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•Blinatumomab is associated with improved post-transplant survival in B-ALL patients.•Blinatumomab is not associated with increased relapse post-transplant.•Blinatumomab is safe in the setting of post-transplant cyclophosphamide.

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1ISin OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.

•PTCy-based GVHD prophylaxis was associated with improvement in GRFS, NRM, and OS after MSD PBSC HSCT without increasing relapse risk.•The addition of ATG to PTCy was associated with an increase in CMV and EBV reactivation without further improving GRFS.

This analysis from the multicenter, open-label, phase 3 BFORE trial reports efficacy and safety of bosutinib in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) after five years’ follow-up. Patients were randomized to 400-mg once-daily bosutinib (n= 268) or imatinib (n= 268; three untreated). At study completion, 59.7% of bosutinib- and 58.1% of imatinib-treated patients remained on study treatment. Median duration of treatment and time on study was 55 months in both groups. Cumulative major molecular response (MMR) rate by 5 years was higher with bosutinib versus imatinib (73.9% vs. 64.6%; odds ratio, 1.57 [95% CI, 1.08–2.28]), as were cumulative MR4(58.2% vs. 48.1%; 1.50 [1.07–2.12]) and MR4.5(47.4% vs. 36.6%; 1.57 [1.11–2.22]) rates. Superior MR with bosutinib versus imatinib was consistent across Sokal risk groups, with greatest benefit seen in patients with high risk. Treatment-emergent adverse events (TEAEs) were consistent with 12-month data. After 5 years of follow-up there was an increase in the incidence of cardiac, effusion, renal, and vascular TEAEs in bosutinib- and imatinib-treated patients, but overall, no new safety signals were identified. These final results support 400-mg once-daily bosutinib as standard-of-care in patients with newly diagnosed CP CML.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

In PACE (Ponatinib Ph+ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IStranscript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.govas NCT02467270.

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

There is an increased need for allogeneic hematopoietic stem-cell transplantation (allo-HCT) globally and this causes more pressure on transplant units. This study aims to identify predictors of prolonged LOS for patients (pts) who underwent allo-HCT at Princess Margret Cancer Centre (PMCC).

Central nervous system (CNS) involvement of graft versus host disease (GvHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). CNS GvHD symptoms are heterogeneous and include cerebrovascular manifestations, demyelinating disease and immune-mediated encephalitis. The 2010 consensus conference on GVHD provided a framework to diagnose this syndrome (1)

Certain subgroups of patients may be particularly vulnerable to cognitive decline after treatment with allogeneic hematopoietic stem cell transplant (HCT). The objective of this study was to identify predictors of cognitive functioning changes within the first 6 months after HCT. Fifty-eight adults treated with allogeneic HCT (53% male, mean 48 years of age) completed neuropsychological tests of learning/memory, psychomotor efficiency/processing speed, and executive functioning/working memory at three time points: pre-HCT and day 100 and 6 months post transplant. On average, there was significant improvement in learning/memory (p= 0.002), psychomotor efficiency/processing speed (p< 0.0001), and executive functioning/working memory (p< 0.0001), at 6 months. Multilevel modeling identified predictors of divergence from this trajectory; Karnofsky performance status <80 was associated with worsening learning/memory over time; peak severity of acute graft-versus-host disease >=Grade 2 was associated with worsening psychomotor efficiency/processing speed; and greater years of education predicted a faster improvement in psychomotor efficiency/processing speed. Other factors were associated with cognitive functioning over time: higher intelligence quotient (IQ) was associated with better cognitive functioning, and older age, being male, and greater pretransplant comorbidities were associated with worse cognitive functioning. Overall, cognitive performance appears to improve over the first 6 months after transplant. However, pretransplant and posttransplant factors may influence this trajectory.

Post allogenic hematopoietic cell transplant (HCT) hemophagocytic lymphohistiocytosis (HLH) is an aggressive disease with unknown etiology. It has a poorly understood pathophysiology and poor outcome if untreated early. It’s a state of hypercytokinemia. There are many proposed diagnostic criteria for Post HCT HLH. It usually occurs early in the first 2–6 weeks after allogeneic HCT but can present late. The incidence is highest among cord blood transplant compared with other sources of stem cells with a higher incidence in HLA mismatch donors. Post HCT HLH has a marked low survival rate, when compared with Non-HLH post HCT patients and specifically poor outcome is associated in patients with liver dysfunction, graft failure, and those with endothelial complications. Steroid is the mainstay treatment which can be followed up by cyclosporine and etoposide though an optimal therapy is not known. Intravenous immunoglobulin (IVIg) has been tried in virus associated HLH. Second bone marrow transplant is a rescue procedure in patient with HLH due to graft failure, though a very careful selection of individual patients is mandatory. It has been recently found that etoposide based conditioning regimen may reduce HLH post HCT. A prospective study on post HCT HLH are needed to evaluate this unrecognized condition.

Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1variant in a discovery set of CML patients (n= 201) and successfully replicated it in a validation set (n= 270). We also investigated the functional relevance of HMGCLL1blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.

Cytomegalovirus (CMV) serostatus remains an independent adverse risk factor for increased transplant related morbidity and mortality (TRM) in CMV seropositive (CMV+) recipients versus CMV seronegative recipients1,2. Letermovir (LET) is a novel anti-CMV agent that prevents CMV replication through inhibition of the viral terminase complex3and is routinely given as primary prophylaxis for CMV seropositive transplant recipients as it results in a lower risk of clinically significant CMV infections4. At our institution we serve a diverse ethnic population and utilize a heterogenous mixture of donor sources and graft-versus-host-disease (GVHD) prophylaxis. We conducted this study to evaluate the impact of LET in our diverse population to evaluate for LET impact on major outcomes and evaluate for efficacy variations by ethnicity.

In allogeneic hematopoietic stem cell transplantation (HCT) genetic and non-genetic factors are implicated in clinical outcomes 1,2,3. Studies have noted ethnic disparities in transplantation are affected by various factors like stem cell sources, conditioning therapies, and immunosuppressive regimens, resulting in discrepancies in mortality4. Specifically, there are observed inequities in mortality risk post HCT in the unrelated donor setting stratified by ethnicity {e.g., Asian (low risk), White (intermediate risk), and Black (high risk)}4. Outcomes have improved with the use of post-transplant cyclophosphamide (PTCY) for graft-versus-host-disease (GVHD) prophylaxis5and the approval of Letermovir (LET) for cytomegalovirus (CMV) prevention in CMV seropositive patients6. Our study aimed to identify if disparities in outcomes are present by ethnicity as an avenue to identify future research targeting an equitable HCT experience.

•Treo-based conditioning shows better overall survival versus busulfan in MDS patients.•Treosulfan recipients had better relapse free survival and event free survival.•Study reveals treosulfan's efficacy and safety in stem cell transplantation.•First study to evaluate treosulfan with ATG and PTCY, supporting its growing evidence.

Introduction:Allogeneic hematopoietic cell transplant (alloHCT) in elderly patients is a challenge, as with increasing age, there is higher incidence of co-morbidities and pre-frail status. In our recent study on alloHCT in patients 60 years (y) or older, those who were 70y or more had worse outcome and high 2-y non-relapse mortality (NRM) of 53% (Al-Shaibani E et al. Ann Hematol, 2023, 102: 917-926). We therefore implemented a number of changes to improve outcomes in elderly patients undergoing alloHCT. In this study, we analyze transplant outcomes in patients ≥ 70 y, and compare the earlier cohort with the more recent cohort.

Background: We demonstrated that impaired functionality and frailty have a negative impact on survival after allogeneic hematopoietic cell transplantation (HCT) (Salas et al., 2019). This impact is independent of other predictive models including HCT comorbidity index (HCT-CI) and disease risk index (DRI). Cognitive changes are frequently reported among survivors of autologous and allogeneic HCT. However, impact of the presence of cognitive impairment prior to allogeneic HCT has not been studied. We hypothesized that the presence of cognitive impairment before transplantation could have a negative effect on the outcomes of allogeneic HCT.

Background:Ponatinib is a BCR::ABL1 TKI currently approved to potently inhibit all known native and single resistance mutation variants of BCR::ABL1, including T315I. The phase 2 OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; ongoing) trial is evaluating the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. The response-based dosing strategy aims to optimize efficacy and improve the safety of ponatinib. Results from the OPTIC primary analysis and the 3-year update demonstrated an improved risk:benefit ratio for ponatinib starting with 45 mg/d, followed by dose reduction to 15 mg/d upon attaining ≤1% BCR::ABL1IS. We present for the first time the long-term 4-year update of efficacy and safety outcomes from the OPTIC trial.

ABSTRACTIntroduction: BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patientsAreas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents. Published English-language literature was reviewed regarding currently available TKIs; clinical trials repositories were reviewed to identify novel agents recently investigated or under active study.Expert opinion: We recommend discussion with patients and enrolment on an appropriate clinical trial where feasible. In situations where no trials are available, or if patients decline enrolment, we recommend use of an appropriate BCR-ABL directed TKI, selected on the basis of an evaluation of patient risk factors and side effect profile. Allogeneic stem cell transplant continues to have a role though this is generally limited to cases with advanced phases of disease or in cases with resistance-conferring mutations.

Progressive multifocal leukoencephalopathy (PML) is an uncommon infectious complication post allogeneic stem cell transplant. We present a case report of a patient developing this complication with a review of the current literature. It also describes the first use of artesunate in a clinical case of PML with no beneficial effect.

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.

ABSTRACTIntroduction: Therapy of chronic myeloid leukemia (CML) has been completely transformed by the development of tyrosine kinase inhibitors (TKIs). However, a subset of patients will fail TKI therapy due to resistance or intolerance. Omacetaxine mepesuccinate (OM), a protein translation inhibitor, is currently the only approved therapy that does not directly target the kinase domain. It has activity for CML patients irrespective of the phase or underlying kinase domain mutation status.Areas covered: We searched the MEDLINE database for articles published in English on homoharringtonine or omacetaxine from 1970 to present. This article reviews the pharmacokinetics of OM and its clinical evolution for the treatment of CML pre- and post TKI development. Toxicity profile, drug administration and future directions are also discussed.Expert opinion: OM represents a unique addition to the CML therapeutic armamentarium with its distinct mechanism of action and activity. The adverse event profile is manageable and with subcutaneous administration at the approved dose, cardiac toxicity is no longer a concern. The recent approval of home administration will facilitate access to this therapy and increase patient compliance. We conclude with specific scenarios where OM use should be considered in CP and AP-CML patients in the era of TKI therapy.