Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, ...or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.
Reliable treatment options for patients with acute myeloid leukemia with measurable residual disease are limited. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with measurable residual disease.
TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the ...safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.
Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR).
Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination,
= 35 and nivolumab combination,
= 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.
TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
Background
Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). ...Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited.
Methods
This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment.
Results
Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra‐CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF– (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF– patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2‐10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event‐free survival.
Conclusions
MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.
Flow cytometry of cerebrospinal fluid (CSF) is more sensitive and predictive of central nervous system (CNS) relapse risk than a conventional cytospin in the context of hyperCVAD. Future studies should incorporate flow cytometry of CSF into risk‐adapted CNS‐directed treatment strategies.
Abstract
Objectives
We recently performed a single‐arm phase II trial of DA‐EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard ...Hyper‐CVAD.
Methods
We created a retrospective matched cohort of patients who received Hyper‐CVAD (
n
= 69) at our center and otherwise met eligibility criteria for the DA‐EPOCH trial (
n
= 53).
Results
Our outcomes support the use of Hyper‐CVAD over DA‐EPOCH in Ph− disease for both overall survival (OS; HR 0.18,
p
= .004) and event‐free survival (EFS; HR 0.51,
p
= .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97,
p
= .96; EFS HR 0.65,
p
= .21). Rates of morphologic remission and measurable residual‐disease negativity were similar between the regimens. Hyper‐CVAD was associated with significantly more febrile neutropenia (OR 1.9,
p
= .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (
p
< .001) and platelets (
p
< .001) were five‐fold higher with Hyper‐CVAD.
Conclusions
Our findings support continued use of Hyper‐CVAD for Ph− ALL but suggest that DA‐EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA‐EPOCH in resource‐limited settings or when more intense therapy is not feasible.
With increasing therapeutic alternatives available, there is growing interest in tools that accurately identify patients most suitable for intensive acute myeloid leukemia (AML) chemotherapy. ...Nowadays, conceptual criteria proposed by an Italian panel of experts are widely used for this purpose. How accurately these Ferrara criteria predict fitness for intensive chemotherapy is unknown.
We assessed the fitness of adults undergoing intensive AML therapy based on Ferrara criteria and determined the accuracy of this assessment for early mortality and survival prediction.
Among 655 adults who received curative-intent induction or reinduction chemotherapy with 7 days of standard-dose cytarabine and 3 days of an anthracycline ("7+3") CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone), or reduced-dose CLAG-M, 197 (30%) met at least one of the criteria defining unfitness for intensive chemotherapy (F-unfit). Compared with F-fit patients, the overall survival of F-unfit patients was significantly shorter (median, 4.8 months; 95% CI, 3.6 to 6.5 months
36.8 months; 95% CI, 27.4 to 73.0 months;
< .001). When used alone, the Ferrara unfitness assessment was more accurate in predicting day 28 and day 100 mortality than the treatment-related mortality score we developed previously (used binary, ≤ 13.1
> 13.1), as indicated by area under the receiver operating characteristic curve (AUC) values of 0.76 and 0.79 versus 0.66 and 0.62. The predictive accuracy of the Ferrara unfitness assessment could be significantly improved by including additional covariates such as performance status and albumin, yielding AUCs as high as 0.84-0.85 for the prediction of day 28 or day 100 mortality. Prediction of overall survival was less accurate, yielding a c-statistic value as high as 0.75 in multivariable models.
Ferrara unfitness criteria provide a good prediction tool for shorter-term mortality after intensive AML chemotherapy. Our data may serve as a benchmark for expected outcomes with intensive chemotherapy in F-fit and F-unfit patients.
Few patients with cancer, including those with acute myeloid leukemia and high-grade myeloid neoplasms, participate in clinical trials. Broadening standard eligibility criteria may increase clinical ...trial participation. In this retrospective single-center analysis, we identified 442 consecutive newly diagnosed patients from 2014 to 2016. Patients were considered eligible if they had performance status 0-2, normal renal and hepatic function, no recent solid tumor, left ventricular ejection fraction (EF) ≥ 50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI); ineligible patients failed to meet one or more of these criteria. We included 372 patients who received chemotherapy. Ineligible patients represented 40% of the population and had a 1-79-fold greater risk of death (95% CI 1.37, 2.33) than eligible patients. Very few patients had cardiac co-morbidities, including 2% with low EF, 4% with prior CHF, and 5% with prior MI. In multivariable analysis, ineligibility was associated with decreased survival HR 1-44 (95% CI 1-07, 1-93). Allogeneic transplantation, performed in 150 patients (40%), was associated with improved survival HR 0-66, 95% CI (0-48, 0-91). Therefore, standard eligibility characteristics identify a patient population with improved survival. Further treatment options are needed for patients considered ineligible for clinical trials.
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