Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. PATIENTS AND METHODS: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. RESULTS: Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10-6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. CONCLUSION: Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.

Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia.

BACKGROUND: Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. METHODS: Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. RESULTS: Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. CONCLUSION: Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

Electron-Phonon Interaction Contribution to the Total Energy of Group IV Semiconductor Polymorphs: Evaluation and Implications.

In density functional theory (DFT)-based total energy studies, the van der Waals (vdW) and zero-point vibrational energy (ZPVE) correction terms are included to obtain energy differences between polymorphs. We propose and compute a new correction term to the total energy, due to electron-phonon interactions (EPI). We rely on Allen's general formalism, which goes beyond the quasi-harmonic approximation (QHA), to include the free energy contributions due to quasiparticle interactions. We show that, for semiconductors and insulators, the EPI contributions to the free energies of electrons and phonons are the corresponding zero-point energy contributions. Using an approximate version of Allen's formalism in combination with the Allen-Heine theory for EPI corrections, we calculate the zero-point EPI corrections to the total energy for cubic and hexagonal polytypes of carbon, silicon and silicon carbide. The EPI corrections alter the energy differences between polytypes. In SiC polytypes, the EPI correction term is more sensitive to crystal structure than the vdW and ZPVE terms and is thus essential in determining their energy differences. It clearly establishes that the cubic SiC-3C is metastable and hexagonal SiC-4H is the stable polytype. Our results are consistent with the experimental results of Kleykamp. Our study enables the inclusion of EPI corrections as a separate term in the free energy expression. This opens the way to go beyond the QHA by including the contribution of EPI on all thermodynamic properties.

Incidence of adverse effects in patients receiving ponatinib with concomitant azole antifungals.

Ponatinib plus Hyper-CVAD yields a five-year overall survival of 73% in patients with Philadelphia-positive acute lymphoblastic leukemia. Ponatinib dose intensity is associated with increased incidence of adverse effects (AEs), including vascular events. Ponatinib combined with azole antifungals may further increase the risk of AEs due to increased ponatinib exposure. We reviewed 53 patients who received ponatinib with intensive (n = 39; 74%) or low-intensity chemotherapy (n = 14; 26%). Forty-eight patients (91%) received concomitant azole. Ponatinib was commonly initiated at 30 mg (n = 30; 57%) or 45 mg daily (n = 21; 40%). Twenty-six patients (49%) experienced at least one grade ≥3 AE possibly related to ponatinib; 19 (73%) were receiving a ponatinib dose equivalent ≥30mg and 58% >45mg. Eight patients (15%) experienced 10 vascular events, including 1 arterial event; 9 occurred on a ponatinib dose equivalent ≥30mg and 5 occurred while on an azole. Vascular events pose a clinical challenge with the risk potentially increasing with concomitant azoles.

The influence of drug prices, new availability of inexpensive generic imatinib, new approvals, and post-marketing research on the treatment of chronic myeloid leukaemia in the USA.

Several research and market developments in the past 5 years could influence front-line and subsequent-line strategies in chronic myeloid leukaemia. These developments include the increased availability of effective and safe generic imatinib at affordable prices, studies showing that doses of tyrosine kinase inhibitors (TKIs) lower than the approved dose are effective and less toxic, studies showing that dose-adjusted ponatinib therapy at a reduced dose is effective and substantially safer than approved doses, and the approval of asciminib as third-line therapy in 2021. With the availability of an affordable generic imatinib, all patients with chronic myeloid leukaemia globally should be able to access a lifetime supply. The availability of reduced-dose schedules of generic second-generation TKIs, which are less toxic and produce faster deep molecular response than imatinib, might make them more appealing to use as front-line therapy. In the subsequent-line setting, the role of different TKIs as second, third, and later lines of therapy depends on the evolving front-line use. Dose-adjusted ponatinib schedules have shown better efficacy and safety with long-term follow-up. Ponatinib is the favoured therapy for patients with second-generation-TKI resistance or chronic myeloid leukaemia with 944C→T (Thr315Ile)-mutated BCR-ABL1. Studies of asciminib are needed in larger numbers of patients and with longer follow-up than has been done previously to better assess its comparative efficacy, safety, and survival data (vs ponatinib). The role of third-generation TKIs as second-line therapy following front-line resistance to second-generation TKIs needs to be evaluated. New and mature data with TKI therapy in chronic myeloid leukaemia are producing observations that encourage continuous discussion of the optimal treatment recommendations and frameworks in chronic myeloid leukaemia.

Central Nervous System Involvement in Adults with Acute Leukemia: Diagnosis, Prevention, and Management.

PURPOSE OF REVIEW: Recent treatment advances in both acute myeloid leukemia and acute lymphoblastic leukemia have drastically improved outcomes for these diseases, but central nervous system (CNS) relapses still occur. Treatment of CNS disease can be challenging due to the impermeability of the blood-brain barrier to many systemic therapies. RECENT FINDINGS: The diagnosis of CNS leukemia relies on assessment of clinical symptoms, cerebrospinal fluid sampling for conventional cytology and/or flow cytometry, and neuroimaging. While treatment of CNS leukemia with systemic or intrathecal chemotherapy and/or radiation can be curative in some patients, these modalities can also lead to serious toxicities. In the modern era, prophylaxis with intrathecal chemotherapy is the most important strategy to prevent CNS relapses in high risk patients. Accurate risk stratification tools and the use of risk-adapted prophylactic therapy are imperative to improving the outcomes of patients with acute leukemias and preventing the development of CNS leukemia.

Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39 years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2 years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P < 0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.

The clinical development of antibody-drug conjugates - lessons from leukaemia.

Advances in our understanding of cancer biology have enabled drug development to progress towards better targeted therapies that are both more effective and safer owing to their lack of off-target toxicities. In this regard, antibody-drug conjugates (ADCs), which have the potential to combine the selectivity of therapeutic antibodies with the cytotoxicity of highly toxic small molecules, are a rapidly developing drug class. The complex and unique structure of an ADC, composed of a monoclonal antibody conjugated to a potent cytotoxic payload via a chemical linker, is designed to selectively target a specific tumour antigen. The success of an ADC is highly dependent on the specific properties of its components, all of which have implications for the stability, cytotoxicity, pharmacokinetics and antitumour activity of the ADC. The development of therapeutic ADCs, including gemtuzumab ozogamicin and inotuzumab ozogamicin, provided great knowledge of the refinements needed for the optimization of such agents. In this Review, we describe the key components of ADC structure and function and focus on the clinical development and subsequent utilization of two leukaemia-directed ADCs - gemtuzumab ozogamicin and inotuzumab ozogamicin - as well as on the mechanisms of resistance and predictors of response to these two agents.

Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia.

BACKGROUND: The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL. METHODS: We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) compared to conventional hyper-CVAD. RESULTS: Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%. CONCLUSION: The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL.

Treating Leukemia in the Time of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton's tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 high-risk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of "exposure" versus "clinical infectivity," which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is <1-2% worldwide. With a mortality rate of 1-5% in CO-VID-19 patients in the general population and potentially of >30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.

Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia.

Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P.

Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists.

OBJECTIVE: Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC).Data Sources: PubMed and relevant congress abstracts were searched using the term "glasdegib". In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners.Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39-0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. CONCLUSIONS: Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies.

CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis. Importantly, CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, which makes it a useful diagnostic and therapeutic biomarker in hematologic malignancies. Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers. Tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin, has been approved for use in patients with blastic plasmacytoid dendritic cell neoplasm. Multiple clinical trials are investigating the use of various CD123-targeting agents, including chimeric antigen receptor-modified T cells (expressing CD123, monoclonal antibodies, combined CD3-CD123 dual-affinity retargeting antibody therapy, recombinant fusion proteins, and CD123-engager T cells. In this review, we provide an overview of laboratory techniques used to evaluate and monitor CD123 expression, describe the strengths and limitations of detecting this biomarker in guiding therapy decisions, and provide an overview of the pharmacologic principles and strategies used in CD123-targeted therapies.

Optimizing patient selection for treatment-free remission.

The advent of BCR-ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.

Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia.

BACKGROUND: Dasatinib, a potent Bcr-Abl tyrosine kinase inhibitor, is approved for the treatment of chronic-phase chronic myeloid leukemia (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. Dasatinib at 50 mg daily has previously been reported to be active and better tolerated than the approved 100-mg daily dose. The aim of this study was to update the long-term follow-up results of dasatinib at 50 mg daily as frontline therapy for CML-CP. METHODS: Eighty-three patients with newly diagnosed CML-CP received dasatinib at 50 mg daily. Eligibility and response criteria were standards used in previous protocols. RESULTS: After a minimum follow-up of 12 months, 81 patients were evaluable. Two patients came off the study in less than 3 months. The rates of BCR-ABL1 transcript levels (International Standard) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively. The cumulative rates for a complete cytogenetic response by 6 and 12 months were 77% and 95%, respectively. The cumulative rates for a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction by 12 months were 81%, 55%, and 49%, respectively. Twenty-one patients (25%) had treatment interruptions for a median of 13 days (range, 4-64 days). Five patients (6%) developed pleural effusions; 4 of these patients (80%) required a dose reduction. Two patients (2%) failed to achieve any cytogenetic or molecular response and were taken off the study. At a median follow-up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase. The 2-year event-free and overall survival rates were 100%. CONCLUSIONS: These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose for early CML-CP.

The face of remission induction.

Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient-specific approach rather than the historical 'one-size fits all' model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.

Treatment-free remission in chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) represent a major breakthrough in the treatment of chronic myeloid leukemia (CML). Thanks to these agents, CML has been transformed from a disease with limited treatment options and a dismal prognosis into a more indolent disease with survival comparable to that of the general population. The need for ongoing TKI therapy remains controversial for several reasons, including cost and toxicity. Studies in CML patients with a sustained deep molecular response have demonstrated that stopping TKI therapy is feasible and safe. Given the heterogeneity of results reported in clinical trials, practice guidelines for optimal patient selection and proper monitoring after discontinuation of TKIs are proposed outside of clinical trials. Current data available show that 40% to 60% of patients who stop therapy relapse; molecular relapses typically occur within 6 months, but nearly all relapsing patients regain response upon reinitiation of the TKI. Several factors that predict for relapse have been investigated. Duration of prior TKI therapy, achievement of deep molecular response, depth of molecular response, prior interferon treatment, and Sokal risk score have been shown to be potential predictors for relapse. Leukemia stem cells that are resistant to TKIs, and that persist despite undetectable BCR/ABL1 transcript levels, likely are responsible for disease relapse after discontinuation. Efforts geared toward better identification of low levels of BCR/ABL1 transcript using new techniques such as digital polymerase chain reaction, along with eradicating CML clones using combination therapies with agents such as pegylated interferon or venetoclax with TKIs, will hopefully lead to a functional cure of this disease.