Q4 2023: Additional information and data in acute leukemia

December 19, 2023

Impact of the ICAL on the treatment of acute leukemia; The International Consortium on APL (IC-APL) is an initiative of the International Members Committee of the American Society of Hematology, created in the spirit of international clinical and laboratory collaboration with the aim of reducing the difference in the outcomes of patients with APL treated in developed and developing countries. It congregates leaders of well-established cooperative groups in Europe and North America, and hematologists in Brazil, Chile, Peru, Uruguay, and Paraguay. APL was initially selected as a model disease to test the impact of networking on outcomes because it is a highly curable disease if early diagnosis and specific treatment are promptly established. Full article: https://doi.org/10.1182/bloodadvances.2017002147


Nelarabine: when and how to use in the treatment of T-cell ALL

T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (T-ALL/LBL) is a rare hematologic malignancy most commonly affecting adolescent and young adult males. Outcomes are dismal for patients who relapse, thus, improvement in treatment is needed. Nelarabine, a prodrug of the deoxyguanosine analog 9-β-arabinofuranosylguanine, is uniquely toxic to T lymphoblasts, compared with B lymphoblasts and normal lymphocytes, and has been developed for the treatment of T-ALL/LBL. Based on phase 1 and 2 trials in children and adults, single-agent nelarabine is approved for treatment of patients with relapsed or refractory T-ALL/LBL, with the major adverse effect being central and peripheral neurotoxicity. Since its approval in 2005, nelarabine has been studied in combination with other chemotherapy agents for relapsed disease and is also being studied as a component of initial treatment in pediatric and adult patients.

Nelarabine represents a valuable agent for the treatment of T-ALL. The strongest evidence supports the use of nelarabine for the treatment of early relapse, with retrospective data suggesting improved chance of response when used in combination with other chemotherapy such as CTX and etoposide. Durable clinical benefit requires consolidation with allo-HSCT. The role of nelarabine in the initial treatment of T-ALL is less established, although supported for treatment of young patients with HR T-ALL in combination with the COG 0434 backbone with benefit related to reduction in CNS relapse. The benefit of nelarabine in other contexts including in combination with other frontline adult and pediatric regimens, and for treatment of persistent MRD, is not established. For those treated with nelarabine, neurotoxicity appears to be a modest and manageable risk in appropriately selected patients but vigilance is required. (Ref: https://doi.org/10.1182/bloodadvances.2023010303)

Short_NGS vs BCR-Abl PCR_AmJHematol 2023

The takeaways from the data are:

  • clonoSEQ is more prognostic in Ph+ ALL than traditional BCR-Abl RT-PCR
  • The differing prognostic values of these two assays for these patients are consistent with other reports that the lymphoid component (as measured by clonoSEQ) is distinct from, and more aggressive than, the myeloid component (as measured by BCR-Abl RT-PCT).

Midostaurin plus daunorubicin or idarubicin for young and older adults with FLT3-mutated AML: RATIFY phase 3b trial:

In this study, midostaurin in combination with intensive chemotherapy provided high response rates, irrespective of patient age, induction regimen (“7+3” or “5+2”), or the type of anthracycline used (daunorubicin or idarubicin) during the induction therapy. Overall, 80.7% of patients achieved CR + CRi and 65.3% of patients achieved CR, with similar rates observed in patient subgroup analyses based on age, induction regimen, induction drug, and gender. These response rates support the results observed in the RATIFY study, in which 59% of patients who received midostaurin achieved CR.21 The results from this study also align with those from a phase 2 study (the German-Austrian AMLSG trial) of midostaurin in combination with standard induction and consolidation chemotherapy, followed by SCT, which allowed for enrollment of adult patients aged up to 70 years; similar CR + CRi rates were observed after induction in younger and older patients, with a manageable safety profile.24,25 Furthermore, the multivariate analysis from the AMLSG trial showed significant beneficial effect of midostaurin on EFS and OS in both younger and older patients (61-70 years). Full article: https://doi.org/10.1182/bloodadvances.2023009847

Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory AML: 

 Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response syndrome (CRS), followed by weekly dosing (1.7 μg/kg, Cohort -1D). In 16 of 120 patients, at least 1 treatment-emergent adverse event was classified as a dose-limiting toxicity. CRS, the most common adverse event (59.2%), managed with premedication, were mostly ≤grade 2. A secondary objective was assessment of efficacy in patients with CD123-expressing leukemias. A total of 10 of 111 (9.0%) efficacy-evaluable patients with AML achieved an overall response of morphologic leukemia-free state or better with an overall objective response rate (ORR) of 9.0%. Response was only observed in patients receiving a target dose of 0.75 μg/kg or higher (n = 87) in which the efficacy-evaluable ORR was 11.5%. Response was associated with lower baseline blast counts in blood and bone marrow (<25%) suggesting potential benefit. (Ref: https://doi.org/10.1182/bloodadvances.2023010956)

Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Loo et al report the results of a phase 2, placebo-controlled study of adding sorafenib to intensive induction chemotherapy for patients with FLT3-ITD AML. The authors report that event-free survival and overall survival were not improved by sorafenib in this setting. However, the study suggests that sorafenib may improve survival in those patients undergoing transplant in first remission; a larger study would be required to confirm this. (Ref; https://doi.org/10.1182/blood.2023020301).

Cigarette smoke exposure accelerates AML progression in FLT3-ITD models

Past work reports smokers with AML have worse survival outcomes than nonsmokers; however, to the best of our knowledge, this is the first study to model cigarette smoke exposure in FLT3-mutant AML–bearing mice to examine potential molecular mediators of leukemia progression and chemotherapy resistance. SE accelerated disease progression in 3 FLT3-ITD AML mouse models. SC upon leukemia engraftment slowed acceleration, providing the first evidence that smoking and cessation deliver “go” and “no-go” signals to FLT3-ITD AML cells. Because many patients with cancer continue smoking after their diagnosis, these data from xenograft models provide evidence for cessation recommendations, but it will require further validation in primary AML samples. Additionally, mass cytometry revealed that SE increased protein expression of MCL-1, DNMT3B, and RUNX1. MCL-1 inhibitors are currently being investigated for AML treatment, especially in association with resistance to venetoclax,and RUNX1 mutations occur in 10% of patients with AML and are associated with inferior prognosis. Cumulatively, our data provide novel insights into previously undescribed molecular regulators of aggressive disease seen in patients with AML with histories of smoking. (Ref: https://doi.org/10.1182/bloodadvances.2023010111)

Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study:

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed.

These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. (ref: https://doi.org/10.1182/bloodadvances.2023010943)

Vitamin C and D supplementation in AML

  • Vitamin C/D treatment was associated with less complications during chemotherapy and restores the vitamin D level before allogeneic hematopoietic cell transplantation in patients with AML.

  • Vitamin C/D treatment was not associated with better OS except in patients with AML with NPM1 mutations.

Full article: https://doi.org/10.1182/bloodadvances.2023010559


A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. An analysis comprising 173 adults with AML and 93 with ALL who received a haplo-HSCT in Europe. All grafts were T cell–depleted peripheral blood progenitor cells from a direct family or other related donor. The results show that haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor. (ref: https://doi.org/10.1182/blood-2008-02-140095)


Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark

  • Outcomes in a multicenter BPDCN population in the modern era provide a benchmark before targeted therapy.

  • Age <60 years, normal karyotype, and TdT positivity were associated with improved survival; pralatrexate and enasidenib had activity in BPDCN.

Full article: https://doi.org/10.1182/blood.2019001144

Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm

We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo-HSCT, n = 14; auto-HSCT, n = 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P = .11), respectively, and progression-free survival rates were 73% and 48% (P = .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials. (Ref: https://doi.org/10.1182/blood-2015-01-621268)

Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: a retrospective study from the European Group for Blood and Marrow Transplantation

Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have a poor prognosis with conventional chemotherapy. In the present study, we retrospectively analyzed the outcome of patients with BPDCN who underwent allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (auto-SCT). A total of 39 patients (allo-SCT, n = 34; auto-SCT, n = 5) were identified in the European Group for Blood and Marrow Transplantation registry. The 34 allo-SCT patients had a median age of 41 years (range, 10-70) and received transplantations from sibling (n = 11) or unrelated donors (n = 23) between 2003 and 2009. MAC was used in 74% of patients. Nineteen allo-SCT patients (56%) received transplantations in first complete remission. The 3-year cumulative incidence of relapse, disease-free survival, and overall survival was 32%, 33%, and 41%, respectively. By univariate comparison, being in first remission at allo-SCT favorably influenced survival, whereas age, donor source, and chronic GVHD had no significant impact. We conclude that high-dose therapy followed by allo-SCT from related or unrelated donors can provide durable remission even in elderly patients with BPDCN. However, it remains to be shown if graft-versus-malignancy effects can contribute significantly to BPDCN control after allo-SCT. (Ref:https://doi.org/10.1182/blood-2012-08-448613)

More articles in BPDCN: https://ashpublications.org/search-results?q=BPDCN&fl_SiteID=1&page=1&qb={%22q%22:%22BPDCN%22}&utm_source=sfmc&utm_medium=email&utm_campaign=Innovations+in+BPDCN-+12-18-23&utm_term=https%3a%2f%2fashpublications.org%2fsearch-results%3fq%3dBPDCN%26fl_SiteID%3d1%26page%3d1%26qb%3d%7b%2522q%2522%3a%2522BPDCN%2522%7d&utm_id=298868&sfmc_id=19426595


Telehealth serious illness care program for older adults with hematologic malignancies: a single-arm pilot study

Older patients with AML and MDS feel shocked and bewildered when diagnosed. Serious illness conversations (SICs) may increase disease understanding and preparations for the future. However, SICs often happen late, in part because of clinician-perceived patient discomfort. Telehealth may promote patient comfort by allowing SICs to take place at home. This study assesses the feasibility and usability of a telehealth-delivered Serious Illness Care Program (SICP) for older adults with AML and MDS. We conducted a single-arm pilot study including 20 older adults with AML and MDS. Feasibility was measured using retention rate, with >80% considered feasible. Usability was measured using telehealth usability questionnaire (TUQ; range, 1-7): >5 considered usable. We collected other outcomes including acceptability and disease understanding and conducted post-visit qualitative interviews to elicit feedback. Hypothesis testing was performed at α = 0.10 owing to the pilot nature and small sample size. Retention rate was 95% (19/20); mean TUQ scores were 5.9 (standard deviation [SD], 0.9) and 5.9 (SD, 1.1) for patients and caregivers, respectively. We found the SICP to be acceptable. The majority of patients found the SICP to be very or extremely worthwhile (88.2%; 15/17), and reported it increased closeness with their clinician (75.0%; 12/16). After their visit, patient estimates of curability, and overall life expectancy aligned more closely with those of their clinicians. In qualitative interviews, most patients said that they would recommend this program to others (89.5%, 17/19). This study demonstrated that delivery of the telehealth SICP to older patients with AML and MDS is feasible, usable, and acceptable. (ref: https://doi.org/10.1182/bloodadvances.2023011046)


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