-like, N=4, 6.1%); MPL mutation (N=1, 1.5%); and triple-negative (N=3, 4.5%). The median time from diagnosis to treatment was 5.8 (1-271) months. The median baseline parameters were white blood cell count (WBC): 6.49 (3.25-33.95) x 10 9/L; haemoglobin (Hb): 12.5 (7.1-15.9) g/dL; platelet count: 495 (113-1114) x 10 9/L; and lactate dehydrogenase: 277 (136-1146) IU/L. The median follow-up was 69 (4-69) weeks, with 61 patients (92%) and 51 patients (77%) having completed 24 and 48 weeks of treatment respectively. Responses in Hb, WBC and platelet were 75%, 82% and 74% respectively at 24 weeks, and 82%, 80% and 71% respectively at 48 weeks. Reduction of MAF at 24 and 48 weeks was achieved for JAK2V617F in 50% (19/38) of patients (≥50%, N=10, 26%; complete, N=3, 8%) and 79% (22/28) of patients (≥50%, N=6, 21%; complete, N=1, 4%) respectively; and for CALR in 44% (7/16) of patients (≥50%, N=1, 6%) and 50% (5/10) of patients (≥50%, N=1, 10%) respectively. Forty-six patients (69.6%) had bone marrow biopsies serially performed, with 42 patients (91%) having stable/improved marrow fibrosis. Eight patients (17.4%) had resolution of marrow fibrosis by 48 weeks. There were 5 discontinuations (personal reasons, N=1; intractable pruritus, N=1; symptom/spleen size progression, N=3). Disease progression (pre-PMF to overt PMF; development of accelerated/blast phase) was not observed. Non-haematological AEs included transaminitis (grade 1-2, N=34); malaise (grade 1-2, N=27; grade 3-4, N=1) and hair loss (grade 1-2, N=21). The most common haematological AE was anaemia (grade 1-2, N=15; grade 3-4, N=6). Conclusion: Ropeg was well-tolerated, effective in cytoreduction and induced molecular and morphologic responses in patients with pre-PMF and low/intermediate-1-risk MF.

Tafasitamab and Lenalidomide in Relapsed/Refractory B-Cell Lymphoma: A Multicenter Retrospective Real-World-Study of Patients from Germany and Austria

Background Publication of the L-MIND-study led to the approval of tafasitamab/lenalidomide (TL) for patients with relapsed oder refractory diffuse large B-cell lymphoma (r/r DLBCL), who were ineligible for autologous stem-cell transplantation (ASCT). The findings of the L-MIND-study showed an overall response rate (ORR) of 60%, complete response rate (CRR) of 43%, median progression free survival (PFS) of 12.1 months, and median overall survival (OS) of 33.5 months. To analyze the real-world characteristics of patients treated with TL, we performed a multicenter retrospective study with patients who were teated with TL since the implementation of the Expanded Access Program (EAP) from 03/2020 until 07/2023. Methods We retrospectively analyzed the outcomes, demographics, data on diagnosis, prior therapies, adverse events (AEs), and treatment after TL of 127 patients with r/r DLBCL treated with TL in Germany and Austria in 18 institutions. OS and PFS are displayed by Kaplan-Meier graphs. Relationships with multiple covariables were calculated by Cox regression. We performed subgroup analyses with prior anti-CD19 therapy, primary refractory disease vs. relapsed disease, IPI, number of prior therapies, treatment after TL, age, and sex. The study was approved by the local Research Ethics Committees. Results Overall, only 37% of our patients met the L-MIND study eligibility criteria; most frequent reasons for ineligibility were more than 3 prior lines of therapy (52%), prior therapy with anti-CD19/IMiDs (19% prior CAR T-cell therapy and Bispecific Antibodies, 7% prior IMiDs), High-Grade-BCL/Follicular Lymphoma Grade 3A/CNS involvement/primary refractory lymphomas/Primary-Mediastinal-BCL/B-ALL (23%), or patients who had lymphoma-specific-therapy within 14 days prior to day 1 dosing with TL (8%). Patient characteristics are stated in Table 1. ORR for the entire cohort (n=127) was 33.1%, CRR 11.8%. Median PFS was 4.7 months (95% CI 6.9 - 11.6), or even 2.9 months (95% CI 2.2 - 3.2) including all causes of death as progression, and median OS 8.9 months (95% CI 5.0 - 11.0) for the whole cohort; see Figure 1. Compared to refractory disease (n=55, 43%), relapsed disease (n=72, 57%) was associated with better ORR (43% vs. 20%, P=0.008). PFS and OS were worse in the primary refractory compared to the relapsed group (median PFS 1.7 vs. 5.3 months, HR 2.79, 95% CI 1.82-4.28, P<0.001; median OS 4.5 vs. 12.9 months, HR 2.72, 95% CI 1.53-4.33, P<0.001). 36% of the patients had a low IPI (0-2, low risk), 55% had a higher IPI (3-5, high risk) at primary diagnosis. ORR (40% vs. 30%) and OS (median OS 9.1 vs. 5.6 months HR 1.76, 95% CI 1.04-2.99) were higher in the lower risk group than in the higher risk group. Fewer prior lines of therapy (1-2 vs. ≥3) were associated with longer median PFS (median 3.3 vs. 1.9 months HR 1.13 per additional line, 95% CI 1.00-1.28, P=0.057) and longer median OS (median 12.5 vs. 5.2 months HR 1.18, 95% CI 1.01-1.37, P=0.039). Median time between the administration of the last prior therapy and TL were 6.4 months. No significant relationships were found for age, sex, and preceding CAR-T treatment. Prior CAR T-cell therapy (24 of 127 patients, post-CAR T-cohort) showed only small differences in ORR (37.5%), PFS (7.9 months with CAR T vs. 12 months without CAR T) or OS (9.2 months with CAR T vs. 12.4 months without CAR T); CRR was higher than in patients not treated with CAR T prior to TL (21% vs. 9.7%). 10 of the analyzed 127 patients received CAR T-cell therapy after TL. Within this subgroup, ORR was 50%. In 2 of these 10 patients TL was used as bridging therapy to CAR T; 1 of 2 patients reached a PR, the other one died before CAR T-cell therapy. The most common hematological AE was neutropenia (67%), the most common non-hematological AEs included infections (31%) and rash and itching (9%). Conclusions We show that the outcomes including ORR, PFS and OS in the real-world setting were lower than observed in the preceding phase II clinical trial (L-MIND). TL seems to be less feasible for patients that show high-risk features; comorbidities, age, dose reductions and the number of pretreatment lines may add to this. The data suggests that TL can still be used after CAR T-cell therapy or as a bridge to CAR T-cell therapy. Our findings on the frequency of observed AEs are consistent with the L-MIND-study.

Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis.

Adverse-risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse-risk AML. Thirteen de novo AML patients with adverse-risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3-21), HHT (1 mg/m2 days 1-5) and cytarabine (100 mg/m2 days 1-5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi-parameter flow cytometry (MFC). Grade 3-4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3-4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow-up of 10 months (range 4-19), median overall survival and event-free survival were not reached. VHA may be a promising and well-tolerated regimen in de novo adverse-risk AML.

Hematologic and lymphatic system toxicities associated with immune checkpoint inhibitors: a real-world study.

Introduction: Immune checkpoint inhibitors (ICIs) exert antitumor responses in many types of cancer but may also induce serious or fatal toxicities that affect all organ systems, including the hematologic and lymphatic systems. However, the risk of hematologic and lymphatic system toxicities following different ICI treatments remains unknown. This study aimed to describe the hematologic and lymphatic system toxicities associated with different ICI regimens and the impact of combining ICIs with anti-vascular endothelial growth factor drugs using the United States Food and Drug Administration Adverse Event Reporting System pharmacovigilance database. Methods: The reporting odds ratio (ROR) and information component (IC) indices were used to identify disproportionate reporting of ICI-associated hematologic and lymphatic adverse events (AEs). Results: We extracted 10,971 ICI-associated hematologic and lymphatic AEs from 35,417,155 reports. These AEs were more frequently reported in female patients (ROR: 1.04 95% confidence interval [CI]: 1.01-1.07) and younger patients (ROR: 1.05 95% CI: 1.01-1.09). The disseminated intravascular coagulation fatality rate (63.97%) was the highest among the reported preferred terms, despite its low incidence (3.32%). The time to onset of ICI-related hematologic and lymphatic AEs was relatively short, with 77.44% reported within 3months. Disproportionate analysis showed that most ICIs were associated with significant overreporting of hematologic and lymphatic AEs (IC025: 0.34 and ROR025: 2.10). Hematologic and lymphatic system AEs were more frequently reported in patients treated with anti-programmed cell death protein 1/programmed cell death ligand 1 monotherapy than in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 monotherapy (ROR: 1.54, 95% CI: 1.38-1.71), with atezolizumab showing the strongest signal (ROR025: 4.19, IC025: 1.00). In patients receiving combined treatment, ICIs plus bevacizumab exerted a higher disproportion signal than monotherapy (ROR: 161, 95% CI: 1.75-1.88). Discussion: The spectrum of hematologic and lymphatic AEs differed according to the ICI regimen. Early recognition and management of ICI-related hematologic and lymphatic AEs are vital in clinical practice.

Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study

Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study

Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section.

A Review of Hematological Complications and Treatment in COVID-19.

COVID-19, caused by SARS-CoV-2, and its variants have spread rapidly across the globe in the past few years, resulting in millions of deaths worldwide. Hematological diseases and complications associated with COVID-19 severely impact the mortality and morbidity rates of patients; therefore, there is a need for oversight on what pharmaceutical therapies are prescribed to hematologically at-risk patients. Thrombocytopenia, hemoglobinemia, leukopenia, and leukocytosis are all seen at increased rates in patients infected with COVID-19 and become more prominent in patients with severe COVID-19. Further, COVID-19 therapeutics may be associated with hematological complications, and this became more important in immunocompromised patients with hematological conditions as they are at higher risk of hematological complications after treatment. Thus, it is important to understand and treat COVID-19 patients with underlying hematological conditions with caution. Hematological changes during COVID-19 infection and treatment are important because they may serve as biomarkers as well as to evaluate the treatment response, which will help in changing treatment strategies. In this literature review, we discuss the hematological complications associated with COVID-19, the mechanisms, treatment groups, and adverse effects of commonly used COVID-19 therapies, followed by the hematological adverse events that could arise due to therapeutic agents used in COVID-19.

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials.

Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.

Real-world results of venetoclax combined with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukemia

ABSTRACTObjectivesYoung adults with acute myeloid leukemia (AML) often fail to achieve permanent complete remission (CR) and frequently relapse, indicating an urgent need to explore effective salvage therapies. Recent advances in AML treatment have been attributed to the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax (VEN) with hypomethylating agents (HMAs); however, the use of this combination in young adults with relapsed or refractory (R/R) AML has not been reported.MethodsWe retrospectively examined 31 young patients with R/R AML treated with VEN plus an HMA. We evaluated the demographic data, cytogenetic characteristics, AML types, response rates, and transplantation-related data for the patients in our cohort.ResultsThe combination of VEN + HMA yielded a CR rate of 48.4%. The most prominent hematologic adverse event was neutropenia, which occurred in all patients, with 90.3% of cases being grade ≥3. Non-hematologic toxicities were relatively mild and infrequent, with an incidence of 45.2%. More than half of the patients with sustained CR had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT), of whom two died of transplant-related complications.ConclusionOur results showed that the combination of VEN + HMA appeared to be a highly effective and well-tolerated salvage therapy option for young patients with R/R AML, enabling more young patients to proceed to potentially curative allo-HSCT. However, additional, well-designed studies with larger numbers of patients are required to confirm the advantages of VEN + HMA in this population.

Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses.

Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure; 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient (< 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.

2041P The prevalence of hematologic adverse events (HAEs) and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients (pts) with advanced high grade ovarian carcinoma (aHGOC) receiving PARP inhibitor (PARPi), with or without a germline BRCA pathogenic variant

2041P The prevalence of hematologic adverse events (HAEs) and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients (pts) with advanced high grade ovarian carcinoma (aHGOC) receiving PARP inhibitor (PARPi), with or without a germline BRCA pathogenic variant

Safety of Single High-Dose Liposomal Amphotericin B for Induction Treatment of Cryptococcal Meningitis and Histoplasmosis in People With HIV: A Systematic Review and Meta-analysis.

Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

To compare the efficacy and incidence of severe hematological adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.

Nine-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma

AbstractAlthough chemoimmunotherapy is the current standard of care for initial treatment of mantle cell lymphoma (MCL), newer data suggest that there may be a role for a chemotherapy-free approach. We report the 9-year follow-up results of a multicenter, phase 2 study of lenalidomide plus rituximab (LR) as the initial treatment of MCL. The LR doublet is used as induction and maintenance until progression, with optional discontinuation after 3 years. We previously reported an overall response rate of 92% in evaluable patients, with 64% achieving a complete response. At a median follow-up of 103 months, 17 of 36 evaluable patients (47%) remain in remission. The 9-year progression-free survival and overall survival were 51% and 66%, respectively. During maintenance, hematologic adverse events included asymptomatic grade 3 or 4 cytopenia (42% neutropenia, 5% thrombocytopenia, and 3% anemia) and mostly grade 1 to 2 infections managed in the outpatient setting (50% upper respiratory infections, 21% urinary tract infections, 16% sinusitis, 16% cellulitis, and 13% pneumonia, with 5% requiring hospitalization). More patients developed grade 1 and 2 neuropathy during maintenance therapy (29%) than during induction therapy (8%). Twenty-one percent of patients developed secondary malignancies, including 5% with invasive malignancies, whereas the remainder were noninvasive skin cancers treated with local skin-directed therapy. Two patients permanently discontinued therapy because of concerns of immunosuppression during the COVID-19 pandemic. With long-term follow-up, LR continues to demonstrate prolonged, durable responses with manageable safety as initial induction therapy. This trial was registered at www.clinicaltrials.gov as #NCT01472562.

Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA)

PurposeThis phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians’ choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). Patients and methodsThe initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). ResultsA total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7–24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0–10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1–79.0]. For patients who received ribociclib + ET, grade 3–4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3–4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died – 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. ConclusionThe results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. Trial registrationAnti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

Adverse event costs associated with first-line therapy for advanced non-small cell lung cancer in the United States: An analysis of clinical trials of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, have demonstrated substantial survival benefits in patients with advanced non-small cell lung cancer (NSCLC). However, there is limited evidence on their relative safety profiles and adverse event (AE)-related cost burden. OBJECTIVE: To compare the AE management costs of nivolumab plus ipilimumab with and without limited chemotherapy with those of chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy in a first-line setting among patients with advanced NSCLC. METHODS: The mean per-patient AE costs were estimated using the incidence of all-cause grade 3/4 AEs with any-grade incidence greater than or equal to 15% and the corresponding costs of AE management in the inpatient setting. AE rates were obtained from individual patient data from the CheckMate 227 and CheckMate 9LA trials for nivolumab plus ipilimumab with/without limited chemotherapy and aggregated data from the KEYNOTE-189 and KEYNOTE-407 trials for pembrolizumab plus chemotherapy and the IMpower130 trial for atezolizumab plus chemotherapy. AE management costs from the third-party payer perspective were estimated based on inpatient medical costs from the 2016 United States Healthcare Cost and Utilization Project National Inpatient Sample. All costs were inflated to 2020 US dollars. RESULTS: Nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were associated with lower per-patient grade 3/4 AE costs compared with chemotherapy ($1,708 and $624 lower over the treatment course, respectively). Compared with pembrolizumab plus chemotherapy, nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs in patients with nonsquamous histology (difference: -$4,866) and squamous histology (difference: -$3,795), and nivolumab plus ipilimumab with limited chemotherapy also had lower AE costs for both nonsquamous (difference: -$2,800) and squamous (difference: -$2,753) disease. Similarly, nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were also associated with lower AE costs ($11,400 and $8,809 lower, respectively) compared with atezolizumab plus chemotherapy among patients with nonsquamous disease. In particular, nivolumab plus ipilimumab without or with limited chemotherapy were associated with much lower AE costs of hematological AEs compared with chemotherapy and other immune checkpoint inhibitor-based treatments in combination with a full course of chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab with/without limited chemotherapy was associated with lower AE management costs compared with chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy as first-line treatment for advanced NSCLC. The AE cost benefits were largely driven by the lower cost burden for hematological AEs for nivolumab plus ipilimumab with/without limited chemotherapy. DISCLOSURES This study was supported by Bristol-Myers Squibb. The sponsor was involved in all aspects of the work and in the decision to submit the manuscript for publication. Dr Stenehjem has received consulting fees from Bristol-Myers Squibb. Dr Lubinga was an employee of Bristol-Myers Squibb at the time of the study's conduct and holds stock/options. Drs Betts and Wu are employees of Analysis Group, Inc., a consulting company that has received funding from Bristol-Myers Squibb for this research.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.