The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized ...that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine LDAC) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.
This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with incomplete blood count recovery); secondary end points were overall survival, disease-free survival (DFS), overall response rate, and toxicity.
A total of 60 patients were treated; median age was 68 years (range, 57-84 years). By European LeukemiaNet, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. Fifty-six of 60 evaluable patients responded (composite CR: 93%) and 84% were negative for measurable residual disease. There was one death (2%) within 4 weeks. With a median follow-up of 22.1 months, the median overall survival and DFS have not yet been reached. The most frequent grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33) and pneumonia (n = 14). One patient developed grade 4 tumor lysis syndrome.
Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed AML. The rates of overall survival and DFS are encouraging. Further study of this non-anthracycline-containing backbone in younger patients, unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies is warranted.
There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural ...killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19
B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10
and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .
Background
Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who ...have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN‐based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53mut) over standard therapy is undefined.
Methods
In this single‐institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN‐based (n = 58) and non–VEN‐based (n = 180) regimens.
Results
Patients who received VEN‐based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non–VEN‐based regimens. Compared with patients who received non–VEN‐based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse‐free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN‐based regimens, regardless of age or intensity of treatment.
Conclusions
The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53mut AML.
The benefit of venetoclax‐based therapy over standard approaches in patients with newly diagnosed, TP53‐mutated acute myeloid leukemia (AML) needs to be better defined. Although the addition of venetoclax to standard therapy is associated with numerically higher response rates, there is no improvement in overall or relapse‐free survival compared with standard therapy in patients with newly diagnosed, TP53‐mutated AML.
Background
Despite the well‐defined role of minimal residual disease (MRD) monitoring by real‐time quantitative polymerase chain reaction (RT‐PCR) for RUNX1/RUNX1T1 and CBFB‐MYH11 transcripts in core ...binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).
Methods
Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis.
Results
MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3‐year overall survival (OS) and leukemia‐free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD‐negative patients had 3‐year OS and LFS rates of 100% and 100%, respectively. Thirty‐five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT‐PCR, and 14 (40%) were MRDpos. The presence of MRD by RT‐PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2).
Conclusions
Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT‐PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.
Positive minimal residual disease (MRD) monitoring by real‐time quantitative polymerase chain reaction (RT‐PCR) before transplantation is not associated with an increased risk of relapse in patients with core binding factor (CBF) acute myeloid leukemia (AML). Frequent MRD monitoring by RT‐PCR at early time points after transplantation may allow the identification of patients with CBF AML at higher risk of relapse.
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, ...Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1 mg/kg at day 28 and <0.5 mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n = 51) or steroids alone (n = 30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
Allogeneic SCT for older patients remains challenging at least in part due to graft-versus-host disease (GVHD) and higher non-relapse mortality (NRM). We conducted a prospective pilot study primarily ...for older patients undergoing matched unrelated donor (MUD) SCT using a reduced-intensity (RIC) melphalan-based conditioning and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis with tacrolimus and mycophenolate mofetil. Twenty-two patients (median age 64, IQR 58, 66) underwent RIC MUD SCT for high-risk hematological malignancies including AML/MDS (73%), CML/MPD (18%), and other (10%). Two (9%) patients had early death; the rest (100%) engrafted. After a median follow-up of 17 months, 11 patients were alive and disease-free with an estimated 2-year progression-free (PFS) and overall (OS) survival of 48%. The cumulative incidences of grades 2-4 and 3-4 acute GVHD (aGVHD) at day + 100 and 2-years were 32 and 4%, and 59 and 24%, respectively. No cases of chronic GVHD (cGVHD) were noted. However, late acute GVHD was observed in 6 (27%) patients. In conclusion, RIC MUD SCT with melphalan-based conditioning and PTCy-based GVHD-based prophylaxis for older patients appears effective in controlling relapse. While cGVHD was not seen and early aGVHD appears controllable, a significant proportion developed late aGVHD responsible for higher NRM seen in these patients.
HIV-positive patients with hematologic malignancies are frequently not considered for treatment with allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of reported high morbidity ...and mortality with this procedure and scant published experience. Advances in HIV care and supportive care for allo-HSCT prompted us to review our experience since 2010, after we instituted multidisciplinary management of HIV-infected patients during the peritransplant period.
We retrospectively reviewed the records of all HIV-positive patients who received allo-HSCT at our institution since 2010.
Five patients with various hematologic malignancies received allo-HSCT from matched related (two) or unrelated (three) donors since 2010. All patients received tenofovir (TDF)/emtricitabine in combination with either efavirenz (one) or raltegravir (four) and engrafted a median of 17 days after transplant. The most common infection was cytomegalovirus viremia, with six episodes in four patients, controlled with antivirals. There was no transplant-related mortality. Three patients relapsed 6, 7, and 13 months after transplant, and two were alive and well after 42 and 55 months. HIV viral load remained undetectable and CD4 cell count increased progressively. One patient had acute renal failure and improved with hydration and replacement of TDF with abacavir.
Our patients received allo-HSCT without transplant-related mortality or major infectious complications. Their HIV viral load remained undetectable without the use of protease inhibitors or need to discontinue antiretroviral therapy. One patient had acute renal failure that resolved after discontinuation of TDF. Our findings support considering selected HIV-infected patients for allo-HSCT when indicated for the management of their hematologic malignancies.
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