Search

CD123 "expression" is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies. [ABSTRACT FROM AUTHOR]

Summary: Therapy‐related acute lymphoblastic leukaemia (tr‐ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr‐ALL, likely due to high prevalence and excellent curable rate for non‐metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse‐free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr‐ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr‐ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT. [ABSTRACT FROM AUTHOR]

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35–298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation. [ABSTRACT FROM AUTHOR]

Patients with chronic graft versus host disease (cGVHD) have low circulating regulatory T cells (Tregs). Interleukin-2(IL-2) is a growth factor for Tregs, and clinical trials have explored its use in cGVHD patients. Here we will discuss the biology of IL-2, its rationale for use and results of clinical trials in cGVHD. We also describe its mechanisms of action and alteration in gene expression in T-cell subsets after treatment with low dose IL-2 and photopheresis. Clinical trials using Low dose IL-2 have been done at single centers in small patient series. The majority of the clinical responses seen with IL-2 in cGVHD are classified as partial responses and efficacy as a single agent is limited. Compared to currently approved oral therapies, it has to be administered subcutaneously and requires specialized processing for compounding and storage limiting its widespread use. Its use is associated with constitutional symptoms and local injection site reactions. Local reactions can be easily managed by supportive care practices like rotation of injection sites and premeditations, constitutional symptoms resolve with, dose reduction (25–50%) allowing for continued therapy. Additional studies are needed to define optimal combination strategies with approved agents. Longer acting formulations of IL-2 that require less frequent dosing may also improve patient compliance. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS. [ABSTRACT FROM AUTHOR]

Introduction: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. Methods: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Results: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). Conclusions: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin −21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway. In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable. Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs. [ABSTRACT FROM AUTHOR]

Rearrangements of I lysine [K] methyltransferase 2 A i ( I KMT2A i ) gene, previously known as the I MLL i gene, occur in 3 to 7% of adult patients with de novo AML and are enriched in therapy-related disease, particularly after treatment with topoisomerase II inhibitors [[1]]. Response and survival of patients with KMT2A rearranged acute myeloid leukemia (AML) receiving venetoclax in combination with hypomethylating agent therapy (HMA). The inferior prognosis of KMT2A rearranged AML patients undergoing alloSCT presents an opportunity for post-transplant maintenance trials with therapies targeting KMT2A. [Extracted from the article]

The 1-year OS for HCT patients (21 patients) was 85% (95% CI 61-95%) compared to 41% (95% CI 16-65%) in non-HCT patients in cCR (14 patients). The 1-year LFS in patients who underwent HCT (21 patients) was 67% (95% CI 41-84%) I versus i 33% (95% CI 10-57%) in non-HCT patients in cCR (14 patients). [Extracted from the article]

Background: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease–positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19– disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. Methods: This study retrospectively reviewed the outcomes of adult patients with B‐cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013‐2021) and analyzed factors associated with treatment response and EMD failure. Results: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P =.049) and no history of previous EMD (P =.019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P =.005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P =.012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. Conclusions: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. Lay Summary: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia.A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites.Most extramedullary failure cases retain CD19 expression. Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. [ABSTRACT FROM AUTHOR]

• The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (VEN-HMA) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) is associated with favorable HCT outcomes. • VEN-HMA could allow more patients of older age to proceed to potentially curative alloHCT. • AlloHCT outcomes are particularly good in patients who undergo HCT in complete remission after VEN-HMA therapy. The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML. [ABSTRACT FROM AUTHOR]

The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood transplantation (UCBT) after reduced-intensity conditioning regimens in patients aged ≥70 years with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) between 2010 and 2014. During this period 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT: 10 UCBT, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor alloHCT. In UCBT, cumulative incidences of nonrelapse mortality and relapse were 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Rates of overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seemed to be similar to that of patients aged 60 to 69 years receiving UCBT (n = 60) and patients aged ≥70 years receiving HLA full-matched sibling donor transplantation (n = 9). These results suggest that UCBT is feasible in selected AML/MDS patients aged ≥70 years. In fact, UCBT shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCBT are promising; however, larger studies with a longer follow-up are needed. [ABSTRACT FROM AUTHOR]

Identification of anti-apoptotic properties of the Bcl2 protein has offered novel treatment options in many malignancies including AML. Venetoclax, a Bcl2 inhibitor, has shown promising results as upfront therapy in elderly patients (pts) and relapse/refractory (R/R) AML, when combined with hypomethylating agents (HMA). Yet, due to the high relapse risk, allogenic HCT remains as the only curative option for these high risk populations. To date, outcomes of HCT after prior therapy with Venetoclax + HMA have not been described. Also, as Venetoclax induces aplasia of antigen presenting cells expressing Bcl2, we hypothesized that pre-HCT treatment with venetoclax may be associated with a lower risk for GvHD. We retrospectively analyzed 26 consecutive AML pts who underwent HCT at our institution from 2016 to 2018 with final line of systemic therapy of venetoclax + HMA. Pts were not eligible for upfront standard induction chemotherapy (n=8) or had R/R disease (n=18). Fifteen pts received ≥2 lines of therapy and 3 had previous HCT. CR/CRi was achieved in 62% (n=16), of which 3 pts had minimal residual disease and the rest (n=10) had persistent disease prior to HCT. Donors were matched related (n=8), matched unrelated (n=16), or haploidentical (n=2). Conditioning regimen was myeloablative (38.5%) or reduced intensity (61.5%). Most pts (n=24, 92.3%) received PBMCs as the graft source. Tacrolimus/Sirolimus (Tac/Sir) was administered in most pts (n=20, 77%) for GvHD prophylaxis. Descriptive statistics were used for baseline characteristics. Kaplan-Meier and cumulative incidence curves were constructed for overall survival (OS), progression-free survival (PFS), relapse, none-relapse mortality (NRM), and aGvHD. Median age at the time of HCT was 59 years (range: 18-73). Median time to neutrophil and platelet engraftment were 17 days (range: 14-20) and 20 days (range: 16-61), respectively. With a median follow up of 4.5 months (range: 1.4-18.6), 6 months relapse rate was 12% (95% CI: 0.16-0.54) and 100 day NRM was 4% (95% CI: 0.02-0.34). Grade II-IV aGvHD at 100 days was noted in 34% (95% CI: 0.15-0.51). One-year OS and PFS for all pts were 72% (95% CI: 0.43-0.88) and 40% (95% CI: 0.16-0.63), respectively. For patients in CR at the time of HCT, 1-year OS was 80% (95%CI: 37-95) and PFS was 38% (95%CI: 0.08-0.69) (Fig 1). Only one patient who had been treated with three lines of systemic therapy prior to HCT experienced veno-occlusive disease. Thus, administration of Venetoclax-based salvage regimen as a bridge to HCT is safe with no added immediate toxicities post-HCT. Our early outcome data are promising for this otherwise high-risk population. Our data also justify further studies on the role and impact of Venetoclax and its anti-Bcl2 properties as a component of the conditioning regimen or as post-HCT maintenance. [ABSTRACT FROM AUTHOR]

Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors.We retrospectively reviewed 40 patients between 2017–2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML.Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups.Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size. [ABSTRACT FROM AUTHOR]

ABSTRACT The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT. [ABSTRACT FROM AUTHOR]

Data on pretransplantation minimal residual disease (MRD) and outcomes of umbilical cord blood transplantation (UCBT) are limited. Out of the 143 patients with acute lymphoblastic leukemia (ALL) who underwent UCBT at the University of Minnesota between 2004 and 2010, we evaluated 86 patients with available MRD assessment data by 4- and 8-color flow cytometry analysis immediately before transplantation. Ten patients (11.6%) were MRD-positive, and 76 were MRD-negative (88.4%). Most of the patients (82%) received myeloablative conditioning. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. In multivariate analysis, age, disease status (complete remission [CR] 1 versus CR2/CR3), disease group (precursor B cell ALL versus Philadelphia chromosome–positive ALL versus T cell ALL), and time to transplantation had no impact on relapse. Patients with MRD before UCBT had a greater incidence of relapse at 2 years (relapse rate, 30%; 95% confidence interval [CI], 4%-56%) and lower 3-year disease-free survival (30%; 95% CI, 7%-58%) compared with those without MRD (relapse rate, 16%; 95% CI, 8%-25%; P = .05; disease-free survival, 55%; 95% CI, 43%-66%; P = .02). Our data suggest that in patients with ALL, achieving an MRD-negative state before UCBT improves outcomes. [Copyright &y& Elsevier]